Our quest for an “ideal” COVID vaccine heads to the nose.

Right from the outset of the pandemic, Associate Professor Ashley St John from Duke-NUS’ Emerging Infectious Diseases Programme set her focus on finding ways to make vaccines better, a need she knew from previous pandemic experiences that would continue to challenge scientists.

Today, she and her team, together with collaborators from both of Duke-NUS’ parent universities, published the results of a head-to-head comparison of a novel COVID-19 vaccine that is either injected into the arm or sprayed into the nose in eBioMedicine.

Mucosal marvels

Unlike the injections many of us have accepted into our arms, St John’s vaccine candidate can also be given as a spray to target the mucosal tissues lining our nasal passages.

An intranasal vaccine holds exciting implications for “greater cross-protective function” and an immune response that is “more long-lived and retains a longer memory”, remarks St John.

“The idea is that when we’re challenged with a pathogen or a vaccine, our immune system tries to not only record what kind of pathogen it is, and how that pathogen looks, it also tries to record where it sensed it.

“You don’t expect SARS-CoV-2 to be injected in your skin by a mosquito. So, we need a different type of immune response that comes through our nasal passages.”

Switching tacks for changing needs

Working with collaborators from Duke University and the National University of Singapore among others, St John’s team were able to scrutinise the difference in immune reaction between the two administration routes of their vaccine candidate. They also tested the candidate with and without the use of adjuvants—substances added to vaccines to enhance the body’s immune response.

As expected, they found that only giving the vaccine through the nose activated the immune system in the mucosal lining. This protection is defined by a type of antibody called Immunoglobulin A, or IgA. Compared with the common Immunoglobulin G, or IgG, which circulate in the blood and are quick to be activated and deactivated, IgA are abundant in mucosal membranes like those in the nose and throat, and wane more slowly. And being present at the site of entry for the virus means a much faster call to action.

The merits of preserving memory

But it was not just the front-line antibody response that proved to provide stronger protection. The team also observed that T cells seemed to be ‘imprinted’ by the environment where they encountered the virus first. When the vaccine was given through the nose, this triggered the generation of T cells with a systemic response to threats, that were perhaps better suited for identifying pathogens at multiple sites in the body. Given the length of the airways and the diversity of tissue type along the way, these T cells were programmed to not merely protect where they were originally located, but to move out, travel along the bloodstream, and disperse information to diverse tissues along the way.

The main function of these cells, the scientists observed, was not to directly fight the virus but to remember the virus and release daughter cells that could stay behind and fight when the same virus infiltrated the body again.

To top it off, these long-lived memory T cells were produced in far greater numbers when the vaccine was administered through the nose.

St John explains: “It’s almost as if by giving a mucosal challenge, it’s giving this instruction that the nasal passages and lungs are going to need surveillance.” This long-lasting vigilance, built on the memory of the pathogen, is crucial to keeping the body protected beyond the initial challenge.

Skewing away from specialisation: the case for cross-protection

There are also other advantages in using a mucosal challenge.

“The other thing we observed was this neutralising antibody response, which was more cross-protective, and that, I think, is also a very important point. It’s not just that we’re getting better IgA, we’re also getting better IgG,” she notes.

Usually, if the immune system encounters a specific challenge repeatedly, it learns to be very efficient and fast acting in responding to that particular target. However, the broad antibody response elicited by St John’s mucosal vaccine candidate didn’t just effectively neutralise the form of the virus administered, it was also able to take out viruses that looked similar.

“If you keep some antibodies that are not quite as good at neutralising the original virus, you might have the ability to neutralise more viruses,” she says. “And we were able to preserve many of the antibodies that are outcompeted in lymph nodes [when the vaccine is given by injection] by targeting the mucosal tissue.”

The exciting implication, of course, is that a broader cross-protective response potentially protects against a wider spectrum of SARS-CoV-2 variants—variants such as JN.1, which continue to infect millions of people worldwide. In addition, as the memory of the mucosal challenge fades more slowly, fewer booster vaccinations may potentially be required for the same levels of protection.

At this point, we may have moved away from the acute phase of the pandemic, but continually emerging new variants and changing needs, such as a demand for fewer boosters, longer-lived protection or simply a needle-free vaccine alternative, present a need for improving currently available COVID-19 vaccines—and promising developments in vaccine candidates, such as this one, can only chart the way forward.

COVID is the worst pandemic in living memory. An international team of scientists has now uncovered another grim distinguishing feature: the COVID pandemic can be considered two back-to-back pandemics, caused by two different serotypes of the same virus.

By focusing on the immune system’s response to viruses, the scientists from Duke-NUS and Singapore, the Global South and Europe determined that SARS-related coronaviruses fall into three serotypes: SARS-CoV-1, SARS-CoV-2 and its earlier Delta and Beta variants, and Omicron. Their findings were published today in the journal hlife.

“The strong selective pressure driven by population immunity favours the emergence of new virus variants. Omicron variants are distinct from their ancestral SARS-CoV-2 virus and can be regarded as a distinct group in the context of antibody immune responses. This implies that pre-existing SARS-CoV-2 immunity is insufficient to prevent current and future infections,” said first author Dr Tan Chee Wah, a principal research scientist with renowned virologist Professor Wang Linfa’s lab in the Emerging Infectious Diseases Programme at Duke-NUS in a media statement to announce the findings.

This was the first time that a comprehensive panel of human serum samples from unvaccinated individuals who had been infected with various SARS-related coronaviruses was used to measure the immune system’s ability to neutralise or eliminate the different viruses.

By focusing on the antibody response, rather than the virus’ genetic sequence, the team found that Omicron — in particular its earlier offspring BA.1, BA.2 and BA.5 — triggers an immune reaction that more closely resembles the reaction stimulated by SARS-CoV-1. The Duke-NUS team, together with international collaborators, had previously shown that Omicron evolved to escape the immune response better than other variants and related coronaviruses in humans, bats and pangolins.

This latest advance confirms that to formulate an effective vaccination strategy, we need to reframe our approach, said co-first author Dr Zhu Feng, a senior research fellow in Wang’s lab: “It is critical for us to understand how newly emerging variants affect our immune system. In this light, serotyping has been a highly useful and proven approach to classify sub-species of viruses such as dengue viruses. The findings will impact future vaccine development and research on immunity testing using antibodies.”

Maintaining the current vaccination technology, which works well for stable viruses like measles and polio, will make eradication of SARS-related viruses in humans an impossible task.

“Viruses such as measles and polioviruses have evolved little to no change in their sensitivity to vaccine-induced immunity for decades,” said Wang, who is the senior author of the paper. “This is not the case for the coronavirus spike protein. Its high structural plasticity, coupled with the vast diversity of animal coronaviruses, makes complete eradication an impossible task with current technology. We need vaccines that can provide protection against the broad spectrum of coronavirus serotypes.”

And Wang’s team would publish their latest advances on this front just days later.

In a breakthrough that brings hope to people at risk of severe COVID-19, scientists at Duke-NUS Medical School have identified the driver behind some of the most serious COVID-19 complications, including pneumonia, breathlessness as well as potentially fatal cardiovascular events like blood clots and strokes. Their findings, published in the Journal of Clinical Investigation today, identified a type of immune cell called mast cells as the culprit, pointing to new therapeutic targets for preventing pneumonia and acute respiratory distress syndrome seen in the most vulnerable patients.

Mast cells are a type of immune cell that acts as a first responder for the immune system. These cells play a vital role in detecting and clearing foreign substances including viruses and bacteria but can become overactivated. When that happens, they drive fluid build-up, bleeding and other lung damage.

Yet despite their widespread presence and relatively large size, these immune cells have largely been overlooked as scientists raced to decode how the immune system responds to SARS-CoV-2 infection.

Using preclinical models of COVID-19, the international team of scientists led by Associate Professor Ashley St John from Duke-NUS’ Emerging Infectious Diseases Programme, uncovered that widespread activation of mast cells coincided with fluid build-up, bleeding and other severe lung damage, resembling the most serious complications seen in humans.

“Our results show that mast cells are essential contributors to the severe lung damage induced by SARS-CoV-2 infection,” says first author Ms Janessa Tan, a research assistant in Assoc Prof St John’s lab at Duke-NUS. “Targeting mast cell activation may represent a viable approach to reduce harmful inflammation and improve patient outcomes.”

Analysis of blood samples from COVID-19 patients confirmed the link between mast cell hyperactivity and disease severity. Levels of a mast-cell product called chymase were significantly higher in patients with severe COVID-19 compared with mild cases or healthy individuals.

“This study sheds new light on the immune mechanisms driving COVID-19 severity and long-term complications,” says St John, who is the senior author. “It sets the stage for investigating mast cell-stabilising drugs as an intervention to prevent severe lung damage in patients.”

Through their analysis of the human mast cell response at both the protein and gene-expression level, the scientists were also able to implicate mast cells in driving the severe vascular effects of COVID-19.

“COVID-19 can result in patients requiring hospitalisation due to pneumonia, but it also causes blood clots, strokes and cardiovascular events that can turn fatal. Our study suggests that mast cells may connect the lung and vascular pathologies through their influence on inflammation, clotting and vessel integrity,” adds St John, who collaborated on this study with colleagues from Australia, Singapore, including the National University of Singapore and Singapore General Hospital, as well as Duke University Medical Centre in the United States.

 A phase III clinical trial, initiated in collaboration with Duke-NUS, Duke University School of Medicine and Sen-Jam Pharmaceutical Partners, is underway. The trial is investigating the use of an already licensed mast cell-stabilising drug in combination with a non-steroidal anti-inflammatory drug on severe COVID-19. The trial is underway in Nepal with results expected in 2024.

“Hopefully, this discovery can improve outcomes for vulnerable patients who still need to be hospitalised because of the severity of their infection,” says St John, who hopes to bring additional trial sites to the ongoing clinical trial so that they can further speed up recruitment of eligible patients.

Pandemic restrictions may have been rolled back across the world, but SARS-CoV-2 continues to circulate, mutate and cause severe illness in vulnerable people as once-effective antibodies no longer bring any relief. At the same time, scientists are locked in an ongoing race against the virus to develop a vaccine that protects against more than just the known SARS-CoV-2 variants.

Now, an international research effort, led by scientists from Duke-NUS, has identified a set of exceptionally potent antibodies that offer new hope against the sarbecovirus family of coronaviruses that includes SARS-CoV-1 and SARS-CoV-2.

“We sought to address the lack of therapeutic monoclonal antibodies for treatment and prophylaxis of high-risk COVID-19 patients,” says Professor Wang Linfa from Duke-NUS’ Emerging Infectious Diseases Programme, “as all previously approved monoclonal antibodies have lost efficacy against new SARS-CoV-2 variants.”

Building on his team’s discovery in 2021 that people who had been infected with SARS-CoV-1 and were later vaccinated against SARS-CoV-2 produced powerful antibodies, Wang gathered an international team of experts to delve deeper into these immune cells.

Working with experts from the University of Melbourne, the Fred Hutchinson Cancer Research Centre in the US and the National University of Singapore, Wang and his team found that six antibodies conferred broad protection against SARS-CoV-1 and SARS-CoV-2.

“The bulk of the monoclonal antibodies we isolated were able to cross-neutralise both SARS-CoV-1 and SARS-CoV-2 viruses, which differ by more than 20 per cent from each other, suggesting that there are important and conserved epitopes that are shared between SARS-CoV-1 and SARS-CoV-2, as well as potentially amongst many members of the sarbecovirus family,” says Dr Chia Wan Ni, a former postdoctoral fellow in Wang’s lab who was the first author of this latest discovery, published in Science Advances.

Sifting further, they found that three of the six antibodies stood out as exceptionally broad and potent, proving capable of neutralising all tested SARS-related viruses at very low concentrations.

“But E7, the best monoclonal antibody we isolated, demonstrated a neutralising breadth that supersedes all reported monoclonal antibodies and continues to neutralise newly emerging Omicron variants at good potency,” says Chia.

E7’s power rests in its ability to tie up two parts of the virus’ spike protein so that the spike remains locked in its inactive form and the virus cannot shape-shift to infect cells and trigger illness.

“The E7 antibody may become a strong asset to help prevent the next outbreak caused by sarbecoviruses,” says Chia. It could be used, for example, as an anti-viral therapeutic for patients at high risk of developing severe disease or as a prophylactic for frontline workers and close contacts of confirmed cases to ringfence and restrict the spread of disease.

“Use of antibodies in both of these scenarios early in an outbreak can buy time for vaccines to be developed and will greatly reduce the mortality and disease burden,” adds Chia.

The findings’ wider implications also offer hope that the human immune system can be educated to become more resilient against coronaviruses of this family.

“We demonstrate that induction of broad sarbecovirus-neutralising antibodies is possible—it just needs the right immunogenic sequence and method of delivery,” says Wang. This could be, for example, by exposing individuals to two or three sarbecovirus vaccines that are significantly different so that the conserved neutralising flags—or epitopes—can be targeted by the immune system.

“This provides hope that the design of a universal coronavirus vaccine is achievable,” adds Wang.

These antibodies have been licensed to Singapore biotech start-up CoV Biotechnology for further development.

COVID-19 has highlighted the need for a universal vaccine that remains effective against all variants of a virus family. In their review, published today in Cell Host and Microbe, scientists from Duke-NUS and their collaborators assess the progress made in the development of such vaccines against three virus families that pose a high risk of triggering Disease X: henipaviruses, influenza viruses and coronaviruses.

“Viruses from these three families mutate frequently, thrive in many different species of wild animals and can range from mild to fatal,” says Professor Wang Linfa, the senior author of the review who has been studying ways to develop a broadly protective pan-sarbecovirus vaccine.

Reviewing the development of vaccines and monoclonal antibodies against the three viral threats, Wang and his co-authors, including Dr Tan Chee Wah, draw out four lessons:

1. No one vaccine platform reigns supreme: the effectiveness of a vaccine depends on the virus, natural reservoirs, the extent of mutations and the level of immunity required to remain protected.
2. Successful development depends on knowledge accumulated over decades: scientists had already developed the mRNA platform and studied the Spike protein extensively before the pandemic hit.
3. Broadly neutralising antibodies have been isolated for each of the three virus families: despite this, no vaccines have resulted from these discoveries yet, and more work is needed to reverse engineer an effective vaccine from these.
4. Neutralising monoclonal antibodies against viruses with high pandemic potential could be used as a first-line containment strategy in a new outbreak: though costly, this could mitigate outbreaks while the development of family-wide vaccines remains ongoing.

“We are working on a third-generation COVID vaccine that could protect against sarbecoviruses, the subgroup of coronaviruses that includes SARS-CoV and SARS-CoV-2,” says Tan, who is a senior research fellow in Wang’s lab and the first author of the review paper.

“While a pan-sarbecovirus vaccine seems possible,” says Wang, “a vaccine that targets even broader groups of coronaviruses — a real ‘dream vaccine’ — remains elusive at the moment.

“But what is most important is that we continue to invest in finding a solution now so that we can react quicker when Disease X strikes. We need a paradigm shift to make vaccine development proactive or pre-emptive rather than reactive as we used to do.”

“What you are going to see in this book are some wonderful stories. And not unexpectedly they focus on our Emerging Infectious Diseases Programme, they focus on our BSL3 [biosafety level 3 lab] and the staff that kept that going and all the terrific work they did. But I want to acknowledge in addition folks that didn’t end up in this book that did some amazing things in the past three years,” added Professor Patrick Casey, Senior Vice-Dean for Research in his remarks at the event.

From volunteering at quarantine facilities and staffing wards to ensuring that research work could continue, everyone at Duke-NUS pitched in, said Casey.

“It just reminds us every day that people matter. People can make a difference. Everybody can make a difference in the end. And hopefully this is going to make a difference in helping us be ready for the next time [a pandemic] comes because it probably will come again in our lifetimes and we’re going to be much more ready.”

Joining forces, Casey and representatives from the Emerging Infectious Diseases Programme, the Centre for Outbreak Preparedness along with Senior Vice-Dean for Corporate Affairs Ms Karen Chang unveiled the book.

When asked to name her highlight of the evening, Principal Research Scientist Eugenia Ong, whose story is captured in the book said, “Seeing the book and receiving these thoughtfully drawn portraits.”

“We are used to writing our own experience in journals,” reflected Dr Danny Tng, an adjunct research fellow and Duke-NUS alumnus from the Class of 2019, “having a third person tell our story is very different. But I hope my juniors will be encouraged to take up similar roles next time.”

Speaking about the motivation behind the book and this microsite, Director of Communications & Strategic Relations Mr Anirudh Sharma said after the event: “Throughout the pandemic, our people—scientists, clinician-scientists and educators alike—provided solutions, clarified mis- and disinformation and went the extra mile to help the world. Now that we are emerging from the immediate shadow of COVID, we wanted to pay tribute to all their great work by capturing those hectic and intense early days and sharing the moments of inspiration that led to their discoveries. We are delighted by the amazing feedback we have received from readers so far.”

An international effort led by the University of Minnesota’s Centre for Infectious Disease Research and Policy, published a comprehensive and cohesive framework and timeline to accelerate research and development into broadly protective COVID vaccines that are suitable and accessible for global use.

Funded by the Bill and Melinda Gates Foundation and The Rockefeller Foundation, the roadmap was drawn up in consultation with 50 international subject matter experts and recognised leaders in the field of emerging infectious diseases. Among the taskforce experts is Professor Wang Linfa from Duke-NUS’ Emerging Infectious Diseases Programme.

The roadmap, which was published online today in Vaccine, identified five high-priority milestones relevant to vaccine development, including virology, immunology and immune correlates of protection, vaccinology, animal and human infection models, and policy and financing.

Speaking during the virtual launch of the framework that would take place in April, Wang highlighted that to develop a better vaccine, we need to understand the virus better.

“This is the largest single-stand RNA virus and because of their large genome, coronaviruses mutate easily and are prone to recombination,” said Wang.

And while many of coronaviruses originate from bats, they commonly infect an intermediate host — which enables viruses to adapt for easier transmission and amplifies them — before they trigger a sustained spillover into humans.

That’s why, Wang believes, the best way to prevent a pandemic is to screen intermediate hosts to pick up emerging viral threats. To do that, Wang called for precision serological surveillance tools that can pick up antibodies even after the virus has been eliminated by the immune system.

“This will give us a much more sensitive approach and a broader picture of the prevalence, dynamics and transmission patterns of these viruses,” explained Wang.

If preventing the spillover into humans is not possible, added Wang, the next best preventative strategy would be an early warning system which relies on surveillance in hospitals and communities, so that immediate containment strategies can be deployed.

In the hospitals, surveillance should focus on patients who become severely sick from an illness with no known origin who have had contact with animals, outlined Wang. In the community, the alarm bells should be triggered by any cluster of cases that may or may not have severe disease but that share common symptoms, where the disease has no known origin and links to animals are documented. 

“In such a situation, we could create a defensive ring if we now take the time to develop tools such as broadly protective vaccines and virus neutralising antibodies,” says Wang. “And to do that, we need to establish a transparent and active, internationally collaborative network during peace time.”

Anxiety and depression may cost Singapore nearly S$16 billion a year, or 2.9 per cent of the nation’s gross domestic product. That’s the headline figure Professor Eric Finkelstein and his collaborators from the Institute of Mental Health calculated from a survey of adults in Singapore, in which they found that two in ten adults reported experiencing symptoms of either depression or anxiety, or both. This was the first study to estimate the prevalence and economic burden of depression and anxiety in Singapore after the peak of the COVID-19 pandemic.

“There was much anecdotal evidence suggesting this was the likely outcome, we were just the first to put a number to it,” says Finkelstein, from Duke-NUS’ Health Services and Systems Research Programme who led the study. “So, I wasn’t surprised by the findings.”

And it was not just anecdotal evidence. When Finkelstein took the pulse of the nation’s mental state and their perceived risks of COVID-19 back in 2020, he found that out of 897 participants, 23 per cent reported moderate and severe anxiety, levels that were significantly higher than previous mental health studies suggested.

To quantify the full economic impact of these conditions, Finkelstein and his collaborators surveyed 2,348 adults, who completed a depression and anxiety screening questionnaire on behalf of the 5,725 adults living in their households between April and June 2022. Published in BMC Psychiatry today, the team reported that 14 per cent of adults experienced symptoms indicative of depression and 15 per cent had symptoms consistent with anxiety.

Those whose screening indicated that they may suffer from either condition were asked to complete a more detailed questionnaire, which the researchers used to quantify the total economic loss.

And the vast majority of this loss — more than 81 per cent — came from reduced productivity as affected individuals tended to continue working but at a level far lower than their potential, with absenteeism and use of healthcare resources accounting for the remainder.

The researchers further discovered that of those who screened positive for depression or anxiety, only half had been formally diagnosed, while only a third reported seeking help for their conditions and even fewer sought the support of a mental health provider.

“Most concerning is the high rate of symptoms among those who do not appear to be actively being treated and the large reduction in productivity that results,” says Finkelstein. “This is a major hit on both health and economic output.”

Globally, the World Health Organisation estimates that COVID-19 added 53.2 million cases of depression and 76.2 million cases of anxiety since the start of the pandemic.

“Greater efforts to encourage undiagnosed cases to seek treatment, expanded access to peer support programmes, increased efforts to improve mental health literacy and reduce stigma, and greater training among community resources such as general practitioners and allied health professionals to diagnose and treat mental health symptoms are all part of a successful recovery strategy for the whole population,” said Associate Professor Daniel Fung, who is the chief executive officer of the Institute of Mental Health, and a co-author of the study, in a media statement that would go out publicise the findings.

Scientists from Duke-NUS detected long-lasting immune cells that fight SARS-CoV-2 in the noses of vaccinated individuals who were subsequently infected with COVID-19.

“The SARS-CoV-2 virus initially enters and replicates in the upper respiratory tract, with nasal cells maintaining high levels of virus replication for several days,” said Professor Antonio Bertoletti from the Emerging Infectious Diseases Programme at Duke-NUS, who led the study.

Having this group of virus-fighting immune cells, called T cells, present in the nose could provide an “immediate layer of protection against SARS-CoV-2,” added Bertoletti.

While studying nasal swab samples collected from volunteers, Bertoletti and his team found virus-specific T cells only in the noses of individuals who were infected by SARS-CoV-2 after completing their vaccination.

The nasal-based T cells persisted for at least 20 weeks and recognised various SARS-CoV-2 proteins, reported the group in the Journal of Experimental Medicine. These cells also recognise various viral proteins and will be alerted to variants including the Omicron variant despite its spike protein mutations, ensuring continued nasal-based immunity against SARS-CoV-2.

However, further studies are needed to understand the role of these virus-specific T cells in SARS-CoV-2 protection, and the longevity of these immune cells beyond 20 weeks.

A rapid test that measures the body’s active immune T-cell defenses against SARS-CoV-2 was developed by a research team that includes Duke-NUS researchers.

The new method, which requires less than 1 ml of blood, is easy to perform, making it adaptable for mass testing of patient samples noted the researchers in their paper pubished in Nature.

Detecting SARS-CoV-2-specific T-cell activation is the test’s key innovation over its conventional counterparts which measure other indicators of the body’s immune response during a viral infection, such as the presence of viral particles or virus-specific antibodies.

“T cells protect from disease,” said study co-author Professor Antonio Bertoletti with Duke-NUS’ Emerging Infectious Disease Programme. They “recognise the infected cells ... and destroy them. T cells are also important for the efficient maturation of B cells, [which] also help to produce antibodies,” he said in a response to Channel NewsAsia.

Because it detects T-cell responses, the test provides an alternative for studying the SARS-CoV-2 immunity of immunocompromised individuals who do not produce as many antibodies compared with healthy individuals. The results could also determine if vaccinated individuals remain protected against future COVID-19 infections.

Besides that, this innovation has another advantage: while it was formulated to detect the degree of cellular immunity to SARS-CoV-2, the same technology can be applied to measure the body’s T-cell responses to other viral infections. It is “an urgently needed complement to the currently available tests,” the authors wrote, adding that the test could help inform vaccination strategies based on the levels of immune protection in target populations.

Duke-NUS today launched the Centre for Outbreak Preparedness or COP. The new Centre will improve health security across South and Southeast Asia, by partnering institutions like the Bill and Melinda Gates Foundation, the World Health Organisation and Singapore-based partners.

“Duke-NUS is proud to contribute to Singapore’s decisive and effective actions to fight COVID-19,” said Duke-NUS Dean Professor Thomas Coffman at the Centre’s launch, which was attended by some 100 guests from the biomedical and healthcare sector. “And now, as we are emerging from the pandemic, it is important that we remember the lessons we learnt over the past two-plus years and use these to prepare for the next one.”

AT THE LAUNCH OF THE NEW CENTRE, DPM HENG (FRONT ROW, CENTRE) URGED ETERNAL VIGILANCE

Deputy Prime Minister and Coordinating Minister for Economic Policies Mr Heng Swee Keat, who also attended the launch, added: “Overall, pandemic preparedness requires eternal vigilance and continuous investment, year in, year out. It requires us to learn from each pandemic and unlearn some past practices. So that when the next one strikes, we are ready.”

The event ended with a panel discussion moderated by The Straits Times Senior Health Correspondent Ms Salma Khalik about how to enhance the region’s capacity to innovate and intervene against future health threats.

THE PANEL DISCUSSED HOW TO ENHANCE THE REGION'S CAPACITY TO INNOVATE AND INTERVENE AGAINST FUTURE HEALTH THREATS

The discussion tied into the Centre’s flagship project, the Asia Pathogen Genomics Initiative (APGI). The APGI — which is funded by the Bill and Melinda Gates Foundation — brings together 11 countries in the region and focuses on genomic surveillance and epidemiology. Its three key operational thrusts are regional roadmap development, national-global alignment and capacity enhancement.

“If the pandemic has taught us anything, it is that we are interdependent and that we are strongest when we are working together,” said Professor Paul Pronyk, the director of the Centre for Outbreak Preparedness, at the launch. “Partnerships between institutions, between countries, between continents are the crux and core mission of COP.”

Ms Kamini Kunasegaran made the Bertoletti lab’s pivot from studying the hepatitis B virus to SARS-CoV-2 a practical reality. She achieved this by reorganising reagents and adapting what the lab had learnt about studying T cells in hepatitis B-infected patients to work for SARS-CoV-2-infected and vaccinated people. And all that in a matter of weeks.

KAMINI KUNASEGARAN (CENTRE) CELEBRATES HER AWARD WITH SUPERVISOR ANTONIO BERTOLETTI (RIGHT) AND TEAMMATE NINA LE BERT (LEFT) // CREDIT: NINA LE BERT

“Kamini was the figure who made our ‘lab transformation’ a reality,” says Professor Antonio Bertoletti from Duke-NUS’ Emerging Infectious Diseases Programme.

“She did this not only working alone but by involving and motivating young research technicians and PhD students, creating a dedicated laboratory team that produced extremely high-quality results in a new area of research in a very short time,” he added. 

The results of those efforts speak for themselves: by July 2020, the team had published a paper in Nature despite having had to conduct their experiments under the tightest COVID-19 restrictions imposed by the Singapore government, working all hours as samples came in.

In recognition of these stellar accomplishments, Kamini today received the Asian Scientist Lab Tech of the Year 2021 MiRXES COVID-19 Hero Award from MiRXES CEO Dr Zhou Lihan at a ceremony held in Gardens by the Bay’s Flower Dome.

KAMINI, JOINED BY BERTOLETTI ON STAGE, RECEIVES HER AWARD FROM MIRXES CEO ZHOU LIHAN // CREDIT: NINA LE BERT

Recalling her reaction to the news, Kamini says: “I was pleasantly surprised and delighted to have received this award. More importantly, I am thankful for being part of a wonderful team for giving me the opportunity to contribute to the fight against COVID-19.”

Kidney transplant recipients and donors in Singapore felt less distressed during the COVID-19 pandemic than the general population around the world, reported clinician-scientist and kidney specialist Professor Tazeen H Jafar, from the Health Services and Systems Research Programme at Duke-NUS, and her colleagues.

While some 14 per cent of donors and recipients reported feeling anxious, stressed or depressed during the pandemic, Jafar and her colleagues, including Drs Sobhana Thangaraju and Terrence Kee from SingHealth, found that this was almost two times lower than the global average of 30 per cent in the general population and almost four times lower than high-risk individuals living with pre-existing conditions such as cancer, type 2 diabetes and COVID-19.

In the paper, published in BMC Nephrology, Jafar and her team placed this overall resilience to pandemic-induced psychological distress in the context of Singapore’s health policies and resources, attributing their findings to Singapore’s low COVID-19 rates and resulting low mortality, “which was likely due to efficient national responses and high-quality medical care,” they wrote.

“Specifically, since the start of the outbreak, the Singapore government had proactively established official COVID-19 resources and subscription services, as well as frequent briefings and press conferences by the Prime Minister and other officials, to keep the public informed of the latest COVID-19 situation in Singapore.”

In their paper, the team also pointed to robust contact tracing, mask-wearing, social distancing, financial aid schemes and the nationwide distribution of free masks and sanitisers as specific factors which helped alleviate psychological distress.

Where distress was associated with personal and social factors, the researchers saw an opportunity for implementing proactive health education policies: “Focused health education targeting younger adults, unmarried individuals, non-Singapore citizens, and those with worse health conditions could potentially prevent psychological distress in high-risk kidney transplant recipients and the donor population.”

A novel combination therapy today received the greenlight to proceed with testing from regulators in Nepal. The project resulted from a collaboration between Sen-Jam Pharmaceutical Partners, Duke-NUS in Singapore and Duke University School of Medicine. The partnership was first announced in August 2021.

The phase II study will test the efficacy of an oral combination therapy that joins an antihistamine with a non-steroidal anti-inflammatory drug to mitigate severe symptoms and hospitalisation due to COVID-19. The researchers — including Associate Professor Ashley St John from Duke-NUS and Professor Alexander Limkakeng from Duke — believe that in combination the two will disrupt the body’s inflammatory process.

President Madam Halimah Yacob presented Professor Wang Linfa with the Science Medal at the 2021 President’s Science and Technology Awards in recognition of his global leadership in solving the SARS-CoV-2 pandemic and advancing our understanding of bat biology and emerging infectious diseases.

WANG LINFA ACCEPTS THE SCIENCE MEDAL FROM PRESIDENT MADAM HALIMAH YACOB AT A CEREMONY HELD AT THE ISTANA TODAY // CREDIT: A*STAR

“I am very honoured to receive this prestigious award, which is the highest honour given to a scientist in Singapore. I hope that the award will enable me to play an even more important role in contributing to science in Singapore and inspire the next generation of scientists,” said Wang at the time.

Through his extensive work in bat biology and emerging viruses, he established bats as a new way to study zoonotic transmission of viral diseases. Using bats, he unravelled the mystery behind this small mammal’s ability to stay healthy despite harbouring numerous viruses. This expertise enabled him to contribute to the regional responses to recent viral epidemics and pandemics, including Nipah, SARS — where he traced the virus’ origins to bats — and COVID-19.

Among his contributions to the fight against COVID-19, Wang and his team developed a novel surrogate virus neutralisation test — the only FDA-authorised serological test — and a third-generation coronavirus vaccine strategy that could potentially combat not only known SARS-CoV-2 variants, but also other coronaviruses that may emerge in the future.

As a member of multiple pandemic response committees, including several World Health Organisation COVID-19 committees, Singapore’s COVID-19 Research Workgroup, and the Scientific Advisory Committee of the Coalition for Epidemic Preparedness Innovations or CEPI, Wang provided expert advice to enable them to better respond to epidemics and pandemics. He is also a fellow of prestigious academic bodies, including the Australian Academy of Technology and Engineering, and the American Academy of Microbiology.

Adding his congratulations to Wang’s prestigious national recognition, Professor Thomas Coffman, Dean of Duke-NUS, said at the time: “Any one of Linfa’s accomplishments make him a worthy recipient of the President’s Science Award but the constellation of his accomplishments during this pandemic, drawn from a career spent studying bats and emerging viruses, makes this a particularly fitting tribute. His contribution to Singapore and the world will be counted in millions of lives impacted.”

WANG LINFA (BACK LEFT) JOINS FELLOW RECIPIENTS, WHO INCLUDE SINGHEALTH GROUP CEO AND DUKE-NUS GOVERNING BOARD MEMBER CLINICAL PROFESSOR IVY NG (FOURTH FROM LEFT), TO MARK THE 2021 PRESIDENT'S SCIENCE AND TECHNOLOGY AWARDS // CREDIT: A*STAR

Alongside Wang, Duke-NUS Governing Board Member and SingHealth Group CEO Clinical Professor Ivy Ng was honoured with the President’s Science and Technology Medal “for her outstanding leadership in the advancement of academic medicine in Singapore through developing health and biomedical sciences research and innovation, nurturing clinical research talent, and establishing strategic partnerships among academia, healthcare, and industry, to improve healthcare infrastructure”.

SARS-CoV-2 testing was an integral part of many people’s lives in Singapore. With access to anti-COVID pills from primary-care settings on the horizon, the eye-watering, sinus-stinging experience of an Antigen Rapid Test (ART) swab looked set to stay on beyond the need for routine testing.

To spare everyone’s sniffers, a team of scientists from Duke-NUS, its academic medical partner SingHealth and the National University of Singapore developed a saliva-based SARS-CoV-2 ART that showed promise in early clinical testing, nearly matching the sensitivity to the gold standard Polymerase Chain Reaction (PCR) test.

Dubbed the Parallel Amplified Saliva Rapid Point-of-Care Test, or PASPORT, the technology leverages a proprietary on-kit amplification technique, developed by Duke-NUS alumnus Dr Danny Tng, to produce results from a saliva sample in minutes.

Like other ARTs, PASPORT uses nanoparticles to bind the virus. But it is also coated with a second type of nanoparticles. These bind to the first set to amplify the signal. Because of its two-stage amplification, PASPORT can detect the virus at much lower viral loads, making it more sensitive at flagging SARS-CoV-2.

This also means that it can be used any time of the day, even after eating or drinking. The results of a clinical study involving more than 100 participants, which were published in Microchimica Acta on 6 December 2021, showed that PASPORT’s sensitivity in detecting the virus was 97 per cent and its specificity, 90.6 per cent.

“A reliable and painless saliva antigen test that is affordable and convenient to perform would encourage more [people] to be tested, and more frequent testing,” said lead inventor Tng, a medical officer with the Department of Infectious Diseases at SGH, and adjunct research fellow with Duke-NUS’ Emerging Infectious Diseases Programme in a media release issued today.

Tng, who graduated from Duke-NUS in 2019, added, “This may enable us to manage COVID-19 more effectively not only at the point of care, but also in settings such as airports, conventions and even at home.”

Requiring only saliva pooled in the mouth, the test is simple and easy to use.

“With this, we hope that more people will do the test as a personal act of social responsibility before engaging, especially, in large-scale events or gatherings,” said Professor Soo Khee Chee, a senior co-inventor of the test, who is Benjamin Sheares Professor in Academic Medicine with the SingHealth Duke-NUS Oncology Academic Clinical Programme.

Duke-NUS and SingHealth filed intellectual property protection for the invention and entered into a licence agreement with Digital Life Line, a Singapore-based company. The inventors hoped that through close collaboration with commercial partners, the product could be out in the market as soon as possible as countries around the world moved to making treatments available faster and in primary healthcare settings.

“[Oral antiviral drugs] will need to be given as early as possible after illness onset for maximal benefit,” said Professor Ooi Eng Eong from the Emerging Infectious Diseases Programme during a press briefing today.

“A test that can be self-administered or used on-site in the primary care setting may mitigate the need for cases to be managed at the hospitals.”

In a Nature paper published today, scientists from University College London together with collaborators from across the United Kingdom, Europe and Singapore, reported that boosting T cells that target the highly conserved region of the SARS-CoV-2 genome can supplement spike-specific antibodies in next-generation vaccines against emerging coronaviruses.

Putting the findings in simple terms, Professor Antonio Bertoletti from Duke-NUS’ Emerging Infectious Diseases Programme, who was one of the senior authors on the paper, explained that the study found that people — in this instance healthcare workers — who had been exposed to SARS-CoV-2 but never became infected, nonetheless produced T cells that targeted a protein that is essential in the early stages of the SARS-CoV-2 replication cycle, called polymerase protein.

In fact, what the researchers found, Bertoletti explained, was that in this group, these very specific T cells were not only present but could be made to multiply to abort infection in lab tests.

“Designing vaccines that activate polymerase-specific T cells could add a further layer of protection and be more effective in the early containment of the virus compared to spike-only vaccines as the polymerase protein is synthesised early after infection,” explained Bertoletti in a tweet issued by the School at the time.

What’s more, this protein is highly conserved across different coronaviruses in humans and animals.

“Vaccines that activate polymerase-specific T cells could possibly protect not only from current viruses but also from ones that have yet to emerge,” suggested Bertoletti.

This evening, the COVID-19 Research Workgroup was recognised at the National Medical Excellence Awards for its notable efforts in shaping the pandemic response in Singapore. The group’s findings also improved infection control methods, public health policies and the development of diagnostic and treatment methods.

This large, multi-disciplinary and inter-institutional group included Dr Chia Wan Ni, a then-research fellow with the Emerging Infectious Diseases Programme at Duke-NUS, along with then Associate Professor David Lye and Dr Barnaby Young from the National Centre for Infectious Diseases and A*STAR’s Professor Lisa Ng. The four recipients received their National Clinical Excellence Team Award from Minister for Health Mr Ong Ye Kung at an event held at the Shangri-La Hotel on Orchard.

REPRESENTING THE COVID-19 RESEARCH WORKGROUP FROM L-R: LISA NG, CHIA WAN NI, BARNABY YOUNG AND DAVID LYE // CREDIT: NATIONAL CENTRE FOR INFECTIOUS DISEASES

“I am part of a very amazing team,” said Chia, who represented Professor Wang Linfa’s entire team that night. “Everyone contributed very significantly at the highest level and I am proud of what our group at Duke-NUS has contributed to the national fight against COVID-19.”

Professor Thomas Coffman, Dean of Duke-NUS, said at the time: “I am particularly proud that the COVID-19 Research Workgroup is being recognised for their stellar achievements. Their drive and commitment to improving lives has made an impact that is reverberating well beyond our borders.”

The “shadow pandemic” of psychological distress is this clinician-scientist’s top concern.

“This year, the mental health day is of even greater significance as COVID-19 has ravaged the health systems disrupted lives and exacerbated the rising burden of mental health disorders globally,” said Professor Tazeen H Jafar from Duke-NUS’ Health Services and Systems Research Programme as she opened a panel held to coincide with World Mental Health Day. The discussion topic was spot on — the global mental health challenges of a post-pandemic world.

And she would know. Late in 2020, Jafar and her team had published the results of a systematic review and meta-analysis that synthesised the results of 68 studies involving 288,830 participants from 19 countries. What Jafar got was a snapshot of the global mental health situation, spanning low-, middle- and high-income countries.

“Our findings were — and remain — quite alarming,” reflects Jafar. “We under-appreciated how severe these issues were.”

One in three adults suffered from psychological distress during the pandemic. With COVID-19-induced lockdowns, quarantines and social distancing as well as job losses and other stressors, this “shadow pandemic” knew no boundaries.

While she had initially expected some countries to emerge more resilient than others, her results showed that the mental health crisis was truly a global one. Roughly 33 per cent of the general population was anxious. And 30 per cent experienced depressive symptoms.

“It was an eye-opener,” she says of the study. “It screamed ‘Gee, people need help.’”

Looking out for the vulnerable

Jafar, a practising kidney specialist and global health expert with a root specialisation in cardiometabolic diseases, had embarked on this project because mental health is intricately linked with these conditions.

“And COVID-19 unfortunately attacked and impacted people with cardiovascular disease risk factors, with hypertension and diabetes disproportionately,” she explains. “And mental health was a huge issue because it impacts how they take care of themselves.”

But her findings — true for country after country — had implications for almost all reaches of society, often affecting those most vulnerable the most. Among those most likely to experience anxiety and depression were women, younger adults, individuals of lower socioeconomic status as well as those living in more rural areas.

The consequences will be long-lasting and far-reaching, economic and societal, she worries.

“If you have a large proportion of the population who won’t be able to reach their full potential, the impact will be felt at the national level,” she says.

All the more so as this shadow pandemic was playing out in the context of very performance-driven societies, creating a negative spiral where the rise of unhappiness would feed the rise of chronic illnesses like diabetes and cardiovascular diseases.

“It is just going to be a very unhealthy setting both in the short and long term,” adds Jafar.

Huge issues call for huge solutions

Jafar had long been advocating for mental health to be integrated into physical health programmes and vice-versa. When COVID-19 hit, this project was a natural extension of her work.

“Optimal cardiovascular and metabolic disease risk reduction requires addressing mental health as well as other pharmacological and lifestyle interventions,” she explains.

She uses her seats on boards of funding and advisory bodies, such as the Medical Research Council in the United Kingdom, to advocate for large-scale programmes that tackle mental health disorders. She calls for more recreational activities and healthcare resources to be directed to high-risk populations.

A concerted effort is necessary to reduce the rural-urban, socioeconomic and gender disparities in psychological distress created by the pandemic, she notes.

TAZEEN H JAFAR DREAMS OF CREATING LARGE-SCALE, CUSTOMISABLE, LOW-COST PROGRAMMES THAT BENEFIT EVERYONE

But for programmes to scale up, policymakers and institutions have to address a shortage of qualified counsellors, psychotherapists and health workers with different levels of mental health expertise. “We need to train more people going into these fields and we need to create awareness,” she emphasises.

“Mental health is a huge issue,” stresses Jafar.

While anxiety and depression remain mild for most, they still have a deep impact on people’s lives. And if left unaddressed, personal mental health struggles will have larger implications for society.

“Even minor things will lead to people not being as productive, not reaching their potential,” warns Jafar. “This could have a very negative impact, potentially, from a long-term perspective, unless — and until — we intervene.”

Championing holistic care

This holistic care approach, which treats mental and physical health as one, is a COVID-19 intervention that Jafar actively champions. It may also be the key to bolstering public healthcare systems during a protracted pandemic.

The coronavirus disproportionately impacted those with existing conditions, influencing the severity of disease, need for intensive care, and even the probability of death. Jafar’s kidney transplant patients, who take immunosuppressive medication, remain extremely vulnerable. And her study showed that those at higher risk of severe infection were more likely to experience anxiety and depression.

More robust treatment plans can target these intersecting problems by offering mental health support alongside lifestyle management and pharmacological interventions.

With her own patients, Jafar tries to assess their mental health regularly. She provides counselling and introduces coping strategies whenever she can.

“Measure and intervene, measure and intervene,” she affirms. “That’s what we have to do; that’s how we make a difference.”

Jafar hopes that the wider medical community will also adopt such a strategy. “A comprehensive, optimal cardiovascular and renal risk reduction strategy requires addressing mental health in addition to the pharmacological and other lifestyle interventions,” she elaborates.

More, such holistic care has to be available to everyone.

At the heart of Jafar’s work is an unflinching focus on public health equity — the belief that everyone should have access to quality medical care.

“I’ve done large programmes,” she says. “What I want next is a big non-communicable disease — or a chronic disease control — programme which brings things together holistically. How can we deliver packages that are uniform, so that they can be applied in different countries? Both high-income countries and low-income countries.”

“Programmes that are customisable; but not something that’s just only going be for that one little population of one hospital,” she continues. “I want things that can go to the masses. To the public; so that the vast majority of people can benefit from that; that are cost-effective.

“I want to eliminate the disparities, that’s my dream.”

Speaking at the second-anniversary celebration of the National Centre for Infectious Diseases (NCID), Deputy Prime Minister and Coordinating Minister for Economic Policies Mr Heng Swee Keat highlighted that preparing for the next pandemic would be a key area of the national Research, Innovation and Enterprise 2025 plans.

“We will be developing a national R&D Programme for Epidemic Preparedness and Response, or PREPARE in short,” he said. “PREPARE will further strengthen our capabilities to prevent, prepare for and respond to future epidemics, by working with our local research partners, including NCID, and building a regional network to foster collaborations.”

In the months to come,  Duke-NUS Professor Wang Linfa would be appointed to helm this new programme as its executive director.

For the longest time, the study of T cells remained the domain of specialist research laboratories like Professor Antonio Bertoletti’s lab at Duke-NUS. With an acute frontline need for a full picture of the body’s immune response to SARS-CoV-2 infection and vaccination, Bertoletti and his team developed a simple and rapid method to measure the T-cell immune response to SARS-CoV-2.

Their discovery, published in The Journal of Clinical Investigation, applied the principle of monitoring T cells by proxy that is used in the diagnosis of diseases like tuberculosis. When the researchers added small fragments of the SARS-CoV-2 spike protein to the blood from people who had been vaccinated against or recovered from SARS-CoV-2, the T cells in the sample released signalling molecules called cytokines that could easily be detected.

Building on that, they showed that the test, called a cytokine release assay, could reliably identify and quantify specific T cells in these samples. This test, then, not only shed light on the presence of T cells. It could also determine their functionality against SARS-CoV-2.

ANTONIO BERTOLETTI AND HIS TEAM'S WORK ON T CELLS LED TO THE DEVELOPMENT OF A TEST THAT CAN RELIABLY DETECT SARS-COV-2-SPECIFIC T CELLS, A FIRST STEP TO MORE LARGE AND RAPID T-CELL STUDIES

Validated using blood from more than 200 patients who were recruited with the help of the team’s clinical partners at Singapore General Hospital, National University Hospital and the National Centre for Infectious Diseases, this discovery offers a simple, fast and accurate test — well-suited for routine and large-scale measurements.

“This discovery allows a rapid and large-scale expansion of studies to track T-cell activity across the world, while not requiring specialised or expensive equipment,” emphasised Bertoletti, the study’s corresponding author, at the time the paper was published.

“The study results confirm that the level of antibodies against SARS-CoV-2 in blood samples does not always correlate with the T-cell response. With this rapid test, we can help define the correlates of protection from T cells and antibodies for the development of COVID-19 vaccines.”

To bring this discovery to clinics around the world, Duke-NUS licensed the assay to Hyris, an innovation-based biotechnology company.

This Duke-NUS virologist aims to break SARS-CoV-2 infection cycles at a molecular level.

Assistant Professor Ooi Yaw Shin had not been back to visit his loved ones in Penang ever since the pandemic began. This even though the Malaysian island is merely a 90-minute flight away from Singapore.

“One of the reasons I moved back to this region was that I would be closer to home,” says Ooi, who had moved from Stanford to Duke-NUS in December 2019. “I remember calling my mom when I arrived, telling her: ‘Yeah, I just started my lab. I may not be coming home this Chinese New Year but I promise I’ll definitely come back in April or May for Qing Ming.’” Referring to the Chinese festival where families pay their respects to the deceased at their tombs.

“I never got the chance to leave,” Ooi finishes, deadpan.

Instead, he buried himself in work, researching fundamental questions about SARS-CoV-2: How exactly does the virus get into human cells?

“If we know which doors and windows a virus uses to break into our cells, we may be able to design new drugs, and perhaps improve vaccine designs,” he explains. 

Ooi and his team with Duke-NUS’ Emerging Infectious Diseases Programme specialise in identifying the factors that enable viruses to flourish within host cells. They turned to dissect the mechanics of a SARS-CoV-2 infection, searching for any weak links in the viral infection processes.

Tracing the path of invasion

Leveraging the latest gene-editing tool CRISPR, Ooi zooms in on virus-host interaction at the cellular level.

“With CRISPR, we can switch each of the 20,000 genes off or on in the human genome,” explains Ooi.

Like a surgeon with a scalpel, Ooi cuts the genetic material of cells to introduce or remove genes with precision, searching for candidate genes that are associated with the body’s susceptibility to viral infections.

“By finding out which genes are important and drugging them, we may potentially stop SARS-CoV-2 from infecting us,” he says.

Which is what he and his team set about to uncover.

Bringing everything to bear

With his years of experience, Ooi has always taken a broad approach to tackling viral threats. And so he studies a range of viruses — including respiratory viruses such as seasonal coronaviruses, human parainfluenza viruses as well as arboviruses such as the mosquito-borne dengue and chikungunya viruses.

“If we can find a feature shared by multiple viruses, the interventions we discover could be helpful across a range of viruses,” he explains. “Our director, Gavin Smith, he’s a world-class expert on respiratory viruses. He’s already worked on human seasonal coronaviruses before this outbreak so he had all the samples we could use and study.”

While coronavirus research is currently experiencing a surge in interest and funding, things had not always been that way.

Before COVID-19 hit, Ooi could name fewer than five laboratories across the world that were active in coronavirus research.

There was simply not enough public interest and funding, he shares, as previous coronavirus outbreaks had been limited in scale — and in the case of SARS, the virus vanished completely, perhaps because of effective containment strategies, or maybe a bit of luck. And the remaining coronaviruses that circulate in the human population as common colds were just not priorities.

But with its potent mix of transmissibility and infectivity, COVID-19’s unprecedented economic and social damage transformed the global public health agenda.

“Let me put it this way: a lot of the worst-case scenarios we predicted in decades of scientific papers and grant proposals had unfortunately become a reality,” remarks Ooi grimly.

A sneaky pathogen

Even for experienced virologists like Ooi, COVID-19 research was tough.

The widespread pandemic lockdowns had resulted in laboratory facilities being shut, assay turnaround times bottlenecked, and reagent shipments delayed.

“With lockdown delays, we got scooped multiple times as studies like ours were published. While we are confident that we still have unique findings to report, it is a constant race to get our findings validated and published,” he reveals.

But that doesn’t mean he and his team were idle. Far from it. While they battled supply chain issues, they also set about consolidating a comprehensive review of the intra-cellular goings-on that unfold when a SARS-CoV-2 virus infiltrates a cell.

Unlike most viruses Ooi had studied, which are faithful to a single mode of entry into human cells, SARS-CoV-2 turned out to have access to a side door, too.

As everyone soon learnt, it latches onto cells using the angiotensin-converting enzyme 2 or ACE2 receptor and merges with the cell surface membrane. Once inside the cell, the virus dumps its genetic material, which hijacks host cells’ machinery to generate copies of the virus for release.

But SARS-CoV-2 can also wiggle its way into cells when it is taken up by cells after binding to receptors on its surface, a process called endocytosis.

“SARS-Cov-2 just waits for its endocytic elevator ride to arrive and hijacks this mechanism to get in. It’s a very patient and sneaky pathogen,” Ooi says with a laugh.

Research that matters

Despite the initial setbacks, his team was soon doing what they are best at: getting busy decoding the threats posed by viruses and tapping the support the SARS-CoV-2 spotlight had brought.

To this end, he is part of a group of scientists from Duke-NUS led by Gavin Smith, who received funding to research human parainfluenza viruses, which cause respiratory infections like the influenza virus. Unlike influenza, there is no vaccine that currently protects against parainfluenza infections.

“This is a really good sign,” Ooi says. “It means we can hopefully continue to do good science over the next five to ten years — before attention fades and people lose sight of why this research matters.”

And while he looks forward to what’s to come, being at the forefront was at times a double-edged sword.

“In February, I could see the infection trend in Malaysia going up. And my extended family — my father’s side — they still wanted to throw a big Chinese New Year party like every year,” says Ooi, who had to play the “bad guy”. “I told them ‘Please don’t. All 50 unvaccinated people having lunch or dinner together is going to be disastrous.’”

“And they said, ‘OK, we’ll discuss among the senior folks in the family.’ Then, ‘Thank you for your suggestion. We’ll look into it’,” he shares.

Ooi’s relatives did eventually cancel that large gathering.

Having been apart for more than 18 months now — their big Chinese New Year reunion would be all the more joyous for the wait. While Ooi waited for that to happen, work in his lab continued, generating intel that would give us an edge against infectious diseases like COVID-19.

By August 2021, the world was once again in the midst of a rapidly swelling wave of SARS-CoV-2 infections, with new information and insights continuing to come out at an exponential rate.

Taking a leaf from the ancient Chinese general Sun Tzu, researchers from Duke-NUS who specialise in studying the human response to viral infections decided to review all that was known about the intra-cellular goings-on in the human body leading as SARS-CoV-2 infects the cells. Their review article, published in Current Opinion in Virology, they hoped, would help consolidate what was known about the virus and spur the development of new vaccines and antiviral therapeutics.

The team, led by Assistant Professor Ooi Yaw Shin from Duke-NUS’ Emerging Infectious Diseases Programme, laid out the sequence of events in a SARS-CoV-2 infection cycle: SARS-CoV-2 infections begin when the virus’ spike protein locks onto receptors such as the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of cells.

Two main entry routes, then, become available for SARS-CoV-2: the virus either fuses directly with the membrane coating the cell or it is taken into the cell after binding to certain receptors. Either way, success is achieved once the virus matures and fuses with the cell membrane.

OOI YAW SHIN STUDIES WHICH GENES ARE HIJACKED BY SARS-COV-2 AND WHAT THE VIRUS NEEDS TO INFECT A HUMAN CELL AND SPREAD TO OTHER CELLS

Once that happens, the virus unloads its RNA genome in the cell’s cytoplasm, where the viral RNA payload hijacks the cellular copying mechanism to generate viral proteins. Some of these proteins are assembled into new viruses, while others seize control of the machinery in the infected cell, forcing the cell to channel its resources into synthesising more viruses.

Accordingly, existing drugs that target pro-viral factors could potentially be repurposed, the researchers pointed out, to forestall SARS-CoV-2 infection. Such a repurposing could form the primary line of treatment for the COVID-19; with new drugs taking time to invent, trial and be approved for human use, the researchers noted.

They added that “selecting a suitable host target essential for a virus, but dispensable for a host remains challenging.”

A Duke-NUS research team chats candidly about their mission to develop a dream vaccine.

“Once we publish this New England paper, all the people who have access to it will immediately start their experiments to prove us right. Or prove us wrong,” says Dr Chia Wan Ni, a then-research fellow with Professor Wang Linfa’s lab at Duke-NUS. “So, we’ll be competing with the whole world.”

“That’s science, right? You must muster a bit of competition. Then you become better,” adds her co-author and lab mate Dr Tan Chee Wah, a senior research fellow.

The paper that had both of them so excited appeared in the discipline-defining The New England Journal of Medicine, and provided the first glimpse of broadly neutralising antibodies produced by SARS-CoV-1 survivors who had received the Pfizer-BioNTech mRNA vaccine.

Neutralising antibodies that were powerful enough to fight not just SARS-CoV-2 and its variants of concern (VOC) but also other animal-borne coronaviruses that could trigger SARS-3 or SARS-4 — never mind that the SARS-CoV-1 infections took place almost two decades ago in 2003.

“And if our science leads to a real product — like a real vaccine that actually can be used for boosters — then…,” Tan trails off, leaving the enormity of the thought unspoken.

“If it works, that means our science is true. And correct,” Chia chimes in. “It’s a good feeling to be validated by others.”

They laugh, in mixed satisfaction and disbelief, at how their work had escalated since the start of the pandemic.

FROM DIAGNOSTICS TO A DREAM VACCINE, WANG LINFA'S TEAM USED THEIR NOVEL SURROGATE VIRUS NEUTRALISATION TEST TO IDENTIFY ANTIBODIES THAT FIGHT MORE THAN JUST SARS-COV-2

First, they were just doing their own research. Then their serological testing methods helped Singapore’s health authorities link two of the largest SARS-CoV-2 clusters; the cPass™ serological test kit for the rapid detection of SARS-CoV-2 neutralising antibodies followed.

Now, this New England paper; their laugh simply means Is this big breakthrough really happening? To us? 

Expanding upon their breakthrough

They had possibly just hit the science jackpot. But after the long hours in the lab and at their desks as well as that frenzy of writing up the data and the month-long peer review fact-checking process, they felt like they were suddenly put on hold as they impatiently waited for news from the journal.

Tan shakes his head. “When our paper was first accepted in principle, I kept asking Prof Wang, ‘When’re they officially accepting our paper? Are they going to reject us or what?’”

“Then after the official acceptance, I kept asking Prof Wang ‘When’re they publishing our paper?’” Tan continues, deadpanning. “It was a very long wait.”

Because until it was published, they could not share their excitement with the wider world nor receive the validation of other labs corroborating their findings.

“I think everyone of us has our secret tree hole to tell all these things to,” adds Chia.

Secret tree holes aside, the team relied on each other during these moments.

“It’s good to have someone to talk to, and just hash things out, and just feel amazed at the whole situation,” she concludes.

Also, the New England paper didn’t, Chia points out, mean the end of that particular research avenue for them.

“Now the question is whether people who’ve already been given the SARS-CoV-2 vaccine, if they’re given a SARS-CoV-1 spike protein, will that have the same effect? That is what we’re testing,” she says.

And how do they feel about their increased prominence overall?

They are, after all, no longer just a lab working on their research. No. They are part of the larger, nationwide, even global, research work network intervening against the pandemic.

“Now we get to work with multiple parties and we get to see interpersonal relationships,” says Chia. “We get to know more about how things work in Singapore.”

“We can contribute to the country,” answers a quietly satisfied Tan. “So it’s good.”

By studying the neutralising antibodies of SARS survivors who had been vaccinated against SARS-CoV-2, a cross-disciplinary research team led by Professor Wang Linfa from Duke-NUS’ Emerging Infectious Diseases Programme identified powerful antibodies that could neutralise not just SARS-CoV-1 and SARS-CoV-2 but also similar viruses in the same sub-genus of coronaviruses.

Published in the New England Journal of Medicine, the researchers — Drs Tan Chee Wah and Chia Wan Ni among them — reported that while most survivors of the 2003 SARS-CoV-1 outbreak retained neutralising antibodies, these antibodies were not able to neutralise SARS-CoV-2. It was only after being vaccinated with an mRNA vaccine that they produced these broadly neutralising antibodies.

 
WANG LINFA TALKS ABOUT THE SIGNIFICANCE OF THIS PAPER ON MEDICUS - THE PODCAST  (MEDICUS)

Using an advanced version of the surrogate virus neutralisation test, which in its original format had been commercialised as cPass™, the team confirmed that these neutralising antibodies could knock out up to 10 different coronaviruses that belong to a sub-genus of beta-coronaviruses called sarbecoviruses. These include SARS-CoV-1 and SARS-CoV-2 as well as several pre-emergent viruses identified in bats and pangolins. 

Speaking at a news conference announcing the discovery, Wang said that this could become an alternative to variant-specific booster strategies, called 2GCoVax.

“We think this provides the scientific foundation to try a new boosting strategy—we call that 3GCoVax—to combat different variants including the current four and future ones,” said Wang during a press briefing, adding that the same principle could be used to produce therapeutic antibodies.

He went on to note that the World Health Organisation was targeting to have the majority of the global population vaccinated with existing vaccines in a year’s time.

“If we boost that population with the 3GCoVax,” he said, “we also potentially can be ready to fight and prevent the next pandemic of SARS-3 or SARS-4.”

SARS-CoV-2’s inflammation profile is something quite unique, immunologist Associate Professor Ashley St John realised early in February 2020. While most resources had been diverted to contain the pandemic and uncover the first building blocks — such as the genomic sequence of the virus — that would underpin subsequent discovery science, St John knew she, too, could contribute and make a difference.

“While the initial steps were very competitive, unanswered questions would continue to challenge scientists,” says St John, who is from Duke-NUS’ Emerging Infectious Diseases Programme.

Her previous experience of applying her expertise during an outbreak — that time the Zika outbreak — had given her the confidence to take the plunge this time and investigate a familiar target: mast cells, the type of white blood cell that is responsible for immediate allergic reactions in an unfamiliar landscape.

“That experience taught me that if you go ahead and try to contribute, it can pay off. So, my goal was to ask specific questions and establish the systems to address more questions as we learnt more about the virus.”

THE DRUG COCKTAIL TESTED CONSISTS OF TWO DRUGS, INCLUDING ONE WHOSE MAST CELL-STABILISING PROPERTIES ST JOHN BELIEVES COULD HELP TACKLE SEVERE COVID-19

Taking measured risks

A clinician-scientist’s journey through the pandemic.

“It was all about the exit strategy,” Professor Marcus Ong declares. How to prepare Singapore — and its healthcare system — for the transition to living with COVID-19.

Ong had his finger on the pulse of this pandemic and the public health measures necessary to tackle it since the start of 2020. And his estimates came backed by data — concrete figures extracted from the healthcare system. He would feed the data into simulations to predict the likely impact of different “what ifs”.

“So the idea of a simulation model is that you can play with things in the virtual world before you test them out in the real world,” explains Ong, who is the director of the Health Services and Systems Research (HSSR) Programme at Duke-NUS. “Ten years ago, we would not have been able to pull this off. During SARS, we were using Excel spreadsheets, best guesses and consensus by experts.”

This time round, the entire HSSR Programme came together, driving a four-pronged research approach called the COVID-19 Virtual Disease Health System Outbreak Model for Singapore, aptly abbreviated to CoViD-SOS. Through it, they addressed issues from the impact of the pandemic on vulnerable people and on mental health to the virus’ impact on hospital services and the effectiveness of different public health measures.

And right from the start, Ong’s models predicted three possible ways in which things could end. The virus could, as had happened during the first SARS outbreak, trigger one tidal wave of infections — “about fifty, sixty thousand cases” — before petering out. Or it could release repeated but progressively less intense waves over the next two to three years; where vaccines and new treatments coupled with safe distancing measures would be key.

“The last scenario was pandemic moving to endemic. Which was what we ended up in, where it becomes like tuberculosis or seasonal influenza and we have to live with it for a long time,” finishes Ong, who takes no satisfaction from having called the pandemic’s trajectory correctly from the outset.

“All the scenarios were quite grim and I would have been happy to be proven wrong. But we demonstrated that health services research can address an issue of national value and that helped bring this field into the realms of operations, decision-making, clinical policy and treatment,” he adds.

Ong and his team’s simulation results have helped — and continue to help — Singapore prepare for vastly different eventualities. They influenced the pandemic response strategies at the hospital and national level.

“I think I can help people more at a systems level, a population level,” says Ong, who also works regular shifts as a senior doctor in the emergency department of Singapore’s largest hospital, Singapore General Hospital. “Research, innovation and education are just as important as our clinical service.”

Why Singapore works

Ong’s concerns about the national healthcare system during the pandemic stem from personal experience. H1N1. SARS. And an understanding of the mechanics at work in a complex multi-factorial healthcare system.

“You can’t just leave the healthcare system to fight this battle alone,” he says, thinking about his fellow clinicians and frontline healthcare providers, many of whom worked extra shifts to keep services running. “They will get overwhelmed. That’s what happened in many other countries.

“In some countries, the rest of the population did their own thing and left the frontline healthcare system to carry on alone — that’s not sustainable.”

Indeed, the continuing overload of hospitals in the United States, the plea by the United Kingdom’s government to stay home to protect the National Health Service during the year-end holiday season and some contradictory public healthcare policy responses in other Asian countries, all bear out his warning.

“Singapore showed that it’s a combination of three things,” says Ong about the nation’s success in keeping people safe during the pandemic. “Healthcare system. Leadership. Social capital.”

He points to the fact that “if your government response and your social capital are poor, it’s still a disaster”.

And preparedness, especially, makes this combination work.

“All the hard work, preparation and planning,” Ong elaborates. “Having stockpiles of equipment, personal protective equipment and drugs. Having legislation in place that we can pull up to effect quarantine. All these have served Singapore well. If we had not had these, we wouldn’t have been able to have such a comprehensive response.”

He notes, too, that his colleagues from the Emerging Infectious Diseases Programme at Duke-NUS Jenny Low and Ooi Eng Eong along with many others were at the forefront of communicating science to the public and allaying their fears over vaccines. But Ong warns that nothing will ever convince everyone to take a SARS-CoV-2 vaccine.

So as the country eyed a future of living with SARS-CoV-2, a paradigm shift would be required; a balancing act, then, that would protect vulnerable groups while maintaining the capabilities of the healthcare system.

“In the emergency department, we already had a new paradigm for managing all our patients. Red, yellow, green,” details Ong about added triage protocols for the pandemic–endemic era. These new protocols run parallel to existing Priority I, II and III classifications that identify patients by the seriousness of their condition upon admittance at the emergency department and run all the way to general inpatient and isolation wards.

Red is for high-risk infected cases who need treatment in isolation-type facilities where air, for safety, flows in rather than out. Green is for low-risk patients and the newly introduced yellow lane is an intermediate risk rating.

“[It’s for] those with some kind of respiratory infection or contact history. Lower risk, but you still need some precautions,” Ong says.

And Ong sees some mitigation strategies as being extendable to social events in general — different measures for different immunity levels. It would help Singapore get back to life as normal while protecting the vulnerable.

“You may come to a point where you go to church and there’s one service for the vaccinated,” he muses. “And another for the unvaccinated.” His prediction would once again be spot on as Singapore would introduce vaccine-differentiated measures in early 2022.

A test of resilience

Reflecting on the first year of the pandemic, Ong calls it the toughest year of his life. No downtime. Additional shifts at the emergency department. Running and repeating simulations to predict the virus’ next move. And some challenges on the family front as his daughter, who has Tourette’s syndrome, was struggling to come to terms with the condition while preparing for the Primary School Leaving Examination (PSLE).

“She had lost interest in everything she used to enjoy. She would come home from school, head into her room and slam the door,” remembers Ong. “The last straw was when she developed selective mutism and didn’t utter a word to me for months because she couldn’t express herself.”

The Circuit Breaker saw Ong’s overseas work and conference travel grind to a halt and his two sons return home — the older one from law school in the UK and the younger one from the Singapore University of Technology and Design’s student dorms. This homecoming had a pleasantly unexpected impact on his daughter.

“She is very close to her older brothers, but both had been away at university,” recalls Ong. “So, when the Circuit Breaker came, they came back and she could talk and joke with them.”

“The other big benefit for her was that she didn’t have to spend hours travelling to school. She was happy to learn at home and by the end of the year, she exceeded all our expectations during PSLE,” adds Ong.

Family time also improved. Ong could regularly prepare lunch for his daughter and read the Bible with her at night.

But the biggest and most unexpected pay-off was that all these changes helped ease the pressures and stresses on Ong’s daughter and she could open up again.

“The Circuit Breaker gave me my daughter back, God works in mysterious ways!” says Ong.

He also drew support from the men’s cell group he leads at church, where he sees everyday examples of resilience and courage — from the retrenched regional manager who pedals through Grab deliveries in order to feed his three children to the university graduate clawing back his life after years of incapacitation with mental health issues.

“Resilience is knowing that you’ve been knocked down yet still having the courage to stand up,” says Ong. “You don’t give up. That is the quality of resilience, and I learned resilience from these guys.”

Public and political discussions are, as Ong noted, becoming all about the exit strategy from the pandemic, about Singaporeans picking themselves up, dusting themselves off, and getting back into the saddle.

“You can survive for 40 days without food, probably one or two days without water and about 10 minutes without oxygen,” says Ong. “But you can’t survive without hope. And we have hope by sharing a common purpose which is beyond just yourself.

A data scientist’s calculations help steer the healthcare system through the pandemic.

“New numbers need to come into play,” says Sean Lam, a then-assistant professor with Duke-NUS who also heads the data science team at the SingHealth Duke-NUS Academic Medical Centre, about the outlook on the pandemic as Singapore ramped up its vaccination programme.

As of 23 June, five million doses of the SARS-CoV-2 vaccine had been administered to residents in Singapore, and in an effort to increase the roll-out rate, the government had announced an accelerated vaccination programme that would come into effect on 26 June.

“We would have to watch the evolution carefully,” he recalls. “What the impact on morbidity and mortality would be as well as the easing of some of the restrictions.”

Lam would know. Having spent more than a decade modelling the day-to-day operations across Singapore’s largest healthcare cluster, SingHealth, and developing predictive algorithms for clinical and management use, Lam and his team of data scientists and analysts were quick to respond when SARS-CoV-2 reached Singapore.

They adjusted their models and fine-tuned them with the rapidly emerging and evolving information on the virus; models that would help hospital executives and operations managers plan where to focus resources so that the health system could weather the surge in patients.

“We were first asked to model how a surge in patients would affect the hospitals and the overall patient load,” remembers Lam.

This model made the best use of the scattered data from published sources on hand at that time—Big Data, after all, had to start smaller somewhere.

“We developed a model and shared that with the Ministry of Health,” recalls Lam about that early modelling. “They took some of those recommendations.”

With some additional resources from the Ministry, Lam as part of the Health Services and Systems Research (HSSR) team at Duke-NUS put forward a comprehensive multi-pronged modelling approach called COVID-19 Virtual Disease Health System Outbreak Model for Singapore, aptly abbreviated to CoViD-SOS.

Defining the trees to see the forest

By April, they were working flat out on the projects, which for Lam meant supporting healthcare operations teams at SingHealth in their resource planning through dynamic modelling that could forecast different scenarios accurately even as the data evolved.

“We had a systems dynamics model,” says Lam. “It could consider more complex interactions, the feedback-effects, loops, etc, leading to the ability to uncover emergent behaviours and unforeseen consequences. We also brought in a variety of other considerations such as public health interventions, workflow modifications and even social behaviours.”

“We built our simulation models at the micro and meso levels to get the most accurate estimates for a variety of problem statements,” he adds.

As policy and treatment courses changed over the coming months, Lam’s models, too, evolved.

“There were policy changes like the introduction of step-down facilities and community care facilities. Those, as well as new policies implemented at the hospital level, would all affect our predictions.”

Throughout the pandemic, he continued to share his insights at the SingHealth Disease Outbreak Committee as well as other hospital-level operational committees, some of which he and his team published in journals including Frontiers in Public Health and the International Journal of Medical Informatics.

Big Data analysis captures the widening ripples triggered by the pandemic

But it wasn’t just the direct effects of COVID-19 on hospitals that concerned Lam.

He also studied the impact of delayed and cancelled routine surgeries, and the impact on patients who faced delayed care or were unable to visit the hospital. And how the hospital could plan for resumption of business as usual.

“How could we plan to best manage the backlog of surgeries but ensure that we would have enough beds, operating theatre capacity, diagnostic facilities and the necessary healthcare manpower,” explains Lam. Those models helped the  Singapore General Hospital resume its operations and effectively tackle the backlog that had been caused by the delays imposed by the pandemic.

Reflecting on the most intense period of the pandemic, Lam finds satisfaction from his behind-the-scenes perspective; knowing the what-ifs that were avoided. When COVID-19 cases were high, Lam’s models painted a grim picture. Without any intervention, he saw towering peaks almost shooting off the charts. In the end, events unfolded differently.

“It was good to see that the interventions were effective and that we avoided the worst-case scenarios completely,” says Lam.

It also felt good to return to the projects that had to be set aside to free time for COVID-19 projects. These projects included ongoing studies of how to optimise healthcare resources for pandemics or disaster management.

“Some of the other research activities are related to respiratory medicine, cancer screening and diagnosis, diabetes and chronic diseases. The team has also been deep in the trenches working to implement the next-generation data science platform for SingHealth,” he says.

Peacetime practice powers pandemic performance

Pandemic-era research on SARS-CoV-2 had a noticeable and immediate impact. It was driven by an existential urgency — the virus spread rapidly, impelled lockdowns, overwhelmed unprepared health systems and caused mass deaths.

Yet, Lam approached — and continues to approach — these social and institutional anxieties unfazed. After all, there’s no better time to prepare for war than during peacetime.

“If you’ve not been doing this data modelling, and suddenly you’re called to do something like it — it’s like starting in a whole new research field. During the middle of a pandemic. You’d better not take it up,” he says.

“But here, we’ve been doing this all along, we’ve been doing this,” Lam emphasises. “So, whenever we’re called up to do this, we are always ready to take up the challenge.”

cPass™, the novel surrogate virus neutralisation test (sVNT) invented by Duke-NUS and co-developed with A*STAR’s Diagnostics Development Hub and GenScript Biotech, received notice of allowance for its patent application today.

As clinical trials showed, cPass offered a marked improvement over other SARS-CoV-2 test kits. It specifically detects neutralising antibodies which are effective against the virus. It produces reliable results within an hour, where other tests require several days, and needs neither live samples nor the stringent biosafety level 3 measures required for other tests.

WANG LINFA DEMONSTRATES HOW TO USE THE TEST

“Instead of using the whole virus, you just use a piece of protein,” explains Professor Wang Linfa, lead inventor of the test and a professor with the Emerging Infectious Diseases at Duke-NUS. “So, you have the receptor and the key part of the viral spike protein that docks onto the receptor. And you can mimic the live virus neutralisation test in a test tube.”

Where Wang and his team invented cPass, GenScript optimised and refined it into a commercial product, tapping its global network and manufacturing capacity to launch cPass, which would become used across the globe.

“It took only 14 months to receive the notice of allowance, which we view as a strong validation of the innovative sVNT detection methodology,” said Dr Li Zhu, executive director and chief strategy officer at GenScript at the time.

The United States Food and Drug Administration had already granted emergency use authorisation in November 2020.

This clinician-scientist would rather trade all her accomplishments for a COVID-free 2020.

“There was no way that any one of us anticipated that it could grow to the kind of scale that we saw,” reflects Dr Jenny Low, a then-associate professor with Duke-NUS’ Emerging Infectious Diseases Programme.

As an infectious disease physician, Low had seen a number of outbreaks flare up before being quickly contained. Even the first SARS outbreak in 2003 — although devastating — lasted only a matter of months before life went back to normal.

“But most of us came to the realisation that we will have to live with this for a long time to come.”

While the sheer scale may have surprised some, Low and her colleagues at Duke-NUS and across the road at Singapore General Hospital (SGH), where the clinician-scientist works, were prepared for the outbreak.

“We always knew, that these events are ‘whens’ not ‘ifs’, so mentally we’re prepared,” she says shrugging.

Life in a flash

Low — like most other healthcare workers and infectious diseases scientists — had been working at breakneck speed for the past almost 18 months. Bolstered by the lessons learnt from the 2003 SARS outbreak, the robust screening system ensured that symptomatic patients were quickly identified, isolated and tested.

Just around Chinese New Year with the number of suspected cases snowballing, Low who divides her time between clinical work and research had to take on full-time clinical duties; her colleagues were already away on long-planned trips across the Malaysia-Singapore border and would have to quarantine once they returned.

“I was doing calls 24 hours for four days in a row,” Low recalls. “And at night, my phone was going off every 15 minutes. People wanted to know what to do with all these suspected cases, what risk factors to consider, whether these cases should be isolated.”

Those early days just flew by.

“Comparing this experience with working through SARS, I had a lot more energy back then,” muses Low. “I didn’t have kids either, but now I have four! There was a difference in my energy level, stamina and time,” she adds.

Despite being pressed for time, Low and her collaborators managed to share their early experiences dealing with this novel virus in a slew of publications, which included a report on the first three cases admitted to SGH as well as a larger report about the disease in 18 patients, which was published in the Journal of the American Medical Association.

By April 2020, she was finally able to focus on her research duties, joining the fray by recruiting patients for a range of clinical trials to evaluate potential treatments and other interventions to help people sick with COVID-19 as well as to examine the immune response and disease progression of infected individuals.

“I was having to deal with the speed needed to accelerate the research,” laughs Low, who also heads SingHealth’s early phase clinical trials unit, the Investigational Medicine Unit. “It was crazy. I was really racing against time and racing against everyone else.”

The most demanding leg of that race involved shepherding the Arcturus vaccine candidate, ARCT-021, Singapore’s first locally tested vaccine project against the virus, through early phase clinical testing.

“It was a very exciting time,” says Low of the days leading up to National Day 2020 as she and the team geared up for the first clinical trial.

But unlike other mRNA vaccines, ARCT-021 included a self-replicating component that had not been used in a vaccine. While her long-time collaborator  Professor Ooi Eng Eong, who led the preclinical testing, was on tenterhooks as the first doses were administered, Low felt quietly confident.

“By the time we started working on the vaccine with Arcturus, they were recruiting children with a rare inherited disorder in New Zealand for a trial using this platform and had safety data from their early phase study. Since we were using the same platform, I didn’t foresee much of an issue,” says Low.

Still, as the first doses were administered, Low remained on hand, vigilant for signs of an anaphylactic reaction in her participants. She did the same whenever the dosing was increased.

In the end, out of the more than 100 volunteers, all but two adverse events experienced by the participants were mild or moderate. And the vaccine candidate was greenlighted for further testing at the end of 2020.

Bittersweet moment that heralds the slow return to normal

Just as the vaccine entered the next phase of testing, the other frontrunners were shipped to countries across the world for real-world use. While that proved to be a bittersweet moment, Low was glad that the world had access to vaccines — vaccines that could prevent severe disease and help the world emerge from the pandemic.

And she has no regrets.

“The world got lucky. We had a ready platform that had been developed for cancer that could be designed into vaccines,” she says, pointing to the need for continued innovation.

“If we look around us to see what’s happening in the world now, there quite clearly aren’t enough vaccines for the short term,” adds Low, who co-directs the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS).

“So, when there’re more available vaccines on the market, ones that can be administered as a single dose, that’s going to benefit more people.”

And the faster vaccines could be made available, the better, as the long tail of the pandemic was starting to take its toll on people’s wellbeing.

The intermittent tightening and loosening of safe distancing measures had resulted in corresponding changes to work routines and school life. And home itself became an added source of mental stress.

“It was very difficult managing work plus home-based learning,” recalls Low. “I think for all of us, the difficulty lay more in coping with just how long the pandemic was lasting.”

But she knew, too, that after the vaccines were rolled out, there was a good chance that the situation in Singapore could return to some semblance of what it was like pre-COVID.

“With more people vaccinated, we can quickly get our vaccination rates in this country to cross the 60 per cent magic mark,” she muses.

“That number’s not going to get us herd immunity, but it’s going to get us a level good enough that we can handle small outbreaks without having to reimpose restrictions,” she continues.

As it would turn out, the wily virus would require a close-to-perfect vaccination rate to adequately cushion its impact on an exhausted healthcare system and fatigued economy before safety measures would be significantly relaxed.

Like all scars, Low knows that they will heal with time. By the time the pandemic is a peculiar memory of the past, Low wishes that the medical community’s recommendations will guide individual behaviour more.

“We have always strongly advocated masking up, yearly flu vaccination and pneumococcal vaccines and staying away from crowded places to our at-risk patients with damaged and vulnerable lungs,” she says. “Hopefully, people will be convinced.”

As for Low, she continued to pursue new projects profiling immune responses to vaccines and infection to gain a better understanding of the evolving virus. Colleagues, too, tapped her expertise for other research projects including saliva testing and N95 mask re-usage. It was fulfilling, purposeful work and resulted — and would continue to result — in, as Low says, “many publications and fantastic research achievements”.

But she would trade a normal 2020 for all these accomplishments any day.

“It makes me realise that I’ve missed so many things that I can do in normal times. I’ll do more travelling,” she lists for when the pandemic ends. “I obviously wasn’t taking enough breaks. I wasn’t spending enough time with family. Maybe I’ll catch up on all this.”

She laughs with a touch of self-deprecating awareness.

“I guess the whole world thinks the same.”

Trekking in the Himalayas was when this big Twitter fan first caught wind of a new virus.

Twenty-twenty is going to be an amazing year, Dr Ruklanthi — or Rukie — de Alwis remembers thinking as she and her husband trekked in the Himalayas in late 2019, even as their Twitter feeds started carrying news of a pneumonia of unknown cause. Soon, the cause began to be attributed to a SARS-like virus.

De Alwis, a then-senior research fellow with Duke-NUS’ Emerging Infectious Diseases Programme, was looking forward to studying the human antibody response to viruses that cause neglected tropical diseases like chikungunya and dengue, and advance the search for effective vaccines against these scourges.

In particular, she was keen to shed light on the different signals that emanate from the stems of Y-shaped antibody molecules; signals that beckon other parts of the immune system to help protect against infection. At least that’s how they are supposed to work.

“The plot thickens because that stem portion can either protect or make the infection more severe,” says de Alwis, who also held an appointment with the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS). “And that is something that has not been very closely studied.”

But as the first weeks of January rolled by, the novel coronavirus started to take root in Singapore, spreading beyond holidaymakers to the community.

As de Alwis watched cases creeping up, she felt agitated, an urgency to lend her skills had built in her. Sitting dispirited at the café at Duke-NUS, she was spotted by a principal investigator (PI) whom she admires.

“When I confided in this PI, she told me to just ask and gave me that push that I needed,” recalls de Alwis who works closely with Professor Ooi Eng Eong and then Associate Professor Jenny Low.

Plucking up the courage, de Alwis approached Ooi.

“I was sure I could help out somehow as we knew nothing about the antibody response patients were having,” says de Alwis, who had been developing a series of antibody tests using her National Medical Research Council Young Individual Research grant.

“I had these easily adaptable tests ready,” she adds. 

Yes, of course! was Ooi’s response and de Alwis plunged into the planning and preparatory work for a new vaccine project as the contract for the work was being finalised between Arcturus Therapeutics and Duke-NUS.

Stepping on the rollercoaster

The weeks and months that followed were a blur of activity, filled with scientific discussions on what and how many constructs to test, reading up on the literature from SARS to find the best leads, organising reagents and ensuring all the necessary supplies were on hand for the moment the contract was signed.

While they waited for the go-ahead, de Alwis and Ooi delved into a concern that niggled in their minds: Some early reports of preclinical studies had hinted at antibodies possibly going rogue, sending signals — or effector functions as they are known — that helped the invading pathogen. Similar effects had been observed in preclinical work for some vaccine constructs that had been developed against the SARS-CoV-1 coronavirus.

“There were some reports that instead of having all these beautifully protective effector functions, the virus uses the same portion of the antibody to get into an immune cell, causing an infection in the immune cell,” she explains. “And at that point we knew very little about SARS-CoV-2.”

Reflecting on the resulting review, de Alwis is glad that the antibody-dependent enhancement effect didn’t materialise in subsequent studies.

“We didn’t see the same effect in our preclinical vaccine studies, fortunately,” she says.

Just as Singapore entered the Circuit Breaker, the vaccine work unfurled in earnest, setting de Alwis and her colleagues off on a rollercoaster ride. With limited reagents and even less time, de Alwis and the team were under pressure to make every experiment count. Frequent and detailed discussions with the whole team and their partners were the norm.

So, despite being assigned to the afternoon shift, de Alwis’ day started early, her morning filled with meetings with teams in the US, analysing the latest data and planning the next steps.

Around 2pm, she would begin her shift in the lab.

“Sometimes, there were days, when I’d stay till 1am or 2am,” she recalls. “We were running on adrenaline.”

One bright spark during those sleep-scarce rollercoaster days was the company of her family. Based in Sri Lanka, which is two-and-a-half hours behind Singapore, she would videocall them as she worked late into the night, the gentle chatter helping her stay focused on her work.

Like the joy her family brought, the shared excitement and enthusiasm from the team in Singapore was another source of happiness.

“It was nice to have the team to discuss the data with. For the vaccine development project, seeing any signal was so exciting, we were (literally) jumping. That doesn’t happen in peacetime,” laughs de Alwis.

Emerging from the pandemic

While excitement ran high, the need to validate the science — that required the team to run the same experiments for each clinical trial participant at different time points to ensure they had a complete picture — meant that the team had to stay focused.

“I’m very much an academic scientist,” admits de Alwis. “So, if there is something super interesting, I want to follow it. But when you’re doing a clinical trial, there is one goal and you got to stay focused.”

“That was the hardest part of it.”

They didn’t just have to stay focused on the goal, they also had to meticulously document every sample and each step of their experiments.

“It was a highly stressful time,” says de Alwis. “But I also learnt a lot in the process and it showed me that I had skills that I could contribute which made it a very fulfilling experience.”

Her — and the wider team’s — experience was immortalised through the documentary “The Vaccine Quest”. Like the vaccine development project, it was another new experience for de Alwis, who would in the past have passed on such an opportunity; valuing her privacy more.

“I was thinking that if sharing my experience motivates more young scientists to do this sort of thing, then why not,” says de Alwis, who is determined to continue to engage with a wider audience about science.

As for her scientific ambitions, the pandemic lent a wider focus. 

“It has increased my focus on regional development,” shares de Alwis, who realised that to see a vaccine through its full development journey she would have to find a role that takes her beyond Singapore. Because by the time Phase III trials were due to start, Singapore had implemented an effective nationwide vaccination programme and successfully lowered its community transmission rates; essentially making Singapore no longer a suitable location for testing a COVID-19 vaccine in Phase III trials. 

This thought sparked another dormant passion of de Alwis’: a desire to give back.

“I come from Sri Lanka, and I really want to be able to give back all that I’ve learnt,” said de Alwis.

When she learnt that Duke-NUS was setting up a new centre — a centre that would work with low-resourced partners around Asia to ensure humanity’s defences against the next outbreak are strengthened — she saw a perfect opportunity.

“The pandemic showed us that we have a long way to go before everyone has equal access to health care,” she says. “And right now, we have an opportunity to strengthen the region in terms of tracking diseases, developing vaccines and fortifying our regional health security.”

The Centre’s director Professor Paul Pronyk was keen to bring her on board and within days, had offered her a new appointment: as an assistant professor with the Emerging Infectious Diseases (EID) Programme at Duke-NUS and the new Centre for Outbreak Preparedness as its deputy director, effective from third quarter of 2022.

“With these two complementary roles, I now act like a bridge, helping our EID folks translate their discoveries into meaningful impact through our partners across the Asian region,” she explains, “a bit like a matchmaker.” 

The second episode of “The Vaccine Quest”, a two-part Channel NewsAsia documentary, was released today.

SOURCE: CHANNEL NEWSASIA (youtube)

In this episode, the story picks up with the team one step closer to the finish line. They had cleared preclinical hurdles in record time and human trials were underway. As the study progressed, though, other vaccine candidates finished ahead of them.

Science communication remains vital during a pandemic.

“Let’s say there’s a misunderstanding, or a myth or whatever that’s being circulated. If we as professionals don’t speak up, then we are lending credence to that belief system,” says Professor Ooi Eng Eong.

“So, every time I see a journalist, I feel that I should do this,” he explains. “Because if I don’t, then from where else would the public get their information?”

Ooi had good reason to feel responsible. He co-directs the Viral Research and Experimental Medicine Centre @ SingHealth Duke-NUS (ViREMiCS) and is a professor with Duke-NUS’ Emerging Infectious Diseases Programme. He also worked through the first SARS outbreak and gained extensive knowledge and experience in designing effective vaccines. His advice on SARS-CoV-2, then, came backed by decades of research, and he offered it with a desire to keep the public safe.

In the absence of a reliable source of knowledge, misinformation about SARS-CoV-2 was filling the void, spreading worldwide through social media and conspiracy websites. The situation became so grave that by February 2020, World Health Organisation Director-General Dr Tedros Ghebreyesus noted that the world is “not just fighting an epidemic; we’re fighting an infodemic. Fake news spreads faster and more easily than this virus, and is just as dangerous.” 

During those early months, Singapore’s online spaces, too, had seen malicious rumours mushroom; rumours claiming that hospitals, MRT stations and shopping malls were SARS-CoV-2 hotspots, calling for people to avoid them.

“The science is one thing. But communicating the science and overcoming [misguided] belief — especially what comes up from social media — that’s a completely different world,” shares Ooi.

His colleague, Dr Ruklanthi de Alwis, a then-senior research fellow, points out that many of these malicious rumours used legitimate concerns to spread their misinformation.

“Just going in and saying, no you’re wrong is not the way to win this,” says de Alwis. “So, I really tried to listen to their concerns first because maybe with some I could still reason.”

“And not tackling that part would eventually hinder us. Because someday we won’t be able to get the vaccine into enough people; we won’t be able to get it in fast enough. And if it’s not fast enough, we won’t come out from this outbreak,” adds Ooi.

“There’s a small pocket of the population that was hesitant; they were resistant to taking vaccines,” adds Ooi’s colleague at ViREMiCS, Dr Eugenia Ong. “Because often you have one or two people who write something, and send it out on social media. And you know social media. It gets passed on from one to a billion other people.”

Part of this public propensity for rumour-mongering and confusion during the early days stemmed from three simple facts: the new virus spread easily and exponentially; the world had no treatments, never mind a vaccine; and levels of trust in governments and science varied.

“I started taking the time to explain. I tried to engage,” says de Alwis. “I made sure that the science was true and yet simplified in a manner that anyone could understand.”

It was in this spirit that the three of them along with then- Associate Professor Jenny Low and former colleague, Dr Esther Gan, shared their experience of developing the vaccine in a documentary, called “ The Vaccine Quest”.

“I was always happy when someone asked me about vaccines and whether they should take them. It gave me a chance to explain,” says Ong.

While the documentary may have been one of the more in-depth pieces of media coverage, the team were joined by other faculty members — including Associate Professor Ashley St John and Professor Wang Linfa — in the fight against misinformation.

But most importantly?

“If you don’t know where the information came from, and if you don’t know if it’s true,” says Ong, “Don’t spread it."

The first episode of “The Vaccine Quest”, a two-part documentary, aired on Channel NewsAsia today. The documentary followed the scientists and clinician-scientists from Duke-NUS and SingHealth as well as staff of the US-based messenger RNA medicines company Arcturus Therapeutics, on a quest for a vaccine. In the first episode, Duke-NUS and SingHealth experts ready this novel vaccine candidate for human trials.

SOURCE: CHANNEL NEWSASIA (YOUTUBE)

The body’s ability to mount a virus-specific T-cell response is not necessarily linked with symptom severity a new study by Duke-NUS researchers and colleagues from the Saw Swee Hock School of Public Health at the National University of Singapore found.

People who were infected with SARS-CoV-2, but showed no symptoms of infection, produced virus-specific T cells in a similar quantity to those who did experience symptoms, the researchers discovered.

But unlike in symptomatic individuals, the T-cell immune response in asymptomatic people was more efficient, releasing more signalling molecules, called cytokines, that are important for viral control, in particular interferon gamma and interleukin-2.

These findings, published in the Journal of Experimental Medicine, were the first to show, through direct comparison, that SARS-CoV-2-specific cellular immune responses were more efficient in asymptomatic than symptomatic individuals.

Professor Antonio Bertoletti from Duke-NUS’ Emerging Infectious Diseases Programme and the corresponding author of the study, observed: “It would be good news for patients to know that they are developing an efficient cellular immune response after a symptom-free infection. Our study opens the door for further large-scale T-cell testing, which could match the speed of antibody testing.”

Among the 65 new fellows inducted into the American Academy of Microbiology, Professor Wang Linfa from Duke-NUS’ Emerging Infectious Diseases Programme was a more unusual candidate.

The trained biochemist won over members of the Academy, which is the honorific leadership group within the American Society for Microbiology (ASM), following a highly selective peer-review process of how much his scientific achievements and original contributions have advanced microbiology.

“I am delighted and deeply humbled by this honour. I look forward to being a part of ASM’s mission to promote and advance microbial sciences,” said Wang when he received the news.

Wang played a pivotal role in deepening our understanding of the likely origins of the ongoing COVID-19 pandemic. During the early days of the pandemic, his team was among the first in the world to culture the SARS-CoV-2 virus from patient samples and developed serological antibody tests to identify an important missing link between two major COVID-19 clusters in Singapore. His team also invented cPass™, the world’s first surrogate SARS-CoV-2 serological test to rapidly detect neutralising antibodies that does not require containment facilities or live biological materials.

Professor Thomas Coffman, Dean of Duke-NUS, said at the time: “We are extremely proud of Linfa for being elected to this prestigious Academy. This is a testament to his passion, leadership and tremendous contributions to the field of infectious diseases. I look forward to his continued success and seeing more of our young scientists follow in his footsteps.”

Fellows in the Academy represent all subspecialties of the microbial sciences and are involved in basic and applied research, teaching, public health, industry and government service. The Class of 2021 hailed from Australia, Canada, Singapore, China, France, Ireland, Sweden, Slovenia, and Mexico, the United Kingdom and the United States.

Life went on despite the rapid pace of the pandemic. Martin Linster, newly promoted to assistant professor, and his wife, Marina, welcomed a baby girl, Norah, as others on the Little Red dot were busy ushering in the Lunar New Year.

Norah was the first Lunar New Year baby delivered at Singapore General Hospital (SGH) in the Year of the Ox. She is the Linsters’ second child and little sister to Bruno, then three years old.

“Ushering in the Year of the Ox with renewed hope and endless joy! SGH’s first Lunar New Year baby was delivered at 2.41am this morning,” celebrated SGH’s social media team, not long after Norah’s birth.

“You should at least sit at the breakfast table with everybody before you leave again,” muses Linster about life’s unstoppable flow. “You can’t have the people who love you waiting forever.”

SARS-CoV-2-related coronaviruses are circulating in wildlife across Southeast Asia. This finding stemmed from a study of bats and pangolins in Thailand.

Published in Nature Communications, the international team of researchers led by Duke-NUS experts found that 13 out of the 100 horseshoe bats studied tested positive for these SARS-CoV-2-like coronaviruses. These positive results all contained a particular genetic sequence that is 95.86 per cent identical to the corresponding section in human SARS-CoV-2, 96.21 and 94.48 per cent identical to the bat-borne CoV-RaTG13 and CoVRmYN02 viruses, respectively.

When testing for past infections using the Duke-NUS-invented surrogate virus neutralisation test cPass™, the team further found that one of ten pangolin serum samples screened showed a strong surrogate virus neutralisation test (sVNT) reading, exceeding 90 per cent. This corroborated published findings that pangolins are susceptible to infection by such viruses.

The research team, which included Professor Wang Linfa, then-Senior Research Fellows Drs Tan Chee Wah and Chia Wan Ni from the Emerging Infectious Diseases Programme at Duke-NUS, was confident that this finding demonstrates that coronaviruses with a high degree of genetic relatedness to SARS-CoV-2 are widely present in bats across many nations and regions in Asia.

The team also observed that these coronaviruses have been detected in bats across an area of approximately 4,800km, spanning from Iwata Prefecture in Japan in the north and Zhejiang province in China in the east to Yunnan in the southwest of China and southward in Chachoengsao, Thailand.

The great genetic diversity and plasticity of these viral genomes suggested to the team that the immediate progenitor virus of SARS-CoV-2 could be, with intensified and internationally coordinated surveillance, traceable.

In an award that recognised all the “selfless workers and volunteers who stepped forward” during the first year of the pandemic, The Straits Times recognised Professor Ooi Eng Eong from Duke-NUS’ Emerging Infectious Diseases Programme, for his contribution to the development of vaccines.

Ooi was part of a group of five COVID-19 frontliners from the healthcare, research, security and public health sectors, who received the honour in the name of all who fought the SARS-CoV-2 virus on the frontlines.



Now in its sixth year, the Singaporean of the Year Award honours Singaporeans who have made a positive and sustainable impact on society, and celebrates the triumph of the human spirit.

In late 2020, Ooi was also among a group known as the virus busters who received The Straits Times’ Asians of the Year Award.

One in three adults experienced COVID-19-related psychological distress. These were the findings of a research team led by clinician-scientist Professor Tazeen H Jafar from the Health Services and Systems Research Programme at Duke-NUS. First published in PLOS ONE on 28 December 2020, the team’s findings focused on gender, age, residential area and socioeconomic status.

Those at higher risk of COVID-19 infection, such as suspected or confirmed cases, people with a history of underlying chronic medical or mental health conditions as well as those in hard-hit areas, were understandably more prone to psychological distress.

But the study also revealed that younger people, mainly those below the age of 25, had higher odds of feeling distressed because this was most likely their first experience of an outbreak and they had greater exposure to media dispensing COVID-19 updates including information from unreliable sources.

Other groups that were particularly vulnerable included women and people in lower socioeconomic strata, particularly those with lower income and fewer years of education. They were prone to anticipate bearing financially disastrous medical expenses and loss of income. Rural dwellers also faced greater anxiety compared with urbanites due to their poorer healthcare infrastructure as well as less-developed economic, sanitary and educational resources.

“Understanding these factors is crucial for designing preventive programmes and mental health resource planning during the rapidly evolving COVID-19 outbreak,” explained Jafar at the time.

The findings were the result of a meta-analysis of 68 studies conducted during the pandemic, encompassing 288,830 participants from 19 countries. Here, the team systematically reviewed factors associated with psychological distress among the predominantly general population. This contrasted with the majority of other research studies, which were largely centred on the mental health of healthcare workers.

The report, Jafar hoped would help policymakers identify the urban-rural, socioeconomic and gender disparities in COVID-19-related psychological distress and ensure equitable healthcare across population segments.

Comparing T-cell responses between different groups of COVID-19 patients, researchers from Duke-NUS found that people who had mild symptoms produced the strongest virus-specific T cells early on in their infections. The researchers, who published their findings in Cell Reports, also noted that the immune response in people who had more severe disease was dominated by a rapid appearance of large quantities of antibodies.

The secretion of interferon-gamma-secreting SARS-CoV-2-specific T cells, in particular, characterised the immune response in those with mild infections. Interferon gamma (IFN-γ) is the primary activator of macrophages, which play a key role in fighting foreign pathogens including viruses. It also recruits other immune cells, including a type of T cell, known as natural killer cells, and neutrophils.

“Our data supports the idea that SARS-CoV-2-specific T cells play an important role in the rapid control of viral infection and eventual clearance of the disease,” said Dr Martin Linster, a then-senior research fellow with Duke-NUS’ Emerging Infectious Diseases Programme and the co-author of this study in a media statement at the time.

The quantity of these IFN-γ-secreting T cells also increased progressively while the SARS-CoV-2 infection resolved. Their peak was detected within 15 days after onset of symptoms in eight of the twelve patients studied.

The most robust functional T-cell response, further, was detected in patients with mild symptoms who cleared the virus early.

When the study was published, Professor Antonio Bertoletti, the corresponding author of this study, called for more efforts to adopt a more holistic view of immune responses to SARS-CoV-2: “It is time that T-cell monitoring should be considered in providing a comprehensive understanding of the immune response against SARS-CoV-2. This would also mean that a vaccine will likely be more effective if a concurrent induction of both antibodies and T cells occurs.”

On the first anniversary of the release of the SARS-CoV-2 sequence, the professor in Duke-NUS’ Emerging Infectious Diseases Programme reflects on rallying his lab to sequence SARS-CoV-2 and the need to lay the groundwork now for an even faster start—next time.

“I hope they manage to lock that down,” was Professor Gavin Smith’s first thought when news broke in December 2019 that a novel virus was spreading from Wuhan.

“Because if they don’t, it’ll probably become a pandemic.”

But they couldn’t—and it did. The transportation hub was finally closed to the outside world on 23 January 2020. By then, 286 people around the globe were already suffering from—and spreading—the highly infectious novel coronavirus.

And two of these virus carriers, travellers from Wuhan, were already warded in Singapore.

By then, Smith had already become involved. The professor with Duke-NUS’ Emerging Infectious Diseases Programme is a multi-disciplinary researcher who is a renowned expert on respiratory viruses. His team is trained in fieldwork, biosafety level 3 (BSL3) research and the genomic mapping of viruses.

The immediate ask of Smith and his team was to be ready to sequence the novel virus once it hit Singapore’s shores. With that data in hand, they and other scientists could then trace the virus’ journey and identify new mutations over time.

“In the early days, the sequencing data is crucial for contact tracing, so that we can know whether the virus is spreading in the community and monitor how it is adapting to being transmitted by humans,” says Smith, reflecting on how this had all begun.

Comparing the sequences with clinical outcomes would also help to spot mutations that could affect the infectivity, transmissibility and severity of the virus. That’s how his team went on to discover a large deletion in one of the virus’ key genes, called ORF8.

 “It was a massive deletion that was quite unexpected,” recalls Smith.

RESEARCH ON THE EVOLUTION OF THE VIRUS, WHICH LED TO DISCOVERIES LIKE THE ORF8 DELECTON BY SMITH AND SU, DEMONSTRATES HOW VIRUSES ADAPT TO THEIR HOSTS THROUGH TRANSMISSION

While Smith’s focus was on the genetic evolution of the virus, sequencing data also underpinned the work of other scientists who used it to develop new tests, better treatments and vaccines.

But all that came later. First, Smith’s team scrutinised the first sequence released to the world of the novel coronavirus, comparing it to existing sequences of similar viruses from animals and humans.

A sequence in sight

Genetic sequencing involves finding out how the four chemical bases in the virus’ RNA—its guanines, cytosines, adenines and uracils—repeat to form a unique chain that can be compared with other chains from the same virus.

“Early on in any pandemic, it’s really useful to have sequencing data,” says Smith. “And the first sequence was released from the Chinese group.”

“We immediately started comparing that sequence with other known coronavirus sequences so that we were prepared for when the first sequences came from patients in Singapore.”

Smith’s lab, reflecting the team’s interests and skills, is set up to sequence respiratory pathogens. Moreover, the team had worked on human coronaviruses—“the regular ones”, says Smith—before SARS-CoV-2.

“Preparation is what we do every day,” says Smith of his team’s mission.

The team travels around the world, working with—and training—partners to conduct robust surveillance of the viruses circulating in animals, particularly bats and small mammals like rats—hotbeds for disease X. They are used to doing their work in protective coveralls. They are accredited N95 mask fitters and used to wearing such masks or even respirators while working. They are experts at handling all kinds of pathogens.

“This kind of research builds capacity,” says Smith. And capacity is precisely what is needed during a pandemic. Ready capacity meant that the team was set to examine the 30,000 bases that make up this novel coronavirus.

“Our focus was on trying to generate the sequencing data as quickly as possible and making sure that we weren’t messing it up,” recalls Smith.

The result—Duke-NUS was the third institution in the world to culture and isolate the SARS-CoV-2 virus, sharing its sequence with the world on 30 January 2020, a mere seven days after the first case of SARS-CoV-2 was detected in Singapore.

“It was an achievement and it shows that we have the capacity to do this work. More importantly, it meant we had the virus and we could start to study it. And it was key for [Professor Wang] Linfa developing the cPass™ that’s become widely used. That was very satisfying.”

Adapting as a family

It was satisfying, too, to be able to reassure his children—seven and eleven at the time—who would bring home the latest talk from the classroom.

“They would come home from school and tell us what they’d heard from their friends,” Smith smiles. “Then we just say ‘Oh, you know that’s not quite what’s going on. This is really what’s happening.”

Together with his wife, Yvonne Su, a then assistant professor with the Emerging Infectious Diseases team, he would reassure them: Yes, this virus is a problem. Yes, it is real. No, you don’t need to be scared.

Were his kids ever scared for their parents? “No, they don’t have any such concept [of what our work involves],” chuckles Smith. “They would forget about it for a while and then a month later, you’d get the same question.”

“We’d say ‘You do know we work on this, right?’”

“And they go ‘Oh? Really?’”

In the months that followed those helter-skelter early days, home-based learning would be added to the mix as the outbreak transformed into a rampant pandemic.

“We were struggling to work out what was going on with the home-based learning, particularly as we were still in the lab every day” says Smith.

“At the same time, we were doing this extra job supporting the national effort to sequence early virus samples that we’d been given, while also still having to do all the regular work and look after the team because everybody was uncertain about what was going on, and it was really stressful.”

Dealing with uncertainty and the joy of new knowledge

By March 2020, it had become clear that the world faced an escalated threat, one that kept on confounding even the highest echelons of public health officials with its unpredictability. A senior World Health Organisation (WHO) official, for example, stated during this time that the asymptomatic transmission of the virus was “very rare”; more senior WHO officials backtracked on the comment the following day.

“What really surprised me was the number of assumptions that were made,” recalls Smith. “That led to definitive statements which were really unhelpful especially at a time when no one really had a clue.”

But the pandemic also brought pleasant surprises. With its mix of bat researchers, immunologists, virologists and vaccinologists, Duke-NUS’ Emerging Infectious Diseases Programme, though small compared with other infectious diseases teams, packed a solid punch.

“In hindsight that was a very effective unit to have. Given how small our department is we made an oversized contribution both nationally and internationally when it comes to the COVID response,” says Smith, who in a year’s time would go on to become the programme’s director.

He was especially impressed with the “amazing” research on the immune system’s T cells by immunologist and a fellow professor with the Programme  Antonio Bertoletti and how Bertoletti contributed a new understanding of how these cells might counteract the severity of a SARS-CoV-2 infection.

But throughout the heat of the outbreak Smith stuck to one guiding principle—his research should make for a world free from the pandemic.

“Contrary to what some on social media claimed, scientists are overwhelmingly good people,” he shares. “We do this type of stuff because we’re interested in helping.”

“And so, even though people were completely burnt out, they still felt that it’s a duty to try and find solutions.”

The way to the next pandemic

Solutions for Smith meant vaccinations being rolled-out globally and, in future, making Duke-NUS an institution that remained ready to help tackle the next pandemic event.

“The ideal situation is that as immunity builds globally, whether through vaccination or natural infection, the overall severity of the disease becomes less,” he notes.

“It’ll hopefully settle down to a level of severity that’s no greater—but hopefully less— than flu. But even then, it is still a big deal. It is an enormous cost to society."

His crystal-ball gazing would turn out to be spot on. And looking to the next pandemic, Smith muses:

“Pandemics aren’t rare. If you look at the exposure of humans to pathogens in animals, it is enormous.”

While most such exposures or spillovers don’t trigger a pandemic, they happen all the time. And it only takes one virus that happens to be readily transmissible between humans to spark the next outbreak.

With this constant threat, the only response is preparedness.

“We have all sorts of disaster plans right? Fires. Earthquakes and tsunamis. Floods. We now have to have a pandemic preparedness plan that should be updated to match the capacity and skills of the team,” says Smith.

“Before this, the idea that a department or a school should have a pandemic preparedness plan was kind of laughable, right?”

He gestures, already knowing the answer. Yes, it was. Not anymore.

Studying the information conveyed in genes, this scientist recalls the intense days of the pandemic.

“The complication came because we didn’t know very much about this virus,” recalls Dr Eugenia Ong, then a then-senior research fellow with Duke-NUS’ Emerging Infectious Diseases Programme about the early days when the first cases of the novel coronavirus were detected in a family who presented at Singapore General Hospital in January 2020.

Dealing with the unknown, cautiously

Facing a then-unknown threat, Ong, who studies gene expression in human samples in response to infections, vaccines and treatments, worked with the team on how to safely study these samples.

Mitigating steps included treating the samples with heat and “chemical cleans” that killed the virus but kept everything else intact. They also included wearing two sets of gloves, disposable gowns and N95 masks on top of the usual safety gear required in the lab.

While Ong worked out the rapidly growing number of experiments the team wanted to do and responded to a deluge of emails, patient samples kept coming from the hospital.

“So the first few days and weeks, we were just collecting and freezing the samples while we waited for the approvals to come in,” recalls Ong, who is also part of the team at the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS).

Ong and the team froze the samples, ready to be analysed in batches when they had a large enough number of samples.

Once they got the greenlight, they started by studying the gene expression of patients over the course of their illness until they had recovered.

“It is one of the most highly cited papers that I have,” laughs Ong. “It gained quite a bit of traction. There was a lot of interest around what was happening on a molecular level in these patients.”

At the same time, other projects came online with samples from various clinical trials coming in throughout the day.

“It started to feel more intense when we went into the Circuit Breaker,” remembers Ong. “With the split team arrangement, we had to do a lot of coordinating.”

At the same time, Ong was onboarding Ayesa Syenina who had just successfully defended her thesis and was now joining the lab as a full-time staff. Between the two of them, they oversaw the coordination and tracking of clinical trial samples, with Ong taking the morning shift and Syenina covering the afternoon.

“But she really had to hold her own during those days,” says Ong. “We had regular catch-ups in the evening. They were long days.”

The joy of discovery

Mentoring new colleagues aside, Ong and the team were also gearing up to start on the human trials for Singapore’s first locally tested vaccine, which Duke-NUS was co-developing with Arcturus Therapeutics — from having all the necessary reagents and tests ready to spelling out the finer points of how the samples would be transferred between the trial site and the lab.

“Starting on the vaccine project was a nice transition as we had stopped sampling patients from the hospital with numbers so low by then,” recalls Ong.

By National Day 2020, Ong and the team at ViREMiCS were ready. It was the last moment of calm before the storm hit.

“It was pretty intense and intensive after that point in time,” remembers Ong. “We wanted to get everything right. Because, really, with clinical trial samples, you need to get it right the first time.”

The last tube of blood from the final follow-up visit was drawn in January 2021, capping an intense four-month period.

“It was a lot of work, I won’t underplay that,” she says, her tone suggesting that it was also hugely satisfying work.

“We had these moments when we were the first to see results and the patterns that emerged,” offers Ong by way of explanation.

Bringing discovery to benefit testing science

“What is interesting is the contrast between this virus versus SARS,” muses Ong.

“I remember SARS, because I was in secondary school then. We got an extra week of June holidays because they were trying to keep everyone at home.”

“That disease was more severe,” Ong continues. “Because of that, more people died.” Bringing that virus to a hard stop.

“SARS-CoV-2, though, was a different beast. There was a lot more effective transmission that we were seeing with the variants that were coming up,” explains Ong. “And the question was: Would the vaccines protect against these variants?”

For Ong, that question led to further investigations into the immune response and whether it differed between vaccination and infection; and whether age, gender and health mattered.

“We started a follow-up study with some of the participants from the Phase I study to look at long-term immunogenicity from the vaccine, looking specifically at T-cell responses to find out how long these responses actually last,” explains Ong.

“In parallel, we were also looking at healthcare workers who received the mRNA vaccine,” she adds, explaining that they were tracking the incidence of side effects and investigating the molecular triggers behind them.

“Running these in parallel allowed us to really dissect what happened at the molecular level in participants.”

The need for a self-sufficient Singapore motivates one researcher’s quest for a SARS-CoV-2 vaccine.

“It is not unreasonable for countries to buy insurance in the form of vaccines to protect lives and livelihoods,” muses infectious disease expert Professor Ooi Eng Eong. “But better still would be for a country to be self-sufficient. We should be able to make our own vaccines.”

And he did more than just muse.

Putting his thoughts into action, Ooi leveraged his experience with dengue and SARS as well as his lab’s deep know-how about what makes an effective vaccine to embark on a quest to enhance Singapore’s vaccine expertise, test drive processes and protocols with the hopes of producing a new COVID-19 vaccine for the world.

That motivation — to contribute to a resilient and self-sufficient Singapore — made him and his long-time collaborator then-Associate Professor Jenny Low the perfect partners for biotechnology company Arcturus Therapeutics, which had a self-replicating mRNA SARS-CoV-2 vaccine concept and ready candidates that needed to be assessed, optimised and tested.

A known quality

The gravity of what was to come first hit Ooi in January 2020 when it was confirmed that a SARS-like virus was behind the outbreak.

Oh no, will this be a repeat of 2003? That was Ooi’s initial thought. The 2003 SARS outbreak had been testing for Ooi, standing out for its long days and short weekends. He’d unstintingly run experiments in one of Singapore’s two biosafety level 3 (BSL3) labs — the high-security facilities needed to study infectious airborne pathogens — for anyone who needed answers, and distributed inactivated viruses to colleagues for use as a control to ensure diagnostic equipment was returning accurate results.

And it was thanks to this experience that Ooi felt confident that Singapore was more prepared this time. SARS had been a watershed moment, highlighting the need for infection control infrastructure; an infrastructure that even had a dry-run in 2009.

He pauses briefly. “But the SARS label was also a bit of a red herring because we all thought that we should be able to control this outbreak as quickly as we had SARS,” he says. “That turned out to be wrong.”

Even as he authored one of the first close-ups of the inflammatory and immune response in patients infected with this novel SARS virus, he still thought — hoped — the outbreak could be contained.

“Those were the first three cases and I thought that would be it,” laughs Ooi, fully aware of how wishful that thinking turned out to be.

Embarking on a moon-shot collaboration

But as SARS-CoV-2 infections continued to spread in Singapore and around the world through undetected networks of pre-symptomatic and asymptomatic carriers, Ooi knew that as the co-director of the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS), he could — and should — intervene on a larger scale.

“It was mid-February when the EDB [Economic Development Board] asked if we would collaborate with a company they’d been talking to,” says Ooi.

Discussions between Duke-NUS and Arcturus started roughly a fortnight later. About a month later, with knowledge of how they could complement each other, both parties agreed to embark on this vaccine project together.

“After that, life became very busy,” deadpans Ooi.

Arcturus delivered their vaccine candidates to Ooi and his team for analysis. Unlike other mRNA vaccines, the self-replicating nature of this vaccine meant that the mRNA in the vaccine could be amplified in the body, making it possible to have an effective vaccine at a lower dose. The patient’s immune system responds by producing antibodies and other immune cells to fight off the spike protein’s simulated infection then and there while forming a lasting memory of the threat.

“We thought we could contribute because of what we’ve been doing with dengue and yellow fever. We understood what attributes to look for in a vaccine candidate,” explains Ooi.

After carefully and systematically studying the different candidates’ attributes, Ooi and his team identified ARCT-021 as the most promising. In their preclinical studies, the self-replication process boosted ARCT-021’s performance markedly when compared with other mRNA vaccines. But it was also the one part of the vaccine that had not been tested in humans yet.

“My worry was that no matter how well we looked at it during the preclinical stage, that there would still be a surprise when it goes into humans, resulting in unexpected side effects,” says Ooi.

After a stringent set of tests, the company and regulators greenlighted the first phase of human trials. Despite that, Ooi and his collaborator, Low, a senior consultant with the Department of Infectious Diseases at Singapore General Hospital (SGH), who led the clinical trials kept a careful watch for possible side effects in the volunteers.

“I was very nervous,” confesses Ooi. “I think I was nervous throughout the entire Phase I.”

During this phase, the clinical trial team administered increasingly higher doses of ARCT-021 to the volunteers. They stopped when those who received the highest dose showed the first side effects.

Then, it was over to Arcturus with the data and on to the next phase.

“The initial set of data was enough to support the start of Phase II trials,” says Ooi.

Indeed, today, the Health Sciences Authority gave the greenlight to proceed with the next phase.

Around the same time, Ooi and his team also began delving deeper into the data to decode the immune response, so they could be better prepared in the fight against the coronavirus, as variants of concern would clearly continue to emerge.

Reflecting on his involvement in the most hotly contested race in human history, Ooi admits that “it was a bit daunting” to be one of more than 100 vaccine candidates that had commenced development as early as April 2020.

With only a fraction of vaccine development projects progressing to Phase I trials eventually, he did not know what to expect.

“But we were able to take it through to the next stage of trials,” says Ooi with some relief.

“Each new phase of testing uncovered new lessons for us to learn and we’re now consolidating these lessons to explore ways in which to create other vaccines,” he adds.

With hindsight, would he have done anything differently?

“The one thing that I wish we could have done,” considers Ooi, “was to have the resources to do more than one vaccine. But other than that, I wouldn’t change anything. Because we were given an opportunity to use what we had learnt to benefit Singapore and the world.”

A stark inevitability

There is a slide Ooi is fond of showing during his talks. It charts a stark sense of the inevitable: the first twenty-one years of the 21st century alone have seen eight major disease outbreaks.

OOI'S SLIDE THAT DEMONSTRATES THE FREQUENCY OF OUTBREAKS // CREDIT: DARREN MOK / OOI ENG EONG

That means one outbreak every two-and-a-half years, which means the next one might be just around the corner.

“We need to invest in preparedness,” he says, noting that there is always talk about improvements and measures during outbreaks.

"We need to be self-sufficient,” he emphasises. “In Southeast Asia, we should not have to continually rely on shipping vaccines from Europe or North America,” he says. “To meet our needs, we should be able to make our own. And distribute it to our neighbours.”

Ooi also sees the experience gained from developing ARCT-021 as propelling future and further long-lasting healthcare solutions for the region.

He hopes that countries will invest in even more robust medical research ecosystems.

“Countries need to put aside a certain sum of money. Keep the infrastructure going,” he explains. “So that when you need, you can tap into that science.”

For his role in spearheading vaccine development, Professor Ooi Eng Eong from Duke-NUS’ Emerging Infectious Diseases Programme, was one of six individuals honoured with The Straits Times’ Asians of the Year Award. Collectively known as Asia’s virus busters, these scientists played instrumental roles in advancing Asia’s fight against SARS-CoV-2, representing the entire trajectory of the pandemic response.

Already in its ninth run, The Straits Times’ Asians of the Year Award honours an individual, a group of people or an institution that has made the news and significantly contributed to their society, country or Asia as a whole.

“SARS is gone and it won’t be coming back, so this is a waste of money,” immunologist  Associate Professor Ashley St John was told many years ago when she applied for funding for a SARS-CoV-1 vaccine project. “It seems unbelievable now.”

So, she focused instead on flaviviruses, such as dengue, that have a large burden and display an interesting immunological basis in their disease progression. A choice for which St John from Duke-NUS’ Emerging Infectious Diseases Programme was rewarded today with the Young Researcher Award from the National University of Singapore (NUS). She was one of two researchers under the age of 40 who were recognised for their impact and promise in research.

“Ashley is a brilliant young scientist who is already recognised among the top researchers in her field. As a viral immunologist, Ashley studies immune responses to viral infections and her work has significant translational impact,” said Professor Chen Tsuhan, NUS Deputy President for Research and Technology in his citation.

One example of the translational impact of St John’s work was the clinical trial of a novel therapeutic strategy against dengue that came out of her studies on vascular leakage.

Being singled out among her colleagues across NUS is humbling, said St John of her reaction at the time.

“This award also makes me feel challenged to continue contributing to science and making research advances that are meaningful. I hope that other young researchers who are just starting their careers, and particularly young women in science, can see that there are many rewards to pursuing research even as it requires significant effort and resilience,” she said at the time.

Part of her award includes a research grant of $10,000 that awardees can use to pursue a high-risk, high-reward project and St John already knows what she wants to investigate — the neuro-immune interface.

“The nervous system and the immune system communicate with each other in surprising ways and I hope to identify some novel communication signals occurring in the brain during infection using state-of-the-art single-cell sequencing,” she said.

In bestowing the award on her, Chen also cited St John’s passion for science communication and outstanding mentoring of graduate students, something that is central to her philosophy.

“I love working with other scientists to address big questions and one of the most fun aspects of that for me is training graduate students,” said St John, who hopes to continue building her research programme into one that addresses scientific questions and translates findings into products and therapeutics that can improve lives.

The University Awards recognise excellence in educating and nurturing talent, advancing knowledge, fostering innovation and contributing to country and society. Awards are presented across five categories — Outstanding Educator, Young Researcher, Research Recognition, Outstanding Service and Special Commendation.

Alongside St John, SingHealth Group CEO and Duke-NUS Governing Board member Professor Ivy Ng was also honoured. Ng, who was instrumental in shaping the SingHealth Duke-NUS Academic Medical Centre, received the Outstanding Service Award, which honours accomplished and respected individuals from the NUS community who have distinguished themselves through their sustained and exceptional contributions in serving the University and society.

From Hendra to SARS-CoV-1, Wang Linfa brought all this experience to bear in the fight against COVID-19.

“It took me six months to convince the FDA,” says Professor Wang Linfa about the road to getting his invention — a simple yet impactful solution to easily test for neutralising antibodies against SARS-CoV-2 — authorised for emergency use by the United States Food and Drug Administration (FDA) today. “Many 3am meetings.”

The test, called cPass™ which he’d developed with his team at Duke-NUS, is one of Wang’s many contributions to help the world combat the pandemic. It detects whether a person — or animal — has been exposed to the SARS-CoV-2 virus or vaccinated against it. It does this by detecting, from a serological sample such as blood, if a person has the specific antibodies which neutralise the virus. It does this without the need for a live virus or cells and delivers results in just an hour. cPass is, in sum, a world-first invention.

WANG LINFA AND HIS TEAM PROUDLY PRESENT THEIR INVENTION — cPASS™, A NOVEL WAY TO DETECT NEUTRALISING ANTIBODIES

“In the history of the FDA, they have never approved serology to measure neutralising antibodies,” notes Wang. “Not just for SARS-CoV-2 for any virus. The reason is that testing traditionally can only be done with live agents — live viruses and live cells.”

“So how can you regulate it to make sure that that assay is performed identically in thousand different labs? There’s no way. Quality assurance is impossible when you have a live virus in a live cell. ‘Wow’, I thought, ‘that’s a very high bar to cross.’”

But since cPass does away with this need, governments, as well as clinicians and researchers, can use cPass to measure immunity in the community, trace close contacts and evaluate vaccines and therapeutics.

“We still don’t really know how this pandemic started and we still didn’t know how we could get out. That was my focus,” says Wang. “Because if we don’t know how it started, we cannot prevent another pandemic.”

“And,” Wang pauses for emphasis here, “the old, powerful serology; it’s highly specific. The serological approach can play a key role in answering those problems.”

Lessons from horses to bats

Serology is the study of antibodies in blood and for Wang, a tried-and-tested strategy to get answers long after the virus has moved on. And Wang has 30 years of experience conducting such investigations — most notably during the 1994 Hendra virus outbreak in Australia and the 2003 SARS outbreak in Singapore and Asia.

The Hendra outbreak, remembers Wang, was the moment when the full potential of serology became clear to him. In those days, he had worked at the Australian Animal Health Laboratory — now the Australian Centre for Disease Preparedness—under the Commonwealth Scientific and Industrial Research Organisation (CSIRO). And Hendra, named by Wang after the Brisbane suburb from which it originated, is a virus that can be fatal to horses and humans. It causes haemorrhages, meningitis and respiratory dysfunction such as a build-up of fluid in the lungs.

Hendra’s transmissibility from its natural reservoir to humans, though, was not understood initially. Polymerase chain reaction (PCR) tests of tissues taken from different animals, which the research team collected in order to study the virus’ origin, all turned up negative.

“So, I said, ‘Serology’. Let’s go searching for Hendra virus antibodies and we’ll test as many different animals as possible,” Wang continues.

“We tested 42 different animals. Koalas, snakes, birds—everything. Eventually, we found an antibody in bats,” recalls Wang who found these antibodies in a particular type of bats called flying foxes, or bats of the genus pteropus. With this knowledge, more precise laboratory research and public health measures were implemented against Hendra.

WANG LINFA IS ONE OF THE WORLD'S LEADING EXPERTS ON BAT-BORNE VIRUSES AND BAT BIOLOG

He brought the same expertise to curb the deadly Nipah virus outbreak which killed 109 out of 276 people infected in Singapore and Malaysia between 1998 and 1999.

As Wang pursued serological testing, though, he soon came up against its limits.

“In our field, we always say that the gold standard is the virus neutralisation test. But for virus neutralisation tests, you need a live virus for the base,” explains Wang. For diseases like Hendra and Nipah that meant Wang and his team could only handle them in the most secure facilities, a biosafety level 4 lab. That made the job so much harder for them.

“I needed something that was a surrogate, so we could mimic this,” says Wang.

“So instead of using the whole virus, we just used a piece of protein,” Wang continues. That concept, developed using the Nipah virus, Wang published in 2007 to little fanfare.

Regardless, his surrogate method made testing for viruses easier, which, in turn, unlocked more data at a faster rate for policymakers, doctors and other researchers.

And cPass, the most current iteration of this concept, which Wang developed with his team at Duke-NUS, works exactly along the same principles of surrogacy and usability.

“We envisaged very early on that neutralising antibody testing would be important,” notes Wang about the anticipated bottleneck in testing. “[We] just wanted to do something that’d solve that issue.”

A proposal for the world

cPass may emerge as an internationally renowned intervention against the pandemic. And Wang’s own star rose to new heights; his network grown exponentially among fellow scientists and decision-makers. But Wang believes that he can play an even bigger role.

“The dream for me is that one day — one day — people can treat viruses and pandemics totally apolitically. Treat them as a common enemy,” he says. “And then, in peacetime, build-up an intelligence, resource and knowledge-sharing network.”

“That, to me, is the only way to prevent the next pandemic.”

Wang thinks for a moment about his contributions.

“I’m very proud that we have cPass. And we had something else very significant in the pipeline. But that’s less than 50 per cent,” he says. “The more than 50 per cent is the political will and the international system and mechanisms to work together and achieve early warning, early prevention.”

The United States Food and Drug Administration (FDA) today authorised the emergency use of cPass™, a world-first kit for detecting antibodies that neutralise SARS-CoV-2 easily, efficiently and quickly.

Where other similar tests can take up to several days, cPass returns results within an hour. It requires neither live virus cells nor complex laboratory procedures and is easy to use.

cPass was invented by Professor Wang Linfa’s team from the Emerging Infectious Diseases Programme at Duke-NUS, and co-developed with biotechnology group GenScript Biotech and A*STAR’s Diagnostics Development Hub.

WANG LINFA INVENTED cPASS EARLIER THIS YEAR TO SOLVE A TESTING BOTTLENECK

“FDA approval of cPass as ‘the first test that detects neutralising antibodies (against SARS-CoV-2)’ is an important landmark in the fight against the COVID-19 pandemic. As the first and only commercial kit with such capability, this serological test will have wide-ranging applications and is another demonstration of the high-quality science and translational research that distinguishes Duke-NUS and Singapore,” said Professor Thomas Coffman, Dean of Duke-NUS, at the time.

The addition of cPass to the arsenal of diagnostics was timely as it could be used to help verify the efficacy of vaccines, determine infection levels in different communities and support contact tracing measures as many countries were battling a surge in COVID-19 cases.

Reflecting on the moment when he received the news, Wang says, “The beauty of cPass is that it is such a simple concept but one that can have a huge impact. I was both relieved and incredulous that we had done what no one had done before by getting the FDA to approve a serological test for neutralising antibodies.”

“This is an incredible recognition for our team and the Singapore research and biotech landscape,” adds Wang. “The total critical mass of Singaporean biomedical R&D is less than one per cent of the world’s, and yet we are the international leader in this area for COVID-19.”

Twenty-two per cent of Singapore residents said that they would never choose to get vaccinated, a survey led by Duke-NUS health economist Professor Eric Finkelstein found. Herd immunity, resultingly, may be difficult to achieve locally without a vaccine mandate, Finkelstein and his colleagues argued in an opinion piece published today in The Straits Times.

The refusal the scientists observed was not only driven by price as participants were asked to respond to different scenarios, including opting for an immediate and free vaccine, paying a randomly-varied price two months later or never be vaccinated.

ERIC FINKELSTEIN'S SURVEY OF PUBLIC OPINION ABOUT COVID-19 AND VACCINATION FOUND THAT MANY BELIEVED THEY HAD A HIGH CHANCE OF BEING INFECTED DESPITE LOW COMMUNITY TRANSMISSION RATES AT THE TIME, YET MANY REMAINED SKEPTICAL ABOUT VACCINATION

Forty-two per cent of respondents said that a S$100 price tag would make them get vaccinated for free immediately, Finkelstein and colleagues noted. Another 35 per cent would wait for two months — and pay the vaccine provider — in order to gauge the safety and efficacy of the vaccine. A S$6,000 price tag, on the other hand, had a double-sided effect: it would increase the immediate take-up of the vaccine to fifty-two per cent, but also drive up the percentage of people who would completely refuse a vaccine.

Herd immunity is the point where enough people — generally around 60 to 70 per cent of the population — are immunised against a virus either through prior exposure or vaccination and thereby prevent its onward transmission. The low exposure rate in Singapore, resulting from measures such as quarantines, safe distancing and contact tracing, indicated that a vaccination rate below 70 per cent would be insufficient for stopping the spread of SARS-CoV-2.

“[Vaccine] uptake could be increased by public health messaging campaigns reminding Singaporeans that although vaccination is an individual choice, vaccination benefits all of us due to herd immunity,” Finkelstein and his co-authors wrote. “Combating COVID-19—by heeding measures such as keeping a safe distance from others and wearing masks—is truly a community effort.”

How did COVID-19 affect Singapore’s national mood?

“The one thing that I’m qualified and interested in is the mental health aspect of COVID-19,” says Professor Eric Finkelstein.

“So, I did a study to get at the incidence of depression and anxiety during the pandemic,” he continues, referring to a study whose findings were published in the International Journal of Health Policy and Management today.

As a professor with the Health Services and Systems Research Programme at Duke-NUS, Finkelstein was uniquely placed to analyse the impact of COVID-19 on Singapore’s population, from both economic and behavioural perspectives.

“The idea was to generate data to develop interventions aimed at addressing mental health needs in Singapore,” says Finkelstein, who is also the executive director of the Lien Centre for Palliative Care.

“I wanted to find the unmet need for people who have these mental health conditions, but who are not accessing the health system,” expands Finkelstein. “To see if there might be opportunities to follow up and provide access to care.”

But mental health had not been his initial research focus.

Finkelstein was conducting an unrelated survey in 2020 when, out of interest, he decided to add some questions about the impact of COVID-19.

The responses were varied but had one thing in common — more and more, people were experiencing mental health issues.

“That’s a hidden problem in Singapore,” says Finkelstein.

Indeed, the Singapore Association for Mental Health reported a 50 per cent increase in calls made to its helpline in February and March 2020 compared with the average it received between April 2019 and January 2020.

He adds, “Now is that because of this pandemic? Or because of the interventions that have been put in place? It’s hard to know.”

Nonetheless, between lockdowns, lost work opportunities and the devastating effects of social isolation, it was clear COVID-19 was taking its toll.

Exposing Singapore’s ‘hidden problem’

Unlike tallying COVID-19 case numbers, exposing the damage to a nation’s collective mental health was a trickier task.

Finkelstein’s expertise in surveying public health behaviours came into play here.

He and his team adapted quickly to online surveying. Where they used to interview patients in clinics or their homes, they were now speaking with people over the phone.

“It’s not as good,” Finkelstein admits. “I mean you can’t read body language or facial expressions, and we survey a lot of patients, so we look for signs of fatigue or distress.”

“When you’re on the phone you just don’t have that same ability.”

Despite the challenges of online work, the results were clear. Out of 897 participants, 23 per cent reported moderate to severe anxiety, significantly higher than previous mental health surveys.

Younger people, people with chronic conditions, children or those with a lower trust in government were found to have higher levels of anxiety about COVID-19 and a higher perceived risk of being infected.

However, the risk perception of these participants was also skewed. Nearly half feared they would be admitted to the Intensive Care Unit if they were to contract COVID-19; just under a third believed they would die.

The study also found that 40 per cent of people with chronic conditions had missed a healthcare appointment for fear of contracting COVID-19.

“I think COVID-19 has shed some light on the high rates of undiagnosed mental health problems in the region,” says Finkelstein. “But this problem existed before COVID-19 and will exist after COVID-19.”

But the health economist in him still wanted to quantify the total economic burden and he would go on to field a study to do just that. Between reduced productivity, lost work opportunities and unemployment, what exactly was the financial aspect of this shadow pandemic?

He’s determined to investigate this issue, and his hunches are usually spot on. You don’t become one of the world’s most highly cited researchers three years running without a finely tuned research intuition.

Needles or needless

Finkelstein already had a catalogue of studies on incentivising people to act on public health measures.

In the past, he researched how financial and behavioural incentives impact obesity, weight loss and palliative care.

This area of expertise translates directly to the issue of vaccination.

“The willingness or unwillingness of people to vaccinate is definitely an interesting topic,” muses Finkelstein.

In an online poll on vaccination, 22 per cent of respondents answered that they would never get vaccinated.

Most countries were finding a stubborn percentage of the population who were refusing to budge on this issue. So, what held those people back?

“It’s what economists call ‘elasticity’ — their willingness to vaccinate and to what extent we need to ‘bribe’ our population,” explains Finkelstein, adding that if the vaccine is free, people don’t rush to get it because they know they can get it later.

In the end, it would take a mandate and vaccination-differentiated measures as well as a new variant that causes more severe disease to achieve the vaccination rates necessary for re-opening.

Calculating the costs

As an economist, the price of the pandemic has been a consistent theme in Finkelstein’s research. The price of vaccines, the price of testing, and of course, the price of lockdowns.

Interestingly, in 2017, before SARS-CoV-2 had entered the lexicons of everyday language, Finkelstein had already been analysing Singapore’s responsiveness to lockdowns.

His research was based on previous pandemics in Asia such as H1N1 in 2009, and SARS-CoV-1in 2003.

What he and his colleagues found in this 2017 study, published in BMJ Open in early 2018, was that Singapore residents willingly supported government restrictions if these restrictions reduced transmission.

The respondents were split into two key groups: the mortality-averse and the tax-averse. To gain support from both groups, public health measures need to stress the necessity of lockdowns to reduce mortality, while minimising the economic impact on society.

Overall, Finkelstein’s 2017 findings on Singapore’s receptiveness to lockdowns rang true in 2020, when he focused his research on the cost of lockdowns on mental health.

“I think by the end of 2020, we’d done a great job in arresting the spread of the pandemic, but I think it came at a pretty high cost,” says Finkelstein of Singapore’s first brush with the virus.

“If you look at mental health services in Singapore, certainly, you can see that rates of depression or mental illness are way up.”

He wrote — and would continue to write — commentaries highlighting that circuit breaker measures were delaying tactics.

As Finkelstein sees it, this globalised world means that SARS-CoV-2 will always be lurking.

So, while public health measures would always be necessary, it was similarly important to prioritise individual mental health measures.

Finkelstein says it is about how we learn to live with COVID-19. It is how governments and communities improve treatment options, reduce mortality rates and encourage vaccination.

“You can’t live your life in your basement forever,” Finkelstein says.

“Once you realise that these variants will be around indefinitely, at some point you’re going to…realise that and recognise that you can mitigate those risks, but you can’t reduce them to zero.”

Leveraging the pandemic, this surgeon-innovator proves that even in healthcare, new ideas can be turned into innovations fast.

“Why should nasopharyngeal swabs be only done by doctors or specialists?” asks Dr Rena Dharmawan. For Dharmawan, a then-associate consultant with the Department of Head and Neck Surgery in the Division of Surgery and Surgical Oncology at Singapore General Hospital and the National Cancer Centre Singapore, this question was not rhetorical.

By late April, specialists like Dharmawan had been deployed in droves first to emergency rooms, later to dorms across Singapore. Their task? To conduct nose swabs for intensive SARS-CoV-2 testing, while ensuring that the tests were performed accurately and without injury to patients.

They worked long shifts in full-body hazmat suits and N95 masks to protect against infection.

They risked not just their personal safety but that of their families. “It was worrying,” says Dharmawan, who admits that the uncertainty of the pandemic made her feel very uncomfortable. “I have two young kids, and I really didn’t want to expose them to the virus.”

In times of crisis, the speed of innovation can make or break a nation’s response. The pressure was building as Singapore experienced its first large-scale outbreak. Each clinician saw up to 130 patients per shift, starting at 9am, ending at 5pm. Dharmawan recalls that almost all were COVID-positive.

As infections spread, the need for testing — not just those at risk of having the virus in the community but travellers too — skyrocketed. And Dharmawan, a serial innovator and a then-assistant professor of clinical innovation with Duke-NUS Office of Innovation and Entrepreneurship, was clear about one thing: if she could harness the power of automation, she would be able to develop a better, more efficient and cheaper way of doing this.

“Couldn’t swab tests be as simple as getting a check at an optometrist? Step into a booth, put your head here, get your nose swabbed, and get your results. That was the grand idea,” Dharmawan remembers thinking.

And she had never been one to stop at thinking.

Clinicians and engineers, assemble

Dharmawan wears multiple hats at work. She is a cancer surgeon as well as an enthusiastic innovator with a background in bioengineering. She was an entrepreneur-in-residence with the Centre for Technology and Development at Duke-NUS and is an alumnus of the School’s very first cohort of graduates, the Class of 2011.

And she already had plenty of experience under her belt.

“I became ‘addicted’ to innovation early on,” says Dharmawan, who had already co-founded several Singapore-based startups while completing her residency training including home-based haemorrhoids management solution Privi Medical as well as on-demand healthcare platform Jaga-Me.

At the suggestion of her innovator-mentor, Dharmawan and a group of SingHealth clinicians banded together in April 2020 with medical robotics company Biobot Surgical. The company had previously developed a surgical robot with a probe that was similar to what Dharmawan had in mind.

It took them a mere three weeks to develop a prototype. “Of course, it was more of a metal skeleton then,” remarks Dharmawan, “but it worked.”

A four-month miracle

The team’s target development timeline was ambitious. “What I wanted to prove was that amidst COVID, we could build a commercially viable solution in just a few months,” says Dharmawan.

The biggest roadblock Dharmawan had to navigate was the requirement back then for wet ink signatures on agreements and contracts.

“These are COVID times, and electronic signatures exist; so why did we need to bring documents to people’s houses to get signatures in-person?” she recalls, shrugging. She was once again operating ahead of the status quo, which would soon see electronic signing implemented across the School.

No matter. After a few trans-island journeys, Dharmawan and her team secured the documents required. By July 2020, the world’s first patient-controlled nasopharyngeal swab robot — SwabBot — was ready for clinical trials.

Dharmawan still remembers the reaction of a senior urologist when she presented her innovation at a SingHealth COVID-19 taskforce meeting. His first comment, Dharmawan recalls, was: “‘You know that your team basically did what we took ten years to do, right?’”. He was referring to the iSR’obot Mona Lisa prostate biopsy robot, which had also been developed in collaboration with Biobot and that contained the same mechanism central to Dharmawan’s prototype.

“SwabBot is much simpler, and obviously Biobot’s experience counts,” acknowledges Dharmawan, “But it’s still a miracle that we pushed this through in four months.”

Quality swabs in seconds

White, sleek and about the size of a large house cat, the SwabBot prototype looked friendly and was easy to use.

Users would take a seat, rest their hands on its handles, place their nose against the disposable nose piece, and gently press their chin against a conveniently located button. And in just 20 seconds, the swab was done. Throughout the process, the user was in full control, and able to start and end the swab at will. And thanks to that feature which makes use of a quirk in human psychology, SwabBot users reported less discomfort.

“Just like how you can’t tickle yourself, you experience less pain when you are fully in control compared to having someone twirl a swab in your nose,” Dharmawan explains.

While swabbing pressure varies with human swabbers, SwabBot’s touch sensor was calibrated to the delicate sensitivity of a surgeon performing microvascular surgery. “It retracts on encountering resistance, and if it is not a good quality swab, it tells you to please do it again until you pass,” says Dharmawan.

All this meant that SwabBot yielded swabs of consistently high quality. This while offering to decrease the swabber’s exposure risk and reduce the need for trained manpower.

Contributing to the wider clinician-innovator ecosystem

When it comes to new technologies and innovations, healthcare has traditionally been among the last industries to adopt them. But the pandemic shook this state of affairs, accelerating digital health innovation as virtual consultations and digital platforms became commonplace.

And credit for Singapore’s growing biotech and medtech innovation space goes to institutions such as Duke-NUS and SingHealth, says Dharmawan. “They are making it a lot easier for anyone with a promising idea to navigate the research ecosystem.”

With SwabBot in the hands of Biobot, Dharmawan embarked on the next project: a programme for Duke-NUS medical students to discover the innovation bug, just as she had. Offered to Duke-NUS medical students, who spend their third year immersed in research, Dharmawan planned to bring them together with peers from other NUS schools, clinicians and industry partners to conceptualise, develop and prototype an innovation.

“By bringing products to market, be it through startups, licensing, or multinational company spinoffs, we can create a multiplier effect that impacts the lives of our patients,” she says, hoping that like her, these students will grow into similarly passionate innovators. Called the Health Innovator Programme, it would go on to be officially launched on 23 September 2022.

STUDENTS FROM THE INAUGURAL COHORT OF THE DUKE-NUS HEALTH INNOVATOR PROGRAMME TALK ABOUT WHAT MOTIVATED THEM TO APPLY AT THE LAUNCH OF THE PROGRAMME

While she started with medical students, she hopes to engage residents — clinicians who are pursuing their specialist training — in the future, too.

“They are young and savvy. If they see the light when their idea is licensed or spun-off, I think they could get hooked and carry on even as they become consultants,” explains Dharmawan, who was in the midst of pursuing an Executive MBA, a qualification she hoped will further boost her projects.

Eventually, she hopes to develop a sustainable funding pipeline not just from public grants but also private funding. Her moon-shot goal? To build an independent laboratory that drives innovations, works closely with industry and engineering stakeholders and delivers a training programme that feeds into a sustainable ecosystem of clinician-innovators.

“To me, that would be the dream.”

Six months after serial entrepreneur and cancer surgeon then- Clinical Assistant Professor Rena Dharmawan first conceptualised the idea, she along with a team of clinicians from the National Cancer Centre Singapore (NCCS) and engineers from local medical robotics company Biobot Surgical unveiled SwabBot, the world’s first automated nasal swab robot.

The robot prototype, which occupies about the space of a large house cat on a table, is fast but gentle. Its entire collection process lasts just 20 seconds, half the time of a manual swab test. Despite its mechanical appearance, it has a soft touch, delivered with surgical precision. It is fully controlled by the person being tested, making the experience less uncomfortable.

“When patients are empowered and fully in control of the swabbing process, they are mentally prepared and experience subjectively less pain,” said Dharmawan, a then-associate consultant at NCCS and then-Entrepreneur-in-Residence with Duke-NUS’ Centre for Technology and Development, in an interview at the time.

SOURCE: THE BIG STORY BY THE STRAITS TIMES (YOUTUBE)

The promise of SwabBot was to reduce the risks and costs of manual swabbing. Nasal samples would be more accurate, while swabbers would be less likely to be exposed to the virus.  and need less training to do their work.

“SwabBot never needs to stop for lunch and never suffers from fatigue,” said Dr Luke Tay, one of the project’s team members and a consultant at Singapore General Hospital at the time.

“Furthermore, the sample quality remains consistent even though nose structures can vary in size and shapes.”

Prestige Singapore named Dr Eugenia Ong, a then-senior research fellow both with Duke-NUS’ Emerging Infectious Diseases Programme and the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS), among its list of Singapore’s most successful, innovative and influential young people.

Ong made the 2020 list for her role in leading the development of novel molecular tests that shortened the bench-to-bedside timeline for vaccines and drugs against infectious diseases such as COVID-19, as well as for helping ViREMiCS attain ISO 15189 (Medical Testing) accreditation in 2019.

At a time when few genetic changes of SARS-CoV-2 had been described, researchers from Duke-NUS, A*STAR and the National Centre for Infectious Diseases, published two papers describing a new variant of the SARS-CoV-2 virus detected in Singapore, which resulted in milder infections compared with wild-type or ancestral virus infections.

The studies, which were published in the journals mBio and The Lancet, showed that out of the 92 patients with the wild-type virus, 26 required supplementary oxygen, 15 needed admitting to the intensive care unit, and 10 were placed on mechanical ventilation.

None of the 29 patients infected with the new variant, however, needed these interventions. Not only that, they also experienced a lower degree of fever, had more effective T-cell responses and better platelet regulation during the early phase of infection. Only when it came to sore throats did those infected with the new variant fare less well when compared with the group which was infected with the wild-type virus.

This variant had been identified by its deletion of 382 nucleotides, or RNA building blocks, in a section of the viral genome known as open reading frame (ORF) 7b and ORF8. A similar deletion of 29 nucleotides in ORF8 of the original SARS virus had been observed during the 2003 outbreak, resulting in a less infectious SARS-CoV-1 variant, though its severity had not been not examined.

However, evidence suggested that the ORF8 gene, a mystery protein of unclear function, could help the virus evade the immune system and its deletion may have helped to uncloak the virus to the immune system.

The researchers, Professors Gavin Smith and Wang Linfa, and then-Assistant Professor Yvonne Su from the Emerging Infectious Diseases Programme at Duke-NUS among them, noted that patients infected with the variant also had lower concentrations of widely released pro-inflammatory cytokines, chemokines and growth factors that are strongly associated with severe SARS-CoV-2 infections.

“These studies provide the first convincing data showing that an observed genetic change (mutation) in SARS-CoV-2 has affected the severity of disease in patients,” said Smith at the time.

“This further highlights the importance of tracking the genetic diversity of SARS-CoV-2 as the virus continues to evolve,” he added.

Elaborating on the significance of deletion such as this, Smith explains, “Strains like this — which make the virus less dangerous — have the potential to be used for human challenge studies”, referencing a type of study where healthy volunteers are deliberately infected with a virus to test vaccines and treatments.

The first doses of LUNAR-COV19, an investigational self-replicating mRNA SARS-CoV-2 vaccine, developed by Duke-NUS and Arcturus Therapeutics, were administered to a group of healthy volunteers in a trial in Singapore, the company announced today.

The first group of younger volunteers, aged 21 to 55, had all been injected with a dose of the vaccine candidate which became better known as ARCT-021. This marked the beginning of the Phase I/II trial to evaluate the safety of the vaccine. As well as safety, the longitudinal immune responses and T-cell response data would be monitored and inform which dose regimens would be selected for the second phase of the study. That phase would include cohorts in both younger and older adults, aged 56 to 80.

The trial had been brought forward from its original September start date due to promising results from preclinical trials. The preclinical data showed that a single 2µg dose of ARCT-021 was sufficient to trigger the production of neutralising antibodies in 100 per cent of the vaccinated animals. It also induced a type of immune cell known as CD8 T cells, which help the body fight invading pathogens. In the face of a respiratory infection, these cells help to clear viral particles from the lungs by bringing about a robust immune system response.

With the start of this new phase, the Duke-NUS team that had completed much of the preclinical testing shifted gears to receive the clinical trial samples. That meant running the same set of tests for each of the more than 100 trial participants at each time point.

While the work became repetitive after some time, the team was acutely aware of their mission: to generate the data needed to deliver a vaccine that could save lives as fast as possible. The stakes could not have been higher.

“It was a highly stressful time. We had to be extremely rigorous and detailed for these clinical trials,” reflects Dr Ruklanthi de Alwis, a then senior research fellow with the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS). “We kept a good track of samples that came in pretty much every day. Everything was very tightly organised.

Preprints were being uploaded at a fierce rate. Faced with this tsunami of information, Associate Professor Ashley St John from Duke-NUS and then-Postdoctoral Research Scholar Abhay PS Rathore from Duke University published a review of various immune responses in the lung during and after SARS-CoV-2 infection, synthesising what was known at that point and drawing out deeper insights.

The insights of this review, which was published in The Journal of Immunology, could assist in developing a vaccine that protects from SARS-CoV-2 infection without triggering inflammatory immune reactions, the authors hoped. Excessive inflammatory reactions can lead to severely — or even fatally — damaged lungs.

St John and Rathore further described how recovery from SARS-CoV-2 may also be associated with persistent immunological changes. Some patients continued to have reduced numbers of lymphocytes and eosinophils — a type of white blood cell that curbs infection and boosts inflammation — in the weeks after hospital discharge. Others experienced inflammatory symptoms persisting even after recovery. They also reported that pre-existing antibodies against coronaviruses did not necessarily work against SARS-CoV-2.

Unlike other coronaviruses which typically infect cells in the airways, SARS-CoV-2 could also infect endothelial cells, the single-layer cell lining of blood vessels. The review noted that data showed virus particles observed within endothelial cells of the kidney, highlighting that inflammatory immune responses could be far-reaching and trigger organ damage well beyond the lungs. SARS-CoV-2 was also observed to infect secondary lymphoid organs, which, in turn, could cause the white pulp of the spleen, which contains immune cells, to wither.

The review found that the collated risk factors for more severe SARS-CoV-2 infection outcomes included low blood oxygen during a patient’s initial admission for treatment, hypertension, smoking, coronary heart disease, cerebrovascular disease, diabetes, and pre-existing lung diseases. Chronic infections, such as hepatitis B and tuberculosis, were other factors associated with worse infections. Men generally exhibited more severe SARS-CoV-2 infections than women.

Less than six weeks after announcing the commercialisation of a novel serological test, Duke-NUS scientists reported the first testing data.

Invented by Professor Wang Linfa’s team from Duke-NUS and co-developed with A*STAR’s Diagnostics Development Hub and biotech group GenScript, the test was validated with two cohorts of SARS-CoV-2 patients from Singapore and China. The results, published in Nature Biotechnology, showed that the surrogate virus neutralisation test had 99.3 per cent specificity and 95 to 100 per cent sensitivity.

The other major advantage of this invention is that as a surrogate test, it does not require the live virus, and can be completed in as little as an hour in a standard biosafety level 2 laboratory.

THE SCIENCE BEHIND cPASS™ (YOUTUBE)

This surrogate virus neutralisation test contains 96 wells on a plate, which are coated with angiotensin-converting enzyme 2 (ACE2) receptors that the SARS-CoV-2 viruses uses to enter human cells. To this, researchers add a mix of serum from the patient and a solution containing just the part of the virus’ spike protein that binds to the receptor, called the receptor-binding domain, which is fitted with a chemical signal. The signal lights up blue if the viral fragment was able to attach to the ACE2 receptor, indicating that neutralising antibodies are not present in the serum.

This kit represents a key intervention against SARS-CoV-2 for clinicians as well as researchers. It can be used to determine infection rates, herd immunity, predicted humoral protection and vaccine efficacy during clinical trials.

The School’s commercial partner, GenScript, had also filed for Emergency Use Authorisation with the United States Food and Drug Administration.

THE cPASS KIT

This evolutionary biologist-turned-virus-decoder finds that a quarter of Singapore’s diseases stem from a virus variant, and that her daughter helped a classmate through a difficult COVID situation.

There’s a big chunk of sequences missing in some of the SARS-CoV-2 samples from Singapore, realised then-Assistant Professor Yvonne Su as she stared at the next-generation sequencing data displayed on her screen one afternoon in February 2020. She had started compiling the sequences from her lab’s SARS-CoV-2 samples soon after the first case was detected in Singapore. This shouldn’t be happening.

The result had been perplexing. Until then, the sequences had all matched those obtained from the early infections detected in Wuhan; a particular set of adenines here, another string of guanines there, and this short chain of cytosines and uracils clustered exactly where it should. The missing, or deleted, chunk of the virus’ RNA, however, could mean a change in the virus’ behaviour.

But Su took some convincing of her own finding. “My first instinct was is this a sequencing error,” recalls Su, who double-checked her work on different samples. The deletion appeared over and over again.

Still not ready to believe the data, she fired off an email to the lab lead  Professor Gavin Smith — this is odd, could it be a mistake?

After careful review, Smith and Su decided the anomaly was worth investigating further.

They designed specific primers and retested the sequences to pinpoint and verify exactly which sequences were missing. And it was a necessary caution—the general public and scientific community deserved the most accurate information possible.

“We wanted to verify this observation. Whether it was true or not. Because once it’s out in the world, we can’t recover it,” says Su. “It was exciting, but we were very careful—very cautious!—in interpreting our results.”

Their careful work identified a particular SARS-CoV-2 deletion, called Δ382—named for its missing 382 nucleotides or building blocks—that was found in 23.6 per cent of novel coronaviruses locally by February. This deletion was concentrated in a portion of SARS-CoV-2 known as open reading frame (ORF) 8.

Deletions in the same area of the viral genome had also been observed in Australia, Bangladesh, Spain and Taiwan. However, unlike those deletions which appeared to decrease the virus’ ability to replicate, Su and the team found that their variant appeared to be more transmissible than the original, or wild-type, virus but less severe.

Lessons from previous pandemics

In her work, Su had been focusing on the evolution, emergence and transmission of respiratory viruses, primarily seasonal influenza. She studies the whys and hows of these viruses as they transmit between hosts, as well as the seasonal outbreaks which result.

The H1N1 influenza virus subtype which caused the 2009 global swine flu pandemic had been one of her key research projects.

“That was the year when my daughter was born. And in 2010, we all moved to Singapore,” Su remembers; Smith is her husband. “We were fortunate to get the funding for studying the evolution of the H1N1 pandemic.”

They had received thousands of these H1N1 samples from hospitals including Singapore General Hospital and the National University Hospital. Su and her team ended up testing each one individually in order to sequence the full genome. Never mind that each experiment needed more than 20 pairs of primers and many repeat attempts—and that these results did not show any evolution.

“All the virus sequences from the first two years of that pandemic that we extracted were very similar to each other. I panicked a bit,” says Su. “There was nothing for me to work on here.”

Instead of focusing on the differences between sequences in Singapore, Su adopted a larger perspective and started comparing the Singapore H1N1 sequences with those of the rest of the globe. A very clear picture emerged—the spillover event for H1N1, where the virus had first began transferring from swine to human, was marked by “a lot of random mutations”. Two to three years down the line, however, only certain variants had survived to recirculate in human populations.

Su received the SingHealth/Duke-NUS Research Team Award in 2018 for her work on the H1N1 pandemic, and her experience guided her research against SARS-CoV-2 and its variants.

Handling a giant

Adept at handling the series of nucleotides that make up the influenza genome, tackling the giant genome of SARS-CoV-2 had required a deeper breath.

“Influenza’s about 13,000 RNA bases. But SARS-CoV-2’s genome is nearly 30,000,” she notes. “That’s double the size.”

The other challenge had been the explosion in genome sequences uploaded onto the international genome database GISAID. When Su had started on the project, she had just 130 other sequences to compare her data with.

“By the time we were revising the manuscript, there were more than 13,000 genomes,” says Su.

So, they relied on their computational shortcuts developed while studying influenza, which enabled them to randomly select sequences for comparison. Even so, it was a stressful time.

“We had the pressure to write up the paper and get it published,” says Su, who remains grateful for the unstinting commitment from the team who readily pulled long shifts in purposeful excitement of making a difference.

Their findings were published today, but, Su and the team were already getting to grips with their next project: to track the evolution of the virus within the same host over time.

“We wanted to see what the changes are over time within the same host. Some patients may carry the virus longer than others,” says Su. “In influenza, for example, we found intra-host diversity that correlates with other factors such as age and weight.”

Sharing knowledge to help others

During the early months of any pandemic, the many unknowns can easily cause wide-spread fear.

Seventeen years ago, Su hadn’t made the jump to working on viruses yet. When SARS struck Hong Kong, where she lived at the time, life was scary. At the same time, safe distancing measures, split shifts and other measures were not widely used.

“I was more panicked. I didn’t know much about viruses,” recalls Su, remembering the pervasive fear she’d felt of inadvertently bringing the virus home.

This time around, Su felt better equipped. She was assured by the Singapore government’s control measures. And now working on viruses herself, the threat seemed less abstract.

It was also a topic of conversation at home. Whenever her daughter Abigail, then a young tween, asked about the virus, Su and Smith talked to her about it. They reassured her that it’s not as scary as it sounds.

This at-home education planted good seeds.

“One day at work, I received an email from her schoolteacher,” Su shares. “Saying she wanted to thank my daughter Abigail for giving comfort to a classmate whose parents were infected with COVID-19. The parents were in hospital for weeks.”

“My daughter didn’t tell me that story,” says Su proudly. “When I got that email, I thought ‘Okay, we’re not just doing basic science in the lab. We’re educating our next generation as well.’”

With Su and Smith both working long hours and weekends in the lab particularly during the early months of the pandemic, family time remained at a premium.

“I’m fortunate to have two lovely children who don’t complain when we are working for long hours, plus the support of a very good helper. She gives me peace of mind when I am at work, basically,” says Su. “It’s a sacrifice we’ve had to make since the start of the pandemic, and it’s a good opportunity for us to help out.”

She thinks for a while.

“We’re not like staff in hospitals — they’re really dealing with pandemic patients. I admire those frontline workers for their contributions and efforts,” she continues. “For us as scientists, we’re just doing basic science. I’m very honoured to be part of the pandemic response.”

This authority on T cells pivots to lend his expertise to tackle the new threat.

“I’m amazed that initially — the first two, three months — everybody is only speaking about antibodies,” says immunologist Professor Antonio Bertoletti from the Emerging Infectious Diseases Programme at Duke-NUS.

As the pandemic unfolded, Bertoletti noticed public interest in antiviral immunity, his field of expertise, rising rapidly. Friends started asking him about his research.

Yet, the immediate focus on antibodies as the single most important measure of immunity failed to capture the whole story. To fully understand the body’s response to viruses like SARS-CoV-2, Bertoletti points to an overlooked group of immune cells — T cells.

“In any viral infection, there are antibodies and T cells,” he shares. “Antibodies are easy to test, T cells are a little more complicated to test. But that doesn’t mean they don’t exist.”

T cells, the white blood cells that respond to viral infections, have two roles. Helper T cells, or CD4 T cells, survey the body for foreign invaders or pathogens and stimulate the production of antibodies. Killer T cells, or CD8 T cells, destroy cells that have been infiltrated by viruses before they can replicate, alerted to the cells’ distress by the viral antigens hoisted like flags on the surface of the cells. These cells can eventually turn into memory CD8 T cells, ready to strike if the same pathogen appears again.

Compared with antibodies, which prevent infection, T cells target and clear an infection after it has occurred. A robust T cell response can mean the difference between mild or severe illness.

Yet, while T cells are a critical pillar of immunity, they are difficult to measure, which means they are often overlooked by scientists, vaccine manufacturers and the media.

“Nobody believes in T cells,” Bertoletti says, with a wry chuckle.

Immunity from SARS-CoV-2

It is precisely these underdogs in which Bertoletti is interested. His laboratory researches the immunological control of persistent viral infections, those caused by particularly hepatitis B virus, and develops therapies that harness T cells to fight recurring liver cancer caused by the virus.

In early 2020, as SARS-CoV-2 swept across the world, Bertoletti’s focus was quickly drawn to the new and deadly coronavirus.

“I did not think it could spread so fast, in such a short time,” he reflects. “Then everything exploded.”

Cases in Singapore rose steeply. Around the same time, Bertoletti’s hometown in Italy became one of the worst-hit areas. It was no longer a theoretical threat. But it had stopped being that even before then.

In March, Associate Professor Tan Yee-Joo from the National University of Singapore, a long-time collaborator of the Bertoletti lab, had reached out. She and Bertoletti had previously collaborated to understand the T-cell response to SARS-CoV-1, the virus behind the 2003 SARS outbreak. Could Bertoletti now help test COVID-19 patient samples?

The answer was a resounding “yes”. And Bertoletti’s team was well-positioned to start testing immediately. They had on hand the necessary reagents from their earlier work on SARS-CoV-1.

To understand how the body defends itself against SARS-CoV-2, the pathogen behind COVID-19, they used an enzyme-linked immunosorbent spot (ELISpot) assay, a method for monitoring T cells that actively secrete specific signalling proteins or antibodies.

On 6 April 2020, the lab tweeted a picture of their ELISpot results, with the question, “An alternative to the antibody tests?”. The post attracted hundreds of comments and more than 150 retweets.

“We ran the first ten samples and the response was fantastic,” Bertoletti enthuses.

THIS PICTURE OF AN ELISPOT RESULT SHOWED THE PRESENCE OF LARGE NUMBERS OF T CELLS IN COVID-19-RECOVERED PATIENT SAMPLES // CREDIT: BERTOLETTI LAB (TWITTER)

“It was one beautiful ELISpot,” stresses Bertoletti. “And it was the first one in all the world, basically.”

In one of the first publications on this topic, a team of Singapore scientists, led by researchers from Professor Antonio Bertoletti’s lab at Duke-NUS, discovered that people who recovered from COVID-19 or had previously been infected with its precursor SARS-CoV-1, retained long-lasting memory T cells that could confer some level of cell-mediated immunity.

T cells, a key part of the immune system, are activated when an infected cell calls for help. They find the cell in trouble and destroy it before the threat within can spill out of control.

What’s more, the team found that even people who had never been infected by either virus generated SARS-CoV-2-specific T cells.

The findings, published in Nature, suggested that previous infections from SARS-type viruses could confer some level of long-lasting protection against SARS-CoV-2, potentially making people less susceptible to severe infection from this virus.

Studying 96 human donor samples, the researchers found SARS-CoV-2-specific T-cell activity in all the 59 patients who had recovered from SARS-CoV-2 and SARS-CoV-1; never mind that the SARS-CoV-1 infections took place some 17 years ago.

ANTONIO BERTOLETTI (RIGHT) AND FOUR MEMBERS OF HIS TEAM (L-R): NINA LE BERT, ANTHONY TAN, ADELINE CHIA AND KAMINI D/O KUNASEGARAN

Just over half — 19 out of 37 — of the individuals who had never been infected with a SARS-type virus exhibited T-cell activity against SARS-CoV-2.

Virtual telesimulation lessons can be effective alternatives when in-person teaching is not possible, medical researchers including Ms Kirsty Freeman, the then-lead for the Clinical Performance Centre at Duke-NUS, found.

Their findings, published in The Asia Pacific Scholar, showed that if used correctly, telesimulation lessons can sharpen non-tactile aspects of clinical care such as history-taking, executing treatment algorithms and team communication.

With stringent controls on movement and gatherings still in place and high-risk clinical areas like the emergency room (ER) still off limits to students, a team from Duke-NUS along with colleagues from across the SingHealth Duke-NUS Academic Medical Centre transformed a four-week emergency medicine clerkship into a virtual experience for 58 Duke-NUS medical students.

And even with the time and resource crunch, Freeman’s team did not spare any attention to detail.

“An ER is a noisy place,” she noted.

So, her team honed students’ psychological readiness by layering on medical equipment noises for fidelity — this ensured that students were immersed in as life-like an environment as possible, and that they could transition more smoothly into real-world practice.

THE SIMULATION EXPERIENCE CREATED BY KIRSTY FREEMAN AND HER COLLEAGUES ENSURED STUDENTS HAD AS LIFE-LIKE AN EXPERIENCE OF THE BUSY AND NOISY ENVIRONMENT OF AN EMERGENCY ROOM AS POSSIBL

More than 97 per cent of students who provided feedback agreed that participating in the simulations was interesting and useful. Thirty-eight felt that telesimulation provided a good grounding before beginning their real-life clinical work.

However, the student respondents indicated that the limitations of telesimulation included an inability to examine patients, perform procedures and understand non-verbal cues of team members and patients.

Freeman and her research team found, too, that designing the telesimulation according to defined objectives and scheduling it after theory teaching contributed to a successfully executed lesson. Having faculty skilled in debriefing techniques that enable the learner to critically reflect on the telesimulation lesson was also advantageous.

The team, as such, recommended that educators who wish to implement a telesimulation programme should pay particular attention to the learning objectives and debriefing methods.

This immunologist turned a torrent of data about the early immune responses of SARS-CoV-2 patients worldwide into an accessible data stream.

All of the information is coming out on preprints, realised Duke-NUS immunologist Associate Professor Ashley St John some months earlier, after reading another wave of medical journals for early insights on SARS-CoV-2. And people don’t always know how to evaluate the quality of that data.

Offering preprints of SARS-CoV-2 research papers was how academic journals and researchers responded to the urgency of the pandemic, particularly in its initial stages. These papers skip journal queues and backlogs, making research on the virus immediately accessible to — and actionable for — the medical and research community.

The pandemic, however, triggered a surfeit of medical research papers churned out faster than normal. This growing torrent of data needed a macro-level overview, especially during those early furious months of the pandemic. Too much information would lead to confusion, sending scholars down pointless paths and avoidable dead ends.

And so, St John, who investigates immunity and immune pathology, set out to make all these early insights into the novel coronavirus accessible and verifiable.

“The one thing I could do was go through it all,” reflects St John, who was running other projects concurrently. “I told myself ‘I’ll learn, and I’ll put it all in context.’”

An exacting review

“All” here meant sifting through thousands of preprints and published articles before focusing on the most pertinent ones, which St John and her co-author, Abhay PS Rathore, a then-postdoctoral research scholar from Duke University, systematically reviewed. A robust immune response is vital for determining how a disease develops and resolves, yet there weren’t any reviews on SARS-CoV-2 immune responses then. New work was simply coming out too quickly from labs and hospitals across the globe.

More so, these papers mainly informed their readers that this particular result had been observed in this particular lab, and that these results were (or were not) consistent with those from another lab.

“Many of the early literature was highly descriptive,” remembers St John who is part of the Emerging Infectious Diseases Programme at Duke-NUS. “A lot of these preprints that were coming out of China very accurately described the types of changes in the immune cells that you see. The antibody kinetics and responses, for example.”

A good number of publications since supported those initial findings, St John notes. Her review, then, provided a contextual guide to different ways of thinking about — and intervening against — SARS-CoV-2.

“We’re lucky that these first researchers did it right. So, our review was right,” says St John. “And those that hadn’t been peer-reviewed we made sure to flag them as such in the text.”

St John’s mention of these qualifiers indicates one thing key to her review paper which was published today in the highly influential Journal of Immunology: it was exhaustive and exacting. One of its key observations was that SARS-CoV-2 may have long-term effects on the immune system.

While SARS-CoV-2 patients had varied immune responses, some quite notably had a weakened immune system containing fewer white blood cells even weeks after their hospital discharge. Others experienced inflammatory symptoms such as swelling and pain even after recovering from SARS-CoV-2. And a number of patients were at risk of kidney damage—SARS-CoV-2 particles were present there, potentially provoking similar inflammatory symptoms.

St John’s focus, with the review published, shifted back to potential vaccines and therapeutics. Collaborations with Duke-NUS’ parent university in North Carolina, and with the pharmaceutical industry, were imminent possibilities.

Collegiality, compromise and teamwork help Duke-NUS researchers reach warp speed.

“Those of us who worked on COVID-19—at one point, we were the only ones in the building,” recalls Professor Ooi Eng Eong about that period of time where everyone apart from the most essential workers remained at home.

Duke-NUS is, at most times, abuzz with activity. A sample week, for example, might see a PhD candidate defending their thesis about how machine learning systems are valuable for emergency care; researchers gathering for a seminar about the life cycle of immune cells; students, faculty and clinicians streaming into learning spaces; and research teams hard at work in their respective labs.

But as Ooi notes, the Circuit Breaker — which began on 7 April and concluded on 1 June 2020 — changed all that. The nationwide measures, enacted to stop the transmission of COVID-19 in densely-populated Singapore, meant a paradigm shift for school and workplace activities.

Working from home, as well as home-based learning through videoconferences and other online platforms, became the default. Any essential work had to be carried out in compliance with safe distancing measures.

RESEARCH STAFF WERE SPLIT INTO AM/PM SHIFTS, DENOTED BY THE GREY AND WHITE LANYARDS, WHILE ADMIN STAFF FOLLOWED AN ALTERNATE WEEK BUSINESS CONTINUITY PLAN OF BLUE AND ORANGE WEEKS. THE SCHOOL FOLLOWED THIS ARRANGEMENT BEFORE THE CIRCUIT BREAKER AND AGAIN AFTER THE MEASURES WERE EASED

Working hours were staggered. Group events postponed indefinitely. And shift work and splits teams became commonplace—so that only part of the team would need quarantining should someone fall ill.

How did Duke-NUS adapt to it all?

A new way of working

By looking out for each other, for one.

“For the first, five months or six months because of COVID, I’m setting up the lab, and it was a royal pain,” remembers Assistant Professor Ooi Yaw Shin about how it all began for the host-virus interaction lab that he leads. “We could not receive the equipment. We couldn’t…”

He trails off.

“My ex-lab from Stanford, they wanted to ship me some reagents, so that I could start working in the lab,” he continues about the broken international supply chain. “But then we had the Circuit Breaker here. And over there, they had an order for residents to shelter in place.” Such orders are typically used during moments of danger in the United States, mostly to protect people from natural disasters such as hurricanes, and require people to remain indoors until they are given the all clear.

“So, SFO [San Francisco International Airport] was shut down and it was a mess,” says Ooi Yaw Shin. Everything was significantly delayed.”

He brightens up.

“Luckily, Eng Eong and [Wang] Linfa — Gavin [Smith] as well — they shared their resources with me. I could kickstart some basic stuff.”

And it was not just gear that was readily shared among the scientists.

“Whatever we were learning, we were telling each other,” Ooi Eng Eong remembers of those times overall. “I still pop into Antonio [Bertoletti’s] room every time I want to talk to him about T cells. And he’ll come knocking on my door.

“It’s good for science. That’s how we should work. Like this.”

Embracing new — and old — ways of doing things

And for other researchers, the Circuit Breaker meant adapting to new work conditions in order to produce the same results.

Ms Kirsty Freeman, the then-lead for the Clinical Performance Centre, had to re-organise classes and the Objective Structured Clinical Examinations (OSCEs) for final-year medical students — these students needed to graduate, one way or another.

So, Freeman shifted to videoconferencing to deliver some of her medical simulation sessions. And for the exams, she and her team tactically mounted iPads, mobile phones and laptops with webcams in each examination room so that everyone who participated in the exams could do so safely. Here, “duct tape, a selfie stick, two tripods, three IV poles, plastic sheet protectors and countless cable ties” were invaluable.

“I felt like MacGyver,” sums up Ms Freeman.

Meanwhile, Professor Eric Finkelstein, who directs the Lien Centre for Palliative Care at Duke-NUS, and his team quickly pivoted to conduct interviews for their health economics project remotely.

A transition to phone interviews, though, meant that the team had to re-centre their interview techniques around the nuances of voice-only responses.

“It’s not as good. You can’t read body language or faces,” explains Finkelstein. “We survey a lot of patients. We look for signs of fatigue, we look for signs of distress.”

“When you’re on the phone, you just don’t have that same ability,” he continues. “But the team adapted and did the best they could.”

As for Finkelstein himself, he missed going to the office.

“Sitting at home… yeah, I didn’t like it and I don’t like it,” he admits. “I prefer to be in the office, I like the team in the office. But in terms of productivity, I would say we had only a very small reduction in productivity.”

Holding on together for a better tomorrow

All this is not to say that working through the Circuit Breaker was an easy task. It wasn’t.

“Those colleagues with children had to come to work. But their kids were at home doing home-based learning — how did they?” wonders Ms Kamini Kunasegeran, a research assistant from Bertoletti’s lab at Duke-NUS.

“It was a nightmare,” adds her labmate, Ms Adeline Chia, a senior research associate. ‘And researchers were also anxious to know if they could come into the lab or not.”

“Yeah, it was tough to decide who got to come in,” notes Kamini about planning lab shifts and rotas. “But that was not because no one wanted to come in. We all wanted to do our bit.”

The circuit-breaker measures, too, meant putting projects on hold, and for Associate Professor Ashley St John, this required reaching out to support her Duke-NUS colleagues.

“We all had to make compromises,” says St John. With her family in the United States, she often had to pick whether to be with them or with her lab as flights, quarantines and re-entry permits made regular travel impossible.

“We just kept an eye on each other, making sure that everyone was coping with those compromises,” she says. “We were all stretched pretty thin when it came to COVID-19.”

Professor Ian Curran, Vice-Dean for Education at Duke-NUS, echoes this need to keep pushing through trying times.

“You just kept swimming. Kept going. Tomorrow would be better,” he says. “Tomorrow will be better.”

The Duke-NUS Class of 2020 graduated on 29 May 2020 while the nation was still in circuit-breaker mode. But far from being a muted affair, the event became another first in the School’s — and Singapore’s — history by bringing students and faculty together for a virtual declaration of the Hippocratic Oath.

The Oath is a traditional code of ethics, whereby individual physicians collectively pledge to uphold the highest personal and professional standards in their conduct and practice. They promise to “apply, for the benefit of the sick, all measures that are required”. By reciting the Oath, newly minted doctors pledge their commitment to the welfare of their patients as they step into their new roles as doctors; these high ideals and values were never more critical than during Singapore’s fight against the pandemic.

The Class of 2020 faced a difficult final semester before their graduation. The threat posed by the virus had forced the Ministry of Health to suspend all clinical training from 7 February 2020 when the national disease outbreak alert level was raised to orange.

The impact of COVID-19 on clinical training was significant as Professor Ian Curran, Vice-Dean for Education at Duke-NUS, explains: “On a normal ongoing basis, we would have two years out of four in clinical training at any one time. And now all bar the final-year students were back on campus. Our educators flexed rapidly to provide creative and high-quality surrogate learning experiences for all four of our medical cohorts.”

It fell to educators at Duke-NUS like Ms Kirsty Freeman, the then-lead for the Clinical Performance Centre at Duke-NUS, and others across the SingHealth Duke-NUS Academic Medical Centre, to make sure that these medical students had the closest analogue to real-world clinical experiences as was possible under the circumstances.

Freeman and the wider team at Duke-NUS had organised exams through videoconferencing, installing cameras on invigilation room walls and using duct tape and pieces of wood to prop up iPads, so examiners could assess the students fully whilst maintaining all necessary safety measures.

“We were really cognizant of what must we do,” says Freeman reflecting on those days. “To both operate within the restrictions, but still provide students the opportunity to graduate in the expected timeframe.”

Speaking at the virtual ceremony, Professor Thomas Coffman, Dean of Duke-NUS, remarked: “Now, you’re officially doctors who have endured some unprecedented times. Also, probably a little nervous about what comes next, but I can assure you that you’re well prepared for this next phase of your postgraduate clinical training.”

“You’re truly a historical class. You will forever be known as the first Duke-NUS Class to graduate virtually,” he added. “But more importantly, as the Class who graduated in the midst of the COVID-19 pandemic.”

Following their send-off, Duke-NUS’ newest alumni would go on to start work two weeks earlier than originally planned, bolstering the staff numbers of the frontline healthcare workforce as Singapore continued to battle the pandemic at a national level.

cPass™, a simple test to detect whether someone has previously been infected with SARS-CoV-2, was jointly developed by Duke-NUS, A*STAR’s Diagnostics Development Hub (DxD) and global biotechnology group GenScript Biotech.

The test was a more impactful and faster alternative to existing antibody tests. It detects neutralising antibodies which clear SARS-CoV-2 viral infections by preventing coronavirus spike proteins from entering the host body’s cells.

Other SARS-CoV-2 tests simply detect the overall presence of antibodies — including those which do not necessarily block infections.

cPass also detects these SARS-CoV-2 neutralising antibodies within an hour. Other kits and laboratory procedures can take several days to produce results as they have to be carried out in biosecure facilities by personnel specially trained to handle the live virus safely.

“The cPass developed by our team can be used for contact tracing, reservoir or intermediate animal tracking, assessment of herd immunity, longevity of protective immunity and efficacy of different vaccine candidates,” said Professor Wang Linfa, the principal investigator of this collaboration, in a media release issued today.

“It does not require a biosafety containment facility, which makes it immediately accessible to the global community, including many developing nations,” added Wang, who is also an emerging infectious diseases expert from Duke-NUS’ Emerging Infectious Diseases Programme.

In the same release, Ms Sherry Shao, President of the Life Science Group at GenScript, commented that “the collaboration with Duke-NUS is a key example of how global industry and academia work together to make things happen”.

Echoing her sentiments, Professor Thomas Coffman, Dean of Duke-NUS, added, “This innovative platform developed by our researchers will be extremely useful for quick and reliable surveillance to determine how widely a population has gained immunity to SARS-CoV-2. The partnership with GenScript and DxD Hub combines complementary strengths as we work together to fight this global outbreak.”

Duke-NUS’s education team rallies for a second time to deliver clinical exams at the height of the Circuit Breaker.

Having delivered COVID-19-safe high-stakes clinical exams for the graduating cohort of medical students in March, the Duke-NUS education team could be forgiven for thinking that the worst was behind them.

When the Circuit Breaker was announced, the team knew they had to rethink their protocols again for the final round of clinical exams.

“I felt like MacGyver,” says Ms Kirsty Freeman, the then-lead for the Clinical Performance Centre at Duke-NUS, referencing the fictional undercover agent with nifty invention and engineering skills. “We just had to use what was on hand.”

And the Circuit Breaker made necessity the mother of invention.

“We couldn’t go to shops and had no time to buy stuff online. We just had to use what we had and invent solutions through trial and error,” explains Freeman.

“Trial and error”, in this case, meant Freeman and her team repurposing duct tape to prop up mobiles and tablets, using plastic sleeves to hang cameras on walls and perching livestreaming cameras on intravenous poles.

“How could we position cameras to capture images? Who had duct tape and bits and pieces to bring in from home? Could we stick stuff on walls or lean tablets against equipment for a different angle? It was creative,” she laughs.

Going social for examination support

The Observed Structured Clinical Examinations or OSCEs, which officially concluded with their supplementary run in May, went smoothly. In addition to the MacGyver-style improvisations, Freeman and her team developed and executed a five-point operational strategy. They minimised in-person interactions between students and examiners, limited the on-site number of simulated patients and faculty, robustly tested all their repurposed technological solutions, and familiarised every single OSCE participant with the new arrangements.

A DUKE-NUS STUDENT COMPLETES HIS CLINICAL EXAMS, MODIFIED TO ADHERE TO THE TIGHTEST COVID-19 RESTRICTIONS IMPOSED BY THE SINGAPORE GOVERNMENT IN 202

Sixty-two medical students — who are part of the uniquely-trained Duke-NUS Class of 2020 — would graduate on 29 May. 

Freeman, along with their colleagues, would go on to publish their approach in MedEd Publish, which would be downloaded thousands of times as educators looked for ways in which to pandemic-proof exams around the world.

Three national-level studies targeting different segments of Singapore’s population, namely healthcare workers, children and people at high risk of COVID-19 exposure, were launched today.

All three studies would be based on standardised tests of blood samples for antibodies to SARS-CoV-2, the coronavirus which causes COVID-19.

These tests would be carried out at a single centralised laboratory at Duke-NUS. Such standardisation would allow for valid comparisons across various populations despite different sampling methods.

In addition to experts from Duke-NUS, the studies assembled medical researchers and clinicians from Singapore’s public health institutions, the Ministry of Health, DSO National Laboratories and A*STAR.

“At this critical juncture, it is important to know the extent of COVID-19’s exposure in the community, given potential asymptomatic infection and herd immunity,” said Professor Wang Linfa from the Emerging Infectious Diseases Programme at Duke-NUS and a member of the national COVID-19 Research Workgroup.

As the virus could spread around the community through asymptomatic and therefore unhospitalised individuals, these studies would provide insights into the extent to which such cases are underdiagnosed, and how they may contribute to the spread of COVID-19.

Data from these studies would let policymakers map how best to control the long-term spread of COVID-19, identify segments of the population at risk of infection, and who would benefit from a vaccine once one became available.

Singapore would be one of the first countries in the world to conduct such tests on a large scale.

During the early stages of the COVID-19 pandemic, plasma-based therapies were a low-hanging fruit that held the potential of yielding effective treatments — and even vaccine candidates — against this then-unknown virus as they could be moved from bench to bedside fast.

This approach, which was first used as a treatment in the late 1800s, makes use of plasma derived from the blood of people who have recovered from the infection, which is rich in antibodies against the virus. The plasma-derived treatment is then injected into an uninfected individual as a vaccine or an infected person to help fight the infection.

“But some initial preclinical studies showed that in certain situations, some SARS-CoV-1 vaccine candidates could make the infection worse,” says Dr Ruklanthi de Alwis, a then-senior research fellow from the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS).

This happens when antibodies in the plasma that are supposed to fight the virus go rogue and enhance the viral infection instead.

“And because we’ve been studying the mechanisms that make these antibodies go turncoat, we wrote this mini-review about the good and bad of this kind of approach,” explains de Alwis, who wrote the review together with Professor Ooi Eng Eong from Duke-NUS’ Emerging Infectious Diseases Programme and co-director of ViREMiCS.

Drawing on their experience of working with antibodies in all kinds of diseases including dengue where antibodies can switch sides when people are re-infected, they summarised what was known then, what to look out for and how to mitigate this risk in a review article published in the journal eBioMedicine.

They concluded that because of the nature of the data available, the risks appeared to be low, an assessment they would subsequently confirm.

“In terms of antibody-dependent enhancement, we did not see that in subsequent SARS-CoV-2 preclinical studies,” says de Alwis.

Looking back at the role that plasma-based interventions would end up playing, de Alwis says that early hopes of an effective plasma therapy were quickly dashed.

“It still holds true for monoclonal antibodies. If given very early on in an infection, they can be protective against severe disease,” she says. “But plasma therapy, unfortunately, has not shown a lot of protection from disease.”

The government’s key measure to minimise the spread of SARS-CoV-2 saw most businesses, except essential services, adopting a work-from-home model. Schools shifted to home-based learning.

All social gatherings were banned, except for visiting elderly relatives needing assistance.

At Duke-NUS, work shifted to home for a majority. Among the exceptions: the teams pursuing COVID-19-related laboratory research. But even they had to pare down their numbers, running their studies with a skeleton crew.

The Circuit Breaker was scheduled to end on 4 May 2020.

The Bertoletti lab would work flat out through the Circuit Breaker, digging beyond antibodies to discover more about the immune system’s response to SARS-CoV-2.

“We deal with hepatitis B, so we don’t usually see such a big response,” explains Ms Kamini Kunasegaran, a research assistant with Professor Antonio Bertoletti’s laboratory at Duke-NUS, about her team’s first foray into studying SARS-CoV-2. “The SARS-CoV-2 response was really big.”

“That really was the turning point,” adds her lab mate Ms Adeline Chia, a senior research associate. “Everyone got so excited.”

Kamini and Chia were referring to the first quantitative glimpse their team, which is part of Duke-NUS’ Programme of Emerging Infectious Diseases, gained into the body’s T-cell response to the virus on the eve of Singapore’s Circuit Breaker.

Unlike the response to chronic hepatitis B virus (HBV), studying SARS-CoV-2 yielded entirely different results.

“The ELISpot lit up like a Christmas tree,” says Kamini referring to the test they had performed to count SARS-CoV-2-specific T cells.

The test revealed a clear and robust T-cell immune response. After shaking off doubts that something had gone wrong, the team felt excited. And Twitter’s agreement was immediate and emphatic: this was indeed exciting.

The discovery would launch a three-month sprint to a Nature paper.

Look at our first direct ex-vivo ELISpot! Strong #SARSCoV2 specific T cell response in recovered #COVID19 patients. An alternative to the antibody tests? pic.twitter.com/P1FxdXCrmc

— Bertoletti Lab (@bertoletti_lab) April 6, 2020

Working in the new (ab)normal

Of course, such breakthroughs — and their accompanying tweets — are highlights which reveal little of the arduous research process that generated them.

Before the pandemic, the team had been investigating the behaviour of T cells in a body with chronic HBV infection. T cells are immune cells that recognise and target foreign invaders once these have squirrelled their way into the body’s cells.

In chronic HBV infections, the continued presence of the virus elicits a countermeasure response from the body’s T cells, which continue to patrol the bloodstream in low numbers; perhaps one per 10,000 T cells was on the lookout for HBV. With neither side winning, the body reaches a stalemate that the team had been investigating.

But when SARS-CoV-2 struck, the team quickly turned their well-honed expertise to studying T cells in SARS-CoV-2 infections. While that pivot posed no technical difficulties to them, the team had to adapt to the challenges of an unprecedented pandemic.

With the Circuit Breaker looming ahead of them, having everyone together in the laboratory was off the table; this at the precise moment when they needed all hands on deck. Instead, the lockdown and its associated safe distancing measures would whittle the on-site team down to a crew of eight.

“It was chaos in the beginning,” recalls Kamini, who was assigned to the skeleton crew that would work in the lab over the months to come.

DURING THE CIRCUIT BREAKER, THE TEAM EXERCISED THEIR CREATIVITY TO ENSURE FAST AND EFFECTIVE COMMUNICATION BETWEEN THOSE IN THE LAB AND THOSE WORKING REMOTELY

Those who would be allowed back into the lab were further divided into morning and afternoon shifts. Getting their work done in that short span of time would subject them to immense time pressure, and demand clear communication. The team would have to keep in close contact, so they could easily pick up from where the other shift had left off.

“Having a long enough working relationship was important for times like these,” stresses Chia, who coordinated the on-site team.

It would turn out to be a steep learning curve. Even while they navigated the impending new restrictions, the pace of research accelerated. Studying SARS-CoV-2, unlike HBV, meant responding to a dynamic and unpredictable situation.

KAMINI WORKED THROUGHOUT THE CIRCUIT BREAKER, ISOLATING AND STUDYING T CELLS IN PATIENT SAMPLE

And unlike the frozen HBV samples the team was used to handling, they were working with fresh blood samples. That meant time was of the essence.

“We had to collect the samples, process them and then do the experiments straight away,” explains Kamini. “If the sample came in at 5pm, in our HBV work, we could have left it till the next morning before starting our experiments. But with fresh samples, we had to process them immediately.”

Processing alone would take about two hours and only then could they start with their experiments which would take another three hours. Long shifts would become the norm.

With the samples coming directly from patients at Singapore General Hospital and other collaborating institutions across Singapore, the team also would not be able to anticipate the quantity and quality of samples on any given day. There could be a glut, or not a single one. And without a scheduled pool of samples, they could not plan ahead. From day to day, the priorities for what to test in each set of samples would shift.

“It would all depend on the samples, and at that point, what question we wanted to ask,” says Kamini.

Chia chimes in: “Sometimes the decision could only be made on the spot, about what exactly we would do with these precious samples.”

An eye on immunity

That first discovery would open the floodgates to new opportunities.

“The project exploded,” says Chia. “We’re collaborating with even more people, and we have even more samples coming in. But the good thing is, our staff are even more well-trained.”

Novel mRNA vaccines would be introduced in a matter of months, opening another opportunity for the team to study the T-cell response. This time in healthy vaccinated individuals.

The team’s schedule, too, would eventually ease back to some semblance of normalcy. Indeed, the crucible of stress would forge a greater sense of cooperation among the team.

“The teamwork is more pronounced now,” reflects Chia. “We’re all working towards a common goal, and there is a lot of help between people.”

Chasing the blips of excitement

The tweet sent on the eve of the Circuit Breaker would culminate in a Nature paper titled “SARS-CoV-2-specific T-cell immunity in cases of COVID-19 and SARS, and uninfected controls”, on which Kamini and Chia are both co-authors.

It’s one of those rare breakthrough moments — “the little blips of excitement” as Chia puts it.

Reflecting on the speed with which the study progressed — it went from idea to publication in just three months — Kamini remembers her surprise: “Whoa, that was fast.”

For Chia, this blip was all the more thrilling because it proved their strong collaborative spirit.

“It was the first time there were so many people from the lab in the paper. Looking back, it really does feel like a big collective effort.”

A MedEdPublish case study of how Duke-NUS planned and conducted its final-year clinical skills exams under pandemic-era conditions showed that it was possible — even in trying and safely distanced times—for students to complete their exams and graduate as planned without compromising competency.

The authors of the case study, which included Duke-NUS educators Ms Kirsty Freeman and Professor Ian Curran, noted that there were no reports of COVID-19 infections by any person who participated in the three-day Observed Structured Clinical Examinations (OSCEs).

This was achieved by dividing the 56 students undergoing the exams into four separate cohorts with specific faculty and administrative staff assigned to each. As Freeman, Curran and the rest of their team noted that “at no time were students, staff or examiners from different circuits allowed to mix, and all were also given strict instructions about avoiding meeting and socialising” beyond their time in the School.

The educators also noted that having actual patients participating in the pandemic-era OSCEs was challenging. Patient volunteers who had healthcare contact in the fortnight previous were disallowed. Those patients allowed on-site were initially fearful of being infected with COVID-19 — conversely, the risk that these patients might end up spreading COVID-19 to the other OSCE stakeholders also had to be considered.

To mitigate and assure patients, Duke-NUS involved only patients with chronic conditions, minimising their on-site changeovers, and screening patients for travel histories as well as sick family members during the fortnight leading up to the OSCEs.

The Duke-NUS operational measures would go on to guide other medical schools in designing and implementing rigorous clinical skills examinations that, at the same time, minimised the risk to key stakeholders.

Less than two months after this, the team would once again have to re-evaluate these measures to be able to conduct the final set of exams during Singapore’s Circuit Breaker, the most restricted period in Singapore’s fight against COVID-19.

The first volunteer was injected today with an initial dose of an experimental vaccine against SARS-CoV-2 called mRNA-1273 at the Kaiser Permanente Washington Health Research Institute in Seattle, Washington. The vaccine candidate was developed by Moderna, a Massachusetts-based biotechnology company.

More volunteers would follow—for this vaccine candidate and trials for others as the world raced to develop vaccines against this novel virus.

“Finding a safe and effective vaccine to prevent infection with SARS-CoV-2 is an urgent public health priority,” said National Institute of Allergy and Infectious Diseases Director Dr Anthony Fauci as the first injection was administered. “This Phase I study, launched in record speed, is an important first step toward achieving that goal.”

More often associated with the treatment of cancer, immunotherapy could also be used to treat infectious diseases, suggested a team from Duke-NUS.

In a commentary published in the Journal of Experimental Medicine today, Professor Antonio Bertoletti and Senior Research Fellow Dr Anthony Tanoto Tan from Duke-NUS’ Emerging Infectious Diseases Programme made the case that T cells could be extracted and engineered to recognise a viral threat before being reinjected into the blood stream.

These engineered T cells were fitted with either artificially recreated receptors called chimeric antigen receptors (CARs) or naturally occurring ones called T-cell receptors (TCRs) that recognise cells infected either by a specific cancer or virus.

Their observations could also have implications for the newly declared pandemic.

“We demonstrated previously that T cells can be redirected to target the coronavirus responsible for SARS,” said Bertoletti at the time.

“Our team has now begun exploring the potential of CAR/TCR T-cell immunotherapy for controlling the COVID-19-causing virus, SARS-CoV-2, and protecting patients from its symptomatic effects,” Bertoletti would go on to say in a media statement issued by the School on the commentary.

The Bertoletti lab had been studying this method to treat chronic hepatitis B infections and hepatitis B-related liver cancer. The scientific concept was licensed to local biotech start-up, Lion TCR, which brought it to the clinical trial stage in 2018 for liver cancer patients whose cancer had recurred even after transplant.

“This commentary was largely written before the pandemic, but some aspects turned out to be pretty predictive of what was to come,” reflects Bertoletti. “For example, we have since gone on to develop SARS-CoV-2 TCR-redirected T cells and are testing the possibility of using this strategy to treat immunocompromised patients with COVID-19.”

The co-development of a self-replicating mRNA-based vaccine kicked off today. The collaboration combined Arcturus’ STARR technology with Duke-NUS’ rapid screening platform developed by Professor Ooi Eng Eong’s team. The hope was to create an effective, single-dose vaccine in Singapore.

OOI ENG EONG AND HIS TEAM BUILT EXPERTISE IN UNDERSTANDING WHAT CAUSES VACCINATION SIDE EFFECTS, KNOWLEDGE THAT MADE THEM WELL-SUITED TO PARTNER WITH ARCTURUS

Ooi, a dengue researcher at heart, was the lead principal investigator for the preclinical studies, to which he would apply his expertise and understanding of vaccine development to serve the nation.

“We’d been studying how humans respond to the yellow fever vaccine, and found the causes of common vaccine side effects and the genes that need to be switched on or off to produce immune responses that give durable protection. And that’s what we want from a vaccine,” says Ooi, who was keen to leverage this knowledge in the partnership with Arcturus.

“With a solid scientific foundation, we knew what milestones to look out for,” he adds; milestones that would give the team the confidence that they were on the right track in the quest for a COVID-19 vaccine.

“Duke-NUS has been on the front lines in the fight against COVID-19, developing the first serological tests for the infection, and was among the first groups to isolate and culture the virus. The partnership with Arcturus Therapeutics combines complementary strengths as we work together to fight this global outbreak,” said Professor Thomas Coffman, Dean of Duke-NUS, when the deal was announced.

This collaboration came about after weeks of fast-paced talks between Arcturus, Duke-NUS and Singapore’s Economic Development Board.

Commenting on the partnership, Ooi said at the time, “There is a tremendous urgency to develop an effective prevention for the current coronavirus crisis. The Duke-NUS and Arcturus partnership could expedite a solution to this pressing need as we utilise STARR technology to bring a vaccine candidate for clinical testing in the shortest time possible.”

As the first cases of a novel coronavirus were detected in Singapore, a team of clinician-scientists from Duke-NUS and the Viral Research and Experimental Medicine Centre at SingHealth Duke-NUS (ViREMiCS) closely tracked patients’ immune response to help shed light on how this virus interacts with the human immune system.

“By this time, we knew it was a fairly severe disease,” recalls Professor Ooi Eng Eong, from Duke-NUS’ Emerging Infectious Diseases Programme who co-leads ViREMiCS.

“And I thought the first thing we could do is to just find out why some people developed very severe disease while others had only mild symptoms.”

Studying blood and throat swab samples from three SARS-CoV-2 patients, Ooi, who was joined by then-Senior Research Fellow Dr Eugenia Ong, and then-Associate Professor Jenny Low, tracked these patients’ inflammatory and immune responses.

But unlike many other studies carried out around the same time, which would take snapshots at fixed time points, the team decided to collect samples every day.

“We looked at the genes that were turned on or off and whether that could be the underlying reason why some people go on to develop severe disease while searching for some starting points for therapeutic approaches,” Ooi explains.

So they looked at trends in inflammatory responses such as changes in gene expression, levels of cytokines, T-cell responses and viral clearance as well as the impact of re-purposed existing anti-inflammatory treatments on the course of the infection.

“We were able to get a nice pattern of what the immune response looked like,” says Ong. “We detected pro-inflammatory signals through gene expression profiling that correlated with the severity in clinical outcomes, showing that inflammation was a key driver in disease severity.”

With so little known about the virus, they decided to submit their observations on 1 March to Cell Host & Microbe, which would go on to publish the report a month later. It was one of the first — if not the first — paper to do that.

What was the biggest takeaway from that work?

“That the whole process is very dynamic,” says Ooi. “And that we needed to be a lot more specific about what we’re talking about instead of lumping everyone into the same bucket.”

Singapore Prime Minister Mr Lee Hsien Loong and Deputy Prime Minister and Coordinating Minister for Economic Policies Mr Heng Swee Keat publicly commended a team from Duke-NUS for uncovering the hidden link between the Grace Assembly of God and the Life Church and Missions SARS-CoV-2 clusters.

The Prime Minister noted in a Facebook post, published a day earlier, that Cases 83 and 91 from the Life Church and Missions cluster showed only mild symptoms and had not been diagnosed with COVID-19 earlier.

SOURCE: PM LEE HSIEN LOONG (FACEBOOK)

He added that the Duke-NUS serological tests had “subsequently confirmed that they had been infected earlier and linked the two clusters together.”

“This breakthrough would not have been possible without close cooperation among the Ministry of Health, Singapore, Singapore Police Force and researchers from Duke-NUS Medical School, who developed the serological test, the world’s first, here in Singapore. My thanks to all of you for a job well done!”

SOURCE: DPM HENG SWEE KEAT (FACEBOOK)

Deputy PM Heng echoed this sentiment in a Facebook post published today, stating that the Duke-NUS team had “done Singapore proud” by developing the tests. He added that the team did this just weeks after scientists and researchers from A*STAR and Tan Tock Seng Hospital developed a diagnostic test kit for screening suspected SARS-CoV-2 cases.

“This is a world’s first—using serological testing to link different clusters of COVID-19 cases,” he wrote. “Well done to all the scientists and researchers who worked on the diagnostic test kit as well as the serological test—you have made a difference!’’

Chia Wan Ni and Tan Chee Wah, two early career researchers in the “Linfa lab”, achieve a world-first in serological testing and develop a SARS-CoV-2 test.

“Okay, here’s the sample. You go into BSL3 and you do the ELISA, okay?” were the instructions Dr Chia Wan Ni, then a then-research fellow, recalls receiving from her supervisor Professor Wang Linfa; instructions and experiments that would lead to a breakthrough in Singapore’s contact tracing of SARS-CoV-2 cases.

ELISA refers to a testing technique used to detect if someone has been infected with a virus, even long after the virus has cleared. As the test needs to be done with a live virus, it can only be done in top secure biocontainment facilities that adhere to biosafety level 3 (BSL3) standards.

And that’s where Chia was headed as she and the rest of the team from Wang’s laboratory at Duke-NUS were activated to test a particular set of patient samples.

“They want you to go in blind and just work on the sample,” adds Chia’s lab mate and then-research fellow Dr Tan Chee Wah. “After that, whether it turns out positive or negative, you’ll have seen the truth.”

This bias-free approach to testing turned up a milestone discovery. Chia and the team uncovered the missing link between two SARS-CoV-2 clusters early on during the outbreak.

“When Prof Wang explained the entire backstory, we were ‘Whoa! O-kay! This is a first in the world?’” Chia smiles, remembering.

Chia and Tan led the world in the hands-on serological testing for SARS-CoV-2. Using the samples that were sent to them of suspected cases, they searched for the presence of a particular type of antibody that can neutralise the virus. Their work enabled contact tracers to link SARS-CoV-2 infection chains — the church clusters originated from visitors from Wuhan and totalled 31 people in the end. It also enabled the team and others to check the levels of immunity in the community as well as develop vaccines and other therapeutics.

But working with a live virus in highly secure facilities meant that the process was slow. It was time consuming. And expensive.

Faced with this bottleneck, Wang was already thinking of how to create a surrogate test, and he would soon share his back-of-a-napkin sketches with Associate Professor Christopher Laing, School’s then-Senior Associate Dean for Innovation and Entrepreneurship.

And Tan and Chia developed this test alongside him.

These months, understandably, would become the career highlight for Chia and Tan.

All in full gear

Tan and Chia had been busy in Wang’s lab — the “Linfa lab” as it is known around Duke-NUS — since right after Chinese New Year 2020.

DRS CHIA WAN NI (LEFT) AND TAN CHEE WAH (RIGHT) WITH DR ZHU FENG (BACK) WERE MEMBERS OF THE "LINFA LAB" HEADED BY PROFESSOR WANG LINFA (CENTRE

By that time, Wang was already a member of the national COVID-19 Research Workgroup. The lab was divided into groups — one to focus on virology and another on serology — and both had to scale up their output.

“Emerging infectious diseases are a lot closer to my heart,” says Chia. “More than a disease which doesn’t have much impact in our ‘hometown’ here.”

Shifting their focus to this particular virus, accordingly, came naturally to the pair.

“We work very well together as a team. I was mainly taking charge of all the response stuff. Chee Wah was doing all the research,” explains Chia, who became the main point of contact between the lab and external stakeholders.

Staying safe, keeping wary

The development of this new surrogate test that Wang had conceptualised would become another source of anticipation.

“It was the first time I’ve done research and come up with a [commercial] product”, says Tan. “I can’t explain the feeling.”

He laughs.

“Maybe this might happen only once in my life.”

What was certain, though, was that Tan and Chia’s work had made them the go-to source for loved ones who needed information about the pandemic. Chia became a “COVID help desk” for her extended family. She debunked rumours from social media and explained the reasons behind different measures. Tan, similarly, had to reassure his wife about his work in the BSL3.

“My wife was worried. She asked ‘Can you catch the virus in the BSL3?’ I told her in some ways, it’s safer working in the BSL3 environment than the BSL2,” says Tan, referring to the more common type of lab, where less protective equipment is required.

While he may be perfectly safe working in the BSL3, the world around him would have to face this outbreak. And other ones in time to come.

“The next outbreak, I feel, could likely be influenza. Or corona. Likely one of these two,” he speculates when put on the spot.

But what was amply clear to both Tan and Chia was that no one would be safe until everyone is safe.

Serological testing uncovered the hidden link between SARS-CoV-2 clusters associated with two churches in Singapore at a time when the nation was focused on containing the rapidly growing threat of the new virus.

Thought to be the first such use of serology in the world, a team from Duke-NUS assisted local contact tracers by analysing the blood of a married couple who had not previously been diagnosed with SARS-CoV-2 but had been in close contact with the index case of Singapore’s largest church-related SARS-CoV-2 cluster at Grace Assembly of God.

SOURCE: CHANNEL NEWSASIA (YOUTUBE)

Having successfully cultured the virus, the Duke-NUS team used the virus and its genetic material to develop tests to accurately detect virus-specific antibodies that remain in people’s blood long after they recovered from the infection.

With these, the team determined that the couple had previously been infected with the novel coronavirus. Contact tracers were then able to trace the source of the infection, which originated with two travellers who had arrived from Wuhan in January. The visitors had attended a church gathering where they interacted with the couple. The couple, who were not initially linked to the resulting cluster, then met the index case of the Grace Assembly of God cluster.

The final chain comprised 31 people, accounting for a third of all reported infections at that time.

The achievement drew plaudits from Singapore’s Prime Minister, who wrote on his Facebook page to congratulate all involved.

SOURCE: PM LEE HSIEN LOONG (FACEBOOK)

“This breakthrough would not have been possible without close cooperation among the Ministry of Health, Singapore, Singapore Police Force and researchers from Duke-NUS Medical School, who developed the serological test, the world’s first, here in Singapore. My thanks to all of you for a job well done!”

Would there be enough beds? What about nurses? What would the impact be on patients who didn’t have COVID-19? Questions like these drove a multi-disciplinary Duke-NUS research team as they set about planning for the likely effects of COVID-19 on Singapore’s healthcare system.

The project, which brought together the full Health Services and Systems Research (HSSR) team at Duke-NUS and the Health Services Research Centre at SingHealth would inform top-level health policy decisions as the pandemic unfolded.

The team’s first key intervention involved using computer simulations to evaluate the impact of different healthcare policies on Singapore’s rates of disease, mortality, and use of medical services.

These simulations would also evaluate hypothetical policies, enabling the 11-strong SingHealth Duke-NUS team to predict a policy’s effectiveness in three distinct possible scenarios: COVID-19 remains under control, becomes difficult to control with local clusters or results in a full-blown local epidemic.

“You can test out policy A, where ‘Okay, I’m going to convert 50 per cent of the beds [to isolation beds],’” says Professor Marcus Ong, the director of HSSR at Duke-NUS, about how the hospital network would need to pivot to COVID-19 treatment capabilities.

“Or policy B, where I’m conservative; I’m going to convert about 20 per cent of my beds.”

These simulations would be timely. A steady flow of data from public electronic health records would inform and shape their trajectories. And Ong and the team would add qualitative data when running them, inputting stakeholder views and policies to nuance their models.

Key work streams in the research project called COVID-19 Virtual Disease Health System Outbreak Model for Singapore, which aptly abbreviates to CoViD-SOS, would focus on understanding how the virus would affect the workflow of emergency departments, intensive care units, operating theatres and the needs of medically vulnerable patients.

THE HSSR TEAM INVESTIGATED HOW DIFFERENT HEALTH POLICIES WOULD IMPACT SINGAPORE, TAKING INTO CONSIDERATION THE CHALLENGES FACED DURING THE PANDEMIC AS WELL AS SOCIETAL FACTORS

“This is where health systems research came to the forefront and showed its value,” adds Ong, who is also a senior consultant with Singapore General Hospital’s Emergency Department. “By nature, health services research is multi-disciplinary, cross-boundary, and collaborative.”

“Our overall goal was — and continues to be — to minimise the impact of the evolving COVID-19 disease outbreak on Singapore’s healthcare systems.”

“Although the source of 2019-nCoV is yet to be confirmed, early findings suggest a high possibility of a bat origin,” wrote Professor Wang Linfa, then Director of Duke-NUS’ Emerging Infectious Diseases Programme, and a team of international infectious disease experts in the Lancet.

In the article, Wang and his co-authors offered guidelines for managing emerging zoonotic virus outbreaks similar to what the world was about to face. Drawing on six similar outbreaks from the previous 25 years and incorporating the first lessons from this novel coronavirus outbreak, they put forward four key points:

1. A next-generation sequencing-based reporting system

The genome of the suspected novel coronavirus was released before live samples had been isolated. Such early flagging can lead to timelier medical and scientific interventions. A contemporary next-generation sequencing-based reporting system could, therefore, quickly alert the population to suspected outbreaks.

2. Clear guidelines for communicating information to the public 

Balanced communication about suspected emerging zoonotic virus outbreaks is crucial. Clear communication guidelines must be in place to determine what must and must not be reported, to avert panic and enable balanced leadership.

3.  Need for a “One Health” approach to outbreak responses and control

A “One Health” intervention strategy unites experts from various disciplines to solve public health problems. A comprehensive “One Health” team should be involved in future emerging zoonotic virus investigations, and devise wider impact measures for preventing future transmissions.

4.  Name viruses with care

Location-based names for viruses, such as “Wuhan virus” and “China virus” are socially and culturally insensitive. This particular virus should, Wang and the WHO experts suggested, be named “Han acute respiratory syndrome” (HARS-CoV). This, as with SARS and MERS, foregrounds the disease as a symptom. Such a re-emphasis would reduce blame and discrimination during media usage.

An educator adapts to restrictions and being in a new job while alone in a new country.

“So, I started on the tenth of February 2020 and Singapore had just gone into DORSCON Orange,” remembers Ms Kirsty Freeman about the first day of her new job in a new country; a country that had just raised its national disease alert level, the Disease Outbreak Response System Condition or DORSCON, to its second highest level — orange. “I didn’t know what that meant. But I came to work, and there was this bustle — this unusual sort of vibe.”

Freeman discovered why later that day. The School had just had to withdraw every single medical student from the clinical environment. It was a necessary precaution. SARS-CoV-2 had spread to Singapore and the hospitals were on high alert: would this be a replay of the 2003 SARS outbreak? This measure, however, meant no more opportunities for students to take an active role in a real clinical context. Further, clinical supervisors could not judge if these students had mastered the required clinical skills.

As the incoming lead for the Clinical Performance Centre at Duke-NUS, Freeman had been hired to make sure students could take medical theory out of the books and put it into practice. There would be gaps in learning opportunities now, she knew, with these students removed from healthcare institutions.

Freeman’s plans to watch and learn “for probably the first six months” to get “a feel for how the School does things” were out of the window. “The School has a really great history, so you don’t want to come in and force change upon people when you don’t understand how things have come about,” she says.

“But on that first day, I realised my next six months were going to be a little different from what I’d thought.”

Shifting goalposts for simulation classes

Singapore’s DORSCON framework has four colour-coded levels: green, yellow, orange and red. They represent, in that order, the increasing severity of an infectious event in Singapore as well as the steps needed to contain it.

DORSCON Orange meant that the disease was severe and spreading easily among people, but also that it was being contained. Such containment would come with moderate disruptions to daily life, including temperature screenings and quarantines. Additional sector-specific precautions — learnt from the previous SARS outbreak and the H1N1 pandemic in 2009 — were also rolled out, including cohorting of healthcare professionals and visitor restrictions in hospitals. Gatherings of students, too, should be capped at 50 per group.

Any solutions that Freeman and the education team developed over the coming months would need to be in line with these measures.

Freeman, a fellow of the US Society for Simulation in Healthcare, would have to draw deep on her nearly 20 years of experience in delivering simulation-based education, assessment and research as the pandemic evolved.

But finding ways to simulate clinical environments is Freeman’s area of expertise and passion. “I love simulation as a tool to take theory out of the books and put it into practice,” she shares.

Planning for replacement lessons to enable students to acquire the necessary skills to pass the year would be further complicated by the rapidly changing situation on the ground.

KIRSTY FREEMAN WORKS WITH STUDENTS THROUGH A SIMULATED PROCEDURE

“Each week the goalposts were changing. You were never on solid ground,” says Freeman. “We would come up with a great plan but then a couple of days later — guess what? We couldn’t do that anymore because now everyone must be so many metres apart. Or must now have masks and face shields on.”

She shrugs — this was the way things were, and we got on with it.

And so, while the constantly evolving measures were necessary, the educators and examiners would be put to the test.

“It was a new directive almost every other day — each a highly sensible new precaution — but each drove a big red bus through our curriculum plans,” Professor Ian Curran, Vice-Dean for Education, chuckles, remembering those early months. “We had to flex and adapt constantly. Often with just a few hours’ notice. You’re told, mid-afternoon on a Sunday, that you couldn’t rotate your students on Monday.”

“These constant challenges demonstrated the true professionalism, creativity and adaptiveness of our educators as well as the resilience, grit and determination of our students. All characteristics that would stand us and them in good stead as we navigated the challenging years ahead, as we adapted to the new normal,” says Curran, who like Freeman is a fellow of the US Society for Simulation in Healthcare.

The Clinical Performance Centre would also work closely with healthcare organisations and the Ministries of Health and Education in order to obtain critical equipment and resources such as personal protective equipment (PPE) and hand sanitisers so that students could continue learning even if that learning had to be brought back to the School’s campus.

Clinics and wards would be swapped for replicas on the fourth level of the Khoo Teck Puat Building, where students would be trained using high-fidelity, life-sized manikins in life-like environments, working under the same pressures a clinical team might face.

“Simulation ensures that when students have the privilege of interacting with real patients, they are prepared and ready to deliver really great care,” Freeman says.

To maximise training opportunities for students while making sure that group sizes remained within the permitted limits, her team ran simulations on weekends and late into the night.

“I was so proud of all our staff,” she says. “We completely re-envisaged our work life to meet the needs of our students.”

And for those times when in-person would just become impossible, Freeman and the team would create fully online learning opportunities.

“I loved our can-do attitude,” she shares. “Everyone rallied together and said, ‘Who’s got ideas? We don’t know how that’s going to work, but let’s do it!’”

Because right from the start, the School was clear that despite all the restrictions, in just a month’s time, the students would sit their high-stakes clinical exams.

“We felt it was important to validate our students’ own sense of knowing that they’ve made the grade and met the standard,” says Curran of Duke-NUS’ decision to hold these exams. “We also needed to demonstrate to our clinical stakeholders and partners that our students were good to graduate and fit to go into practice.” 

“Planes will fly again”

But what of Freeman’s own needs? The plan had been for her and her loved ones to fly between Australia and Singapore for regular visits. Her husband, too, would fly in from Perth around the middle of the year. Then, they would build their life in Singapore together.

“That didn’t happen,” states Freeman. “I remember sharing with him — it was changing on a weekly basis — this great plan. A couple of days later, that’s up.”

Border restrictions would soon cancel all travel and ground planes. Freeman’s husband would remain in Australia until an unknowable someday.

Looking back, the busyness of work and the creative delight of pottery classes helped, says Freeman. The new bonds forged online — through Zoom catch-ups and spontaneous notes of reassurance — with others in the medical simulation community sparked joy and provided much-needed encouragement and inspiration, too. And she never failed to have a virtual cup of tea with her husband every single day.

“We set our alarms early. Before our working day,” she shares. “Starting at six o’clock every morning, we’d meet each other on video and have breakfast together.”

They would check in on each other during these virtual sessions, asking about their friends and families. It would become the way they maintained their relationship for a long time, also because constant interactions in relationships is part of Freeman’s larger approach to life.

“There’re so many people within Duke-NUS and our larger community here in Singapore who have been more isolated due to the pandemic,” says Freeman. “And we should be just reaching out to each other every now and then to say ‘Hey, guess what? Thinking of you today.’”

Despite the many scuppered plans and constant need to respond and adapt Freeman has no regrets.

“You know what gets me through?” asks Freeman. “I have a job where I feel like I’m making a difference. I’m surrounded by like-minded people who are passionate about medical education and providing access to great healthcare.”

“All that keeps me going. And hopefully, at some point in the future, planes will fly again.”

It was Friday lunchtime when the news came that clinical training across Singapore’s healthcare system was suspended with immediate effect.

All Duke-NUS medical students on clinical postings had to be recalled to campus. The School’s education teams had the weekend to work out the first contingency plan; the first of many revisions to the School’s curricula—“75 curriculum iterations” as Vice-Dean for Education Professor Ian Curran says only half in jest—that would become necessary over the next two years.

“This really demonstrated the professionalism, determination and flexibility of the education teams both within the School and across our clinical training partners to come up with creative, imaginative and effective solutions throughout the pandemic,” reflects Curran.

These constant revisions would ensure the safety of patients, faculty and students as well as enable students’ uninterrupted progression through their training.

“Healthcare systems and the human response to disease are inherently complex adaptive systems,” Curran explains. “They’re constantly evolving. We, too, had to evolve and adapt with them to meet our educational mission.”

After they received the news, Duke-NUS educators and administrators immediately communicated to students and faculty the new Disease Outbreak Response System Condition or DORSCON Orange rules as well as the need for significant and profound changes to their curricula.

“That Friday afternoon, when we were told by the Ministry of Health, ‘That’s it; clinical training’s suspended’, we met all the classes to tell them ‘Right. Go collect your things from the hospitals, because you won’t be allowed back in for the time being,’” Curran shares candidly. “And then we had one hell of a busy weekend working out what we’re going to do.”

It was the first of many such weekends to come. Under the evolving restrictions, Duke-NUS would, over the next days, weeks and months, transition to full e-learning for classes with more than 50 students, develop virtual alternatives to clinical clerkships and work closely with the Ministry of Health and the other medical schools to return students to hospitals and clinics across the country as soon as was safe.

After sitting their final exams in March under full COVID restrictions, the final-year students would return to clinical training in April just as the country entered its national Circuit Breaker.

“This meant we had to ensure our students were fully trained in using personal protective equipment and prepared for entering a completely transformed clinical environment,” says Curran.

This group would go on to successfully complete their clinical training and graduate on time.

“We prioritised the clinical training and final exams for the fourth-year students as we were keen to demonstrate that our students had met all the required clinical, professional and academic standards that ensured they could practise as safe and competent doctors,” expands Curran.

For students in their earlier years, the education team would come up with bespoke solutions to keep their learning on track.

“We took the bold decision to bring forward the research activity for two year groups,” adds Curran. “That move allowed those cohorts to remain actively engaged and progressing through the course while the clinical settings were off-limits.”

Two classes of medical students, then, would in due course complete all components of the world-class Duke-NUS curriculum, albeit in a uniquely sequenced way, thereby cementing their place alongside the other graduated cohorts in the School’s history.

DORSCON — or Disease Outbreak Response System Condition — is a colour-coded framework that tracks disease situations in Singapore, spanning four levels of increasing disease severity: green, yellow, orange and red.

The announcement that DORSCON had changed to orange indicated that COVID-19 was severe and spread from person to person but had not spread widely. The last time DORSCON had been raised to orange was during the 2009 H1N1 pandemic.

With the raised alert level, moderate disruptions to daily life came into effect while hospitals recalibrated operations to reduce the risk of spread. For a medical school like Duke-NUS, the disruption was immediate and far-reaching, testing the School’s adaptability and flexibility.

A veteran of high-containment labs returns to the hot zone just in time to sequence SARS-CoV-2.

Ok, we can’t really mess this one up. That was molecular virologist  Martin Linster’s main thought during those early weeks when he or one of his colleagues collected Singapore’s very first SARS-CoV-2 samples from across the island.

The way he tells it, those errands were straight out of a heist movie.

“We got with a courier the first weeks of the outbreak. We went into the dispatch driver’s lorry just to make sure the samples were safe,” recalls Linster, a then-senior research fellow with the Emerging Infectious Diseases Programme at Duke-NUS.

During those times, the team’s circuit started at Singapore General Hospital around 3pm before proceeding to the basement loading bay of the National Centre for Infectious Diseases. At both stops, they’d swap iceboxes full of triple-sealed patient samples for a signature.

Then, once they were suited up and fitted with a respirator, the team — including Linster — could examine the contents of their iceboxes in the safety of the biosafety level 3 (BSL3) lab.

Securing the cold chain

Linster had not planned to do BSL3 lab work when he moved to Singapore in the mid-2010s as a research fellow. He already had a decade’s worth of investigations within these high-security containment facilities under his belt; it’d be good, he thought, to work elsewhere in the field of emerging infectious diseases after all that.

But after a few years, he started missing BSL3 work and it took little convincing for Linster to join his first Duke-NUS BSL3 project in 2019 — he was accordingly in prime position to contribute his expertise when the virus spread.

“You start up slowly again,” says Linster of his return. He had to re-acclimatise to the sealed-off environment of the BSL3 with its ventilation and noises — “it’s a bit like doing your first scuba dive,” he says. “Then you go full speed when the pandemic hits.”

As a virologist, Linster’s work is vital for tackling how infectious diseases spread. He maps out the genetic sequences of viruses and studies how they infect cells, mutate and importantly for these uncertain days, multiply. His findings underpin the work of other researchers who use these insights to develop treatments, therapies and vaccines.

Previously, Linster worked on “less newsworthy viruses” when he studied human parainfluenza virus in Vietnamese children in 2009. Linster’s analysis showed that a particular strain was responsible for most of the cases, and that diverse virus strains were entering Vietnam.

In 2014, Linster researched how far away an H5 avian influenza is from mutating into an airborne pathogen that readily spreads among its hosts. He found that five positions in the viral genome could be changed so that the virus binds to and infects cells of the new host.

With all this research expertise, Linster was a natural choice to join the team assigned to culture the virus within the BSL3. These cultures would give other scientists a ready supply of the virus for their work.

Here, the courier journeys, iceboxes, and strictly regulated BSL3 were necessities — the Duke-NUS team’s work called for samples and security.

“The question was really, how good was your patient sample?” Linster explains. “Did you manage to keep the cold chain?”

Maintaining the cold chain in this case meant keeping the virus and cells in the samples from SARS-CoV-2 patients alive at a low temperature.

Break the chain, though, and the virus dies. SARS-CoV-2, it turned out, is pretty unstable outside the human body in tropical Singapore.

A MEMBEr OF THE DUKE-NUS TEAM WORKS IN THE BSL3 LAB ON ISOLATING THE NOVEL CORONAVIRUS

After some initial fine-tuning of the experiments, a clear pattern emerged. The team put the virus samples into a carefully selected cell line that allowed the virus to infect the cells and replicate in order to document the effect of infection.

“You look under the microscope,” says Linster. “And you see cell death.”

Cracking the code

This pattern was not necessarily unwelcome. It was what virologists term a “cytopathic effect”. This is when a pathogen invades and causes structural changes in an affected cell.

And Linster and the team didn’t just see their cells die. They watched them bursting all over each other. Such an uncontrollable and messy death typically results from a major injury to cells and is consistent with how viruses affect them.

This was a key clue. Now, they had to wait for their tests to finish running to make sure that this was indeed the work of a virus.

“You think ‘OK, this doesn’t look normal, but was there a bacterial contamination or anything?’” he remembers.

“Then you look at the screen for half an hour to just convince yourself and the rest of the world that this is really positive if you do it over again. Because you could’ve done something wrong.”

In the end, the team’s findings proved accurate; yes, this was all indeed the work of a virus, and here was its genetic code in full. It had taken the team less than a week to complete this feat, which would unlock opportunities for the rest of the scientists at Duke-NUS and beyond to develop tests, treatments and vaccines.

With such an important discovery in their possession, the team was swift to publish their data. They were only the third lab in the world to do so, after ones in China and Australia.

“As a scientist, you want to do something new, right?” he asks. “You say ‘Okay, I’m number three’? Personally, I’m not too much interested in being that hamster in the treadmill.”

A swifter response

Research papers and national and international collaborations resulted regardless.

“There were surprises every day. That was the essence of what kept us going,” says Linster.

For him, one of the most exciting projects to follow would be a collaboration with the lab of Antonio Bertoletti, a colleague and professor with Duke-NUS Emerging Infectious Diseases Programme, who specialises in the study of T cells.

“Characterising the T-cell response, we found something rather unexpected that would be met with strong interest from the world,” says Linster of what they would discover.

Exciting new opportunities aside, Linster believes that the lessons from this pandemic will help us respond more efficiently when future pandemics strike.

He also advocates that the global scientific community, and virologists in particular, should work together on an easily-accessible catalogue of crucial viral mutations that could underpin the next outbreak. It would be a timely tool for researchers by researchers. Such a collaborative effort would, he expects, save lives during any future pandemic.

“It is a lot of effort, but it’s crucial,” muses Linster. “We seriously want to prevent the next pandemic from happening on a scale like the current one.”

Just one week after Singapore detected its first case of SARS-CoV-2 on its shores, scientists at Duke-NUS made a breakthrough. A team of specialised virus hunters cultured the coronavirus from the sample of an infected patient.

This milestone came through collaborations with clinicians and scientists from the National Centre for Infectious Diseases, Singapore General Hospital and the Ministry of Health.

The Duke-NUS culture of this highly infectious virus would go on to underpin many medical interventions against it — from diagnostics to treatments — and contribute to monitoring and surveillance studies.

A GROUP OF SCIENTISTS WORKING IN THE BIOSAFETY LEVEL 3 LABORATORY AT DUKE-NUS WAS ONE OF THE FIRST THREE GROUPS TO CULTURE THE VIRUS

“This is a crucial step forward for Singapore and neighbouring countries in response to the evolving coronavirus outbreak,” said Professor Wang Linfa, Director of the Duke-NUS Emerging Infectious Diseases Programme at the time.

“We will continue our efforts and do our best to serve the nation, the region and the world in controlling this outbreak.”

HEALTHY MONKEY KIDNEY CELLS (LEFT) DIED AFTER INFECTION WITH THE NOVEL CORONAVIRUS (RIGHT)

“This significant breakthrough exemplifies the strong collaborative culture we have with SingHealth, our Academic Medicine partner, as well as the National Centre for Infectious Diseases and the Ministry of Health,” commented Professor Patrick Casey, Senior Vice-Dean for Research at Duke-NUS.

“It will continue to be important in providing insights on potential diagnostics and therapies for this coronavirus outbreak.”

By this time, China had already reported more than 9,000 confirmed infections and 213 deaths.

In Singapore, 13 cases had been confirmed by 2pm that day while results for a further 49 cases remained pending.

The morning after the first case was reported in Singapore, about 10 experts from Duke-NUS’ safety team and Emerging Infectious Diseases (EID) Programme met in a conference room for an urgent meeting. Another five or so dialled in via phone — virtual meetings had yet to become the norm.

“We didn’t really know about Zoom then,” chuckles Professor Patrick Casey, Senior Vice-Dean for Research at Duke-NUS. “So, we met around the table in the conference room about 10 o’clock to talk about what we could do, because the EID professionals were chomping at the bit to study the virus,” he recalls.

This very eventuality—mobilising an effective response to a potential pandemic—formed part of the bedrock of the EID Programme, which had been conceived in the wake of the first SARS outbreak. And Casey recalls many discussions with the Programme’s founding director, Professor Duane Gubler, and his successor, Professor Wang Linfa, about the necessity of being ready for wartime.

“While we talked a lot about wartime and ensuring that our teams were prepared, our recruitment efforts focused on bringing in the right people to do the best research in the area of emerging infectious diseases,” explains Casey, who had joined the School when it was still only a blueprint.

Together, they brought in a team of scientists who specialised in studying different kinds of infectious diseases — from mosquito-borne diseases like dengue and Zika to respiratory viruses like influenza — as well as how these pathogens interact with their hosts — be they mosquitoes or humans

And during that meeting on 24 January, just twelve hours or so after the first case of the novel coronavirus had been detected in Singapore, these inadvertent avengers assembled, ready to step up to serve the nation and the world.

What everyone around the table wanted at that point was to be able to identify and study the virus. They wanted to isolate it. Culture it. Sequence it to unlock treatments, vaccines, diagnostics and determine from where it came.

“We knew we couldn’t begin mitigation protocols until we had the wherewithal to determine the identity of the virus,” says Casey.

On the ground, the EID professionals would adjust their work to focus on this new threat, while the liaison with the Ministry and the university fell to the School’s head of safety.

“The next 72 to 96 hours were really crazy,” remembers Casey.

Reflecting on the work that would blossom out of those intense early days, Casey is fiercely proud.

“I am terribly proud of what our folks would go on to do and how everyone stepped up to the plate. These were the individuals who, during the Circuit Breaker, would work 14 to 16 hours a day,” he says, singling out the teams who would go on to work in the high-security lab while confined into their “space suits” or personal protective equipment.

“Never once did I have to remind anybody to do their bit,” he says. “In fact, I had the opposite: what I had was people stepping up to the plate, asking what more they could do.”

This evening, less than 24 hours after Singapore’s outbreak strategy had been launched, the Ministry of Health confirmed the country’s first case of the novel coronavirus. The new coronavirus had already killed 17 people and infected more than 570 in China.

Singapore’s first reported case, a 66-year-old Chinese man from Wuhan, had arrived in the city-state with his family three days earlier.

On 21 January, he developed a fever and cough, and was diagnosed with pneumonia at Singapore General Hospital the following day. He was isolated and remained in a stable condition.

His nine travelling companions were quarantined for 14 days. A second suspected case was also reported that night.

Earlier that day, the leadership and senior management had discussed the immediate safety implications of the novel virus on the School’s operations during the first monthly operations meeting for 2020.

It was the calm before the storm.

In the SARS-CoV-2 pandemic’s city of origin, a Duke-NUS scientist experiences first-hand an unprecedented level of medical security.

Something awful is coming, Professor Wang Linfa realised that cold mid-January night after he was dropped off at Wuhan’s Tianhe International Airport and had checked in for his flight to Singapore.

Even before he reached passport control, he saw a long line of people building up at a fortified temperature monitoring station manned by airport medical and security staff kitted out in full personal protective equipment.

“Usually you’d just walk through,” says Wang, who leads a lab at Duke-NUS that investigates emerging infectious diseases and bat biology. “But this time, they controlled the flow of people so that only four in a group walked slowly past the three cameras.”

“Most people had to do that twice,” adds Wang, who himself was asked to repeat the process. “That immediately gave you that fearful feeling that something serious is going on.” 

It was, quite evidently, important to be sure. Wang had never, in all his 30-plus years as a researcher, experienced anything of this level, not even during the 2003 SARS outbreak, revising his initial perception of the likely scale of the outbreak: How do I protect myself? I’m not wearing a mask.

Once onboard the Singapore-bound plane, he cleaned his seat handrail with the little wet towel provided. Wuhan is five hours from Singapore, and Wang spent his flight time staying put and interacting as little as possible with the other passengers and cabin crew. He gained a newfound appreciation for his business-class seat — there wasn’t anyone next to him, so he could reassure himself that he was at least within his own airflow space.

Less than a week later, on 23 January 2020, Wang would address his peers in the Duke-NUS boardroom. By then, the confirmed number of novel coronavirus infections would have risen to 581 cases, with all but 10 from China. But those ten would include infections reported from as far afield as the United States and South Korea, hinting at the global spread to come. Even Singapore would be on the verge of reporting its first case.

Wang’s medical research expertise, as well as his inadvertently first-hand ethnographic experience, would become sought after by the School, the Ministries and international health bodies.

Honing expertise one virus at a time

Wang’s long career in research has taken him on several unexpected journeys — being in a city while it began spreading a global pandemic was but the latest. He is a biochemist by training, working in labs around the world from the University of California, Davis, in the United States to Monash University in Victoria, Australia.

While at Monash, a job advertisement caught his eye. The Australian Animal Health Laboratory (now the Australian Centre for Disease Preparedness) under the state-run Commonwealth Scientific and Industrial Research Organisation (CSIRO) was calling for a PhD scholar with a molecular biology background to study infectious diseases. Another Master's researcher, skilled in either biochemistry or protein chemistry, was required there, too. The listing gave him, and his wife, pause.

“It’s almost like insider trading. The advertisement was like it was written for the two of us,” Wang recalls saying to his wife. “And it was a permanent job.”

Wang’s career blossomed. He traced the origins of the Hendra virus in Australia. Helped curb a Nipah virus outbreak in Malaysia. And in 2005, reported that horseshoe bats are major reservoirs of SARS-like coronaviruses. He rose through the ranks from research scientist to CSIRO Office of the Chief Executive Science Leader before joining Duke-NUS in 2012 as Director of and Professor with the Emerging Infectious Diseases Programme.

Here, he leads research teams examining how animals — particularly bats — transmit diseases  between each other and humans, studying why these otherwise innocuous flying mammals harbour a  kaleidoscope of viruses. He also teaches undergraduates, supervises PhD students and communicates  science to the public through media appearances.

WHEN WANG MOVED TO SINGAPORE, HE SET UP A BAT COLONY TO STUDY THESE FLYING MAMMALS THAT HARBOUR A KALEIDOSCOPE OF VIRUSES

Responding to a national call

With decades of experience and his first-hand knowledge of events at the epicentre of this new outbreak, the School and the research community turned to Wang.

The day before that initial meeting in the Duke-NUS Boardroom, Wang would respond to another call — a national call for experts.

The government was forming a national research working group that would inform policy decisions and guide the nation through the pandemic. At the first meeting of the research work group on 22 January 2020, Wang would be asked to spearhead the virology research.

Recalling that meeting, Wang says, “Then I said, ‘Personally, I think serology’s important and I don’t mind leading that, too.’

“And people said, ‘Oh. That’s good. Yeah. Just add that in.’”

With these two duties settled, Wang would do what he had always done — make sense of the unexpected.

Racing to track the new virus and planning for the future

Serology is the study of blood and other bodily fluids. It lets researchers investigate problems with a patient’s immune system, determine if organs and fluid transplants are possible, and identify antibodies produced in response to a foreign substance in the body.

In the context of SARS-CoV-2, patients produce these antibodies even after the virus has left their body. Just under half of the people carrying SARS-CoV-2 do not, and may never, show outward symptoms of illness. Here then, serological tests would let experts like Wang understand just how many people were really infected, how fast the virus was spreading, how fatal it is, and the population segments especially resistant or susceptible to it.

Wang had, while still in Wuhan, alerted his team, including then research fellows Drs Chia Wan Ni and Tan Chee Wah, that they would be looking for neutralising antibodies produced by this novel virus. With the genome published seven days ago, on 11 January, the reagents needed for such serological investigations were en route and the team was ready.

In the weeks after his return, Wang would direct Chia and Tan remotely — through emails, phone calls, and videoconferencing — until mid-February; he would be in voluntary home quarantine for three weeks from 23 January. Never mind that the Government would only declare enhanced quarantine measures for travellers arriving from Wuhan and its province, Hubei, on 28 January; why risk public health needlessly?

There should also be, Wang thought with foresight, a serological kit that can rapidly detect a person’s SARS-CoV-2 virus infection, and to trace the virus’ path.

“In any major disease outbreak, you’ll have different phases. In the initial phases, molecular testing is important,” explains Wang. “But later, serology is much more powerful. Because the virus is gone, but we can still trace [its spread].”

Such a kit, then, would be at least a national-level intervention against the virus’ progress. Meanwhile, though, even as Wang accepted the World Health Organisation’s invitation to sit on its COVID-19 International Health Regulations Emergency Committee, he knew that a new phase of the outbreak was imminent.

“All this was happening before the Chinese New Year. So, every other day, there were a few hundred people directly travelling from Wuhan to Singapore,” Wang notes.

His tone is firm. It is that of a man who already knew that he and his colleagues would, in the months and years to come, face one of the toughest challenges of their careers.

Today, China’s health authorities informed the World Health Organisation that a pneumonia of unknown cause was circulating in the central transport hub city of Wuhan.

Within weeks, the entire world would be drawn into what was to become the largest global crisis since World War II and Duke-NUS Medical School in Singapore would find itself in the very eye of the storm.

From wild speculation to downright mis- and disinformation, the team at Duke-NUS battled more than just the virus, with researchers, particularly from the School’s Emerging Infectious Diseases and Health Services and Systems Research Programmes, stepping up to serve the nation and global community. At the same time, our educators nimbly adapted to a rapidly evolving situation and our students demonstrated their resilience, creativity and compassion.

As you may already have read, many of them worked throughout the Circuit Breaker in heavy personal protective equipment. They missed family gatherings and struggled through home-based learning.

At work, they modelled countless what-ifs. Cultured the virus. Called attention to the growing mental health crisis triggered by the pandemic. Developed diagnostics. Tested vaccines. Planned countless iterations of the curriculum and reconfigured timetables around a highly fluid clinical world. Conducted exams during the height of the Circuit Breaker. Created immersive online training experiences.

Looking back from the lofty vantage of 2023, we are proud that all their work helped the public, replenished the frontlines with much-needed trained manpower, and advanced science and medical education practice.

To capture their memories and experiences — whose impression will inevitably fade with time — the Communications and Strategic Relations team at Duke-NUS set about chronicling the pandemic from Duke-NUS’ perspective. And we invite you to scroll through this timeline to discover all our stories.

This timeline, populated with milestones, scientific publications and the personal stories of the people on the frontline, then, is our tribute to their dedication as well as the commitment from everyone at Duke-NUS, the SingHealth Duke-NUS Academic Medical Centre, our partners as well as every single person who did their bit during the pandemic.

Thank YOU!

The Disease Outbreak Response System Condition or DORSCON alert level was lowered to green on 13 February 2023. While we may be done with SARS-CoV-2, coronaviruses are unlikely to be done with us.

That's why we continue.

Yours sincerely,

Duke-NUS Communications & Strategic Relations

Special thanks to the contributors: Jessie Chew, Chua Li Min, Nicole Lim, Anirudh Sharma and Tan Ruilin; artists: Sci-Illustrate (Endosymbiont GmbH) and Dr Eleonora Adami, @brushandpipette