COVID-19

Prof Wang Linfa and team invented the world’s first SARS-CoV-2 serological test to rapidly detect neutralising antibodies without the need for containment facilities or live biological materials. The test kit, marketed as cPass™, was co-developed and produced in partnership with GenScript Biotech Corporation and the Diagnostics Development Hub (DxD Hub) of Singapore’s Agency for Science, Technology and Research (A*STAR). It can be used to trace close contacts, test potential vaccines and assess the proportion of the population that has already been infected, which is critical as we work out how best to live with COVID-19.

DxD Hub played an important role in obtaining provisional approval from Singapore’s Health Sciences Authority (HSA) for the cPass™ test kit, which is now available to Singapore hospitals.

As the commercial partner responsible for global marketing and distribution, GenScript has—to date—acquired the CE mark for commercial distribution of the test kit in the EU and received Emergency Use Authorisation (EUA) from the US Food and Drug Administration (FDA) on 6 November 2020. It is now also CE marked in Europe, allowing it to be sold freely in any part of the European Economic Area and has received approval from ANVISA in Brazil, ANMAT in Argentina and the Ministry of Health and Prevention (MOHAP) in the United Arab Emirates as a medical device.

As of June 2021, the US Patent and Trade Office has granted the patent application for the novel Surrogate Virus Neutralisation Technology (sVNT) used in cPass, allowing Duke-NUS and GenScript to file a patent for cPass™ in the US. Duke-NUS has also filed patent applications for the sVNT technology in China, Europe and Brazil.

As of late 2021, the cPass™ has built a global presence and is used in more than 50 countries, impacting vaccination strategies as well as deepening our understanding of long-term immunity. It is further being deployed in an ASEAN-wide serological follow-up study of vaccine efficacy, of which Prof Wang is a lead principal investigator.

Building on the cPass™, the team created an improved version of the sVNT that can simultaneously detect neutralising antibodies against different SARS-CoV-2 variants as well as other sarbecoviruses that have yet to emerge. Such testing plays a pivotal role in studies that require accurate side-by-side comparison of neutralising antibody levels against different viruses.

Using this multiplex sVNT, Prof Wang’s team also discovered that people who have recovered from the original SARS virus and are vaccinated against SARS-CoV-2 produce powerful antibodies that can neutralise a wide range of known and yet-to-emerge SARS-related beta-coronaviruses, or sarbecoviruses. Using this insight, the team is currently conducting proof-of-concept studies to develop a third-generation vaccine against different coronaviruses (3GCoVax)—which can also be called the pan-sarbecovirus vaccine—as well as an antibody therapy.

Duke-NUS’ research collaborations with other organisations have resulted in a new partnership with Arcturus Therapeutics, a US-based biotech firm, to develop a SARS-CoV-2 vaccine for Singapore. This partnership, led by Prof Ooi Eng Eong from our EID programme and Co-Director of the Viral Research and Experimental Medicine Centre (ViREMiCS) at the SingHealth Duke-NUS AMC, brought a vaccine candidate to clinical testing by leveraging a unique molecular platform developed at Duke-NUS that enables rapid screening of vaccines for safety and effectiveness, and Arcturus’ self-replicating mRNA STARR™ Technology in combination with their LUNAR® RNA medicine delivery technology.

Through the SingHealth Duke-NUS AMC, we have extensive clinical trialling capacity, and Singapore is an ideal site for such trials, given our multi-ethnic population. The clinical trials started at SingHealth’s Investigational Medicine Unit in Singapore in August 2020 and are ongoing.

Published in Nature in July 2020, Professor Antonio Bertoletti’s team at Duke-NUS, in close collaboration with the National University of Singapore (NUS) Yong Loo Lin School of Medicine, Singapore General Hospital (SGH) and National Centre for Infectious Diseases (NCID), showed that infection and exposure to coronaviruses induce long-lasting memory T cells, which could help in the management of the current pandemic and inform vaccine development.

His team further investigated the changes in virological and immunological parameters in patients with symptomatic acute SARS-CoV-2 infection from onset of the disease to recovery or death. Published in Cell Reports in February 2021, this work provided longitudinal evidence of how SARS-CoV-2-specific T cells play an important role in the rapid control of viral infection and eventual clearance of the disease.

The study of SARS-CoV-2 specific T cells was extended to individuals with asymptomatic SARS-CoV-2 infections. Collaborating with NUS’ Saw Swee Hock School of Public Health, the researchers found that people with asymptomatic infections produce a robust virus-specific T-cell response that, in combination with antibodies, protects them from developing severe COVID-19 disease.

The work, published in Journal of Experimental Medicine in March 2021, also found that while asymptomatic individuals and COVID-19 patients had similar amounts of T cells recognising different SARS-CoV-2 viral proteins, asymptomatic individuals produced higher quantities of the cytokines IFN gamma and IL-2, which are important for viral control.

Following close collaborations with Prof Wang Linfa and other clinical groups in Singapore, Prof Bertoletti’s group further showed that humoral and T-cell responses against SARS-CoV-2 are often independently induced and, thus, antibody measurements alone cannot gauge the level of antiviral immunity induced by vaccines or previous infection.

Working on this finding, Professor Bertoletti, his team and collaborators from the NCID and SGH developed a simple and rapid method to measure the T-cell immune response to SARS-CoV-2. The test—Cytokine Release Assay (CRA)—can reliably identify and quantify specific T cells present in the blood of people who have been vaccinated against or have recovered from SARS-CoV-2 infection.

To bring this discovery to the market, Duke-NUS has licensed the assay to Hyris, an innovation-based biotechnology company, which will leverage its Hyris System™ to further develop this rapid SARS-CoV-2 T-cell test for clinical use globally.

In the latest study by Prof Bertoletti, his team and scientists from University College London found that T cells that recognise a protein necessary in the early stages of SARS-CoV-2 replication, called polymerase protein, are present and expanded in individuals exposed to SARS-CoV-2. As the polymerase protein is synthesised early after infection, 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.

Continuing to advance knowledge and push limitations, Duke-NUS scientists invented a new saliva-based COVID-19 Antigen Rapid Test (ART) technology as part of a research collaboration with partners from Singapore General Hospital (SGH) and National Cancer Centre Singapore (NCCS)—collectively member institutes of the SingHealth Duke-NUS Academic Medical Centre—and the National University of Singapore (NUS). The technology has shown promise in early clinical testing, outperforming existing ARTs and delivering results in minutes, with nearly comparable sensitivity to the gold standard Polymerase Chain Reaction (PCR) test.

Dubbed the Parallel Amplified Saliva rapid POint-of-caRe Test (PASPORT), the technology employs a proprietary on-kit amplification technique to amplify the signal from a person’s saliva, allowing it to be used at any time of the day, regardless of whether an individual has just consumed food or drink – a limitation that makes other saliva-based ART kits less reliable in use. And, unlike available ARTs that use nasal swab samples, the PASPORT kit is more convenient to self-administer as required, such as at the point-of-care or prior to entry to large social events or facilities, to diagnose COVID infection. Like other ARTs, PASPORT produces results in approximately 15 minutes, but with sensitivity close to that of laboratory-based PCR tests and without the need for additional equipment or specially-trained personnel.

With the impending availability of oral antiviral drugs against SARS-CoV-2, COVID-19 could potentially be diagnosed and treated in the primary care setting in the future. A test that can be done on-site will enable doctors to diagnose COVID-19 accurately and prescribe the drugs appropriately. Moreover, with its anticipated low cost and ease of use as compared to PCR tests, PASPORT could aid Singapore and countries around the world in making early diagnosis of COVID-19 to initiate appropriate case management.

The research was published online on Monday, 6 December, 2021, in the journal Microchimica Acta as a feature article in their series, ‘From Bench to Hand’.

Other initiatives based in the EID programme include research by Professor Gavin Smith and Assistant Professor Yvonne Su on genetic changes in the SARS-CoV-2 virus and their potential implications for the course of the COVID-19 pandemic. On the therapeutic front, Associate Professor Ashley St John is partnering with Duke Associate Professor in Surgery Alexander Limkakeng on a clinical trial to test the effectiveness of a mast cell stabilising drug. Our Health Services and Systems Research (HSSR) programme is leading COVID-19-related research on multiple dimensions to inform current and future policy decisions, locally and even globally. Professor Marcus Ong, Director of HSSR, and his team, received close to S$1 million from the National Medical Research Council (NMRC) for a project that aims to minimise the impact of the pandemic on the Singapore health system. The team is working on a virtual outbreak model that can be further developed to simulate disease outbreak scenarios and help enhance our national response to future epidemics.

Other HSSR research efforts on different aspects of COVID-19 are being led by Professors Nicholas Graves, David Bruce Matchar, Ecosse Lamoureux, Eric Andrew Finkelstein and Tazeen Hasan Jafar, Associate Professors Angelique Chan and Liu Nan, as well as Assistant Professors Chetna Malhotra, John Pastor Ansah, Rahul Malhotra, Sean Lam, Semra Ozdemir, Sharon Cohan Sung and Yoon Sung Won. Read more on HSSR's research in this special report.

On the policy front, Professor John CW Lim, Director of our Centre for Regulatory Excellence (CoRE), is working with his colleagues in CoRE and the SingHealth Duke-NUS Global Health Institute (SDGHI) to provide advice, share knowledge, and facilitate collaborative discussions among international and national stakeholders to promote regulatory cooperation, including vaccine development and access.

The SingHealth Duke-NUS AMC is harnessing the collective strengths of Duke-NUS’ medical education and research capabilities, and SingHealth’s clinical expertise to fight the COVID-19 outbreak. Associate Professor Jenny Low, from Duke-NUS’ EID programme and Co-Director of ViREMiCS, is leading work on early-phase adaptive clinical trials of viral therapeutics and vaccine development, as well as the role of innate immune responses in modulating the outcome of infection or vaccination, which may help to improve therapeutic interventions for infectious diseases such as COVID-19.

Other experts working on COVID-19-related research from the SingHealth Duke-NUS AMC include Dr Indumathi Venkatachalam, Professor Leung Wing Hang, Professor Salvatore Albani, Dr Shirin Kalimuddin and Dr Yung Chee Fu.

In addition to these research efforts, Duke-NUS experts, including EID Programme Founding Director Professor Duane Gubler, Professor Gregory Gray, Assoc Prof St. John and Assistant Professor Ooi Yaw Shin, continue to contribute to public education and safety efforts by sharing their insights on coronaviruses with the media as well as tips on how people can stay safe during this pandemic.

In keeping with the imperative on safety, the Duke-NUS administration has embraced all measures put in place by the Singapore Government to ensure the safety of our students, faculty and staff with minimal disruptions to the School’s operations.