Scientists define immunity threshold for protection against COVID-19 in children

Duke-NUS and NUS Medicine scientists define immunity threshold for protection against COVID-19 in children
By Alice Chia, Senior media and content specialist

Credit: iStock.com / Sasiistock

As COVID-19 becomes endemic, an important group of people who continue to require vaccination is future birth cohorts of children. Yet, in the face of everchanging variants, as well as the waning of antibodies with time after each dose, key questions remain: What is the threshold of immune response against SARS-CoV-2 needed to protect against COVID-19 and how many doses of mRNA vaccination are required to reach that threshold?

“This study provides evidence for clinical practice guidelines worldwide for the vaccination of future birth cohorts of children against COVID-19. The evidence supports a two-dose vaccination regimen for children.”
Prof Ooi Eng Eong

Dr Zhong Youjia, a paediatrician based at the National University Hospital and PhD candidate at Duke-NUS, wanted to answer these key questions. This is especially given that development of vaccination policies for future birth cohorts of children is hindered by a lack of information on how long immune responses last, and uncertainty about which arms of the immune response confer protection against disease.

“I got the opportunity to study paediatric vaccine immunology when mRNA COVID-19 vaccines were being rolled out in children, marking the first time that children were receiving an mRNA-based vaccine. We were also able to incorporate all the tools that have been developed based on adult studies since the start of the pandemic, especially on campus in Duke-NUS itself,” said Zhong, who started the study in December 2021.

Working with her PhD supervisor, Professor Ooi Eng Eong from the Emerging Infectious Diseases Research Programme at Duke-NUS, and hospital colleagues Assistant Professor Elizabeth Tham and Professor Lynette Shek, who, like Zhong, are also with the Department of Paediatrics at the NUS Yong Loo Lin School of Medicine (NUS Medicine), the team enrolled 110 healthy children aged 5 to 12 to profile their immune responses to vaccinations, a booster and infection.

Dr Zhong Youjia // Credit: Sean Firoz, Duke-NUS

Prof Ooi Eng Eong // Credit: Duke-NUS

All participants received two doses of the Pfizer/BioNTech mRNA COVID-19 vaccine, 21 days apart. Of these children, 43 received a booster dose five months or later after completing the initial two doses. For one year, the participants periodically donated blood to test their immune response to the vaccine, measuring antibodies, memory B cells, which remember particular infections, and T cells, which destroy cells that have been infected by a virus.

Whenever children displayed symptoms suggesting a SARS-CoV-2 infection, parents were asked to administer an ART. A total of 76 children were confirmed to have developed SARS-CoV-2 infections during the study period.

By studying the children’s immune responses, the team was able to identify the minimum levels of antibodies, memory B cells and T cells needed to protect against symptomatic SARS-CoV-2 infection. These levels of memory B cells and T cells were attained with two doses of mRNA vaccines whereas the levels of neutralising antibodies needed to prevent infection could, in most children, only be attained with hybrid immunity (immunity from two doses of vaccine and one natural infection). In fact, even a third dose of vaccination did not help an individual attain such high levels of neutralising antibodies.

The scientists also confirmed that the levels of antibodies waned with time and their protective capacity decreased when challenged by different forms of the virus. But across the one-year follow up period of the study, memory B cells and T cell responses from two doses of vaccination remained stable with no signs of waning, and a third dose did not boost these responses. The team thus deduced that protection derived from two doses is lasting, and that a third and subsequent dose appear to confer no additional protection.

To explain the layered protection provided by the immune system against the invading virus, the team created an “onion model”, which encapsulates a paradigm shift: rather than just using antibody levels to infer protection from COVID-19, T-cell responses should be used instead.

When SARS-CoV-2 breaks through the first layer of neutralising and binding antibodies, T cells and memory B cells shield us from symptomatic and severe disease // Credit: NUS Yong Loo Lin School of Medicine

Zhong, who is also with Department of Paediatrics at NUS Medicine and the lead author of the study, said, “Just like how the air force, navy and army of a country’s defence forces work together to provide a layered protection against enemy forces, these three arms of the immune system also confer protection in layers—when an enemy like SARS-CoV-2 breaks through the first layer of neutralising antibodies due to viral mutations, T cells and memory B cells can equally protect against COVID-19. Importantly, T cells and memory B cells do not wane, and last for a long time.”

In this study, healthy children who received the third vaccine dose also experienced more side effects, such as fever and pain, than with the first two doses.

Ooi, the supervising scientist of the study, said, “This study provides evidence for clinical practice guidelines worldwide for the vaccination of future birth cohorts of children against COVID-19. The evidence supports a two-dose vaccination regimen for children.”

For Zhong, the study was particularly close to her heart: “I am a mother to one and expecting my second at the moment. As a mother, I am especially humbled by the willingness of many families and children who donated their time and bio samples to our work. It is of paramount importance that research for child health is conducted in the correct target population in order to be directly applicable. I applaud the heroic efforts of the children and families who took part in our study, and hope that more families will support the culture of paediatric research in Singapore.”

The study, which was published in Nature Medicine, also found comparable immune responses in children compared to healthy adults. These findings do not apply, however, to children or adults who are more vulnerable to severe COVID-19, such as older adults and those living with chronic diseases or are immunocompromised. For them, third and subsequent doses of vaccination would still be beneficial.

Next, Zhong and the team plan to investigate why some children develop better T-cell responses than others, since T-cell responses have been identified to be the most important predictor of protection. They hope to identify those children with poorer T-cell responses, and tailor vaccination regimes to their immune systems and improve the future design of mRNA vaccines.