T cells’ capability to fully prevent acute viral infections opens new avenues for vaccine development

• T cells can independently prevent acute viral infections to an extent previously thought only possible with neutralising antibodies.
• Findings challenge the longstanding reliance on neutralising antibodies for assessing viral immunity, and suggest that development of future vaccines must consider both antibody and T-cell responses for comprehensive protection.

 
Singapore, 10 January 2025—Scientists from Duke-NUS Medical School and the Singapore General Hospital have discovered that T cells—white blood cells that can destroy harmful pathogens—can completely prevent viral infection, to an extent previously thought only possible due to neutralising antibodies. Their findings, shown experimentally for the first time in human studies, reshape our understanding of how our immune system works, paving the way for the design of more effective vaccines.

Clusters of T cells, that are part of our immune system protecting us against harmful pathogens, under a microscope. By studying them, Duke-NUS scientists have found that T cells can independently control acute viral infections to an extent previously thought only possible with neutralising antibodies. // Image credit: Antonio Bertoletti, Duke-NUS Medical School

Traditionally, scientists have considered neutralising antibodies (proteins that prevent viruses from entering cells) as the ultimate form of protection against viral diseases. These antibodies bind to viruses to prevent them from infecting cells, such that clinical and lab investigations would find no trace of infection. Such a level of protection is referred to as sterilising immunity. But these latest findings, published in Nature Microbiology, challenge this view, demonstrating that T cells are also capable of controlling viral infection entirely to untraceable extents, even without any neutralising antibodies.

In the study involving 33 healthy adult volunteers aged 21 to 45, scientists employed a cross-vaccination approach by administering a live-attenuated yellow fever vaccine followed by a challenge 28 days later, with a weakened Japanese encephalitis virus, and vice versa. Yellow fever and Japanese encephalitis are genetically related viruses. The weakened strains were not capable of causing disease in the volunteers, but were sufficient to result in mild symptoms and measurable levels of virus in the blood, as well as an immune response necessary for protection. The study was conducted at the SingHealth Investigational Medicine Unit in Singapore from 30 March to 31 Oct 2023.

As the Japanese encephalitis vaccine was constructed using the backbone of the yellow fever vaccine, inoculation with either one of the vaccines generates T cells that are effective against both viruses, but stimulates production of neutralising antibodies that are ineffective against the virus used in the human challenge study. This allowed the scientists to assess how well the T-cells, independent of neutralising antibodies, were able to control the infection.

The results showed that T cells from yellow fever vaccination controlled the Japanese encephalitis vaccine virus challenge infection, reducing both viral loads and antibodies produced. Moreover, when present in high enough levels after vaccination, T cells controlled the challenge infection to undetectable levels in 15 per cent of study participants, to the point that no new antibodies were formed following infection.

Professor Ooi Eng Eong, from Duke-NUS’ Emerging Infectious Diseases Programme and lead author of the study said:

 “We found that T cells can serve as the first line of defence, not just a supportive element in protecting us from acute viral diseases. These findings challenge the current paradigm that antibodies are absolutely vital for protection against acute viral infection. Measuring antibodies alone without considering T cells could underestimate herd immunity—when sufficient numbers of individuals in a population are already protected against specific viruses either through vaccination or previous infections—which is one of the considerations in developing policies on vaccine dosage and frequency.”

Historically, vaccine development has prioritised generating elevated levels of antibodies. This approach may not only limit the efficacy of vaccines but could also hinder our ability to combat variants that escape antibodies but not T cells.

Assistant Professor Shirin Kalimuddin is a Senior Consultant with the Department of Infectious Diseases at the Singapore General Hospital and a faculty member of the Emerging Infectious Diseases Programme at Duke-NUS. The first author of the study said:

“We need to rethink how we design and develop vaccines. Vaccines that generate high levels of antibodies do not necessarily generate high levels of T cells. Development of vaccines must incorporate the viral components that T cells recognise and react against. Indeed, our findings may explain why some vaccines offer better protection against viruses when they are able to trigger a broader T cell response.”

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, added:

“The study findings encourage us to integrate both antibody and T-cell responses to create more effective and comprehensive vaccines. By understanding the unique roles T cells play, especially in viruses like yellow fever, dengue and Zika, all of which are from the same family and could pose a public health threat in Singapore due to Aedes mosquito transmission, we can develop vaccines that target a wider range of viral strains and mutations to control such untreatable diseases.”

Next, the scientists aim to study why certain individuals develop higher T-cell responses to vaccination than others.

Duke-NUS is a leader in medical education and a biomedical research powerhouse, combining basic scientific research with translational knowledge to better understand human biological systems, as well as develop new treatments and vaccines for common diseases affecting millions of people in Singapore and Asia.

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DOI: 10.1038/s41564-024-01903-7