Scientists have found that T cells, which are a type of white blood cell that can eliminate harmful pathogens, can entirely stop viral infections in ways that were previously thought to be possible only with neutralizing antibodies. This discovery alters our perception of the immune system and opens up new possibilities for creating more effective vaccines.
Researchers from Duke-NUS Medical School and Singapore General Hospital have revealed that T cells — white blood cells capable of eradicating harmful pathogens — can fully prevent viral infections, a capability once believed to be exclusive to neutralizing antibodies. This groundbreaking research, reported for the first time in human trials, changes our understanding of immune system functionality and lays the groundwork for better vaccine development.
Historically, scientists viewed neutralizing antibodies (proteins that block viruses from entering cells) as the most effective defense against viral diseases. These antibodies attach to viruses, preventing them from infecting cells, which led to findings of no infection during clinical and laboratory assessments. This kind of protection is known as sterilizing immunity. However, the new findings, published in Nature Microbiology, contest this notion by demonstrating that T cells can also completely control viral infections to undetectable levels without relying on neutralizing antibodies.
In a study involving 33 healthy adults aged 21 to 45, researchers utilized a cross-vaccination technique. Participants received a live-attenuated yellow fever vaccine and were later exposed to a weakened Japanese encephalitis virus 28 days later, and vice versa. Both yellow fever and Japanese encephalitis are related viruses. The weakened strains used in the study couldn’t cause disease in participants but were sufficient enough to induce mild symptoms and measurable viral presence in the blood, alongside the immune response required for protection. The research took place at the SingHealth Investigational Medicine Unit in Singapore from March 30 to October 31, 2023.
Since the Japanese encephalitis vaccine was developed using the yellow fever vaccine’s backbone, immunization with either vaccine leads to the generation of T cells effective against both viruses, although the neutralizing antibodies produced were ineffective against the virus used in the challenge study. This setup allowed scientists to measure how effectively T cells could manage infections independent of the neutralizing antibodies.
The results indicated that T cells activated by the yellow fever vaccine effectively controlled the Japanese encephalitis challenge infection by lowering both viral levels and the amount of antibodies produced. Additionally, when T cells were present in sufficient quantities post-vaccination, they could eliminate the challenge infection to levels that were undetectable in 15 percent of the participants, with no new antibodies generated following the infection.
Lead author Professor Ooi Eng Eong from Duke-NUS’ Emerging Infectious Diseases Programme remarked:
“We discovered that T cells act as the primary defense mechanism rather than merely a supportive role in protecting against acute viral diseases. These insights challenge the existing belief that antibodies are essential for protection against acute viral infections. Focusing solely on antibodies while neglecting T cells could undervalue herd immunity — when a sufficient number of individuals in a population are already protected against specific viruses either through previous infections or vaccination — influencing vaccine policy regarding dose and frequency.”
Traditionally, vaccine development has focused on generating high levels of antibodies. This strategy may not only limit vaccine effectiveness but also impede our ability to respond to variants that can bypass antibodies while remaining vulnerable to T cells.
Assistant Professor Shirin Kalimuddin, a Senior Consultant in the Department of Infectious Diseases at Singapore General Hospital and a faculty member of the Emerging Infectious Diseases Programme at Duke-NUS, emphasized:
“We need to rethink our vaccine design and development approach. Just because vaccines induce high antibody levels does not mean they will also produce high T-cell levels. Vaccine development should incorporate viral components that elicit T cell recognition and response. Our findings might clarify why certain vaccines provide better protection against viruses when they trigger a broader T cell response.”
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, added:
“The results of this study encourage the integration of both antibody and T cell responses to create more effective and comprehensive vaccines. By recognizing the unique functions of T cells, especially regarding viruses like yellow fever, dengue, and Zika, all of which are related and pose public health risks in Singapore due to Aedes mosquito transmission, we can develop vaccines that target a broader array of viral strains and mutations to combat these untreatable diseases.”
Going forward, the researchers plan to investigate why some individuals exhibit stronger T-cell responses to vaccination than others.
Duke-NUS stands at the forefront of medical education and biomedical research, merging fundamental scientific studies with translational knowledge to enhance understanding of human biological systems and to develop new treatments and vaccines for common diseases affecting millions in Singapore and across Asia.
