Active Infection & Immunity Cancer

Rational Design of Cross-protective T cell Vaccines

Funder Wellcome Charity-funded
Recipient organisation University College London
Funding £2.3M
Period Jul 2024 — Jul 2032

In plain English

AI plain-English summary

T-cells that target a specific viral protein complex can block coronavirus infection before it takes hold—even without antibodies. This discovery, made by the grant holder in 2022, overturns the long-held immunological assumption that T-cells alone cannot prevent infection. The problem is that variable viruses like coronaviruses and influenza mutate rapidly, making antibody-based vaccines a moving target. Current vaccines must be updated constantly. This research aims to identify the precise viral fragments—epitopes—within the coronavirus replication-transcription complex that trigger cross-protective T-cells. By combining viral sequence analysis, T-cell receptor profiling, and functional testing, the team will uncover the fundamental rules governing T-cell cross-reactivity across viral strains and even across species. If successful, this work could enable the rational design of pan-coronavirus vaccines that induce infection-blocking T-cell immunity without requiring annual reformulation. The same principles might extend to other rapidly mutating viruses, such as influenza or HIV. This is fundamental science with a clear translational pathway: understanding the molecular basis of T-cell cross-reactivity could shift vaccine design from reactive strain-matching to proactive, broad-spectrum protection.

View original technical description
Keywords: Vaccines, T-cells, Immunology, Virology, Cross-reactivity, Coronavirus, Machine Learning, Proactive Vaccinology, T-cell Receptor. The fundamental problem when designing vaccines for variable viruses is how to induce immunity that can recognise and protect against the breadth of globally circulating viral strains. T-cells have an inherent ability to cross-recognise a wide range of viral sequences because they recognise short linear peptides, in particular within essential conserved non-structural proteins. Challenging the immunological paradigm that T-cells alone cannot block infection, I recently demonstrated that pre-existing T-cells targeting the most conserved proteins across the coronavirus family, the replication-transcription complex (RTC), correlate with protection from detectable SARS-CoV-2 infection in exposed seronegative individuals (Swadling.Nature.2022). This suggests cross- species protection from infection by T-cells alone and that specificity is linked to protective efficacy. It is essential now to identify precisely which epitopes within the RTC are mediating this cross-protection so that we can: 1) integrate analysis of the viral sequence, TCR repertoire, and functional cross-reactivity at these epitopes to elucidate the fundamental rules underpinning T-cell cross-reactivity; 2) use these epitopes in pan-coronavirus vaccines. Ultimately, I will test the hypothesis that 'rational design of vaccines to induce cross-protective T-cell immunity will lead to effective infection blocking vaccines for variable viruses'.

View the original record at the funder ↗

Researchers

Leo Swadling (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Identifying new T-cell targets for SARS-CoV-2 and pan-coronavirus vaccination
Determinants of T-cell cross-immunity in human and animal viruses
Human antigen-specific T cell responses in viral control and immunopathology
Targeting Coronaviruses through Fc-dependent Antibody Activities
Defining high-resolution T-cell correlates of protection in abortive versus seropositive SARS-CoV-2 infection

Original classification

Career Development Award

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