Rational Design of Cross-protective T cell Vaccines (360G-Wellcome-302473_Z_23_Z)

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'.