A third vaccination with a single T cell epitope protects against SARS-CoV-2 infection in the absence of neutralizing antibodies

Abstract

Understanding the mechanisms and impact of booster vaccinations can facilitate decisions on vaccination programmes. This study shows that three doses of the same synthetic peptide vaccine eliciting an exclusive CD8+ T cell response against one SARS-CoV-2 Spike epitope protected all mice against lethal SARS-CoV-2 infection in the K18-hACE2 transgenic mouse model in the absence of neutralizing antibodies, while only a second vaccination with this T cell vaccine was insufficient to provide protection. The third vaccine dose of the single T cell epitope peptide resulted in superior generation of effector-memory T cells in the circulation and tissue-resident memory T (TRM) cells, and these tertiary vaccine-specific CD8+ T cells were characterized by enhanced polyfunctional cytokine production. Moreover, fate mapping showed that a substantial fraction of the tertiary effector-memory CD8+ T cells developed from remigrated TRM cells. Thus, repeated booster vaccinations quantitatively and qualitatively improve the CD8+ T cell response leading to protection against otherwise lethal SARS-CoV-2 infection.SummaryA third dose with a single T cell epitope-vaccine promotes a strong increase in tissue-resident memory CD8+ T cells and fully protects against SARS-CoV-2 infection, while single B cell epitope-eliciting vaccines are unable to provide protection.

Disentangling the relative importance of T cell responses in COVID-19: leading actors or supporting cast?

“…A major issue with analysing the effect of T cells in breakthrough SARS-CoV-2 infection is that nAbs are likely to remain an important confounder. Studies of 'T cell-only' vaccines have the potential to isolate the effects of T cells, and have been conducted in mice and hamsters 19,[69][70][71] . In these animal models of high-dose infection, high levels of vaccine-induced CD8 + T cells (~3-10% of total CD8 + T cells in the spleen of mice when measured with tetramers 70 ) can be present at the time of challenge, and this led to reductions in viral levels (~2-30-fold) and protection from disease 70,71 .…”

“…Studies of 'T cell-only' vaccines have the potential to isolate the effects of T cells, and have been conducted in mice and hamsters 19,[69][70][71] . In these animal models of high-dose infection, high levels of vaccine-induced CD8 + T cells (~3-10% of total CD8 + T cells in the spleen of mice when measured with tetramers 70 ) can be present at the time of challenge, and this led to reductions in viral levels (~2-30-fold) and protection from disease 70,71 . High levels of T cells were also induced in the lungs after intranasal or intravenous administration of vaccines in mice 72 , which may have contributed to the protection observed.…”