mRNA vaccine-induced T cells respond identically to SARS-CoV-2 variants of concern but differ in longevity and homing properties depending on prior infection status.

While mRNA vaccines are proving highly efficacious against SARS-CoV-2, it is important to determine how booster doses and prior infection influence the immune defense they elicit, and whether they protect against variants. Focusing on the T cell response, we conducted a longitudinal study of infection-naïve and COVID-19 convalescent donors before vaccination and after their first and second vaccine doses, using a high-parameter CyTOF analysis to phenotype their SARS-CoV-2-specific T cells. Vaccine-elicited spike-specific T cells responded similarly to stimulation by spike epitopes from the ancestral, B.1.1.7 and B.1.351 variant strains, both in terms of cell numbers and phenotypes. In infection-naïve individuals, the second dose boosted the quantity and altered the phenotypic properties of SARS-CoV-2-specific T cells, while in convalescents the second dose changed neither. Spike-specific T cells from convalescent vaccinees differed strikingly from those of infection-naïve vaccinees, with phenotypic features suggesting superior long-term persistence and ability to home to the respiratory tract including the nasopharynx. These results provide reassurance that vaccine-elicited T cells respond robustly to emerging viral variants, confirm that convalescents may not need a second vaccine dose, and suggest that vaccinated convalescents may have more persistent nasopharynx-homing SARS-CoV-2-specific T cells compared to their infection-naïve counterparts.

Vaccination is one of the best ways to prevent severe COVID-19. Two doses of mRNA vaccine protect against serious illness caused by the coronavirus SARS-CoV-2. They do this, in part, by encouraging the immune system to make specialised proteins known as antibodies that recognise the virus. Most of the vaccine research so far has focussed on these antibodies, but they are only one part of the immune response. Vaccines also activate immune cells called T cells. These cells have two main roles, coordinating the immune response and killing cells infected with viruses. It is likely that they play a key role in preventing severe COVID-19. There are many kinds of T cells, each with a different role. Currently, the identity and characteristics of the T cells that protect against COVID-19 is unclear. Different types of T cells have unique proteins on their surface. Examining these proteins can reveal details about how the T cells work, which part of the virus they recognise, and which part of the body they protect. A tool called cytometry by time of flight allows researchers to measure these proteins, one cell at a time. Using this technique, Neidleman, Luo et al. investigated T cells from 11 people before vaccination and after their first and second doses. Five people had never had COVID-19 before, and six had already recovered from COVID-19. Neidleman, Luo et al. found that the T cells recognizing SARS-CoV-2 in the two groups differed. In people who had never had COVID-19 before, the second dose of vaccine improved the quality and quantity of the T cells. The same was not true for people who had already recovered from COVID-19. However, although their T cells did not improve further after a second vaccine dose, they did show signs that they might offer more protection overall. The proteins on the cells suggest that they might last longer, and that they might specifically protect the nose, throat and lungs. Neidleman, Luo et al. also found that, for both groups, T cells activated by vaccination responded in the same way to different variants of the virus. This work highlights the importance of getting both vaccine doses for people who have never had COVID-19. It also suggests that vaccination in people who have had COVID-19 may generate better T cells. Larger studies could show whether these patterns remain true across the wider population. If so, it is possible that delivering vaccines to the nose or throat could boost immunity by mimicking natural infection. This might encourage T cells to make the surface proteins that allow them to home to these areas.

Protracted yet Coordinated Differentiation of Long-Lived SARS-CoV-2-Specific CD8+ T Cells during Convalescence.

CD8+ T cells can potentiate long-lived immunity against COVID-19. We screened longitudinally-sampled convalescent human donors against SARS-CoV-2 tetramers and identified a participant with an immunodominant response against residues 322 to 311 of nucleocapsid (Nuc322-331), a peptide conserved in all variants of concern reported to date. We conducted 38-parameter cytometry by time of flight on tetramer-identified Nuc322-331-specific CD8+ T cells and on CD4+ and CD8+ T cells recognizing the entire nucleocapsid and spike proteins, and took 32 serological measurements. We discovered a coordination of the Nuc322-331-specific CD8+ T response with both the CD4+ T cell and Ab pillars of adaptive immunity. Over the approximately six month period of convalescence monitored, we observed a slow and progressive decrease in the activation state and polyfunctionality of Nuc322-331-specific CD8+ T cells, accompanied by an increase in their lymph node-homing and homeostatic proliferation potential. These results suggest that following a typical case of mild COVID-19, SARS-CoV-2-specific CD8+ T cells not only persist but continuously differentiate in a coordinated fashion well into convalescence into a state characteristic of long-lived, self-renewing memory.

SARS-CoV-2-Specific T Cells Exhibit Phenotypic Features of Helper Function, Lack of Terminal Differentiation, and High Proliferation Potential.

Convalescing coronavirus disease 2019 (COVID-19) patients mount robust T cell responses against SARS-CoV-2, suggesting an important role of T cells in viral clearance. To date, the phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Using 38-parameter CyTOF, we phenotyped longitudinal specimens of SARS-CoV-2-specific CD4+ and CD8+ T cells from nine individuals who recovered from mild COVID-19. SARS-CoV-2-specific CD4+ T cells were exclusively Th1 cells and predominantly Tcm cells with phenotypic features of robust helper function. SARS-CoV-2-specific CD8+ T cells were predominantly Temra cells in a state of less terminal differentiation than most Temra cells. Subsets of SARS-CoV-2-specific T cells express CD127, can proliferate homeostatically, and can persist for over 2 months. Our results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection and support an important role of SARS-CoV-2-specific T cells in host control of COVID-19.