In a recent study published in the Proceedings of the National Academy of Sciences (PNAS) journal, researchers showed the significance of T cell-based immunity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants exhibiting evasion to antibody-centric immunity.
The first-generation coronavirus disease 2019 (COVID-19) vaccinations have been vital in diminishing severe SARS-CoV-2 infections and hospitalizations. Yet, repeating COVID-19 waves linked to the advent of SARS-CoV-2 mutants possessing immune-evasive traits have decreased vaccine efficacy. Thus, immunity established by first-generation SARS-CoV-2 vaccines might not impart efficient and long-lasting protection against COVID-19, possibly because of diminishing immunity or weak antibody cross-reactivity to novel viral variants.
On the other hand, T cells identify preserved nonmutable SARS-CoV-2 epitopes, and hence T cell-based vaccines might give broader protection against the viral mutants. Notably, a significant information gap in the search for widely protective COVID-19 vaccinations is the level to which vaccine-triggered systemic or mucosal memory T cells safeguard against antibody-elusive SARS-CoV-2 variants.
About the study
The present study evaluated whether lung-resident or systemic CD8 and CD4 T cells immunized against SARS-CoV-2 mutants with or without virus-neutralizing antibodies, using adjuvanted SARS-CoV-2 spike (S) protein-based vaccines that induce robust T cell responses.
The team used keratin 18-human angiotensin-converting enzyme 2 (K18-hACE2) transgenic mice and seven- to 12-week-old C57BL/6J (B6) mice for conducting the experiments. All vaccines were administered to anesthetized mice in saline with SARS-CoV-2 recombinant S Protein and adjuvants intranasally (IN) or subcutaneously to the tail base. Further, mice were immunized twice at a three-week interval. Single-cell suspensions of lungs and spleens were prepared and stained for cellular components. The authors conducted ex vivo cytokine analysis and flow cytometry on the processed tissues.
The viral strains used included the human CoV (hCoV)-19/South Africa/KRISP-EC-K005321/2020 (SA strain) and the SARS-CoV-2 United States of America (USA)-Washington (WA)1/2020 (WA strain). Mice were challenged with the viral strains to induce sublethal and lethal infections via the IN route. In addition, anti-CD8 and -CD4 antibodies were administered IN and intravenously to the animals to assess the protective immunity afforded by the CD8 and CD4 T cells.
On the whole, the study results showed that mucosal SARS-CoV-2 immunization using adjuvanted S protein-centered vaccines generated antibodies and tissue-resident memories (Trms) in airways, and parenteral vaccination evoked circulating memory CD8 and CD4 T cells and antibodies. The existence of systemic or mucosal T cell and humoral immunity efficiently safeguarded from the homologous SARS-CoV-2 WA strain. Further, immunity dependent on CD4 T cells and not CD8 was significant for protection against the WA sequence. Interestingly, although unhelped memory CD8 T cells expanded, they failed to safeguard against the WA strain in CD4 T cell-depleted mice.
Most notably, systemic or mucosal memory T cells, in combination with non-neutralizing antibodies, probably conferred efficient protective immunity to the SA SARS-CoV-2 B.1.351 (β) variant even without measurable virus-neutralizing antibodies in the serum or respiratory tract. Vaccine-evoked pulmonary memory CD8 and CD4 T cells perform nonredundant functions in establishing immunity against the SARS-CoV-2 B.1.351 variant, in contrast to the weaker role of vaccine-induced CD8 T cells in vaccine immunity to the WA strain.
The team depicted that systemic migratory memory T cells and TRMs could protect against COVID-19. Additionally, the authors discovered that both memory CD8 and CD4 T cells help protect against the SARS-CoV-2 B.1.351 variant, but the specific pathways were unclear.
Discussions and conclusions
According to the study findings, parenteral or mucosal adjuvanted COVID-19 S protein-centered vaccinations provided efficient SARS-CoV-2 control and protection against lung pathology in the presence or lack of neutralizing antibodies. The immunity induced by mucosal memory CD8 T cells was practically useless in the existence of antibodies successfully neutralizing the challenge virus. Further, the authors found that unhelped mucosal memory CD8 T cells did not protect from homologous SARS-CoV-2 without neutralizing antibodies and CD4 T cells.
Notably, the team discovered that without measurable virus-neutralizing antibodies, lung-resident or systemic CD4 and helped CD8 T cells conferred significant protection against the more antibody-resistant SARS-CoV-2 B1.351 variant in the absence of lung immunopathology. Induction of mucosal and systemic memory T cells targeted against conserved viral epitopes might thus be a viable technique for protecting against SARS-CoV-2 mutants resistant to neutralizing antibodies.
Taken together, the present research showed that adjuvanted SARS-CoV-2 S protein-based investigational vaccines evoked robust systemic or respiratory CD8 and CD4 T cell memory and immunized against COVID-19 without requiring virus-neutralizing antibodies.
As a result, the authors mentioned that the generation of T cell-based COVID-19 vaccines might be critical in protecting against SARS-CoV-2 mutants exhibiting antibody-escape characteristics that could circumvent immunity established by existing vaccinations. Indeed, the team stated that the current findings have important implications for establishing T cell-directed immunomodulation and widely protective COVID-19 vaccines.
- Kingstad-Bakke, B., Lee, W., Chandrasekar, S., Gasper, D., Salas-Quinchucua, C., Cleven, T., Sullivan, J., Talaat, A., Osorio, J. and Suresh, M., (2022). Vaccine-induced systemic and mucosal T cell immunity to SARS-CoV-2 viral variants. Proceedings of the National Academy of Sciences (PNAS). doi: https://doi.org/10.1073/pnas.2118312119 https://www.pnas.org/doi/suppl/10.1073/pnas.2118312119