Distinct Requirements for CD4⁺ T Cell Help for Immune Responses Induced by mRNA and Adenovirus-Vector SARS-CoV-2 Vaccines

CD4⁺ T cells have been established as central orchestrators of cellular and humoral immune responses to infection or vaccination. However, the need for CD4⁺ T cell help to generate primary CD8⁺ T cell responses is variable depending on the infectious agent or vaccine and yet consistently required for the recall of CD8⁺ T cell memory responses or antibody responses. Given the deployment of new vaccine platforms such as nucleoside-modified mRNA vaccines, we sought to elucidate the requirement for CD4⁺ T cell help in the induction of cellular and antibody responses to mRNA and adenovirus (Ad)-vectored vaccines against SARS-CoV-2. Using antibody-mediated depletion of CD4⁺ T cells in a mouse immunization model, we observed that CD4⁺ T cell help was dispensable for both primary and secondary CD8⁺ T cell responses to the BNT162b2 and mRNA-1273 mRNA vaccines but required for the AZD1222 Ad-vectored vaccine. Nonetheless, CD4⁺ T cell help was needed by both mRNA and Ad-vectored vaccine platforms for the generation of antibodies, demonstrating the centrality of CD4⁺ T cells in vaccine-induced protective immunity against SARS-CoV-2. Ultimately, this highlights the shared and distinct regulation of humoral and cellular responses induced by these vaccine platforms.