Conserved CD4 T-cell responses correlate with antibody neutralization in solid organ transplant recipients after bivalent SARS-CoV-2 vaccination.

Introduction: Vaccines against SARS-CoV-2 and influenza require reformulation due to viral evolution. It remains unclear how vaccination against evolving antigens influences T-cell responses and the impact of reformulation on T-cell responses to new variants in immunocompromised hosts. Solid organ transplant recipients (SOTRs) had significantly lower antibody levels following vaccination and required repeated boosting during the COVID-19 pandemic. Methods: With the introduction of the Omicron spike (S) to the bivalent mRNA vaccines in 2022, the relative contribution of T-cell responses cross-reactive for Omicron mutated S sequences was assessed via intracellular cytokine staining using peptide pools containing conserved or mutated S sequences. Results: S-specific CD4 T cells recognize both conserved and Omicron mutated S sequences pre- and post-bivalent vaccination, even in the absence of evidence of prior infection as detected by T-cell responses to a novel peptide pool. CD4 T-cell responses to both conserved and Omicron mutated sequences correlated with antibody pseudo-neutralization of BA.5 S. Importantly, pre-bivalent conserved S CD4 T-cell responses significantly correlated with antibody pseudo-neutralization of BA.5 S post-bivalent. Discussion: These results emphasize the importance of conserved and cross-reactive responses in vaccine immunogenicity, providing a mechanism through which repeated boosting enhances vaccine immunogenicity in SOTRs and other immunocompromised populations.