Heterologous versus homologous boosting elicits qualitatively distinct, BA.5–crossreactive T cells in transplant recipients

BACKGROUND. The SARS-CoV-2 Omicron BA.5 subvariant escapes vaccination-induced neutralizing antibodies because of mutations in the spike (S) protein. Solid organ transplant recipients (SOTRs) develop high COVID-19 morbidity and poor Omicron variant recognition after COVID-19 vaccination. T cell responses may provide a second line of defense. Therefore, understanding which vaccine regimens induce robust, conserved T cell responses is critical. METHODS. We evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4⁺ and CD8⁺ T cell responses from SOTRs in a national, prospective, observational trial (n = 75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or 2 doses of mRNA followed by Ad26.COV2.S (heterologous boosting). RESULTS. Homologous boosting with 3 mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated lower pseudo-neutralization against BA.5 compared with the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared with ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4⁺ T cell responses, with polyfunctional IL-21⁺ peripheral T follicular helper cells increased in mRNA-1273 compared with BNT162b2. IL-21⁺ cells correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8⁺ responses compared to homologous boosting. CONCLUSION. Boosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants in SOTRs, but alternative vaccine strategies are required to induce robust CD8⁺ T cell responses.