Heterologous versus homologous boosting regimens elicit qualitatively distinct, BA.5 cross reactive T cells in transplant recipients

Abstract

Abstract The Omicron BA.5 subvariant of SARS-CoV-2 markedly escapes neutralizing antibodies induced by vaccination due to mutations in the Spike (S) protein. Solid organ transplant recipients (SOTRs) suffer high COVID-19 morbidity, yet show poor ancestral strain recognition after COVID-19 vaccination. CD8+ T cell responses may provide a crucial second line of defense. Therefore, it is critical to understand which vaccine regimens induce robust, conserved T cell responses. We evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4 and CD8 T cell responses in SOTRs following homologous mRNA (mRNA-1273 or BNT16b2) or heterologous Ad26.COV2.S (JNJ-78436735) boosting. Homologous boosting with three mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated significantly lower pseudo-neutralization against BA.5 compared to the ancestral strain. In contrast, S-specific T cells maintained cross-reactivity against BA.5 compared to ancestral recognition. Homologous boosting induced higher polyfunctional CD4 T cells with phenotypes associated with metabolic and immunologic activation. Comparing two mRNA platforms, mRNA-1273 induced significantly higher IL-21+ peripheral T follicular helper cells and increased antibody titers compared to BNT16b2. Heterologous boosting with Ad26.COV2.S did not increase CD8 responses compared to homologous boosting, as CD8 responses were low across all individuals. These data demonstrate that boosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants of concern in SOTRs, but currently available boosting strategies do not induce robust CD8 T cell responses. U01AI138897 U54CA260491