T-Cell Mediated Immunity Following Sequential Heterologous Vaccination Regimens

Abstract

Sequential heterologous vaccination, in which a prime dose from one platform is followed by a boost from a different platform, moved from an emergency improvisation during the COVID-19 pandemic into standing public health guidance in several countries, and generated an unusually large, well-controlled body of human data on how platform-switching shapes T-cell mediated immunity. This short communication synthesizes findings from the Com-COV platform trials, independent European heterologous-schedule cohorts, the CombiVacS and COV-BOOST booster trials, and the T-cell epitope and variant-cross-reactivity literature underpinning them. Across these studies, heterologous regimens combining an adenoviral-vector prime with an mRNA boost, or an mRNA boost after single-dose Ad26.COV2.S priming, consistently induced spike-specific CD4+ and CD8+ T-cell responses that were comparable to or larger than those from homologous schedules, generally without a consistent tolerability penalty once the full regimen was considered. Mechanistic and variant-cross-reactivity data suggest this advantage reflects a broader, multi-epitope T-cell repertoire that is less vulnerable to spike mutations than the neutralizing-antibody response. We conclude that heterologous prime-boost vaccination is a well-evidenced strategy for eliciting robust cellular immunity, while noting that most available evidence covers only months-long follow-up and a limited set of platform combinations.