Comparative analysis of adenovirus, mRNA, and protein vaccines reveals context-dependent immunogenicity and efficacy

Despite the widespread use of adenovirus, mRNA, and protein-based vaccines during the COVID-19 pandemic, their relative immunological profiles and protective efficacies remain incompletely defined. Here, we compared antigen kinetics, innate and adaptive immune responses, and protective efficacy following Ad5, mRNA, and protein vaccination in mice. Ad5 induced the most sustained antigen expression, but mRNA induced the most potent IFN responses, associated with robust antigen presentation and costimulation. Unlike Ad5 vaccines, which were hindered by preexisting vector immunity, mRNA vaccines retained efficacy after repeated use. As a single-dose regimen, Ad5 vaccines elicited higher immune responses. However, as a prime-boost regimen, and particularly in Ad5 seropositive mice, mRNA vaccines were more immunogenic than the other vaccine platforms. These findings highlight strengths of each vaccine platform and underscore the importance of host serostatus in determining optimal vaccine performance.