Systems vaccinology analysis of saRNA immunization identifies an acute innate immune signature correlated with adaptive immunity.

Self-amplifying ribonucleic acid (saRNA) vaccines are a next-generation RNA vaccine platform with great potential. Systems vaccinology provides a potent tool to interrogate vaccine-induced responses in volunteers and to dissect the mechanisms by which vaccines elicit a protective immune response or cause reactogenicity. In the current study, we performed transcriptomic analysis on blood samples collected from volunteers vaccinated as part of a phase I study of an saRNA vaccine expressing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen. We observed significant gene over-expression following both the prime and boost vaccinations. Over-expressed genes were predominantly associated with type I interferon signaling pathways and innate immune cell recruitment. This transcriptomic signature was reflected by an increase in cytokines in the plasma at the same time points and a significant increase in monocytes in the blood, both of which correlated with the antibody response to the vaccine. When individuals were segregated by the degree of reactogenicity, we also detected differences in gene expression related to immune responses. Overall, results show that saRNA induces a potent, acute inflammatory response with similarities to other RNA vaccines, and it will be important to further dissect the role of the over-expressed genes in immunogenicity and reactogenicity.