Remarkable potency has been demonstrated for mRNA vaccines in reducing the global burden of the ongoing COVID-19 pandemic. This vaccine platform has been extended to encode an alphavirus replicase that self-amplifies the full length mRNA and SARS-CoV-2 spike (S) transgene (self-amplifying mRNA or sa mRNA). However, early phase clinical trials of sa-mRNA COVID-19 vaccine candidates have questioned the potential of this platform to develop potent vaccines. We examined the immune gene response to a candidate sa-mRNA vaccine against COVID-19, and compared our findings to the host response to other forms of vaccines. In blood samples from healthy volunteers that participated in a phase I/II clinical trial, greater induction of transcripts involved in Toll-like receptor (TLR) signalling, antigen presentation and complement activation at 1 day post-vaccination was associated with higher anti-S antibody titers. Conversely, transcripts involved in T-cell maturation at day 7 post-vaccination informed the magnitude of eventual anti-S T-cell responses. The transcriptomic signature for ARCT-021 vaccination strongly correlated with live viral vector vaccines, adjuvanted vaccines and BNT162b2. Correlation with live attenuated vaccines was weaker. Our findings suggest the potential for sa-mRNA to be further developed to be among the most potent forms of vaccines in our arsenal to prevent infectious diseases.