A comparative multiomic atlas of human immunity to multiple COVID-19 vaccines

The development of multiple COVID-19 vaccines created a unique opportunity to compare human immunity to distinct vaccine platforms encoding the same antigen. Here, we present a longitudinal comparative analysis of innate and adaptive immune responses to the Matrix-M-adjuvanted Novavax (NX) and chimpanzee adenovirus-based AstraZeneca (AZ) vaccines in 161 healthy South African volunteers across three doses over an 11-month period. Prime-boost NX vaccination (~3 weeks apart) elicited stronger antibody responses than two AZ vaccine doses administered ~8 weeks apart. In a different cohort, an NX booster administered 6–10 months after the primary series elicited the highest antibody titers among the three study groups. Both vaccines stimulated innate antiviral and inflammatory gene expression signatures within two days of vaccination. However, the strongest responses were after AZ priming and NX boosting, coinciding with plasma IFN-α and IFN-γ induction, respectively, consistent with distinct patterns of innate immune activation induced by each vaccine when administered according to its clinically approved regimen. Transcriptional signatures of plasmablast responses were significantly induced after the second and booster but not primary NX vaccination, whereas these responses appeared after primary but not secondary AZ vaccination. Single-cell RNA sequencing revealed a multicellular origin of the innate transcriptional responses. A meta-analysis comparing immune responses induced by NX and AZ with those from a historical Pfizer-BioNTech mRNA vaccine cohort identified shared interferon-related signatures across all three cohorts and suggested pathways specific to each vaccine. Collectively, these data provide a comprehensive multiomic atlas of human immunity to three different COVID-19 vaccines.