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

ABSTRACT: The rapid development of multiple COVID-19 vaccines, based on mRNA, recombinant adenoviral vectors and adjuvanted proteins, was critical to curtailing the global pandemic, and 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 a 11-month period collected between 2021 and 2022. Prime-boost NX vaccination (~3 weeks apart) elicited significantly stronger binding and neutralizing antibody responses than two AZ vaccine doses administered ~8 weeks apart. A NX booster administered 6–8 months later further increased the antibody titers that persisted for atleast 6 months. 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-a and IFN-g induction, respectively, demonstrating distinct innate immune mechanisms induced by each vaccine. Transcriptional signatures of plasmablast responses that predict the magnitude of antibody responses were significantly induced 7 days 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. Finally, a meta-analysis integrating immune responses induced by NX and AZ with those induced by the Pfizer-BioNTech mRNA vaccine demonstrated shared interferon-related signatures across all three platforms, while genes expression following mRNA vaccination was uniquely enriched in reactome pathways related to mRNA splicing, ubiquitination and proteasome processing, and class I mediated antigen presentation. Collectively, these data provide a comprehensive multiomic atlas of human immunity across three different COVID-19 vaccine platforms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320554 | GEO | 2026/08/13

REPOSITORIES: GEO

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Project description:Authorization of the Matrix-M-adjuvanted R21 vaccine by three countries and its subsequent endorsement by the World Health Organization (WHO) for malaria prevention in children is a milestone in the fight against malaria. Yet, to meet the unprecedented demand for malarial vaccines, there is a pressing need for additional adjuvants that induce robust and durable vaccine-induced immunity. Here, we performed a comparative assessment of three clinically relevant adjuvants (an alum formulation of the TLR7/8 agonist 3M-052 (3M-052+Alum), the TLR4 agonist GLA-LSQ (GLA in liposome QS-21 formulation), and Matrix-M, the currently approved adjuvant for R21) for their capacity to induce durable immune responses to the R21 malaria vaccine in non-human primates. Immunization of macaques with R21 adjuvanted with 3M-052+Alum on a 0, 8, and 24-week schedule elicited anti-circumsporozoite antibody responses comparable in magnitude to the R21/Matrix-M vaccine and persisted up to 72 weeks with a half-life of 337 (264 – 459) days. A booster dose at 72 weeks induced an antigen-specific recall response, similar to the R21/Matrix-M vaccination. In contrast, R21/GLA-LSQ immunization induced a considerably lower and short-lived response. Consistent with the durability of serum antibody responses, Matrix-M and 3M-052+Alum induced long-lived plasma cells in the bone marrow and other tissues, including the spleen, but GLA-LSQ stimulated only short-lived plasmablasts. Finally, we show distinct innate immune signatures early after vaccination with these adjuvants. While 3M-052+Alum stimulated potent and persistent antiviral transcriptional and cytokine signatures after primary and booster immunizations, Matrix-M induced an enhanced expression of interferon- and Th2-related signatures more highly after the booster vaccination. Collectively, these findings provide a comparative database on the immune responses of three clinically relevant adjuvants with R21 and highlight the promise of 3M-052+Alum as an additional adjuvant for the R21 malaria vaccine.

Project description:The COVID-19 pandemic has prompted vaccine development efforts on an unprecedented scale. Vaccines based on mRNA technology have emerged as particularly attractive due to their high efficacy and short development timelines. However, relatively little is known about the factors contributing to the development of protective immunity by this new class of vaccines. We employed a high-temporal-resolution transcriptome profiling approach to investigate responses to COVID-19 mRNA vaccination. A cohort of 23 subjects was recruited and changes in blood transcript abundance were measured daily for 9 days post-priming and post-booster vaccination via RNA sequencing. Antibody responses were measured on days 7 and 14 post-vaccination using a custom multiplex assay. Marked differences were observed between responses to the priming and booster doses, with the latter inducing widespread changes in blood transcript abundance consistent with those found in patients with acute viral respiratory infections. The delineation of interferon responses at a high-temporal frequency also suggested that the priming and booster doses elicited distinct types of responses that peaked on day 2 post-priming dose and day 1 post-booster dose. The booster dose also induced inflammation on day 1 and erythroid cell signatures as well as an atypical plasmablast signature on day 4. Notably, this plasmablast signature, together with the post-booster interferon response signature, correlated with the antibody response levels induced on day 14 after the booster dose. Taken together, this work provides a detailed map of the antibody and transcriptional responses to the first and second doses of a new class of vaccine and yields important insights into the mechanisms underlying their immunogenicity. Furthermore, our results suggest that implementing high-temporal-frequency immune profiling protocols may provide an opportunity to better resolve the immune responses elicited by the growing number of available COVID-19 vaccines.

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

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