AS03-Adjuvanted H5N1 Avian Influenza Vaccine Modulates Early Innate Immune Signatures in Human Peripheral Blood Mononuclear Cells

Abstract

Background. Adjuvant System 03 (AS03) markedly enhances responses to influenza A/H5N1 vaccines, but the mechanisms of this enhancement are incompletely understood. Methods. Using ribonucleic acid sequencing on peripheral blood mononuclear cells (PBMCs) from AS03-adjuvanted and unadjuvanted inactivated H5N1 vaccine recipients, we identified differentially expressed genes, enriched pathways, and genes that correlated with serologic responses. We compared bulk PBMC findings with our previously published assessments of flow-sorted immune cell types. Results. AS03-adjuvanted vaccine induced the strongest differential signals on day 1 postvaccination, activating multiple innate immune pathways including interferon and JAK-STAT signaling, Fcγ receptor (FcγR)-mediated phagocytosis, and antigen processing and presentation. Changes in signal transduction and immunoglobulin genes predicted peak hemagglutinin inhibition (HAI) titers. Compared with individual immune cell types, activated PBMC genes and pathways were most similar to innate immune cells. However, several pathways were unique to PBMCs, and several pathways identified in individual cell types were absent in PBMCs. Conclusions. Transcriptomic analysis of PBMCs after AS03-adjuvanted H5N1 vaccination revealed early activation of innate immune signaling, including a 5-to 8-fold upregulation of FcγR1A/1B/1C genes. Several early gene responses were correlated with HAI titer, indicating links with the adaptive immune response. Although PBMCs and cell-specific results shared key innate immune signals, unique signals were identified by both approaches.

Phase 2 Randomized Trial of an AS03 Adjuvanted Plant-Based Virus-Like Particle Vaccine for Covid-19 in Healthy Adults, Older Adults and Adults with Comorbidities

“…Although only the 3.75 µg dose level of CoVLP was used in the Phase study, data from the Phase 1 trial that included groups given unadjuvanted CoVLP at three dose levels (3.75, 7.5 and 15µg/dose) showed that local and systemic reactogenicity was higher in adjuvanted groups as compared to non-adjuvanted groups, as would be expected from its use with other antigens 25,33,34 . As expected 26 and has been observed for mRNA, adenovirus vector, inactivated virus, and recombinant protein-based COVID-19 vaccines [35][36][37][38][39][40][41][42] reduced reactogenicity was observed in the older adults. The safety profile in the Older Adults was consistent with the safety profile in the Adult population no new safety concerns were reported relative to our phase 1 study, suggesting that CoVLP+AS03 is well-tolerated in healthy individuals 18 years of age and older.…”

Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses

“…Three other genes correlated with antibody responses at this timepoint and are known to be induced by IFN-γ signaling: STAT1 (transcription factor for interferon inducible genes), IFIT1 and IFIT2 (proteins that inhibit expression of viral messenger RNA [32]). STAT1 also predicts delayed antibody responses in other vaccine studies [33,34].…”

Transcriptomic and Metabolic Responses to a Live-Attenuated Francisella tularensis Vaccine

“…A critical question for the field of vaccinology is whether metabolite profiles can predict the downstream cellular and/or adaptive responses that are fundamental to immunological protection against pathogens. Here, we employed elastic net regularized linear regression, which was successfully applied to similar contexts [ 7 , 8 ], to test metabolites as predictors of antibody response (peak tularemia-specific microagglutination titer) or peak CD4+ and CD8+ T cell activation. The input set included log 2 -fold changes for all metabolites that were in the final analysis dataset (3741 C18 and 6562 for HILIC).…”

“…The application of high-throughput technologies to assess cell-wide changes in gene expression, protein abundance, small molecules, and lipids opens a new opportunity to better understand the mechanisms of vaccines and human immune responses [ 3 , 4 , 5 , 6 , 7 , 8 ]. For example, transcriptomics studies to assess changes in gene expression in PBMCs or individual cell types revealed detailed information on immune signaling pathway activation following vaccination against H5N1 influenza when given with AS03 vaccine adjuvant and identified early markers that correlated with later protection [ 7 , 8 ]. Metabolomics measures global metabolite profiles, reflecting both cellular metabolism and systemic metabolite signals [ 9 , 10 ] and similarly promises to reveal biomarkers that correlate with vaccine protection or other phenotypes of interest.…”