Chemokine responses to mRNA vaccination reveal targets for novel genetic adjuvant strategies 3045

Description Despite advancements in vaccine technology that improve efficacy, many vaccines only confer short-lived immunity. Vaccine formulations can be improved using adjuvants that increase inflammation and elicit specific immune activation profiles. To identify immunological signatures of the immune response to COVID-19 mRNA vaccines that could be further potentiated using adjuvants, K18-hACE2 mice were administered dilutions of mRNA-1273 vaccine and antibody levels were tracked monthly after boosting. Six months post-boost, mice were subjected to SARS-CoV-2 challenge to determine minimum protective vaccine doses. Based on the determination of dose-specific protection profiles, corresponding innate immune signatures were further examined. Antibody production and protection correlated to increases in immune cells expressing interferon stimulated genes within the draining lymph nodes. High expression of proinflammatory chemokines CXCL10 and CXCL13 was observed in animals with high antibody titers. CXCL10 but not CXCL13 expression was lower in aged mice and correlated to decreased titers. To improve antibody responses to low doses of mRNA antigen, we co-administered diluted mRNA-1273 with known adjuvants or with LNPs containing Cxcl10 or Cxcl13 mRNA. The administration of Cxcl13-mRNA resulted in an increase in antigen-specific serum antibodies. Together, these data demonstrate that CXCL13 is a novel target for strategies that could improve the antibody responses to mRNA vaccines. Funding Sources Research supported by FHD’s NIH grant: 5R01AI153250-03 The WVU Flow Cytometry & Single Cell Core Facility is supported by the Institutional Development Awards (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant numbers P30GM121322 (TME CoBRE)