A systems biology approach to identifying mechanisms underlying enhanced reactogenicity after mRNA-based vaccination

Abstract Significance to the VA: Vaccine hesitancy toward COVID-19 mRNA vaccines remains a significant challenge. Identifying ways to reduce hesitancy is a key objective of these studies. Reactogenicity refers to adverse events (AEs) that occur shortly after vaccination as a physical manifestation of the inflammatory response. Understanding which reactogenic mechanisms are most closely linked to enhanced immunogenicity is crucial for designing interventions that mitigate negatively perceived side eKects without compromising the protective immune response. The veteran population includes a high proportion of older, multimorbid individuals who are particularly susceptible to severe morbidity and mortality from SARS-CoV-2 and RSV, both of which have approved mRNA vaccines, and influenza, for which an mRNA vaccine is anticipated soon. As the use of mRNA vaccine platforms increases, eKorts to facilitate their acceptance and utilization are essential for veteran health. Innovation and Impact: To our knowledge, no NIH-supported studies are investigating mRNA vaccine reactogenicity using systems biology approaches, particularly in VA priority cohorts, as indicated by NIH RePORTER and ClinicalTrials.gov. No comprehensive systems biology studies have focused on identifying specific pathways and molecules associated with AEs from mRNA vaccines. This innovative approach can help VA providers explain vaccine use and AEs, increasing uptake. Additionally, our findings could inform strategies to reduce AEs while maintaining protective immune responses. Specific Aims: Aim 1: Determine the mechanisms underlying reactogenicity by assessing local and systemic AEs following mRNA COVID-19 vaccination. Hypothesis: The development of AEs is associated with interferome and inflammasome pathway activation, leading to increased inflammatory cytokine and chemokine levels and enhanced immune activation. Additionally, pre-existing metabolic pathway perturbations may exacerbate AEs and serve as potential therapeutic targets. Aim 2: Identify mechanisms specific to reactogenicity versus protective immune response or those common to both. Hypothesis: Some mechanisms linked to severe AEs are also associated with stronger vaccine-induced immune responses. Aim 3: Model the impact of age and sex on mRNA COVID-19 vaccine-induced reactogenicity and immune response. Hypothesis: Older individuals, due to higher baseline inflammatory signatures, exhibit altered AE development and vaccine-specific immune responses following mRNA vaccination. Methodology: Veterans and, if necessary, some non-veterans will be enrolled to meet study targets. Participants will receive standard-of-care Pfizer or Moderna mRNA COVID-19 vaccines. Reactogenicity will be assessed clinically, and blood samples will be analyzed for cellular and transcriptomic changes, as well as vaccine-specific immune responses. Comprehensive systems biology analysis will compare individuals with high versus low AEs. Path to Translation/Implementation: Vaccine education interventions enhance trust in CDC recommendations and address concerns about rapid vaccine development and side eKects. Understanding the mechanisms driving reactogenicity will provide essential information to health care providers for patient education. Additionally, our findings may inform therapies or vaccine modifications to reduce AEs while preserving immune protection. Project Number: 1I01RD001550-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: DAVID CANADAY | Institution: LOUIS STOKES CLEVELAND VA MEDICAL CENTER, CLEVELAND, OH | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 INFA-G (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11300093