The Innate Immune Setpoint in Infection and Vaccination: Balancing Protection, Reactogenicity, and Immunopathology

Innate immunity sits at the center of both protective host defense and immune-mediated harm. During natural infection, innate sensing pathways initiate rapid inflammatory programs that can limit pathogen replication, shape tissue containment, and guide durable T and B cell memory. Yet the same signals can cause collateral damage and severe disease when they are excessive, prolonged, mistimed, or occur in sensitive anatomical sites. In parallel, vaccines must engage innate immunity to generate robust immunity, while keeping expected short-term side effects and rare adverse events within acceptable safety limits. This creates a core tension: vaccines often aim to mimic key features of infection without fully replicating infection-associated pathology.This Research Topic focuses on the idea of an “innate immune setpoint”—a Goldilocks window of magnitude, timing, duration, and tissue context of innate activation that best balances protection, reactogenicity, and immunopathology across infection and vaccination. Here, protection is defined broadly to include reduced susceptibility to infection, lower pathogen burden, prevention of severe disease, improved clinical outcomes, and (where relevant) reduced transmission and improved durability of immune memory. Reactogenicity refers to predictable, transient inflammatory responses following vaccination (local and systemic symptoms such as pain, fever, fatigue) and associated short-lived biomarker changes. Immunopathology refers to harmful immune-mediated tissue injury and dysregulated inflammation during infection or after immunization, including exaggerated cytokine responses and organ-specific damage, and may encompass mechanistic studies relevant to rare vaccine-associated inflammatory syndromes when evidence supports immune causality.We welcome mechanistic, systems, translational, and clinical studies that define which innate pathways and signatures promote effective priming and memory, how vaccine platforms and adjuvants tune these responses, and how host factors and immune history shift what “optimal” looks like. Submissions that connect innate signatures to functional outcomes—protection, pathology, transmission, and durability—are especially encouraged, including work that explicitly distinguishes correlates of protection from correlates of reactogenicity or immunopathology.We welcome articles addressing, but not limited to, the following themes:-Comparative innate immune programs in natural infection versus vaccination, and what “useful mimicry” means in practice.-PRRs and downstream pathways (e.g., TLRs, RIG-I–like receptors, cGAS–STING, -NLRs/inflammasomes) that shape adaptive immunity and protective outcomes.-Defining the Goldilocks window: dose, kinetics, and duration of innate activation linked to protection versus tissue injury and clinical severity.-Reactogenicity vs immunogenicity: when inflammation predicts better immunity, when it is neutral, and when it signals avoidable harm.-How vaccine platforms and formulations tune innate signatures (mRNA/LNP, viral vectors, protein + adjuvant, nanoparticles, live-attenuated).-Mucosal versus systemic innate immunity, tissue-specific programs, and implications for sterilizing immunity and transmission blocking.-Systems immunology approaches (omics, single-cell, spatial, computational) that identify predictive innate signatures and mechanisms.-Biomarkers and correlates: frameworks to separate correlates of protection from correlates of reactogenicity or immunopathology, and to link signatures to clinical endpoints.-Host heterogeneity and immune history (age, sex, comorbidities, microbiome, prior infection/vaccination, imprinting, trained immunity) as setpoint shifters.-Translational modulation of innate immunity to boost weak responses or reduce pathology (timing, targets, and safety considerations).Topic Editor Roland Zahn is employed by Johnson & Johnson and is founder of the private company Vidamune. Dr. Zahn holds multiple patents in the field of vaccines. All other Topic Editors declare no competing interests with regards to the Research Topic subject. Topic editors: DeGaulle I. Chigbu, Roland Zahn, Juliana Melgaço Source: https://www.frontiersin.org/research-topics/77994/the-innate-immune-setpoint-in-infection-and-vaccination-balancing-protection-reactogenicity-and-immunopathology