LNP‑mRNA vaccine adverse events markedly reduced by IL‑1 pathway blockade
Balance between vaccine efficacy and adverse events
mRNA vaccines demonstrate high efficacy but frequently cause adverse events such as fever and pain. Elucidating the precise mechanisms that drive these reactions has been a major challenge.
HMGB1‑IL‑1 pathway: the hidden driver of adverse events
The research team discovered in mouse models that LNP‑mRNA strongly induces HMGB1 release and multiple cytokines, particularly IL‑1. Blocking IL‑1 markedly reduced adverse events while preserving antibody generation.
Findings translate to humans: fever and antibodies are dissociated signals
In a clinical cohort, activation of the IL‑1 pathway correlated strongly with fever severity but did not affect neutralizing antibody levels. This indicates that adverse events can be suppressed without compromising immune protection.
Next‑generation vaccines: efficacy without adverse events
Future development may focus on IL‑1 inhibitors or refined LNP designs to minimize adverse events in mRNA vaccines. Such approaches could be the key to safer large‑scale immunization campaigns.
Lipid nanoparticle (LNP)-mRNA vaccines robustly activate immune responses, contributing to their high efficacy and frequent adverse reactions (ARs). Here, we identified an LNP-mRNA formulation with a more favorable balanced immunogenicity-reactogenicity profile. Immune profiling in a mouse model defined the reactogenic LNP-mRNA vaccine as a potent inducer of HMGB1 release, pro-inflammatory cytokine production, and concurrent neutrophil infiltration. HMGB1 induced TNF-α secretion from monocyte subsets, yet in vivo blockade studies revealed the contribution of multiple cytokines (TNF-α, IL-1, and IL-6) to reactogenicity. Among the reactogenic cytokines, IL-1 was identified as the key mediator of vaccine-induced ARs, but was dispensable for humoral immunity. The clinical relevance was confirmed in a well-controlled vaccine cohort where IL-1 pathway activation correlated with fever severity but not with neutralizing antibody titers. We dissected early innate pathways specifically linked to vaccine reactogenicity, providing a rationale for selectively reducing ARs in next-generation vaccines.
This study identified the specific immune pathway that mediates post‑vaccination adverse events such as fever. Demonstrating that adverse events can be reduced while maintaining protective immunity means that individuals can receive vaccines with greater confidence and safety.