IL-1 signaling central to mRNA vaccine fever uncoupled from antibody responses in mice
Can fever be reduced while preserving antibody responses?
A study suggests that fever caused by lipid nanoparticle (LNP)–mRNA vaccines can be partly separated from antibody responses. In mice, the researchers found that eliminating the IL-1 receptor suppressed post-vaccination fever while preserving antibody responses. In humans, they observed an association between IL-1-related markers and systemic adverse reactions, but did not test the effects of blocking IL-1. The study is a full research article published in the journal npj Vaccines in 2026.
LNPs are carriers that deliver mRNA into cells. The researchers varied the ionizable lipid component of the LNPs and assessed both immunogenicity—the ability to induce an immune response—and reactogenicity—the tendency to cause post-vaccination reactions such as fever.
Changing the lipid reduced fever and the decline in activity
The researchers gave young adult female mice two intramuscular injections of a COVID-19 spike mRNA vaccine, 21 days apart, and measured body temperature and activity. The comparator, SM-102 LNP, is an experimental formulation using the same lipid composition as the Moderna vaccine. Fever peaked about 4 hours after the second dose, and nighttime activity decreased.
After generating candidates with 23 lipids, the researchers evaluated the 20 with mRNA encapsulation efficiency above 80%. The Lipid 5 formulation caused less fever and a smaller reduction in activity than SM-102. Several immune measures, including antigen-binding IgG and germinal-center and memory B cells, were similar. However, at the same mRNA dose, SM-102 produced higher pseudovirus neutralizing antibody titers, and Lipid 5 also elicited a somewhat lower CD8 T-cell response. Reactogenicity remained lower with Lipid 5 when formulations were compared at doses that produced similar neutralizing antibody titers, but not all immune responses were maintained at the same level.
IL-1 was important for fever but did not fully explain the decline in activity
In experiments blocking inflammatory signals, an IL-1 receptor-blocking antibody most clearly suppressed fever. Blocking the IL-6 receptor or TNF-α also reduced fever, indicating that multiple inflammatory signals are involved. Mice lacking the IL-1 receptor showed no detectable rise in body temperature, while their antigen-specific B-cell, IgG, and neutralizing antibody responses were similar to those of normal mice. However, activity did not fully recover, indicating that factors beyond IL-1 also play a role. In the blocking-antibody experiments, the effect on activity recovery was limited.
The SM-102 formulation also strongly induced the release of HMGB1, a damage-associated signaling protein. In cell experiments, HMGB1 promoted TNF-α production by macrophages and monocytes. The researchers proposed that this pathway could amplify IL-1-related inflammation, but the full HMGB1→TNF-α→IL-1 pathway was not established in these experiments.
Human data showed an association, not the effect of blocking IL-1
The human analysis was an observational study that reanalyzed existing data from 90 Japanese people who had received three doses of BNT162b2. Levels of IL-1 receptor antagonist (IL-1RA) and two chemokines, CXCL9 and CXCL10, measured the day after the third dose, were significantly correlated with systemic adverse-reaction scores recorded over the 7 days after vaccination. Correlation coefficients for the three markers ranged from 0.42 to 0.47. IL-1RA is a regulator that inhibits IL-1 activity, and its concentration was not correlated with antibody measures such as neutralizing antibody titers. These findings do not provide causal evidence that blocking IL-1 in humans would preserve antibody responses.
The human data came from correlation analyses based on self-reported symptoms, and Lipid 5’s lower reactogenicity was not directly tested in people. The mouse experiments were limited to a single strain, sex, and antigen, and activity measurements alone cannot capture the range of symptoms experienced by people. The researchers stated that dose and long-term safety evaluations are needed before clinical application.
The study design and results can be found in the provided full paper and bibliographic and abstract record.
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 shows why vaccine development should measure both post-vaccination inflammatory reactions and the desired immune response. By assessing body temperature and activity alongside antibody and B-cell measures, and examining the role of IL-1 in receptor-deficient mice, the researchers provided experimental evidence that fever can be reduced while antibody responses are preserved. At the same time, Lipid 5 induced lower neutralizing antibody titers at the same dose and a somewhat lower CD8 T-cell response, showing that reduced reactogenicity alone cannot determine whether a formulation is better. Further development should assess dose-dependent immune responses, reactogenicity in people, durability of immunity, and long-term safety together. This study did not establish that protection against infection would be maintained or that using IL-1 inhibitors at vaccination would be beneficial.