Vaccine study shows immune protection is separate from adjuvant-led side effects

Researchers in Japan have identified distinct immune pathways that govern vaccine efficacy and reactogenicity, challenging long-held assumptions and opening a route to more precise and better tolerated immunisation strategies

A study led by Professor Ken J. Ishii at the Institute of Medical Science, the University of Tokyo, Japan, has shown that the immune mechanisms responsible for vaccine protection can be biologically separated from those that drive adverse reactions, a finding that could reshape the design of future vaccines. 

Vaccines remain central to the prevention of infectious disease, yet their performance can often depend on adjuvants, substances which are added to enhance immune responses. These compounds increase vaccine efficacy but can also induce reactogenicity, such as injection site swelling or a fever.

For decades, the field has operated under the assumption that these beneficial and adverse effects arise from closely linked biological processes which has limited efforts to optimise one without compromising the other.

To address this constraint, the research team examined squalene-based adjuvants, which are widely used in contemporary vaccines owing to their strong immunostimulatory properties. Using mouse models alongside human immune cells, the investigators applied RNA sequencing and flow cytometry to characterise early immune activation following administration. The objective was to determine whether distinct signalling pathways underpin immunogenicity and reactogenicity.

The cytokine interleukin-1 beta (IL-1β) emerged as a central mediator of vaccine efficacy. Acting through CD11c-positive antigen-presenting cells, IL-1β activated signalling via the interleukin-1 receptor and the adaptor protein Myeloid differentiation primary response 88 (MyD88) which led to robust antibody production.

In contrast, local reactogenicity, including tissue swelling, was associated with interleukin-1 alpha (IL-1α), predominantly produced by eosinophils. Systemic effects such as fever were traced to a separate cascade in which IL-1β induced interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) activity.

“The most striking aspect of our findings was that vaccine efficacy and reactogenicity are regulated by entirely different immune mechanisms,” said Professor Ishii.

“This challenges the long-standing assumption that these responses are inseparable,” he said.

Further experiments established that these pathways depend on alpha-tocopherol, a component of certain squalene-based adjuvant formulations. Removal of alpha-tocopherol led to a marked reduction in both immune activation and reactogenicity, which confirmed its central role in initiating these responses. Comparable patterns in human immune cells have indicated that the findings may translate beyond experimental systems.

“Our study demonstrates that immunogenicity and reactogenicity of squalene-based adjuvants are regulated by different cell types and molecular pathways. This suggests potential cellular and cytokine targets for designing next-generation adjuvants that maintain immunogenicity while suppressing adverse effects,” said the authors.

In the short term, the ability to disentangle protective immunity from unwanted inflammatory responses could enable the design of vaccines that produce fewer adverse effects, which may improve patient tolerance and public confidence. In the near term, the work may support the development of more refined adjuvant systems capable of precise immune modulation, an attribute of particular importance in response to emerging infectious threats. Over the longer term, such advances could strengthen global vaccination strategies by improving both efficacy and safety profiles.

By demonstrating that vaccine protection and reactogenicity can arise from distinct biological pathways, the study has provided a framework to guide rational adjuvant design. This conceptual shift offers a credible route to maximise the benefits of vaccination while minimising associated risks.

For further reading please visit: 10.1038/s41541-026-01420-0