Why some vaccine side effects may be avoidable without compromising protection

Vaccines play a critical role in preventing infectious diseases, but their success often depends on adjuvants—substances that enhance immune responses. While these compounds improve vaccine effectiveness, they can also trigger reactogenicity, such as local swelling or fever. For decades, scientists have assumed that these beneficial and adverse effects are closely linked, making it difficult to improve one without affecting the other.

To address this challenge, the research was led by Professor Ken J. Ishii from the Department of Microbiology and Immunology at the Institute of Medical Science, The University of Tokyo, Japan, along with Dr. Yuya Yoshioka, a researcher at the Vaccine R&D Laboratory, Shionogi & Co., Ltd., Osaka, Japan. Their findings were made available online in the npj Vaccines on March 30, 2026.

In this study, the researchers focused on squalene-based adjuvants, which are widely used in modern vaccines and are known for their strong immune-boosting properties. Using mouse models and human immune cells, the team applied a combination of molecular and cellular techniques, including RNA sequencing and flow cytometry, to investigate how these adjuvants activate immune responses shortly after administration. Their goal was to determine whether the pathways driving vaccine protection and reactogenicity could be distinguished at a biological level.

The results revealed a clear separation between these processes. The researchers found that a signaling molecule called IL-1β plays a key role in enhancing vaccine efficacy. Acting through immune cells known as CD11c⁺ cells, IL-1β activates a pathway involving the IL-1 receptor and the adaptor protein MyD88, ultimately promoting strong antibody responses. In contrast, local reactogenicity, such as swelling, was linked to a different molecule, IL-1α, which is produced predominantly by eosinophils. Meanwhile, systemic reactions like fever were driven by a separate pathway involving IL-1β-induced activation of IL-6 and cyclooxygenase-2 (COX2).

"The most striking aspect of our findings was that vaccine efficacy and reactogenicity are regulated by entirely different immune mechanisms," explains Prof. Ishii. "This challenges the long-standing assumption that these responses are inseparable."

Further experiments confirmed that these pathways depend on α-tocopherol, a key component of certain squalene-based adjuvants. Removing this component significantly reduced both immune activation and reactogenicity, highlighting its central role in triggering these responses. Importantly, similar patterns were observed in human immune cells, suggesting that the findings are relevant across species and may translate to clinical settings.

The researchers emphasize that this distinction between immune pathways could be leveraged to improve vaccine design. "Our study demonstrates that immunogenicity and reactogenicity of squalene-based adjuvants are regulated by different cell types and molecular pathways," Dr. Yoshioka notes. "This suggests potential cellular and cytokine targets for designing next-generation adjuvants that maintain immunogenicity while suppressing adverse effects."

The implications of this work extend beyond basic immunology. In the short term, these findings could guide the development of vaccines with fewer reactogenicity, improving patient comfort and increasing public confidence in vaccination programs. In the near term, this research may support the creation of next-generation vaccines that are both highly effective and safer, which is particularly important in responding to emerging infectious diseases. In the longer term, such advances could play a key role in enhancing global vaccination strategies and public health outcomes.

By demonstrating that vaccine protection and reactogenicity can be biologically separated, this study represents an important step forward in vaccine science. It opens new avenues for designing more precise and safer immunization strategies, ultimately helping to maximize the benefits of vaccines while minimizing their risks.

This article was originally published on MedicalXpress Breaking News-and-Events.