University of Tokyo's Groundbreaking Study on Vaccine Adjuvants
In a significant advancement for vaccine development, researchers at the Institute of Medical Science (IMSUT) at the University of Tokyo have elucidated the distinct mechanisms by which vaccine adjuvants stimulate protective immunity while also triggering adverse reactions. This discovery challenges decades-old assumptions and paves the way for safer, more effective vaccines.
The study, published in npj Vaccines on March 30, 2026, highlights how squalene-based adjuvants—commonly used in influenza and pandemic vaccines—activate separate immune pathways. Led by Professor Ken J. Ishii of the Division of Vaccine Science and Dr. Yuya Yoshioka from Shionogi & Co., Ltd., the research demonstrates that protective antibody responses and side effects like swelling or fever are regulated independently at the cellular and molecular levels.
What Are Vaccine Adjuvants and Why Do They Matter?
Vaccine adjuvants are substances added to vaccines to boost the body's immune response to the antigen, the part mimicking the pathogen. The term 'adjuvant' derives from the Latin 'adjuvare,' meaning 'to help.' Without adjuvants, many vaccines would require higher antigen doses or multiple boosters, making them less practical for widespread use.
Historically, aluminum salts (alum) have been the most common adjuvant since the 1920s, but modern vaccines increasingly use oil-in-water emulsions like squalene-based MF59 (in Fluad for seniors) and AS03 (used in H1N1 pandemic vaccines). Squalene, a natural lipid from shark liver or plants, forms stable nanoemulsions that mimic pathogen structures, alerting the innate immune system.
In Japan, where vaccine research thrives amid a focus on public health post-COVID-19, adjuvants are crucial for next-generation vaccines against emerging threats like avian flu or antimicrobial-resistant bacteria. The University of Tokyo's IMSUT has been at the forefront, developing adjuvant databases and novel formulations.
The Challenge of Reactogenicity in Vaccines
Reactogenicity refers to expected side effects post-vaccination, such as injection-site pain, redness, swelling, fatigue, or fever. These are mediated by the innate immune system's cytokine storm—pro-inflammatory signals like interleukin-1 (IL-1), IL-6, and prostaglandins.
Traditionally, scientists believed strong immunogenicity (ability to provoke lasting protection) was inextricably linked to reactogenicity; a potent adjuvant would inevitably cause more side effects. This trade-off has limited adjuvant use, especially in vulnerable groups like the elderly or children, and fueled vaccine hesitancy.
Japan's rigorous vaccine approval process, overseen by the Pharmaceuticals and Medical Devices Agency (PMDA), emphasizes safety. During the COVID-19 rollout, mRNA vaccines without traditional adjuvants were prioritized, but squalene emulsions were explored for boosters.
Methods Employed in the UTokyo Study
The IMSUT team used sophisticated mouse models immunized with ovalbumin antigen plus squalene emulsions mimicking MF59 or AS03. They profiled early immune responses (within 24 hours) using single-cell RNA sequencing, flow cytometry, and cytokine assays.
Key experiments included depleting specific immune cells (e.g., neutrophils, eosinophils, dendritic cells) or blocking receptors like IL-1R or MyD88. Human peripheral blood mononuclear cells (PBMCs) validated findings, showing conserved IL-1 responses in dendritic cells and eosinophils.
They also tested adjuvant variants lacking α-tocopherol (vitamin E derivative), revealing its pivotal role in IL-1 production.
Key Findings: Distinct Pathways for Protection and Side Effects
The research pinpointed IL-1 family cytokines as central orchestrators. IL-1β, produced by various cells, signals through CD11c+ dendritic cells (antigen-presenting cells) via the IL-1 receptor and MyD88 adaptor protein. This pathway matures dendritic cells, promoting T follicular helper cells and germinal center B cells for high-affinity antibodies and long-term memory.
Conversely, local reactogenicity (swelling) stems from IL-1α secreted by eosinophils recruited to the site. Systemic fever arises from IL-1β inducing IL-6 and cyclooxygenase-2 (COX2) in endothelial cells, leading to prostaglandin release.
Strikingly, neutralizing IL-1β or its receptor reduced fever and swelling without impairing antibody titers, proving the pathways are separable.
The Role of α-Tocopherol in Adjuvant Activity
α-Tocopherol emerged as a linchpin. In squalene emulsions, it stabilizes droplets and directly stimulates IL-1 production in innate immune cells. Adjuvants without it showed diminished both efficacy and reactogenicity, underscoring its dual influence but opening doors to modified formulations preserving immunogenicity while curbing inflammation.
This aligns with prior UTokyo work on adjuvant databases, aiding preclinical screening.
Human Relevance and Translational Potential
Human PBMCs mirrored mouse responses: dendritic cells upregulated IL-1β/MyD88 genes, eosinophils IL-1α. This suggests broad applicability beyond rodents.
Professor Ishii noted, “This challenges the long-standing assumption that efficacy and reactogenicity are inseparable.” Dr. Yoshioka added, “We can now target specific cells and cytokines for next-generation adjuvants.”
University of Tokyo's Leadership in Vaccine Research
IMSUT, founded in 1892, is Japan's premier life sciences hub, designated an International Joint Usage/Research Center. Professor Ishii's Division of Vaccine Science, part of the International Vaccine Design Center, has pioneered adjuvant innovation, including self-assembling molecules and databases for 25 adjuvants.
UTokyo's collaborations with pharma like Shionogi exemplify Japan's academia-industry synergy. With over 229 publications, Ishii's lab trains PhD students and postdocs, contributing to Japan's goal of self-reliant vaccine production amid global shortages.
In 2026, UTokyo hosts immunology forums and MEXT-funded projects, bolstering higher education's role in national health security. Explore faculty positions in immunology at UTokyo research jobs.
Implications for Global and Japanese Vaccine Development
This could revolutionize vaccines for pandemics, cancer, or allergies. Safer adjuvants mean higher compliance, vital as WHO estimates vaccines avert 2-3 million deaths yearly, but hesitancy hampers efforts.
In Japan, with an aging population, reactogenicity limits uptake in seniors. Optimized squalene adjuvants could enhance seasonal flu shots. For details, see the full paper at npj Vaccines study.
Broader: informs non-vaccine therapies targeting IL-1 for arthritis or autoinflammation.
Japan's Higher Education Ecosystem in Vaccine Science
Japanese universities like UTokyo, Osaka University, and Keio lead adjuvant R&D. Government initiatives via AMED and MEXT fund adjuvant platforms, training 1,000+ researchers annually.
UTokyo's PhD programs in microbiology emphasize translational research, with alumni at global pharma. Amid Japan's push for 'Society 5.0,' vaccine science integrates AI for adjuvant screening.
Challenges include funding competition, but successes like this bolster rankings—UTokyo tops Asia in immunology.
Photo by Ozgu Ozden on Unsplash
- Key strengths: Interdisciplinary labs blending immunology, nanotechnology.
- Career paths: Postdocs to faculty in vaccine divisions.
- Global ties: Collaborations with UCSD, EU partners.
Future Outlook: Safer Vaccines on the Horizon
Next steps: Clinical trials of IL-1-targeted adjuvants. Precision vaccinology—tailoring adjuvants by age, genetics—could emerge. In Japan, PMDA fast-tracks such innovations.
For students eyeing vaccine careers, UTokyo offers scholarships and internships. Japan's higher ed invests ¥500 billion yearly in life sciences, fostering hubs like IMSUT.
This UTokyo breakthrough exemplifies how university research drives public health, promising vaccines that protect without pain.
Related insights: Japan's adjuvant database aids preclinical testing UTokyo adjuvant database.
