ORIGINAL RESEARCH article
Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
This article is part of the Research TopicInnovative Adjuvant Strategies: Enhancing Vaccine Efficacy Through Transdisciplinary ApproachesView all 12 articles
Application of a Small Molecule Calcium Influx Inducer as a Vaccine Adjuvant: Enhancing Th2-Biased Immune Responses
Provisionally accepted
Yumi Yokoyama
Yukiy Sako
Shiyin YaoFernando GilRenna Cozza
Jasmin JinIan Mclaughlin
Paola Anguiano QuirozTyler BrownNikunj M ShuklaMichael Chan
Maripat Corr
Dennis A. Carson
Tomoko Hayashi*- UCSD, San Diego, United States
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Vaccines are highly effective in preventing the spread of communicable diseases and are critical to overall public health. As immune stimulants vaccine adjuvants augment the level and longevity of these protective responses. Seeking novel adjuvants using parallel high throughput screens and subsequent systematic structure–activity relationship studies we identified an analogue of a hit compound, 2G272, that in screening assays retained in vitro induction of calcium (Ca2+) influx, tetraspanin CD63 EV reporter activity and cell viability. Here, we further our analyses of the biological activity of 2G272 related its potential use as a vaccine adjuvant. 2G272 triggered store-operated Ca2+ entry in murine bone marrow-derived dendritic cells (mBMDC) which was associated with increases in CD80 and CD86 surface expression. In co-culture experiments, this compound significantly enhanced the activation of mBMDCs, thereby amplifying the stimulation of cognate T cell proliferation. This effect on T cells was mediated either through direct engagement with compound stimulated mBMDCs or indirectly via immunostimulatory extracellular vesicles released by 2G272-activated mBMDCs. Intramuscular injection of 2G272 elicited minimal systemic cytokine and chemokine release demonstrating a promising safety profile. When used as an adjuvant with a model antigen, ovalbumin, in a murine vaccination model, 2G272 generated a significant antigen specific IgG1 response with an associated T helper 2 (Th2) cytokine profile. Hence this compound shows promise as an adjuvant if a Th2 response is beneficial or in combination with other agents to provide a balanced immune response in vaccines.
Keywords: adjuvant, Ca2+ influx, dendritic cell, Extracellular vesicle, T helper 2, Vaccine
Received: 12 Sep 2025; Accepted: 30 Jan 2026.
Copyright: © 2026 Yokoyama, Sako, Yao, Gil, Cozza, Jin, Mclaughlin, Anguiano Quiroz, Brown, Shukla, Chan, Corr, Carson and Hayashi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Tomoko Hayashi
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