{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T03:00:32Z","timestamp":1787886032347,"version":"build-2784847793"},"reference-count":36,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>A sublingual vaccine comprising the Poly(I:C) adjuvant and influenza HA antigen was evaluated for safety in both mice and macaque monkeys relative to its intranasal counterpart. Safety was assessed in terms of harmful effects corresponding to the upregulation of the inflammation-associated genes Saa3, Tnf, IL6, IL1b, Ccl2, Timp1, C2, Ifi47, Aif1, Omp, Nos2, and\/or Gzmb in mice and SAA2, TNF, IL6, IL1B, CCL2, TIMP, C2, AIF1, and GZMB in macaques. Quantitative gene expression analyses were performed using RT-qPCR with RNA samples from four tissue types, the olfactory bulb, pons, lung, tongue, and lymph node, from both mice and macaques. In mice, the intranasally delivered vaccine markedly upregulated the inflammation-related genes in the olfactory bulb 1 day and 7 days after vaccination. The adverse effects of intranasal vaccination were also observed in macaques, albeit to a lesser extent than in mice. The intranasal vaccination also upregulated these genes in the pons of both mice and macaques. In contrast, the sublingual vaccine did not adversely affect the olfactory bulb or pons in either mice or macaques. The intranasally administered vaccine significantly upregulated these genes in the lungs only 1 day after vaccination, but not 7 days later, in both mice and macaques. We conclude that intranasal vaccination results in unfavorable side effects corresponding to upregulated inflammatory genes in the brain (olfactory bulb and pons). Sublingual vaccination, however, did not induce these side effects in either mice or macaques and was hence evaluated as safe.<\/jats:p>","DOI":"10.3390\/vaccines13030261","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T10:46:46Z","timestamp":1740739606000},"page":"261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Safety Assessment of a Sublingual Vaccine Formulated with Poly(I:C) Adjuvant and Influenza HA Antigen in Mice and Macaque Monkeys: Comparison with Intranasal Vaccine"],"prefix":"10.3390","volume":"13","author":[{"given":"Tetsuro","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Innovation Research Center, EPS Holdings, Inc., 2-1 Tsukudohachimancho, Shinjuku-ku, Tokyo 162-0815, Japan"},{"name":"EP Mediate Co., Ltd., 1-8 Tsukudocho, Shinjuku-ku, Tokyo 162-0821, Japan"},{"name":"Research Center, EPS Innovative Medicine Co., Ltd., 1-8 Tsukudocho, Shinjuku-ku, Tokyo 162-0821, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fusako","family":"Mitsunaga","sequence":"additional","affiliation":[{"name":"Intelligence & Technology Lab, Inc., 52-1 Fukue, Kaizu-cho, Kaizu 503-0628, Japan"},{"name":"Biomedical Institute, NPO Primate Agora, 52-2 Fukue, Kaizu-cho, Kaizu 503-0628, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kotani","sequence":"additional","affiliation":[{"name":"Innovation Research Center, EPS Holdings, Inc., 2-1 Tsukudohachimancho, Shinjuku-ku, Tokyo 162-0815, Japan"},{"name":"Research Center, EPS Innovative Medicine Co., Ltd., 1-8 Tsukudocho, Shinjuku-ku, Tokyo 162-0821, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Tajima","sequence":"additional","affiliation":[{"name":"Innovation Research Center, EPS Holdings, Inc., 2-1 Tsukudohachimancho, Shinjuku-ku, Tokyo 162-0815, Japan"},{"name":"Research Center, EPS Innovative Medicine Co., Ltd., 1-8 Tsukudocho, Shinjuku-ku, Tokyo 162-0821, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunihiko","family":"Wasaki","sequence":"additional","affiliation":[{"name":"Innovation Research Center, EPS Holdings, Inc., 2-1 Tsukudohachimancho, Shinjuku-ku, Tokyo 162-0815, Japan"},{"name":"EP Mediate Co., Ltd., 1-8 Tsukudocho, Shinjuku-ku, Tokyo 162-0821, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Intelligence & Technology Lab, Inc., 52-1 Fukue, Kaizu-cho, Kaizu 503-0628, Japan"},{"name":"Biomedical Institute, NPO Primate Agora, 52-2 Fukue, Kaizu-cho, Kaizu 503-0628, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.addr.2021.01.003","article-title":"Advances in gene-based vaccine platforms to address the COVID-19 pandemic","volume":"170","author":"Pushparajah","year":"2021","journal-title":"Adv. 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