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Preparedness is necessary to mitigate the worst-case scenario should an H5N1 influenza pandemic occur and justify the development of vaccines against circulating H5N1 viruses of concern. Methods: The production and characterization of egg-based split and inactivated H5Nx of three distinct monovalent antigens from clades 2.3.4.4b, 2.3.2.1c, and 2.3.4 were performed at an industrial scale. These antigens were formulated and their immune responses, when combined or not with IB160 squalene-based oil-in-water emulsion adjuvant in a rat model, were evaluated in a one- or two-dose immunization schedule. IgG antibodies, hemagglutination inhibitions, and microneutralization titers were measured for vaccine-induced immunity and cross-reactivity. Results: Three monovalent vaccines from clades 2.3.4.4b, 2.3.2.1c, and 2.3.4 were produced at an industrial scale and characterized. The immune responses against the monovalent vaccines showed a clade-specific antibody response and the need to combine with IB160 adjuvant for a required immune response. Conclusions: Considering the candidate vaccine viruses (CVVs) with the testing potency reagents available and that the antibody response obtained against the CVVs produced was clade-specific, IDCDC RG-71A is the indicated CVV for the predominant currently circulating H5N1 influenza virus of clade 2.3.4.4b and must be combined with adjuvant to induce a higher and efficacious immune response in a two-dose immunization protocol.<\/jats:p>","DOI":"10.3390\/vaccines13060620","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T08:22:34Z","timestamp":1749457354000},"page":"620","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Production and Immune Response Against Pandemic Influenza Candidate Vaccines as Preparedness Against the Circulating H5N1 Influenza Viruses"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3652-241X","authenticated-orcid":false,"given":"Paulo","family":"Lee Ho","sequence":"first","affiliation":[{"name":"BioIndustrial Center, Butantan Institute and Butantan Foundation, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7941-7535","authenticated-orcid":false,"given":"Yordanka","family":"Medina-Armenteros","sequence":"additional","affiliation":[{"name":"BioIndustrial Center, Butantan Institute and Butantan Foundation, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6303-2144","authenticated-orcid":false,"given":"L\u00edvia","family":"Mendon\u00e7a Munhoz Dati","sequence":"additional","affiliation":[{"name":"BioIndustrial Center, Butantan Institute and Butantan Foundation, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9234-1758","authenticated-orcid":false,"given":"Daniela","family":"Cajado-Carvalho","sequence":"additional","affiliation":[{"name":"BioIndustrial Center, Butantan Institute and Butantan Foundation, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Savio Silva","sequence":"additional","affiliation":[{"name":"BioIndustrial Center, Butantan Institute and Butantan Foundation, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pollyanna","family":"Fernandes Campos","sequence":"additional","affiliation":[{"name":"BioIndustrial Center, Butantan Institute and Butantan Foundation, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia Antonia Estima","family":"Abreu","sequence":"additional","affiliation":[{"name":"BioIndustrial Center, Butantan Institute and Butantan Foundation, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia","family":"Tavares de Castro","sequence":"additional","affiliation":[{"name":"BioIndustrial Center, Butantan Institute and Butantan Foundation, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9547-9477","authenticated-orcid":false,"given":"Paulo Newton","family":"Tonolli","sequence":"additional","affiliation":[{"name":"BioIndustrial Center, Butantan Institute and Butantan Foundation, S\u00e3o Paulo 05503-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahyumi","family":"Fujimori","sequence":"additional","affiliation":[{"name":"BioIndustrial Center, Butantan Institute and Butantan Foundation, S\u00e3o Paulo 05503-900, SP, 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