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In this study, we evaluated immune responses induced by four clinically validated adjuvants\u2014aluminum hydroxide (Al), two water-in-oil emulsions (Montanide ISA720 and ISA51), and an oil-in-water emulsion (Sepivac SWE)\u2014formulated with the prefusion-stabilized ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer (S-2P) in mouse models. Both S-2P:ISA720 and S-2P:ISA51 elicited potent humoral immunity, including cross-neutralizing antibodies against Omicron variants, along with robust interferon gamma-producing T-cell responses in the spleen and lung. Immunization with S-2P:ISA720 conferred complete protection against lethal challenge with the ancestral virus as well as Omicron subvariants BA.5 and BF.7. In contrast, S-2P:Al and S-2P:SWE elicited substantially weaker antibody responses, undetectable T-cell immunity, and markedly reduced protective efficacy. Prime-boost immunization with S-2P:ISA720 induced sustained peak antibody titers against both homologous SARS-CoV-2 and the Omicron BA.2 subvariant, affording complete protection for up to 17 weeks post-vaccination. While a third dose of S-2P:Al following a prime-boost regimen triggered a robust increase in antibody levels, titers declined rapidly thereafter, recapitulating the decay kinetics observed after the second dose. Both ISA720 and Al formulations exhibited age-dependent declines in antibody responses and protective efficacy. Notably, aged mice displayed markedly attenuated neuroinflammatory responses following SARS-CoV-2 challenge and significantly compromised protection after adoptive transfer of immune serum. These results underscore adjuvant-specific determinants of broad and durable immunity and reveal novel age-related constraints in vaccine-induced protection against SARS-CoV-2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Persistent viral evolution, rapid waning of vaccine-induced immunity, and the heightened vulnerability of elderly populations remain major challenges for COVID-19 vaccination strategies. In this study, we systematically assessed immune responses elicited by the ancestral  spike protein formulated with four distinct adjuvants in mouse models. We demonstrate that an optimized adjuvant formulation markedly enhances the magnitude and breadth of antibody responses, potentiates T-cell immunity, and rapidly induces sustained peak antibody titers against both homologous virus and Omicron variants. Vaccine-induced antibody responses were significantly attenuated in aged mice, and furthermore, both the protective efficacy of antibodies and inflammatory cytokine responses upon viral challenge were impaired in aged animals. These results provide compelling evidence that rational adjuvant selection is critical for enabling recombinant vaccines to achieve rapid-onset, broad, and durable immune protection. Furthermore, our study offers new mechanistic insights into the reduced vaccine efficacy observed in the elderly.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01099-25","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T13:00:09Z","timestamp":1759496409000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Adjuvant-dependent protection of SARS-CoV-2 spike vaccines: comparative immunogenicity of human-applicable formulations"],"prefix":"10.1128","volume":"99","author":[{"given":"Zhendong","family":"Pan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04k21pf91","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, Faculty of Naval Medicine, Naval Medical University","place":["Shanghai, 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