{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:33:33Z","timestamp":1759365213533,"version":"build-2065373602"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2309100"],"award-info":[{"award-number":["2023YFC2309100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["92269118, 92269205"],"award-info":[{"award-number":["92269118, 92269205"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Beyond the role of neutralizing antibodies in protecting against SARS-CoV-2, Fc-mediated antibodies functions may offer additional immune defense. This study aimed to evaluate the Fc-mediated immune responses elicited by aerosolized and intramuscular Ad5-nCoV vaccines in a Chinese population with hybrid immunity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Serum samples were collected from the immunogenicity sub-cohort within a multicenter, partially randomized platform trial comparing aerosolized and intramuscular adenovirus type 5-vectored COVID-19 vaccine (Ad5-nCoV) boosters in adults in China. Participants were enrolled approximately six months after an Omicron wave in late 2022, and randomized to receive a booster dose with aerosolized or intramuscular Ad5-nCoV. Fc-mediated immune responses to wild-type and XBB.1.16 variant spike proteins were assessed by measuring antibody-dependent cellular phagocytosis (ADCP), antibody-dependent neutrophil phagocytosis (ADNP), and antibody-dependent cellular cytotoxicity (ADCC) before vaccination, and at 14 days, 3 months, 6 months post-booster. Correlations between Fc-mediated responses (ADCP, ADNP, ADCC) and neutralizing antibodies, IgG, and IgA levels responses were also analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Intramuscular Ad5-nCoV vaccination significantly induced Fc-mediated effector functions against wild-type spike protein, with peak responses at 14 days post-booster, including ADCP score of 107.21 (95% CI: 84.43-129.99), ADNP score of 133.96 (95% CI: 112.81-155.11), and ADCC fold induction of 9.64 (95% CI: 8.57-10.70). These responses gradually waned over time. In contrast, aerosolized Ad5-nCoV did not significantly enhance ADCP or ADNP, but did elicit notable ADCC responses, peaking at 3 months post-vaccination (fold induction: 7.85,95% CI: 6.66-9.04). Fc-mediated responses to XBB.1.16 were lower than those to the wild-type spike. Notably, the fold reductions in ADCP, ADNP, and ADCC against XBB.1.16 were less pronounced than the corresponding reduction in neutralizing antibody titers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Intramuscular Ad5-nCoV vaccination elicited robust ADCP, ADNP, and ADCC responses, while the aerosolized formulation primarily induced ADCC activity. Fc-mediated effector functions exhibited greater cross-reactivity against emerging variants compared to neutralizing antibodies, but correlated only weakly with neutralizing antibody titers.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1657235","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T05:50:49Z","timestamp":1759297849000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of an aerosolized or intramuscular adenovirus type 5-vectored COVID-19 vaccine on Fc-mediated immune effector functions in a hybrid immunity 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