BACKGROUND:The global mpox outbreak (2022-2024) highlights the need for effective and safe vaccines, particularly for vulnerable populations. The LC16m8 vaccine, an attenuated vaccinia virus strain for smallpox, shows promise in inducing immunity against the monkeypox virus (MPXV). METHODS:We conducted a comprehensive immunological evaluation of LC16m8 in mice, non-human primates, and humans. FINDINGS:LC16m8 induced strong humoural responses in BALB/c, C57BL/6J, and CAST/EiJ mice, targeting MPXV H3, A35, and M1R antigens, promoting germinal centre B cells and follicular helper T cells, essential for long-term immunity. Vaccinated CAST/EiJ mice showed reduced lung MPXV viral loads, demonstrating efficacy. In humans, LC16m8 enhanced neutralising antibodies against multiple MPXV clades, suggesting broad protection. In cynomolgus monkeys, systemic administration caused localised pox lesions without significantly affecting weight, temperature, or haematological parameters. INTERPRETATION:This cross-species immunological analysis provides preclinical and early clinical insights into LC16m8's efficacy and safety against mpox. While LC16m8 enhanced antibody responses against MPXV clade Ia and Ib, further studies are required to evaluate its efficacy, particularly in naive and immunocompromised populations. FUNDING:This research was supported by AMED under Grant Numbers JP243fa727002, JP243fa727001s0703, and JP243fa627001h0003 (K.J.I), JP24jf0126002, JP24fk0108690, JP243fa627001h0003, and JP243fa727002 (K.S), JP243fa727002 (Y.T.), JP243fa727002 and JP243fa627007h0003 (Y.Y.), and by the Research Support Project for Life Science and Drug Discovery (BINDS) from AMED under Grant Number JP23ama121011 (J.T.), and JP23ama121010 (T.S.), and by the Ministry of Education, Culture, Sports, Science and Technology in Japan under Grant Number 23K06577 (E.S.). AMED under Grant Number JP233fa827017 and JP243fa827017 (F.Y.), JP22fk0108501 (M.K.).
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