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Modified vaccinia virus Ankara (MVA), a replication-deficient poxviral vector with an established safety profile, is under clinical investigation as a versatile recombinant vaccine platform against various infectious diseases. In the context of coronavirus disease 2019 (COVID-19), a recombinant MVA-based vaccine candidate expressing the prefusion-stabilized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (MVA-ST) has demonstrated safety, immunogenicity and protection in preclinical studies using different animal models. Furthermore, a phase Ib clinical trial in healthy adults showed that MVA-ST is safe, well-tolerated and immunogenic when used as a booster following mRNA priming. In this study, we evaluated heterologous prime\u2013boost vaccination regimens using MVA-ST as a booster in Syrian hamsters. Hamsters were primed with an mRNA vaccine (BNT162b2, BioNTech\/Pfizer) or the adenoviral vector vaccine Ad26.COV2.S (Janssen) and subsequently boosted with MVA-ST at a dose of 10\u2078 p.f.u. These heterologous vaccination regimens induced robust protection against severe SARS-CoV-2 disease, with superior immunogenicity compared to homologous MVA-ST vaccination. Notably, even a lower booster dose (10\u2077 p.f.u.) of MVA-ST following mRNA priming conferred strong protection against SARS-CoV-2 challenge infection, while still associated with limited viral shedding from the upper respiratory tract. These findings highlight the potential of MVA-ST as a heterologous booster to enhance the immunogenicity and protective efficacy of existing COVID-19 vaccines and also to improve vaccination strategies against other emerging pathogens.<\/jats:p>","DOI":"10.1099\/jgv.0.002180","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T15:16:37Z","timestamp":1763565397000},"source":"Crossref","is-referenced-by-count":1,"title":["Strong immunogenicity and protection against SARS-CoV-2 in hamsters induced by heterologous boost vaccination with an MVA-based COVID-19 vaccine candidate"],"prefix":"10.1099","volume":"106","author":[{"given":"Sonja","family":"Ohrnberger","sequence":"first","affiliation":[{"name":"Institute of Virology, University of Veterinary Medicine Hannover, 30559 Hanover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Meyer zu Natrup","sequence":"additional","affiliation":[{"name":"Institute of 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