ORIGINAL RESEARCH article
Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1675859
Heterologous Prime-Boost Vaccination with VLA2001 and an ORFV-Based Vector Enhances Spike-and Nucleocapsid-Specific Immunity in Mice
Provisionally accepted- 1University of Tübingen, Tübingen, Germany
- 2Naturwissenschaftliches und Medizinisches Institut an der Universitat Tubingen, Reutlingen, Germany
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Heterologous prime–boost vaccination has emerged as a promising approach to enhance immune responses by combining vaccines with complementary mechanisms of antigen delivery and immune activation. Here, we evaluated the immunogenicity of heterologous regimens combining the licensed inactivated SARS-CoV-2 vaccine (VLA2001) with the replication-deficient Orf virus-based vector vaccine (Prime-2-CoV). Using a mouse model, we compared these regimens to homologous vaccinations with each vaccine alone. Among the combinations tested, priming with VLA2001 followed by boosting with Prime-2-CoV induced the strongest spike-specific antibody responses, superior ACE2-binding inhibition against pre-Omicron variants, and robust Th1-biased immunity, with robust CD4⁺ and CD8⁺ T-cell responses. This sequence also enhanced nucleocapsid-specific immunity, underscoring the benefit of multiantigen targeting. These findings highlight the immunological synergy between inactivated whole-virus and ORFV vector vaccines and support the strategic use of Prime-2-CoV as a potent heterologous booster. The ORFV platform's favorable safety profile and Th1-polarizing capacity make it a valuable candidate for future heterologous vaccine strategies beyond SARS-CoV-2.
Keywords: Orf virus, Viral vector, Vaccines, Heterologous prime-boost, SARS-CoV-2, VLA2001
Received: 29 Jul 2025; Accepted: 01 Sep 2025.
Copyright: © 2025 Reguzova, Haug, Metz, Müller, Fandrich, Dulovic and Amann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ralf Amann, University of Tübingen, Tübingen, Germany
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