ORIGINAL RESEARCH article
Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
Heterologous ORFV–Ad26 Vaccination Broadens Antibody Breadth and Amplifies Cellular Immunity against SARS-CoV-2 Spike
Provisionally accepted
- 1Universitatsklinikum Tubingen, Tübingen, Germany
- 2Naturwissenschaftliches und Medizinisches Institut an der Universitat Tubingen, Reutlingen, Germany
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The durability of vaccine-induced immunity is often limited by waning responses, antigenic drift, and anti-vector immunity, highlighting the need for innovative vaccination strategies. Heterologous prime– boost approaches can help overcome these barriers by exploiting the complementary strengths of distinct platforms. Here, we evaluated a replication-deficient Orf virus-based spike vaccine (ORFV-S) in combination with the licensed Ad26 vector vaccine Jcovden (Ad26.COV2.S), using SARS-CoV-2 model. In a clinically aligned intramuscular immunogenicity screen in mice, Jcovden induced strong early anti-spike antibody responses but showed limited boostability, whereas ORFV-S was highly boost-responsive. Mixed regimens outperformed both homologous schedules. ORFV-S prime followed by Jcovden boost elicited the highest spike-binding antibody titers and vigorous CD4⁺ and CD8⁺ T-cell responses with a dominant Th1 profile. In the reverse regimen, ORFV-S boost improved inhibition across multiple SARS-CoV-2 variants, including immune-evasive strains and indicated qualitative improvements in the response breadth. Together, these findings suggest that sequence-dependent effects allow heterologous schedules to emphasize either cellular or humoral arms of the adaptive response.
Keywords: Orf virus, Viral vector, Vaccines, Heterologous prime-boost, SARS-CoV-2, Jcovden
Received: 29 Sep 2025; Accepted: 30 Oct 2025.
Copyright: © 2025 Reguzova, Haug, 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, ralf.amann@ifiz.uni-tuebingen.de
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