Safety and immunogenicity of a first-generation modified vaccinia virus Ankara-vectored SARS-CoV-2 vaccine candidate with mRNA-based booster vaccination: A phase 1 trial

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The rapid development of effective COVID-19 vaccines was enabled by the parallel assessment of multiple candidates early in the pandemic, including candidates based on the Modified Vaccinia virus Ankara (MVA) vector platform. This Phase 1 trial (NCT04569383) evaluated the MVA-based vaccine candidate MVA-SARS-2-S, expressing the full-length native SARS-CoV-2 spike glycoprotein (Wuhan-HU-1). Between October 2020 and May 2021, 30 healthy, SARS-CoV-2–naive adults received two doses of either 107 or 108 international units (IU) of MVA-SARS-2-S 28 days apart, with 6-month follow-up. A subgroup (n = 12) received two BNT162b2 booster vaccinations. Safety and reactogenicity were primary objectives; secondary and exploratory objectives included S1 seroconversion rates, S-domain-specific antibodies, SARS-CoV-2-neutralizing antibodies, and spike-specific T cell responses. MVA-SARS-2-S demonstrated a good safety profile. No severe or serious adverse events occurred. Immunogenicity was poor: S1-specific seroconversion occurred in 0/15 (107 IU group) and 3/15 (108 IU group) participants. Binding antibodies were predominantly directed against the S2 subunit, with peak median anti-S2 fold changes of 6.0 and 5.2 in the 107 IU and 108 IU groups, respectively. Neutralizing antibodies were detected in one participant (108 IU group); spike-specific T cell responses were observed in 5/15 (107 IU group) and 2/13 (108 IU group) participants. Heterologous BNT162b2 vaccination induced S1 seroconversion and detectable neutralizing antibody and T cell responses in all boosted participants, without safety concerns. In conclusion, while MVA-SARS-2-S was well tolerated and did not adversely affect subsequent BNT162b2 boosting, the vaccine candidate elicited insufficient immunogenicity, underscoring the need for optimized antigen design.