Immunogenicity and efficacy of homologous and heterologous NDV and MVA SARS-CoV-2 vaccines in mice and hamsters

Effective vaccination strategies adaptable to emerging viruses like SARS-CoV-2 and capable of inducing robust protective immunity are needed. We evaluated the immunogenicity and protective efficacy of homologous and heterologous prime/boost regimens against SARS-CoV-2 in K18-hACE2 mice and Syrian hamsters using Newcastle disease virus (NDV-HXP-S, intranasal) and modified vaccinia virus Ankara (MVA-S(3P), intramuscular) vectors encoding a prefusion-stabilized SARS-CoV-2 spike (S) protein. All regimens protected against weight loss and markedly reduced viral replication and lung pathology. Vaccination induced serum anti-S and anti-receptor binding domain IgGs and neutralizing antibodies against ancestral virus and variants. In mice, mucosal anti-S IgA and IgG were detected after NDV-HXP-S immunization. Homologous MVA-S(3P)/MVA-S(3P) and heterologous NDV-HXP-S/MVA-S(3P) elicited higher polyfunctional systemic T-cell responses, while homologous NDV-HXP-S/NDV-HXP-S induced stronger pulmonary CD8⁺ T cells. Hamsters vaccinated with NDV-HXP-S exhibited protection of the upper respiratory tract, with the NDV-HXP-S/MVA-S(3P) regimen showing a trend toward reduced direct contact transmission of SARS-CoV-2. These findings demonstrate the capacity of NDV and MVA vector platforms to induce robust systemic and mucosal antigen-specific humoral and T-cell responses against SARS-CoV-2, contributing to protection against both disease and transmission, and support further exploration of these vector platforms for vaccination against SARS-CoV-2 and potentially other pathogens.