Cytomegalovirus-vectored COVID-19 vaccines elicit neutralizing antibodies against the SARS-CoV-2 Omicron variant (BA.2) in mice

Viral vector vaccine represents one of the important research directions of novel vaccines. Viral vectors can efficiently deliver foreign genes and drive robust transgene expression in vivo. Generally, viral vector vaccines can achieve high immunogenicity and rapid response to a new pandemic. However, few types of viral vectors have been thoroughly evaluated for vaccine development, and the application of viral vectors is often limited by packaging capacity, vector immunogenicity, or pre-existing immunity. Cytomegalovirus (CMV) has been regarded as a promising novel vaccine vector because it has the advantages of high package capacity, good safety profiles, and the capacity to induce long-lasting immune responses. In this study, a luciferase-tagged reporter murine CMV (MCMV) was constructed, and the viral dissemination feature in vivo was studied. Furthermore, MCMVs expressing three structural proteins of SARS-CoV-2 were constructed and used to immunize mice. The level of binding antibodies and neutralizing antibodies against the original Wuhan strain and the Omicron variant (BA.2) was compared. Moreover, the CMV vector's transmission capacity and pre-existing immunity's influence on CMV-vectored vaccine efficacy were studied. The results showed that CMV vector could only cause transient systemic, but not persistent, infection. Immunization of CMV-vectored vaccines was able to elicit neutralizing antibodies against the Omicron variant (BA.2). However, the titer of neutralizing antibodies against BA.2 is much lower when compared with the original strain. The studies also showed that the CMV vectors would not cause unexpected viral transmission, and pre-existing immunity might impair the immunogenicity of subsequent CMV-vectored vaccines. Collectively, the CMV-vectored vaccine represents a promising approach to developing novel vaccines against epidemic pathogens. IMPORTANCE Cytomegalovirus (CMV) has been used as a novel viral vector for vaccine development and gene therapy. Coronavirus disease 2019 is an infectious disease caused by the SARS-CoV-2 virus, which is highly mutable and is still circulating globally. The study showed that the CMV viral vector caused transient systemic infection and induced robust transgene expression in vivo. CMV vectors expressing different SARS-CoV-2 proteins were immunogenic and could elicit neutralizing antibodies against a highly mutated Omicron variant (BA.2). The expression level of receptor-binding domain (RBD) protein was higher than that of full-length S protein using CMV as a vaccine vector, and CMV vector expression RBD protein elicited higher RBD-binding and neutralizing antibodies. Moreover, the study showed that CMV-vectored vaccines would not cause unexpected viral transmission, and pre-existing immunity might impair the immunogenicity of subsequent CMV-vectored vaccines. These works provide meaningful insights for the development of a CMV-based vector vaccine platform and the prevention and control strategies for SARS-CoV-2 infection.