A Measles-derived COVID vaccine simultaneously encoding SARS-CoV-2 Spike and Nucleocapsid protein induces superior immunity and protection

The appearance of immune escape variants of SARS-CoV-2 such as Omicron results in loss of efficacy of early vaccines that rely on immune responses against the Spike protein. To generate a vaccine candidate, which triggers more sustained immunity, vaccine strain-derived recombinant measles viruses (MeV) were generated, that encode the conserved nucleocapsid protein N of SARS-CoV-2 alone or in addition to a soluble, stabilized Spike protein solSstab in additional transcription unit(s) of the MeV genome. N or solSstab are uniformly (co-)expressed in cells infected with those recombinant MeV vaccine candidates, which replicate with measles vaccine-like characteristics and are genetically stable. Surprisingly, significantly stronger and more multifunctional T cell responses against either SARS-CoV-2 antigen were induced in IFNAR-/--CD46Ge mice vaccinated with the MeV co-encoding S and N compared to those immunized with MeVs encoding either S or N, while antibody responses where comparable. This higher cellular immunity translated into full protection of highly sensible IFNARko-hACE2 mice upon challenge with SARS-CoV-2, while both cohorts receiving MeV encoding either the solSstab or N antigen were only partially protected. Therefore, the combination of two structural SARS-CoV-2 antigens, S and N, in recombinant MeV results in synergistic immune mechanisms and enhanced protection.