Vaccinia virus-based SARS-CoV-2 vaccine prevents lung immunopathology without antibody-dependent enhancement in female rhesus macaques.

We have developed a recombinant vaccinia vaccine (rDIs-S) against SARS-CoV-2 from an attenuated vaccinia virus (Dairen-I minute-pock variant: DIs strain). The rDIs-S vaccine containing DNA of an S gene of SARS-CoV-2 early-pandemic Pango B strain protected cynomolgus macaques from severe pneumonia caused by a SARS-CoV-2 Pango A strain and induced a broad reactive neutralization antibody against SARS-CoV-2 variants (B.1.1.7, B.1.351, and P.1) in our previous study. In the present study, to further confirm the safety and efficacy of rDIs-S, the vaccine (1 × 108 PFU) was inoculated intradermally into rhesus macaques, which showed antibody-dependent enhancement (ADE) after vaccination with another vaccinia virus vector, MVA carrying a SARS-CoV S gene, and challenge infection with SARS-CoV. The rDIs-S vaccination induced neutralization activity against multiple SARS-CoV-2 variants in plasma of rhesus macaques [100 % (6/6 macaques)] and reduced viral replication of the B.1.1.7 and B.1.351 variants and infiltration of T cells and macrophages into the lungs of rhesus macaques [100 % (5/5 macaques)] after challenge infection with 1 × 107 TCID50 of the two SARS-CoV-2 variants. In the presence of plasma of vaccinated macaques, viral RNA levels in human FcγR-positive cells increased slightly by up to 1.8-folds, but they were much lower than those previously reported in sera of mRNA-vaccinated individuals, in which ADE was anticipated (ratios approximately 10-1000). Thus, rDIs-S induced protective immune responses against SARS-CoV-2 B.1.1.7 and B.1.351 and vaccination with rDIs-S did not enhance pneumonia or replication of SARS-CoV-2, indicating the efficacy and safety of rDIs-S in the rhesus macaque model.