Pathogenesis and transmission of SARS-CoV-2 D614G, Alpha, Gamma, Delta, and Omicron variants in golden hamsters.

Since the emergence of SARS-CoV-2 in humans, novel variants have evolved to become dominant circulating lineages. These include D614G (B.1 lineage), Alpha (B.1.1.7), Gamma (P.1), Delta (B.1.617.2), and Omicron BA.1 (B.1.1.529) and BA.2 (B.1.1.529.2) viruses. Here, we compared the viral replication, pathogenesis, and transmissibility of these variants. Replication kinetics and innate immune response against the viruses were tested in ex vivo human nasal epithelial cells (HNEC) and induced pluripotent stem cell-derived lung organoids (IPSC-LOs), and the golden hamster model was employed to test pathogenicity and potential for transmission by the respiratory route. Delta, BA.1, and BA.2 viruses replicated more efficiently, and outcompeted D614G, Alpha, and Gamma viruses in an HNEC competition assay. BA.1 and BA.2 viruses, however, replicated poorly in IPSC-LOs compared to other variants. Moreover, BA.2 virus infection significantly increased secretion of IFN-λ1, IFN-λ2, IFN-λ3, IL-6, and IL-1RA in HNECs relative to D614G infection, but not in IPSC-LOs. The BA.1 and BA.2 viruses replicated less effectively in hamster lungs compared to the other variants; and while the Gamma virus reached titers comparable to D614G and Delta viruses, it caused greater lung pathology. Lastly, the Gamma and Delta variants transmitted more efficiently by the respiratory route compared to the other viruses, while BA.1 and BA.2 viruses transmitted less efficiently. These findings demonstrate the ongoing utility of experimental risk assessment as SARS-CoV-2 variants continue to evolve.