The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype

Abstract

Variant of concern (VOC) Omicron-BA1 has achieved global predominance in early 2022. Therefore, surveillance and comprehensive characterization of Omicron-BA.1 in advanced primary cell culture systems and multiple animal models is urgently needed. Here, we characterized Omicron-BA.1 and recombinant Omicron-BA.1 spike gene mutants in comparison with VOC Delta in well-differentiated primary human nasal and bronchial epithelial cells in vitro, followed by in vivo fitness characterization in naïve hamsters, ferrets and hACE2-expressing mice, and in immunized hACE2-mice. We demonstrate a spike-mediated enhancement of early replication of Omicron-BA.1 in nasal epithelial cultures, but limited replication in bronchial epithelial cultures. In Syrian hamsters, Delta showed dominance over Omicron-BA.1 and in ferrets, Omicron-BA.1 infection was abortive. In mice expressing the authentic hACE2-receptor, Delta and a Delta spike clone also showed dominance over Omicron-BA.1 and an Omicron-BA.1 spike clone, respectively. Interestingly, in naïve K18-hACE2 mice, we observed Delta spike-mediated increased replication and pathogenicity and Omicron-BA.1 spike-mediated reduced replication and pathogenicity, suggesting that the spike gene is a major determinant of both Delta and Omicron-BA.1 replication and pathogenicity. Finally, the Omicron-BA.1 spike clone was less well controlled by mRNA-vaccination in K18-hACE2-mice and became more competitive compared to the progenitor and Delta spike clones, suggesting that spike gene-mediated immune evasion is another important factor that led to Omicron-BA.1 dominance.

The altered entry pathway and antigenic distance of the SARS-CoV-2 Omicron variant map to separate domains of spike protein

“…Although we have shown the lower severity phenotype of Omicron largely maps to the spike protein, consistent with a recent report by Barut et al 22 , further attenuating mutations may exist in Omicron outside this gene. For example, the recently emerged BA.1 (spike) x Delta recombinant XD, which contains most of the spike gene of BA.1 with the rest of its genome from Delta, is more virulent than whole Omicron 45 , and a recombinant virus bearing a BA.2 spike on a Wuhan-Hu-1 backbone showed higher pathogenicity in a hamster model 46 .…”

“…Omicron lineage isolates also show a lower intrinsic severity than previous VOCs in rodent models such as hamsters [17][18][19][20] . In ex vivo systems, Omicron shows attenuated replication in human cells derived from the lower respiratory tract but rapid replication in upper airway epithelia 21,22 . In vitro, Omicron does not induce syncytia, and the spike protein has low fusogenicity 12,19,23 .…”

No Evidence for the Presence of SARS-CoV-2 in Bank Voles and Other Rodents in Germany, 2020–2022

“…In conclusion, we found no evidence for the presence of SARS-CoV-2 in the surveilled wild rodent populations using serological test systems that have been demonstrated to detect antibodies against diverse VOCs of SARS-CoV-2 [ 35 , 36 ]. Nevertheless, rodents should be included in future monitoring studies, especially in regions with high human population densities and where the beta and gamma variants are more prevalent, and when new virus variants emerge during the continued evolution of SARS-CoV-2 and when the potential of the variants to break cross-species barriers and the capability to expand species tropism to animals is unknown.…”

“…As positive controls, blood samples collected on day 8 (two animals), 12 (one animal) or 21 (three animals) after experimental SARS-CoV-2 inoculation of bank voles [ 19 ] have been tested, the results are shown in Figure 1 . The suitability of the ELISA to detect antibodies directed against diverse VOCs has been shown during experimental infection studies [ 35 , 36 ].…”

A mRNA Vaccine Encoding for a RBD 60-mer Nanoparticle Elicits Neutralizing Antibodies and Protective Immunity Against the SARS-CoV-2 Delta Variant in Transgenic K18-hACE2 Mice

“…In this study we demonstrated that mRNA RBD Delta -NP vaccine elicits a robust neutralizing anti-RBD Delta antibody response with high serum neutralizing titers. For reference, in female K18-hACE2 transgenic mice (7 to 15 weeks old) immunized intramuscularly with a single dose of 1 μg of mRNA vaccine Spikevax (Moderna), after two weeks the neutralizing antibody titers against SARS-CoV-2 with mutation D614G were ranging from 40 to 80 ( 56 ). A robust comparison between two mRNA vaccines encoding for the RBD-NP and the S protein of the same SARS-CoV-2 variant genotype in the same animal model would be of particular interest in future studies with RBD-NP vaccines.…”