SARS-CoV-2 Omicron BA.1 and BA.2 are attenuated in rhesus macaques as compared to Delta

Abstract

Since the emergence of SARS-CoV-2, five different variants of concern (VOCs) have been identified: Alpha, Beta, Gamma, Delta, and Omicron. Because of confounding factors in the human population, such as preexisting immunity, comparing severity of disease caused by different VOCs is challenging. Here, we investigate disease progression in the rhesus macaque model upon inoculation with the Delta, Omicron BA.1, and Omicron BA.2 VOCs. Disease severity in rhesus macaques inoculated with Omicron BA.1 or BA.2 was lower than those inoculated with Delta and resulted in significantly lower viral loads in nasal swabs, bronchial cytology brush samples, and lung tissue in rhesus macaques. Cytokines and chemokines were up-regulated in nasosorption samples of Delta animals compared to Omicron BA.1 and BA.2 animals. Overall, these data suggest that, in rhesus macaques, Omicron replicates to lower levels than the Delta VOC, resulting in reduced clinical disease.

SARS-CoV-2 Variants Show Different Host Cell Proteome Profiles With Delayed Immune Response Activation in Omicron-Infected Cells

“…Therefore, examining the phosphorylation pattern and nuclear translocation post infection of key transcription factors IRF-3 and NF-κB revealed Omicron BA.1 and BA.2 variants to induce a delayed host immune response. In line with this observation, Omicron BA.1 infection was shown to be accompanied by less severe lung inflammation as well as the downregulation of pro-inflammatory cytokines in vivo compared to infection with other variants, possibly due to its impaired replication in lung tissue ( 11 , 12 , 39 , 40 ). In addition, Omicron BA.1 infected patients showed a low systemic inflammatory response compared to patients infected with previous SARS-CoV-2 variants ( 44 ).…”

“…A possible explanation of this shift in cell tropism is inefficient TMPRSS2 mediated cleavage of the S protein of Omicron variants, which results in cell entry dependency on endosomal uptake as well as less fusogenicity ( 12 , 41 ). However, replication kinetics were comparable to SARS-CoV-2 Delta in cells with low endogenous TMPRSS2 expression, like Hela or 293T cells ( 39 , 41 ). This explains our findings of attenuated infection kinetics as well as less severe CPE formation of TMPRSS2-expressing lung epithelial Calu-3 cells infected with Omicron BA.1 and BA.2 variants.…”

“…Omicron BA.1 was shown to possess superior replication kinetics in human nasal and bronchial tissue but attenuated replication kinetics were reported in human lung tissue compared to other SARS-CoV-2 variants ( 37 , 38 ). Notably, although the viral kinetics of Omicron variants were partly different, the replication in lung tissue was impaired in all in vivo models ( 11 , 12 , 13 , 39 , 40 ). The reported lower pathogenicity and increased transmissibility of the Omicron BA.1 variant possibly goes along with a shifted cell tropism.…”

An engineered ACE2 decoy broadly neutralizes Omicron subvariants and shows therapeutic effect in SARS-CoV-2-infected cynomolgus macaques

“…To test the therapeutic effect of 3N39v4-Fc in a non-human primate model, we employed a cynomolgus macaque (CM) and the Delta variant that induces apparent lung pathology as compared with other variants (24). Nine CMs were inoculated with 1 × 10 6 PFU of Delta variant via a combination of intratracheal (i.t.)…”

Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques

“…Using the rhesus macaque model of SARS-CoV-2 infection ( 19 ), we assessed the antiviral activities of both compounds individually and in combination against the SARS-CoV-2 Delta VOC. The Delta VOC was selected as this variant has been shown to cause the most severe infection of all VOCs in rhesus macaques, especially compared with the rather mild infection by Omicron ( 26 ). Usage of the Delta VOC ensured use of the most stringent challenge model to measure treatment efficacy.…”