SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

Abstract

Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs have been introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in developed countries. In late 2021, the Omicron BA.1 variant emerged, with significant genetic differences and clinical effects from other variants of concern (VOC). This variant demonstrated higher numbers of polymorphisms in the gene encoding the Spike (S) protein, and there has been displacement of the dominant Delta variant. Shortly after dominating global spread in early 2022, BA.1 was supplanted by the genetically distinct Omicron lineage BA.2. A sub-lineage of BA.2, designated BA.5 has now started to dominate globally, with the potential to supplant BA.2. To address the relative threat of BA.5, we determined infectivity to particle ratios in primary nasopharyngeal samples and expanded low passage isolates in a well characterised, genetically engineered ACE2/TMPRSS2 cell line. We then assessed the impact of BA.5 infection on humoral neutralisation in vitro, in vaccinated and convalescent cohorts, using concentrated human IgG pooled from thousands of plasma donors, and licensed monoclonal antibody therapies. The infectivity of virus in primary swabs and expanded isolates revealed whilst BA.1 and BA.2 are attenuated through ACE2/TMPRSS2, BA.5 infectivity is equivalent to that of an early 2020 circulating clade and has greater sensitivity to the TMPRSS2 inhibitor Nafamostat. As with BA.1, we observed BA.5 to significantly reduce neutralisation titres across all donors. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth of neutralisation, although the potency was still reduced 7-fold with BA.5. Of all therapeutic antibodies tested, we observed a 14.3-fold reduction using Evusheld and 16.8 reduction using Sotrovimab when neutralising a Clade A versus BA.5 isolate. These results have implications for ongoing tracking and management of Omicron waves globally.

Intrinsic furin-mediated cleavability of the spike S1/S2 site from SARS-CoV-2 variant B.1.1.529 (Omicron)

“…Pathogenicity in animal models was also reduced with Omicron BA.1. Many details of the cleavage-activation process of Omicron remain to be resolved, especially when considering that multiple sub-variants including BA.2, BA.4/5, BA.2.12.1 and BA.2.75 have now emerged—with BA.5 in particular seeming to show infection properties more in line with Delta and the original B.1 strain, including increased syncytia formation, TMPRSS-2 usage and pathogenesis (15, 16). Despite the multiple changes in the spike gene between the various Omicron sub-variants, the S1/S2 “furin” cleavage site has remained unchanged.…”

Longitudinal analysis of serum neutralization of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 in patients receiving monoclonal antibodies

“…As other Omicron sublineages, BA.4 and BA.5 escape most neutralizing mAbs [34][35][36][37][38][39][40][41] . The neutralization profile of BA.4 and BA.5 is similar to that of BA.2, with only Cilgavimab and Bebtelovimab being efficient against these strains with high potency [34][35][36][37][38] .…”

COVID-19 and pregnancy: clinical outcomes; mechanisms, and vaccine efficacy

“…Although current vaccines against COVID-19 seem to be safe and effective during pregnancy, the emerging new variants of SARS-CoV-2 with higher transmissibility and better immune escape abilities raise new questions about effectiveness. The ever-changing Omicron variants have been recently identified to produce a new sub-lineage, BA.5, which is increasingly replacing the older Omicron lineages 214. A high degree of infectivity, similar to that of Delta, and increased transmissibility, like that of an older version of Omicron, have been attributed to this BA.5 variation 214.…”

“…The ever-changing Omicron variants have been recently identified to produce a new sub-lineage, BA.5, which is increasingly replacing the older Omicron lineages 214. A high degree of infectivity, similar to that of Delta, and increased transmissibility, like that of an older version of Omicron, have been attributed to this BA.5 variation 214. Thus, it is crucial to continue vaccine development that includes pregnant individuals in the clinical trials to better cope with the severity of disease, along with continuing further investigation into unique features of SARS-CoV-2 pathogenesis in pregnant individuals.Key pointsPregnant individuals are at greater risk of SARS-CoV-2 infection that could lead to adverse pregnancy outcomes.…”