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 (SARSCoV-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.

Funding Information: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (S.G.T., M.P.D., G.V.M. and W.D.R.), MRF2001684 (A.D.K. and S.G.T.) and a Medical Research Future Fund Antiviral Development Call grant (D.C. and W.D.R.), Medical Research Future Fund COVID-19 grant (MRFF2001684, A.D.K. and S.G.T.) and the New South Wales Health COVID-19 Research Grants Round 2 (S.G.T.)

Declaration of Interests: The authors declare no competing interests.


Ethics Approval Statement: The ADAPT cohort is composed of RT-PCR–confirmed convalescent individuals (incl. some subsequently vaccinated) recruited in Australia since 2020 10. The ADAPT cohort is composed of RT-PCR–confirmed convalescent individuals (incl. some subsequently vaccinated) recruited in Australia since 2020 10. Serum from healthy volunteers vaccinated with ChAdOx1 and BNT162b2 was collected 4 weeks post second-dose vaccination. All human serum samples were obtained with written informed consent from the participants (St Vincent’s Hospital Ethics committee approval numbers 2019/ETH03336; 2020/ETH00964; 2020/ETH02068; 2021/ETH00180).

Keywords: SARS CoV2 Variants, immunotherapeutics, ACE2, TMPRSS2, Omicron