[Correspondence] The effect of cilgavimab and neutralisation by vaccine-induced antibodies in emerging SARS-CoV-2 BA.4 and BA.5 sublineages

Since the first detection of the SARS-CoV-2 omicron variant (B.1.1.529 and sublineages) in November 2021 in South Africa, Botswana, and Hong Kong, several omicron sublineages have evolved. Some of these sublineages, including BA.2.75, BA.4, and BA.5, have shown augmented resistance against antibody-mediated neutralisation.Arora P Kempf A Nehlmeier I et al.Augmented neutralisation resistance of emerging omicron subvariants BA.2.12.1, BA.4, and BA.5.Sheward DJ Kim C Fischbach J et al.Evasion of neutralising antibodies by omicron sublineage BA.2.75.Wang Q Guo Y Iketani S et al.Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5.Thus, these sublineages outcompete earlier Omicron sublineages in populations with pre-existing immune responses due to either infection, or vaccination, or both.Tegally H Moir M Everatt J et al.Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa. In the past months viruses that belong to different BA.4 and BA.5 sublineages and which have mutations at residue R346 (R346T, R346S, or R346S) within the receptor-binding domain of the viral spike S-protein have been detected with increased frequencyChen C Nadeau S Yared M et al.CoV-Spectrum: analysis of globally shared SARS-CoV-2 data to identify and characterize new variants. (appendix p 1) This increased frequency has been detected for sublineages BA.4.6 (R346T or N658S), BA.5.9 (R346I), and BF.7 (R346T). Since the protein S mediates viral entry into cells and constitutes the key target for neutralising antibodies, we investigated whether mutation at R346T, R346S, or R346S might increase infectivity, or neutralisation resistance, or both. For this, we used pseudovirus particles (pp), which have been shown to faithfully model SARS-CoV-2 host-cell entry and its neutralisation.Schmidt F Weisblum Y Muecksch F et al.Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses.Cell entry by BA.4/5 (R346T, R346S, or R346S))pp was reduced compared with entry by BA.4/5pp (reduced by around 1·6 times [Vero, Caco-2] to 2·0 times [293T, Calu-3]) (appendix p 1). By contrast, particles bearing BA.4.6 S protein (BA.4.6pp), which contains mutation R346T jointly with mutation N658S, entered cells with the same efficiency as BA.4–5pp. This result suggests that mutation N658S compensates the negative effect of mutation R346T on host-cell entry. We further investigated S protein-driven cell–cell fusion, which is believed to contribute to pathogenesis.Bussani R Schneider E Zentilin L et al.Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology. No differences between BA.4/5, BA.4/5 (R346T, R346S, or R346S), and BA.4.6 S-proteins were observed (appendix p 1).Next, we analysed neutralisation by monoclonal antibodies for COVID-19 treatment. In line with previous studies,Arora P Kempf A Nehlmeier I et al.Augmented neutralisation resistance of emerging omicron subvariants BA.2.12.1, BA.4, and BA.5.Yamasoba D Kosugi Y Kimura I et al.Neutralisation sensitivity of SARS-CoV-2 omicron subvariants to therapeutic monoclonal antibodies. five of ten antibodies (casirivimab, bamlanivimab, etesevimab, tixagevimab, and regdanvimab) failed to neutralise BA.4/5pp. Furthermore, two antibodies (imdevimab and sotrovimab) showed more than ten times reduced efficacy against BA.4/5pp compared with B.1pp, which harbours the S-protein of a virus that was circulating early during the pandemic. Three antibodies (cilgavimab, bebtelovimab, and S2H97), two of which are in clinical use (cilgavimab and bebtelovimab), retained appreciable neutralisation efficiency against BA.4/5pp. However, BA.4/5 (R346T, R346S, or R346S)pp, and BA.4.6pp largely lost sensitivity against cilgavimab, being only efficiently neutralised by bebtelovimab (appendix p 3).Finally, we assessed neutralisation of S protein-driven cell entry by antibodies elicited upon triple vaccination with different combinations of the BNT162b2 mRNA and AZD1222 adenovirus-based vaccines, and early omicron wave (ie, February–May, 2022, in Germany) breakthrough infection in triple vaccinated individuals (appendix, table). In accordance with previous studies,Arora P Kempf A Nehlmeier I et al.Augmented neutralisation resistance of emerging omicron subvariants BA.2.12.1, BA.4, and BA.5.Wang Q Guo Y Iketani S et al.Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5. neutralisation of BA.4/5pp was reduced compared with B.1pp (by between 3·5 times and 11·5 times). Neutralisation of BA.4/5 (R346T, R346S, or R346S) S)pp and BA.4.6pp was even further reduced compared with BA.4/5pp (by around two times), suggesting that mutations (R346T, R346S, or R346S) further extend the already high neutralisation evasion potential of BA.4 and BA.5 sublineages (appendix p 3).

Our data indicate that emerging BA.4 and BA.5 sublineages harbouring S-protein mutations (R346T, R346S, or R346S) have further extended their capacity to evade neutralisation. As a consequence, the availability of therapeutic antibodies for the treatment of individuals infected with such viruses is further reduced, and infections in triple-vaccinated individuals might become increasingly frequent.

AK, IN, SP, and MH conduct contract research (testing of vaccinee sera for neutralising activity against SARS-CoV-2) for Valneva, unrelated to this work. GMNB served as an advisor for Moderna and acknowledges funding by German Center for Infection Research (grant no 80018019238) and a European Regional Development Fund (Defeat Corona, ZW78–515131). SP served as an advisor for BioNTech, unrelated to this work. SP acknowledges funding by Bundesministerium fur Bildung und Forshung (Bundesministerium fur Bildung und Forshung; 01KI2006D, 01KI20328A, 01KX2021), the EU hunam genetic and immunological determinants of the clinical manifestations of SARS-Cov-2 infection: Towards personalised medicine project (grant agreement number 101057100), the Ministry for Science and Culture of Lower Saxony (147–61031–84, MWK HZI COVID-19), and the German Research Foundation (DFG; PO716/111–, PO716/141–). H-MJ received funding from BMBF (01KI2043, NaFoUniMedCovid19-COVIM: 01KX2021), Bavarian State Ministry for Science and the Arts and DFG through the research training groups RTG1660 and TRR130, the Bayerische Forschungsstiftung (Project CORAd), and the Kastner Foundation. All other authors declare no competing interests.

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