SARS-CoV-2 BA.4/5 infection triggers more cross-reactive FcγRIIIa signaling and neutralization than BA.1, in the context of hybrid immunity

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dc.contributor.author Richardson, Simone I.
dc.contributor.author Mzindle, Nonkululeko
dc.contributor.author Motlou, Thopisang
dc.contributor.author Manamela, Nelia
dc.contributor.author Van der Mescht, Mieke Adri
dc.contributor.author Lambson, Bronwen E.
dc.contributor.author Everatt, Josie
dc.contributor.author Amoako, Daniel Gyamfi
dc.contributor.author Balla, Sashkia
dc.contributor.author Von Gottberg, Anne
dc.contributor.author Wolter, Nicole
dc.contributor.author De Beer, Zelda
dc.contributor.author De Villiers, Talita Roma
dc.contributor.author Bodenstein, Annie
dc.contributor.author Van den Berg, Gretha
dc.contributor.author Abdullah, Fareed
dc.contributor.author Rossouw, Theresa M.
dc.contributor.author Boswell, M.T.
dc.contributor.author Ueckermann, Veronica
dc.contributor.author Bhiman, Jinal N.
dc.contributor.author Moore, Penny L.
dc.date.accessioned 2024-09-03T10:02:12Z
dc.date.issued 2024-07
dc.description.abstract SARS-CoV-2 variants of concern (VOCs) differentially trigger neutralizing and antibody-dependent cellular cytotoxic (ADCC) antibodies with variable cross-reactivity. Omicron BA.4/5 was approved for inclusion in bivalent vaccination boosters, and therefore the antigenic profile of antibodies elicited by this variant is critical to understand. Here, we investigate the ability of BA.4/5-elicited antibodies following the first documented (primary) infection (n = 13) or breakthrough infection after vaccination (n = 9) to mediate neutralization and FcγRIIIa signaling across multiple SARS-CoV-2 variants including XBB.1.5 and BQ.1. Using a pseudovirus neutralization assay and a FcγRIIIa crosslinking assay to measure ADCC potential, we show that unlike SARS-CoV-2 Omicron BA.1, BA.4/5 infection triggers highly cross-reactive functional antibodies. Cross-reactivity was observed both in the absence of prior vaccination and in breakthrough infections following vaccination. However, BQ.1 and XBB.1.5 neutralization and FcγRIIIa signaling were significantly compromised compared to other VOCs, regardless of prior vaccination status. BA.4/5 triggered FcγRIIIa signaling was significantly more resilient against VOCs (<10-fold decrease in magnitude) compared to neutralization (10- to 100-fold decrease). Overall, this study shows that BA.4/5 triggered antibodies are highly cross-reactive compared to those triggered by other variants. Although this is consistent with enhanced neutralization and FcγRIIIa signaling breadth of BA.4/5 vaccine boosters, the reduced activity against XBB.1.5 supports the need to update vaccines with XBB sublineage immunogens to provide adequate coverage of these highly antibody evasive variants. IMPORTANCE : The continued evolution of SARS-CoV-2 has resulted in a number of variants of concern. Of these, the Omicron sublineage is the most immune evasive. Within Omicron, the BA.4/5 sublineage drove the fifth wave of infection in South Africa prior to becoming the dominant variant globally. As a result this spike sequence was approved as part of a bivalent vaccine booster, and rolled out worldwide. We aimed to understand the cross-reactivity of neutralizing and Fc mediated cytotoxic functions elicited by BA.4/5 infection following infection or breakthrough infection. We find that, in contrast to BA.1 which triggered fairly strain-specific antibodies, BA.4/5 triggered antibodies that are highly cross-reactive for neutralization and antibody-dependent cellular cytotoxicity potential. Despite this cross-reactivity, these antibodies are compromised against highly resistant variants such as XBB.1.5 and BQ.1. This suggests that next-generation vaccines will require XBB sublineage immunogens in order to protect against these evasive variants. en_US
dc.description.department Immunology en_US
dc.description.department Internal Medicine en_US
dc.description.embargo 2025-01-02
dc.description.librarian hj2024 en_US
dc.description.sdg SDG-03:Good heatlh and well-being en_US
dc.description.sponsorship he South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa, the SA Medical Research Council SHIP program, the Centre for the AIDS Program of Research (CAPRISA) and the Bill & Melinda Gates Foundation. en_US
dc.description.uri https://journals.asm.org/journal/jvi en_US
dc.identifier.citation Richardson, S.I., Mzindle, N., Motlou, T., Manamela, N.P., Van der Mescht, M.A., Lambson, B.E., Everatt, J., Amoako, D.G., Balla, S., Von Gottberg, A., Wolter, N., De Beer, Z., De Villiers, T.R., Bodenstein, A., Van den Berg, G., Abdullah, F., Rossouw, T.M., Boswell, M.T., Ueckermann, V., Bhiman, J.N. & Moore, P.L. 2024. SARS-CoV-2 BA.4/5 infection triggers more cross-reactive FcγRIIIa signaling and neutralization than BA.1, in the context of hybrid immunity. Journal of Virology 98: e00678-24. https://doi.org/10.1128/jvi.00678-24. en_US
dc.identifier.issn 0022-538X (print)
dc.identifier.issn 1098-5514 (online)
dc.identifier.other 10.1128/jvi.00678-2
dc.identifier.uri http://hdl.handle.net/2263/97986
dc.language.iso en en_US
dc.publisher American Society for Microbiology en_US
dc.rights © 2024 American Society for Microbiology. All Rights Reserved. en_US
dc.subject Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) en_US
dc.subject SDG-03: Good health and well-being en_US
dc.subject Variants of concern (VOCs) en_US
dc.subject Antibody-dependent cellular cytotoxic (ADCC) en_US
dc.title SARS-CoV-2 BA.4/5 infection triggers more cross-reactive FcγRIIIa signaling and neutralization than BA.1, in the context of hybrid immunity en_US
dc.type Postprint Article en_US


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