Sotrovimab therapy elicits antiviral activities against Omicron BQ.1.1 and XBB.1.5 in sera of immunocompromised patients.

Antibodies effective against the recent Omicron sublineages are missing. By taking advantage of a multi-centric prospective cohort of immunocompromised individuals treated for mild-to-moderate COVID-19, Bruel et al. show that administration of 500 mg of sotrovimab induces serum neutralization and antibody-dependent cellular cytotoxicity of BQ.1.1 and XBB.1.5. Therefore, sotrovimab may remain a therapeutic option against these variants.

Antiviral activities of sotrovimab against BQ.1.1 and XBB.1.5 in sera of treated patients.

Background: Monoclonal antibodies (mAbs) targeting the spike of SARS-CoV-2 prevent severe COVID-19. Omicron subvariants BQ.1.1 and XBB.1.5 evade neutralization of therapeutic mAbs, leading to recommendations against their use. Yet, the antiviral activities of mAbs in treated patients remain ill-defined. Methods: We investigated neutralization and antibody-dependent cellular cytotoxicity (ADCC) of D614G, BQ.1.1 and XBB.1.5 in 320 sera from 80 immunocompromised patients with mild-to-moderate COVID-19 prospectively treated with mAbs (sotrovimab, n=29; imdevimab/casirivimab, n=34; cilgavimab/tixagevimab, n=4) or anti-protease (nirmatrelvir/ritonavir, n=13). We measured live-virus neutralization titers and quantified ADCC with a reporter assay. Findings: Only Sotrovimab elicits serum neutralization and ADCC against BQ.1.1 and XBB.1.5. As compared to D614G, sotrovimab neutralization titers of BQ.1.1 and XBB.1.5 are reduced (71- and 58-fold, respectively), but ADCC levels are only slightly decreased (1.4- and 1-fold, for BQ.1.1 and XBB.1.5, respectively). Interpretation: Our results show that sotrovimab is active against BQ.1.1 and XBB.1.5 in treated individuals, suggesting that it may be a valuable therapeutic option.

Polyfunctionality of broadly neutralizing HIV-1 antibodies.

PURPOSE OF REVIEW: The discovery of broadly neutralizing HIV-1 antibodies (bNAbs) has provided a framework for vaccine design and created new hope toward an HIV-1 cure. These antibodies recognize the HIV-1 Envelope and inhibit viral fusion with unprecedented breadth and potency. Beyond their unique neutralization capacity, bNAbs also activate immune cells and interfere with viral spread through nonneutralizing activities. Here, we review the landscape of bNAbs functions and their contribution to clinical efficacy. RECENT FINDINGS: Parallel evaluation of bNAbs nonneutralizing activities using in vivo and in vitro models have revealed how their importance varies across antibodies and strains. Nonneutralizing bNAbs functions target both infected cells and viral particles, leading to their destruction through various mechanisms. Reservoir targeting and prevention in context of suboptimal neutralization highly depends on bNAbs polyfunctionality. We recently showed that bNAbs tether virions at the surface of infected cells, impairing release and forming immune complexes, with consequences that are still to be understood. SUMMARY: Nonneutralizing activities of bNAbs target infected cells, virions, and immune complexes, promoting viral clearance and possibly improving immune responses. We review how these functions participate to the efficacy of bNAbs and how they can be manipulated to improve bNAbs therapies.