Complement augments antibody neutralization of SARS-CoV-2 variants

The complement system is a major effector system of the humoral immune response, but its capacity to cooperate with antibodies to inhibit the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a host remains poorly characterized. Here, we combined authentic virus neutralization, antibody engineering, and single viral particle analysis by flow virometry to show that complement enhances antibody neutralization of SARS-CoV-2. Addition of complement increased neutralization titers of sera from convalescent individuals ( n = 14), vaccinated individuals ( n = 15), and individuals with hybrid immunity ( n = 15) against D614G, BA.1, XBB.1.5, and JN.1 variants by up to 42-fold. D614G and BA.1 displayed a high level of neutralization, which was only slightly improved by adding complement. Conversely, neutralization of XBB.1.5 and JN.1 was weak but strongly enhanced by complement. Among the 32 JN.1 nonneutralizers, 22 regained detectable neutralization in the presence of complement. The enhancement mainly relied on cross-reactive anti-S2 antibodies, but monoclonal antibodies targeting the receptor binding domain and N-terminal domain could also be augmented. Viral inhibition required antibody Fc hexamerization, C1q recruitment, and C3 deposition, but it was independent of the membrane attack complex formed by C9. Consistently, complement components were deposited at the surfaces of viral particles with no detectable virolysis. In sera from individuals with severe COVID-19, both complement-mediated neutralization and anti-S2 antibody levels were associated with improved survival. Overall, our data show that complement potentiates the ability of antispike antibodies to neutralize immune-evasive SARS-CoV-2 variants.

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Publication Details

Journal
Science Translational Medicine
Published
2026-07-22
DOI
https://doi.org/10.1126/scitranslmed.aec6027
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
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article

Complement augments antibody neutralization of SARS-CoV-2 variants

Alexandre Gaudet, Andréa Cottignies-Calamarte, Pierre-André Natella, Martin Killian et al.
Science Translational Medicine
SARS-CoV-2 and COVID-19 Research
article

Complement augments antibody neutralization of SARS-CoV-2 variants

Alexandre Gaudet, Andréa Cottignies-Calamarte, Pierre-André Natella, Martin Killian, G. Ledoux, Pierre Cappy, Elodie Laugel, Sylvie Meireles, Raphaël Favory, Étienne Audureau, A. Pitsch, Marie-Alice Bovy, Pierre‐Henri Commère, Sarah Seng, Sophie Trouillet‐Assant, Ségolène Brichler, Tai Olivier Pham, Timothée Bruel, Cyril Planchais, L Picard, Claire Bourel, Sophie Novault, Stéphane Paul, Slim Fourati, Florence Guivel‐Benhassine, Maud Salmona, Charles‐Édouard Luyt, Diane Descamps, Frédéric Pène, Isabelle Staropoli, Sébastien Jochmans, Olivier Schwartz, Michael White, Nina de Montmollin, Hafid Ait‐Oufella, Mélissa N’Debi, Hugo Mouquet, Marie‐Laure Chaix, Sabina Andreu, Guillaume Chevrel, Guillaume Voiriot, Pierre Rosenbaum, Adrien Joseph, Martin Groznica, Amandine Henry, Elyanne Gault, Amal Chaghouri, Laurent Hocqueloux, Damien Roux, Claudio Garcia-Sanchez, Alexandre Soulier, D Fofana, Vincent Bonny, Pierre Bay, Louis-Marie Jandeaux, Estelle Danche, Lily Bruyère, Ferhat Meziani, Nicolas de Prost, Aurélie Guigon, S. Fafi-Kremer, Jean-François Timsit, Julien Mayaux, Megan Fraissé, Céline Clergue, T Prazuck, J J Bernier, A.-C. Maherault, Mathieu turpin, Tom Perisse, Anne-Marie Roque-Alfonso, David Levy, Kubab Sabah, Alejandro De Cruz, Aura Fantin Rengifo, Keyvan Razazi, Jean-Michel Pawlotsky, Fabrice Uhel, Sébastien Preau, Côme Bureau, Antoine Kimmoun, Stéphane Gaudry, Nicholas Heming, Malo Emery, Antoine Vieillard-Baron, Elie Azoulay, Stephane Marot, Luce Landraud, Quentin Le Hingrat, Anne-Sophie L'honneur, Eric Maury, Mohamed Ader, Armand Mekontso Dessap, SEVARVIR investigators, Damien Contou, Tomas Urbina, Christophe Rodriguez, Laurence Morand-Joubert, Nicolas Mongardon, Djillali Annane
article en

Abstract

The complement system is a major effector system of the humoral immune response, but its capacity to cooperate with antibodies to inhibit the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a host remains poorly characterized. Here, we combined authentic virus neutralization, antibody engineering, and single viral particle analysis by flow virometry to show that complement enhances antibody neutralization of SARS-CoV-2. Addition of complement increased neutralization titers of sera from convalescent individuals ( n = 14), vaccinated individuals ( n = 15), and individuals with hybrid immunity ( n = 15) against D614G, BA.1, XBB.1.5, and JN.1 variants by up to 42-fold. D614G and BA.1 displayed a high level of neutralization, which was only slightly improved by adding complement. Conversely, neutralization of XBB.1.5 and JN.1 was weak but strongly enhanced by complement. Among the 32 JN.1 nonneutralizers, 22 regained detectable neutralization in the presence of complement. The enhancement mainly relied on cross-reactive anti-S2 antibodies, but monoclonal antibodies targeting the receptor binding domain and N-terminal domain could also be augmented. Viral inhibition required antibody Fc hexamerization, C1q recruitment, and C3 deposition, but it was independent of the membrane attack complex formed by C9. Consistently, complement components were deposited at the surfaces of viral particles with no detectable virolysis. In sera from individuals with severe COVID-19, both complement-mediated neutralization and anti-S2 antibody levels were associated with improved survival. Overall, our data show that complement potentiates the ability of antispike antibodies to neutralize immune-evasive SARS-CoV-2 variants.

Science Translational MedicineVol. 18(859)
Université Claude Bernard Lyon 1 (FR), Université d'Orléans (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Institut Pasteur (FR), Université Paris-Est Créteil (FR), Université Paris Cité (FR), Assistance Publique – Hôpitaux de Paris (FR), Hospices Civils de Lyon (FR), Department of Virology (FR), Institut de Recherche Vaccinale (FR), Hôpitaux Universitaires Henri-Mondor (FR), bioMérieux (France) (FR), Centre hospitalier universitaire d'Orléans (FR), Centre Hospitalier Universitaire de Saint-Étienne (FR), Institut Mondor de Recherche Biomédicale (FR), Centre International de Recherche en Infectiologie (FR), Universidad Autónoma de Madrid (ES)
Good health and well-being
Openalex Percentile: Top 8%
SARS-CoV-2 and COVID-19 Research
DOISourceOpenAlex
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