Complement augments antibody neutralization of SARS-CoV-2 variants
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.
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BibTeX
@article{jungbauergroznica2026complement,
title = {{Complement augments antibody neutralization of SARS-CoV-2 variants}},
author = {Martin Jungbauer-Groznica and Pierre Rosenbaum and Isabelle Staropoli and Florence Guivel-Benhassine and Pierre-Henri Commere and Tom Perisse and Lily Bruyère and Aura Fantin Rengifo and Alejandro de Cruz and Andrea Cottignies-Calamarte and Sabina Andreu and Laurent Hocqueloux and Thierry Prazuck and Cyril Planchais and Michael White and Sophie Novault and Sophie Trouillet-Assant and Slim Fourati and Nicolas de Prost and Martin Killian and Stéphane Paul and Olivier Schwartz and Hugo Mouquet and Timothée Bruel},
journal = {Science Translational Medicine},
year = {2026},
month = jul,
doi = {10.1126/scitranslmed.aec6027},
url = {https://pasteur.hal.science/pasteur-05771279v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Complement augments antibody neutralization of SARS-CoV-2 variants
AU - Martin Jungbauer-Groznica
AU - Pierre Rosenbaum
AU - Isabelle Staropoli
AU - Florence Guivel-Benhassine
AU - Pierre-Henri Commere
AU - Tom Perisse
AU - Lily Bruyère
AU - Aura Fantin Rengifo
AU - Alejandro de Cruz
AU - Andrea Cottignies-Calamarte
AU - Sabina Andreu
AU - Laurent Hocqueloux
AU - Thierry Prazuck
AU - Cyril Planchais
AU - Michael White
AU - Sophie Novault
AU - Sophie Trouillet-Assant
AU - Slim Fourati
AU - Nicolas de Prost
AU - Martin Killian
AU - Stéphane Paul
AU - Olivier Schwartz
AU - Hugo Mouquet
AU - Timothée Bruel
PY - 2026
DA - 2026/07/22
JO - Science Translational Medicine
DO - 10.1126/scitranslmed.aec6027
UR - https://pasteur.hal.science/pasteur-05771279v1
AB - 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.
SN - 1946-6234
SN - 1946-6242
ER -