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Publications

Journal Article Ppublish

PubMed: 42485435 DOI: 10.1126/scitranslmed.aec6027

Complement augments antibody neutralization of SARS-CoV-2 variants.

Sci Transl Med 18(859):eaec6027

Authors: Martin Jungbauer-Groznica, Pierre Rosenbaum, Isabelle Staropoli, Florence Guivel-Benhassine, Pierre-Henri Commere, Tom Perisse, Lily Bruyère, Aura Fantin Rengifo, Alejandro De Cruz, Andrea Cottignies-Calamarte, Sabina Andreu, Laurent Hocqueloux, Thierry Prazuck, Cyril Planchais, Michael White, Sophie Novault, Sophie Trouillet-Assant, Slim Fourati, Nicolas de Prost, Martin Killian, Stéphane Paul, Olivier Schwartz, Hugo Mouquet, Timothée Bruel

Affiliations

  • Antiviral Activities of Antibodies Group, Institut Pasteur, Université Paris Cité, Paris, France.
  • Virus and Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France.
  • Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, Paris, France.
  • Flow Cytometry Platform, Institut Pasteur, Université Paris Cité, Paris, France.
  • International Centre of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France.
  • Unité Mixte de Recherche Hospices Civils de Lyon-bioMérieux, Pierre-Bénite, France.
  • Department of Molecular Biology, Universidad Autónoma de Madrid, Madrid, Spain.
  • Service des Maladies Infectieuses et Tropicales, Centre Hospitalier, Orléans, France; IPIC, Laboratoire Interdisciplinaire pour l'Innovation et la Recherche en Santé d'Orléans (LI(2)RSO), Université d'Orléans, Orléans, France.
  • Infectious Disease Epidemiology and Analytics G5 Unit, Institut Pasteur, Université Paris Cité, INSERM U1347, Paris, France.
  • Université Paris-Est-Créteil (UPEC), Créteil, France.
  • IMRB INSERM U955, Team "Viruses, Hepatology, Cancer," Créteil, France.
  • Department of Virology, Hôpitaux Universitaires Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, France.
  • Service de Médecine Intensive Réanimation, DMU Médecine, Hôpitaux Universitaires Henri Mondor, AP-HP (Assistance Publique-Hôpitaux de Paris), Créteil, France.
  • GRC CARMAS, Faculté de Santé de Créteil, UPEC (Université Paris-Est-Créteil), Créteil, France.
  • Department of Internal Medicine, Saint-Etienne University Hospital, Saint-Etienne, France.
  • Immunology and Immuno-monitoring Laboratory INSERM, U1111, CNRS, UMR 5308, CIRI - GIMAP, UCBL 1, UJM, iBiothera, CIC 1408, Saint-Étienne, France.
  • Vaccine Research Institute, Créteil, France.

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.

MeSH

Sars-Cov-2, Virion, Antibodies, Viruses, Immunity, Complement System Proteins, Severe Acute Respiratory Syndrome-Related Coronavirus