Complement-mediated enhancement of SARS-CoV-2 antibody neutralisation potency in vaccinated individuals
With the continued emergence of SARS-CoV-2 variants and concerns of waning immunity, there is a need for better defined correlates of protection to aid future vaccine and therapeutic developments. Whilst neutralising antibody titres are associated with protection, these are typically determined in the absence of the complement system, which has the potential to enhance neutralisation titres and strengthen correlates with protection in vivo. Here we show that replenishment of the complement system in neutralisation assays can significantly enhance neutralisation titres, with up to an ~83-fold increase in neutralisation of the BA.1.1.529 strain using cross-reactive sera from vaccination against the ancestral strain. The magnitude of enhancement significantly varies between individuals, viral strains (wild-type/VIC01 and Omicron/BA.1), and cell lines (Vero E6 and Calu-3), and is abrogated following heat-inactivation of the complement source. Utilising ACE2 competition assays, we show that the mechanism of action is partially mediated by reducing ACE2-spike interactions. Through the addition of compstatin (a C3 inhibitor) to live virus neutralisation assays, the complement protein C3 is shown to be required for maximum efficiency. These findings further our understanding of SARS-CoV-2 immunity and neutralisation, with implications for protection against emerging variants and assessing future vaccine and therapeutic developments.
Authors
- Teresa Lambe (ORCID: https://orcid.org/0000-0001-7711-897X)
- Elspeth Insch
- Ana Hughes (ORCID: https://orcid.org/0000-0001-7274-9422)
- Amanda Kirkham (ORCID: https://orcid.org/0000-0002-2593-7970)
- Michelle Willicombe (ORCID: https://orcid.org/0000-0002-6404-0584)
- Jack Mellors (ORCID: https://orcid.org/0000-0001-7761-8341)
- Alex Richter
- Julian A. Hiscox (ORCID: https://orcid.org/0000-0002-6582-0275)
- Sophia Magwaro
- Jessica Bate (ORCID: https://orcid.org/0000-0003-4933-9497)
- John A. Snowden (ORCID: https://orcid.org/0000-0001-6819-3476)
- David Thomas (ORCID: https://orcid.org/0000-0002-9738-2329)
- Jack Satsangi
- Katie Jeffery (ORCID: https://orcid.org/0000-0002-6506-2689)
- Carl S. Goodyear (ORCID: https://orcid.org/0000-0001-5926-5941)
- Eleanor Barnes (ORCID: https://orcid.org/0000-0002-0860-0831)
- Paul Klenerman (ORCID: https://orcid.org/0000-0003-4307-9161)
- Richard Beesley (ORCID: https://orcid.org/0000-0003-1796-4941)
- Tom Tipton (ORCID: https://orcid.org/0000-0002-0573-528X)
- Lucy R. Wedderburn (ORCID: https://orcid.org/0000-0002-7495-1429)
- Gordon C Cook (ORCID: https://orcid.org/0000-0003-1717-0412)
- Christina Dold (ORCID: https://orcid.org/0000-0003-2314-507X)
- Donal Skelly (ORCID: https://orcid.org/0000-0002-2426-3097)
- Alexander J. Mentzer (ORCID: https://orcid.org/0000-0002-4502-2209)
- John Frater (ORCID: https://orcid.org/0000-0001-7163-7277)
- Lizzie Stafford (ORCID: https://orcid.org/0000-0002-1610-5136)
- Raman Dhaliwal
- Pamela R. Kearns (ORCID: https://orcid.org/0000-0003-2756-5813)
- S. Bowden (ORCID: https://orcid.org/0000-0001-7506-1340)
- Thushan I. de Silva (ORCID: https://orcid.org/0000-0002-6498-9212)
- Stephanie Longet
- Stefan Siebert (ORCID: https://orcid.org/0000-0002-1802-7311)
- Alexandra Deeks (ORCID: https://orcid.org/0000-0001-8895-317X)
- Sean H. Lim (ORCID: https://orcid.org/0000-0002-2768-4858)
- Dan Rea
- Ruairı́ Brugha (ORCID: https://orcid.org/0000-0003-0729-0197)
- Sagida Bibi (ORCID: https://orcid.org/0000-0002-0855-2737)
- Ann Pope (ORCID: https://orcid.org/0000-0001-7458-3294)
- Barbara Kronsteiner (ORCID: https://orcid.org/0000-0003-0867-2867)
- Iain B. McInnes (ORCID: https://orcid.org/0000-0002-6462-4280)
- Miles W. Carroll (ORCID: https://orcid.org/0000-0002-7026-7187)
- Susanna Dunachie (ORCID: https://orcid.org/0000-0001-5665-6293)
- Vicky Churchill
- Christopher P. Conlon (ORCID: https://orcid.org/0000-0002-3531-2464)
- Eilean MacDonald (ORCID: https://orcid.org/0000-0002-5795-3393)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- University of Liverpool (GB)
- Inserm (FR)
- Nuffield Orthopaedic Centre (GB)
- University of Oxford (GB)
- Oxford BioMedica (United Kingdom) (GB)
- Centre International de Recherche en Infectiologie (FR)
- Université Jean Monnet (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-18
- DOI
- https://doi.org/10.1038/s41467-025-57947-8
- Citations
- 8
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 11.17