Complement-mediated enhancement of SARS-CoV-2 antibody neutralisation potency in vaccinated individuals
Abstract
Abstract 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.
Article Details
Authors (46)
Jack Mellors
Raman Dhaliwal
Tom Tipton
Iain McInnes
Stefan Siebert
Pam Kearns
Dan Rea
Gordon Cook
Michelle Willicombe
David Thomas
Thushan de Silva
Lucy Wedderburn
Rossa Brugha
Jessica Bate
Carl Goodyear
Alex Richter
Clinical Immunology Services, University of Birmingham, Birmingham, United Kingdom
John Snowden
Jack Satsangi
Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Sean Hua Lim
Amanda Kirkham
Sarah Bowden
Sophia Magwaro
Ana Hughes
Ann Pope
Elspeth Insch
Vicky Churchill
Richard Beesley
Eilean MacDonald
Sagida Bibi
Christopher P. Conlon
Alexandra S. Deeks
Christina Dold
Susanna Dunachie
John Frater
Katie Jeffery
Barbara Kronsteiner
NDM Centre for Global Health Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
Teresa Lambe
Stephanie Longet
Alexander J. Mentzer
Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Donal Skelly
Lizzie Stafford
Eleanor Barnes
Susanna J. Dunachie
Paul Klenerman
Translational Gastroenterology and Liver Unit, University of Oxford, Oxford, United Kingdom
Julian Hiscox
Miles Carroll