Potent cross-reactive antibodies following Omicron breakthrough in vaccinees

10.1016/j.cell.2022.05.014

Cell

19th May 2022

Contributing to research themes:

Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.

Author list:

Affiliations

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK
Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK
Diamond Light Source Ltd, Harwell Science & Innovation Campus, Didcot, UK
Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Peter Medawar Building for Pathogen Research, Oxford, UK
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
Translational Gastroenterology Unit, University of Oxford, Oxford, UK
Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Viral Pseudotype Unit, Medway School of Pharmacy, University of Kent and Greenwich, Chatham Maritime, Kent ME4 4TB, UK
NIHR Oxford Biomedical Research Centre, Oxford, UK
Centre For Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand
Department of Paediatrics, University of Oxford, Oxford, UK

Authors

Rungtiwa Nutalai,^1,16 Daming Zhou,^2,3,16 Aekkachai Tuekprakhon,^1,16 Helen M. Ginn,^4,16 Piyada Supasa,^1,16
Chang Liu,^1,3,16Jiandong Huo,^2,16 Alexander J. Mentzer,^1,5,16 Helen M.E. Duyvesteyn,² Aiste Dijokaite-Guraliuc,¹
Donal Skelly,^5,6,7Thomas G. Ritter,⁵ Ali Amini,^5,6,8 Sagida Bibi,⁹ Sandra Adele,⁵ Sile Ann Johnson,⁵ Bede Constantinides,¹⁰ Hermione Webster,¹⁰ Nigel Temperton,¹¹ Paul Klenerman,^5,6,8,12 Eleanor Barnes,^5,6,8,12 Susanna J. Dunachie,^5,6,10,13,14 Derrick Crook,¹⁰ Andrew J. Pollard,^9,12 Teresa Lambe,^3,9 Philip Goulder,^6,15 OPTIC consortium, ISARIC4C consortium, Neil G. Paterson,⁴ Mark A. Williams,⁴ David R. Hall,⁴ Juthathip Mongkolsapaya,^1,3 Elizabeth E. Fry,²
Wanwisa Dejnirattisai,¹,* Jingshan Ren,²,* David I. Stuart,^2,3,4,17,* and Gavin R. Screaton^1,3,*