The effect of Omicron breakthrough infection and extended BNT162b2 booster dosing on neutralization breadth against SARS-CoV-2 variants of concern


COVID–19 vaccines are playing a vital role in controlling the COVID–19 pandemic. As SARS–CoV–2 variants encoding mutations in the surface glycoprotein, Spike, continue to emerge, there is increased need to identify immunogens and vaccination regimens that provide the broadest and most durable immune responses. We compared the magnitude and breadth of the neutralizing antibody response, as well as levels of Spike–reactive memory B cells, in individuals receiving a second dose of BNT126b2 at a short (3–4 week) or extended interval (8–12 weeks) and following a third vaccination approximately 6–8 months later. We show that whilst an extended interval between the first two vaccinations can greatly increase the breadth of the immune response and generate a higher proportion of Spike reactive memory B cells, a third vaccination leads to similar levels between the two groups. Furthermore, we show that the third vaccine dose enhances neutralization activity against omicron lineage members BA.1, BA.2 and BA.4/BA.5 and this is further increased following breakthrough infection during the UK omicron wave. These findings are relevant for vaccination strategies in populations where COVID–19 vaccine coverage remains low.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was funded by; Huo Family Foundation Award to MHM and KJD, MRC Genotype–to–Phenotype UK National Virology Consortium ([MR/W005611/1] to MHM and KJD), Fondation Dormeur, Vaduz for funding equipment to KJD, Wellcome Trust Investigator Award [222433/Z/21/Z] to MHM, and Wellcome Trust Multi–User Equipment Grant [208354/Z/17/Z] to MHM. and KJD. CG was supported by the MRC–KCL Doctoral Training Partnership in Biomedical Sciences [MR/N013700/1]. DC was supported by a BBSRC CASE in partnership with GlaxoSmithKline [BB/V509632/1]. This work and the Infectious Diseases Biobank (CM) were supported by the Department of Health via a National Institute for Health Research comprehensive Biomedical Research Centre award to Guy′s and St Thomas′ NHS Foundation Trust in partnership with King′s College London and King′s College Hospital NHS Foundation Trust. This study is part of the EDCTP2 programme supported by the European Union (grant number RIA2020EF–3008 COVAB) (KJD, JF, MHM). The views and opinions of authors expressed herein do not necessarily state or reflect those of EDCTP. This project is supported by a joint initiative between the Botnar Research Centre for Child Health and the European & Developing Countries Clinical Trials Partnership (KJD and JF).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.


The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study used human samples collected with written consent as part of a study entitled ″Antibody responses following COVID–19 vaccination″. Ethical approval was obtained from the King′s College London Infectious Diseases Biobank (IBD) (KDJF–110121) under the terms of the IDB′s ethics permission (REC reference: 19/SC/0232) granted by the South Central – Hampshire B Research Ethics Committee in 2019.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.


I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).


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Data Availability

All data produced in the present work are contained in the manuscript

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