Quantifying the impact of delaying the second COVID-19 vaccine dose in England: a mathematical modelling study

Background The UK was the first country to start national COVID-19 vaccination programmes, initially administering doses 3-weeks apart. However, early evidence of high vaccine effectiveness after the first dose and the emergence of the Alpha variant prompted the UK to extend the interval between doses to 12-weeks. In this study, we quantify the impact of delaying the second vaccine dose on the epidemic in England. Methods We used a previously described model of SARS-CoV-2 transmission and calibrated the model to English surveillance data including hospital admissions, hospital occupancy, seroprevalence data, and population-level PCR testing data using a Bayesian evidence synthesis framework. We modelled and compared the epidemic trajectory assuming that vaccine doses were administered 3-weeks apart against the real vaccine roll-out schedule. We estimated and compared the resulting number of daily infections, hospital admissions, and deaths. A range of scenarios spanning a range of vaccine effectiveness and waning assumptions were investigated. Findings We estimate that delaying the interval between the first and second COVID-19 vaccine doses from 3- to 12-weeks prevented an average 64,000 COVID-19 hospital admissions and 9,400 deaths between 8th December 2020 and 13th September 2021. Similarly, we estimate that the 3-week strategy would have resulted in more infections and deaths compared to the 12-week strategy. Across all sensitivity analyses the 3-week strategy resulted in a greater number of hospital admissions. Interpretation England’s delayed second dose vaccination strategy was informed by early real-world vaccine effectiveness data and a careful assessment of the trade-offs in the context of limited vaccine supplies in a growing epidemic. Our study shows that rapidly providing partial vaccine-induced protection to a larger proportion of the population was successful in reducing the burden of COVID-19 hospitalisations and deaths. There is benefit in carefully considering and adapting guidelines in light of new emerging evidence and the population in question. Funding National Institute for Health Research, UK Medical Research Council, Jameel Institute, Wellcome Trust, and UK Foreign, Commonwealth and Development Office, National Health and Medical Research Council. Evidence before this study We searched PubMed up to 10th June 2022, with no language restrictions using the following search terms: (COVID-19) AND (vaccin*) AND (dose OR dosing) AND (delay OR interval) AND (quant* OR assess* OR impact). We found 14 studies that explored the impact of different vaccine dosing intervals. However, the majority were prospective assessments of optimal vaccination strategies, exploring different trade-offs between vaccine mode of action, vaccine effectiveness, coverage, and availability. Only two studies retrospectively assessed the impact of different vaccination intervals. One assessed the optimal timing during the epidemic to switch to an extended dosing interval, and the other assessed the risk of all-cause mortality and hospitalisations between the two dosing groups. Added value of this study Our data synthesis approach combines real-world evidence from multiple data sources to retrospectively quantify the impact of extending the COVID-19 vaccine dosing interval from the manufacturer recommended 3-weeks to 12-weeks in England. Implications of all the available evidence Our study demonstrates that rapidly providing partial vaccine-induced protection to a larger proportion of the population was successful in reducing the COVID-19 hospitalisations and mortality. This was enabled by rapid and careful monitoring of vaccine effectiveness as nationwide vaccine programmes were initiated, and adaptation of guidelines in light of emerging evidence. ### Competing Interest Statement AC has received payment from Pfizer for teaching of mathematical modelling of infectious diseases. KAMG has received honoraria from Wellcome Genome Campus for lectures. LKW has received consultancy payments from the Wellcome Trust. ABH has received consultancy payments from the World Health Organization for COVID-19 related work. ABH provides COVID-19 modelling advice to the New South Wales Ministry of Health, Australia. ABH was previously engaged by Pfizer Inc to advise on modelling RSV vaccination strategies for which she received no financial compensation. RS is currently employed by the Wellcome Trust, however the Wellcome Trust had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. All other authors declare no competing interests. ### Funding Statement This work was supported jointly by the Wellcome Trust and the Department for International Development (DFID; 221350). We acknowledge joint Centre funding from the UK MRC and DFID (MR/R015600/1). This work was also supported by the NIHR Health Protection Research Unit in Modelling Methodology, a partnership between UKHSA, Imperial College London, and London School of Hygiene & Tropical Medicine (NIHR200908), the Abdul Latif Jameel Foundation, and the EDCTP2 programme supported by the European Union (EU). LKW acknowledges support from a Wellcome Trust Fellowship (grant number 218669/Z/19/Z). ABH acknowledges support from an NHMRC Investigator Grant. For the purpose of open access, the author has applied a 'Creative Commons Attribution' (CC BY) licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics permission was sought for the study via Imperial College London's (London, UK) standard ethical review processes and was approved by the College's Research Governance and Integrity Team (ICREC reference 21IC6945). 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. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. 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). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data files and source code required to reproduce this analysis are publicly available at https://github.com/mrc-ide/sarscov2-roadmap-england