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

Abstract

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 SARS-CoV-2 alpha variant prompted the UK to extend the interval between doses to 12 weeks. In this study, we aimed to quantify the effect of delaying the second vaccine dose in England.

Methods: We used a previously described model of SARS-CoV-2 transmission, calibrated to COVID-19 surveillance data from England, 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 in the counterfactual scenario in which vaccine doses were administered 3 weeks apart against the real reported vaccine roll-out schedule of 12 weeks. We estimated and compared the resulting numbers of daily infections, hospital admissions, and deaths. In sensitivity analyses, we investigated scenarios spanning a range of vaccine effectiveness and waning assumptions.

Findings: In the period from Dec 8, 2020, to Sept 13, 2021, the number of individuals who received a first vaccine dose was higher under the 12-week strategy than the 3-week strategy. For this period, we estimated that delaying the interval between the first and second COVID-19 vaccine doses from 3 to 12 weeks averted a median (calculated as the median of the posterior sample) of 58 000 COVID-19 hospital admissions (291 000 cumulative hospitalisations [95% credible interval 275 000-319 000] under the 3-week strategy vs 233 000 [229 000-238 000] under the 12-week strategy) and 10 100 deaths (64 800 deaths [60 200-68 900] vs 54 700 [52 800-55 600]). Similarly, we estimated that the 3-week strategy would have resulted in more infections compared with the 12-week strategy. Across all sensitivity analyses the 3-week strategy resulted in a greater number of hospital admissions. In results by age group, the 12-week strategy led to more hospitalisations and deaths in older people in spring 2021, but fewer following the emergence of the delta variant during summer 2021.

Interpretation: England's delayed-second-dose vaccination strategy was informed by early real-world data on vaccine effectiveness in the context of limited vaccine supplies in a growing epidemic. Our study shows that rapidly providing partial (single-dose) vaccine-induced protection to a larger proportion of the population was successful in reducing the burden of COVID-19 hospitalisations and deaths overall.

Funding: UK National Institute for Health Research; UK Medical Research Council; Community Jameel; Wellcome Trust; UK Foreign, Commonwealth and Development Office; Australian National Health and Medical Research Council; and EU.

Figure 1

Flow diagram showing an overview of the extended susceptible–exposed–infectious–removed transmission model Blue arrows represent relevant flows in vaccination strata, dark red and purple in hospital pathways, and green in SARS-CoV-2 variant compartments. See appendix 1 for the full diagram with flows describing SARS-CoV-2 variants, vaccination status, and hospital pathways (p 4), and definitions of all variables and parameters (pp 17, 35). S=susceptible. E=exposed. I_A=infected, asymptomatic. I_P=presymptomatic infectious. I_C1=symptomatic, infectious. I_C2=symptomatic, not infectious. H=hospitalised. G_D=severe disease, leading to death (at home). D=deceased (as a result of COVID-19). R=recovered. ⁱ=age or care-home group (5-year age bands from 0−4 years to 75−79 years; ≥80 years age group; care-home worker; and care-home resident). ^j=SARS-CoV-2 variant (alpha, delta, or alpha:delta [ie, infected with delta after a previous infection with alpha]). ^k=vaccination stratum (0, 1, 2, 3). V_k=in vaccination stratum k. λ(t)=force of infection at time t. γ=rate of disease progression. p_C=probability of being symptomatic, given infected. p_H=probability of severe disease requiring hospitalisation, given symptomatic disease. p_GD=probability of death for severe symptomatic cases outside of hospital. p*=probability of COVID-19 diagnosis confirmed before admission to hospital. η=probability of being protected against infection with the SARS-CoV-2 delta variant for those recovered from infection with the SARS-CoV-2 alpha variant. ζ(t)= rate of movement between vaccination strata.

Figure 2

Vaccine effectiveness against the SARS-CoV-2 delta variant over time following the second dose of COVID-19 vaccine Vaccine effectiveness is shown separately for the Oxford–AstraZeneca vaccine (ChAdOx1 nCoV-19; left column) and the Pfizer–BioNTech vaccine (BNT162b2, tozinameran; right column), and for three outcomes: death (A), severe disease (B), and mild disease or infection (C). We assumed the same protection against infection and mild disease. The graphs show data and uncertainty ranges representing vaccine effectiveness estimates from Andrews and colleagues' study, and points corresponding to our model assumptions. We assumed that the Moderna vaccine has the same vaccine effectiveness as BNT162b2. Note: the x-axis differs in the bottom row. Corresponding data for the SARS-CoV-2 alpha variant are provided in appendix 1 (p 11).

Figure 3

COVID-19 vaccine doses administered and epidemic trajectory in England Results are shown for central vaccine effectiveness and waning assumptions (see appendix 1 pp 57–64 for sensitivity analyses results). The vertical dashed lines indicate each step of the UK Government's roadmap out of lockdown, in which non-pharmaceutical interventions were lifted in a stepwise manner: step 1, schools reopened, outdoor gatherings of no more than six people allowed; step 2, non-essential retail opened; step 3, outdoor gatherings up to 30 people allowed, indoor gatherings up to 6 people allowed; step 4, no limits on social contact. The vertical solid line shows the time when the delta variant emerged. (A) Cumulative vaccine doses administered between Dec 8, 2020, and Sept 13, 2021. (B) Daily hospital admissions. Points show the data, lines represent the median model fit under the 12-week strategy and median of the simulated daily hospital admissions under the counterfactual scenario assuming a 3-week delay between vaccine doses. Shaded areas are 95% credible intervals. Uncertainty is greater for the 3-week scenario, which was explored through unconstrained simulations, than for the 12-week fit, which was obtained by particle filtering and is thus more constrained by the data (see appendix 1 pp 4–5 for methods). (C) Cumulative hospital admissions over time under the 12-week and 3-week strategies.

Figure 4

Vaccine-induced protection against COVID-19 (A) Vaccination status within the population for each month for the 12-week strategy (model fit) and 3-week strategy (counterfactual). (B) Proportion of the population without vaccine protection against infection with SARS-CoV-2 alpha or delta variants. Value as presented is the mean protection across all vaccine strata, all age groups, and all regions, weighted by population. (C) Mean (as above) population risk of hospitalisation given infection, for first infections. These estimates account for vaccine-induced protection but not for naturally acquired protection from previous infections.

Figure 5

Modelled daily COVID-19 hospital admissions over time by age group for the 12-week and 3-week strategies Colours show the status of vaccine-induced protection of hospitalised individuals.