Dosing interval strategies for two-dose COVID-19 vaccination in 13 middle-income countries of Europe: Health impact modelling and benefit-risk analysis

Abstract

Background: In settings where the COVID-19 vaccine supply is constrained, extending the intervals between the first and second doses of the COVID-19 vaccine may allow more people receive their first doses earlier. Our aim is to estimate the health impact of COVID-19 vaccination alongside benefit-risk assessment of different dosing intervals in 13 middle-income countries (MICs) of Europe.

Methods: We fitted a dynamic transmission model to country-level daily reported COVID-19 mortality in 13 MICs in Europe (Albania, Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina, Bulgaria, Georgia, Republic of Moldova, Russian Federation, Serbia, North Macedonia, Turkey, and Ukraine). A vaccine product with characteristics similar to those of the Oxford/AstraZeneca COVID-19 (AZD1222) vaccine was used in the base case scenario and was complemented by sensitivity analyses around efficacies similar to other COVID-19 vaccines. Both fixed dosing intervals at 4, 8, 12, 16, and 20 weeks and dose-specific intervals that prioritise specific doses for certain age groups were tested. Optimal intervals minimise COVID-19 mortality between March 2021 and December 2022. We incorporated the emergence of variants of concern (VOCs) into the model and conducted a benefit-risk assessment to quantify the tradeoff between health benefits versus adverse events following immunisation.

Findings: In all countries modelled, optimal strategies are those that prioritise the first doses among older adults (60+ years) or adults (20+ years), which lead to dosing intervals longer than six months. In comparison, a four-week fixed dosing interval may incur 10.1% [range: 4.3% - 19.0%; n = 13 (countries)] more deaths. The rapid waning of the immunity induced by the first dose (i.e. with means ranging 60-120 days as opposed to 360 days in the base case) resulted in shorter optimal dosing intervals of 8-20 weeks. Benefit-risk ratios were the highest for fixed dosing intervals of 8-12 weeks.

Interpretation: We infer that longer dosing intervals of over six months could reduce COVID-19 mortality in MICs of Europe. Certain parameters, such as rapid waning of first-dose induced immunity and increased immune escape through the emergence of VOCs, could significantly shorten the optimal dosing intervals.

Funding: World Health Organization.

Keywords: AEFI, Adverse events following immunisation; COVID-19; MIC, Middle income country; Mathematical modelling; Public health intervention; Quantitative methods; SARS-CoV-2; VE, Vaccine Efficacy; VOC, Variant of Concern; Vaccine policy.

Figure 1

The conceptual diagram describes the underlying mathematical models of SARS-CoV-2 transmission dynamics and COVID-19 vaccination impact. S - susceptible; V₁ - individuals protected by the first dose only; V₂ - individuals protected by both doses; S_w - individuals who have received their first dose but the protection has waned; E - exposed; E_v1 - exposed progressed from individuals in V₁; E_v2 - exposed progressed from individuals in V₂; I_p - pre-clinical infectious individuals; I_c - clinical individuals; I_s - subclinical individuals; R - recovered; R_v1 - previously infected individuals whose infection-induced immunity has yet to wane and who have received the first dose; R_v2 individuals whose infection-induced immunity has yet to wane and who have received both doses.

Figure 2

(a) Vaccine efficacy by effect type, respectively describing onward transmission blocking, infection-, disease-, severe case- and mortality-reducing vaccine efficacies. (b) Sensitivity analysis parameter set that describes a condition where longer dosing interval is associated with larger incremental change incurred by the second doses in infection- and disease-reducing vaccine efficacies. (c) Vaccine supply and allocation conditions by dose. We assume a 24-week delay between the supply of first and second doses. We did not show strategies A2, A3 and A4 as they reflect incremental changes between A1 and A5. Each line represents a country. Refer to Table 1 for descriptions of vaccination strategies.

Figure 3

COVID-19 dosing intervals under strategies B1 and B2. These dosing strategies do not prescribe fixed dosing intervals. Vaccine allocations depend on whether or not coverage goals have been met in specific target groups. The distributions are outputs from dose allocation algorithms that capture such conditional relationships. Refer to Table 1 for descriptions of vaccination strategies.

Figure 4

Percentage difference in mortality for different vaccination strategies relative to strategy B1. Each line represents a country. Detailed descriptions of the vaccine dosing strategies can be found in Table 1. Mean dosing intervals are presented as the second rows of x-axes labels (unit = weeks). Results from sensitivity analyses around the first dose waning durations (360 days vs 120 days) and the emergence of variants of concern (VOCs) are also presented.

Figure 5

Benefit-risk ratios of vaccination strategies. Benefit-risk ratios of the different dosing interval strategies in comparison to strategy A1 are presented. Strategies A1-A5 and B1-B2 are arranged broadly based on mean effective dosing intervals. Each line represents one country. The benefit-risk ratios quantify the change in deaths prevented by the vaccines versus caused by AEFIs as compared to strategy A1. Refer to Table 1 for descriptions of vaccination strategies.