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

Summary 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 could let 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 for low- and middle-income countries of Europe. Methods We fitted a dynamic transmission model to country-level daily reported COVID-19 mortality in 13 low- and middle-income countries in the World Health Organization European Region (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 the Oxford/AstraZeneca COVID-19 (AZD1222) vaccine was used in the base case scenario and was complemented by sensitivity analyses around efficacies related 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 into the model, and also conducted a benefit-risk assessment to quantify the trade-off between health benefits versus adverse events following immunisation. Findings In 12 of the 13 countries, optimal strategies are those that prioritise the first doses among older adults (60+ years) or adults (20-59 years). These strategies lead to dosing intervals longer than six months. In comparison, a four-week fixed dosing interval may incur 10.2% [range: 4.0% - 22.5%; n = 13 (countries)] more deaths. There is generally a negative association between dosing interval and COVID-19 mortality within the range we investigated. Assuming a shorter first dose waning duration of 120 days, as opposed to 360 days in the base case, led to shorter optimal dosing intervals of 8-12 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, which are substantially longer than the current label recommendation for most vaccine products, could reduce COVID-19 mortality in low- and middle-income countries of WHO/Europe. Certain vaccine features, such as fast waning of first doses, significantly shorten the optimal dosing intervals. Funding World Health Organization