AbstractBackgroundAs evidence shows that vaccine immunity to COVID-19 wanes with time and decreases due to variants, several countries are implementing booster vaccination campaigns. The objective of this study was to analyze the morbidity and mortality burdens of different primary and booster vaccination strategies against COVID-19, using France as a case study.MethodsWe used a deterministic, age-structured, compartmental model fitted to hospital admission data and validated against sero-prevalence data in France to analyze the impact of primary and booster vaccination strategies on morbidity and mortality assuming waning of immunity and increased virus transmissibility during winter.FindingsStrategies prioritizing primary vaccinations were systematically more effective than strategies prioritizing boosters. Regarding booster strategies targeting different age groups, their effectiveness varied with the levels of virus transmissibility, and according to the assumed loss of immunity for each age group. If the immunity reduction affects all age groups, people aged 30 to 49 years should be boosted in priority, even for low transmissibility levels. If the immunity reduction is restricted to people older than 65 years, boosting younger people becomes effective only above certain levels of transmissibility.InterpretationIncreasing the primary vaccination coverage should remain a priority to reduce morbidity and mortality due to COVID-19. If a plateau of primary vaccination has been reached, boosting immunity in younger age-groups could prevent more hospitalizations and deaths than boosting the immunity of older people, especially under conditions increasing SARS-CoV-2 transmissibility, or when facing new variants.FundingThe study was partially funded by the French national research agency through project SPHINX-17-CE36-0008-0.Research in contextEvidence before this studyMany countries have started booster vaccination programs against Covid-19, while others are still struggling to vaccinate their population. However, evidence is scarce regarding the optimal vaccination strategy to pursue in a rapidly evolving epidemiological context. A search of the literature on Nov 27 2021, using the terms (booster OR third dose) AND vaccine AND strategy AND (COVID* OR SARS*) AND (effect OR impact), returned 45 studies on PubMed and 1602 on medRxiv. However, very few studies assessed the public health impact of a booster strategy, and none of them compared different allocations strategies between primary and booster vaccinations, or investigated which age-group should be targeted for booster vaccination to maximize the public health impact of the strategy.Added value of this studyUsing an epidemiological model able to replicate the dynamic of the SARS-CoV-2 epidemic and able to account for the use of multiple vaccines and booster, we analyzed the effectiveness of different vaccination strategies, either based on prioritization of primary vaccination versus booster, or based on the age-group targeted for the booster vaccination. We evaluated the strategies in terms of hospitalizations and deaths avoided, in various epidemic scenarios during winter 2021-2022. To our knowledge, this is the first modeling study evaluating such strategies. We found that increasing primary vaccination of all adults is always more beneficial than giving a booster dose to elderly individuals, and that the age-group to target for a booster dose for optimal effectiveness depends on the level of transmission of the virus. As the level of SARS-CoV-2 transmission increases, boosting immunity in younger age-groups becomes the most effective strategy to decrease hospitalizations and deaths in the general population.Implications of all available evidenceCountries that have not reached the plateau of primary vaccination should focus their effort towards extending the overall primary vaccination coverage rather than boosting the immunity of fully vaccinated people, even for elderly individuals that may be facing waning immunity. When considering booster vaccination, the choice of which age groups to target should consider the level of virus transmissibility in the population. Considering the emergence of new, more transmissible SARS-CoV-2 variants, increasing the worldwide vaccination coverage should remain a priority.