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Introduction The Eliminate Yellow fever Epidemics (EYE) strategy was launched in 2017 in response to the resurgence of yellow fever in Africa and the Americas. The strategy relies on several vaccination activities, including preventive mass vaccination campaigns (PMVCs). However, by how much PMVCs are associated with a decreased risk of outbreak to occur has not yet been quantified. Methods and Findings We used the self-controlled case series (SCCS) method to assess the association between the occurrence of yellow fever outbreaks and the implementation of PMVCs at the province level in the African endemic region. As all time-invariant confounders are implicitly controlled for, the SCCS method is an alternative to classical cohort or case-control study designs when the risk of residual confounding is high, in particular confounding by indication. The location and dates of outbreaks were identified from international epidemiological records, and information on PMVCs was provided by coordinators of vaccination activities and international funders. The study sample consisted of provinces that were both affected by an outbreak and targeted for a PMVC between 2005 and 2018. We compared the relative incidence of outbreaks before and after the implementation of a PMVC. The sensitivity of our estimates to a range of assumptions was explored, and the results of the SCCS method were compared to those obtained through a retrospective cohort study design. We further derived the number of yellow fever outbreaks that have been prevented by PMVCs. The study sample consisted of 33 provinces from 11 African countries. Among these, outbreaks occurred during the pre-PMVC period in 26 (79%) provinces versus 7 (21%) occurring in the post-PMVC period. At the province level, the post-PMVC period was associated with a 86% reduction (95% Confidence interval 66% to 94%, p-value A limitation of our study is the fact that it does not account for potential time-varying confounders, such as changing environmental drivers of yellow fever or possibly improved disease surveillance. Conclusion In this study, we provide new empirical evidence of the high preventive impact of PMVCs on yellow fever outbreaks. This study illustrates that the SCCS method can be advantageously applied at the population level in order to evaluate a public health intervention. AUTHOR SUMMARY Why Was This Study Done? Yellow fever is a mosquito-borne vaccine-preventable disease that may cause large urban outbreaks, especially in tropical African regions. Since 2006, Preventive Mass Vaccination Campaigns (PMVCs) have been implemented in many African provinces. These are large scale vaccination campaigns targeting all or most age group in a specific area. The preventive impact PMVCs may have on the risk of yellow fever outbreak has not been quantified yet. What Did the Researchers Do and Find? We used the self-controlled case series (SCCS) method to assess the association between PMVCs and outbreak risk at the province level over 34 African countries between 2005 and 2018. Using this method, we compared pre- and post-PMVC period are compared within each province individually, thus controlling for all possible confounders that do not vary in time, especially the fact that provinces indicated for PMVCs are generally those considered at highest baseline risk of yellow fever (ie confounding by indication). At the province level, we estimated that implementation of PMVCs was associated with an 86% reduction (66% to 94%) in the risk of yellow fever outbreak. Results from a complete cohort analysis provided less reliable results than the SCCS method, likely because of confounding by indication that was not entirely controlled for by adjusting on known drivers of yellow fever. We further estimated that all PMVCs conducted between 2006 and 2018 in Africa may have reduced the total number of yellow fever outbreaks by 34% (22% to 45%). What Do These Findings Mean? These results provide new empirical evidence of the high preventive impact of PMVCs on yellow fever outbreaks. These results may encourage rapid re-scheduling of yellow fever PMVCs that have been postponed due to the COVID-19 pandemic. The SCCS design may be advantageously applied at the population level to assess the impact of public health interventions.

International audience; Yellow Fever (YF) remains a major public health issue in Sub-Saharan Africa and South America, despite the availability of an effective vaccine. In Africa, most YF outbreaks are reported in West Africa. However, urban outbreaks occurred in 2016 in both Angola and the Democratic Republic of Congo (DRC), and imported cases were reported in Chinese workers coming back from Africa. In Central Africa, Cameroon and the Republic of Congo host a high proportion of non-vaccinated populations increasing the risk of urban outbreaks. The main vector is Aedes aegypti and possibly, Aedes albopictus, both being anthropophilic and domestic mosquitoes. Here, we provide evidence that both Ae. aegypti and Ae. albopictus in Cameroon and the Republic of Congo are able to transmit Yellow fever virus (YFV) with higher rates of infection, dissemination, and transmission for Ae. aegypti. We conclude that the potential of both Aedes species to transmit YFV could increase the risk of urban YF transmission and urge public health authorities to intensify their efforts to control domestic vectors, and extend vaccine coverage to prevent major YFV outbreak.