Equity in protection: bridging global data gaps for an EBV vaccine - a systematic review and meta-analysis

IntroductionEpstein-Barr virus (EBV) is linked to multiple malignancies and autoimmune conditions, with different disease burdens globally. Pharmaceutical companies and researchers are placing substantial investment in the development of EBV vaccines. To ensure optimal vaccine roll-out, particularly in resource-limited settings, it is essential to have data on the age at acquisition of EBV. We aimed to systematically review and meta-analyse seroprevalence by age by country, World Health Organization (WHO) region, and country income level; to identify knowledge gaps; and determine an approach to bridge these gaps. MethodsMEDLINE, Embase, and Web of Science databases were searched on March 22, 2022, for studies that measured EBV seroprevalence by age. An updated search was conducted on October 22, 2022. There were no language restrictions. Papers were assessed for quality using an adapted version of the Downs and Black checklist. Seroprevalence by age was estimated using a fixed-effect (country) or random-effects (WHO region, income) meta-analysis. This review has been registered on PROSPERO (CRD42022349900). ResultsOnly one country (United States) had enough data for a country meta-analysis. WHO Regional analyses revealed the Western Pacific region to have a higher seroprevalence at younger age groups than other WHO regions. Country income level better explained seroprevalence trends per age. Middle-income countries displayed a quicker rise to equilibrium seroprevalence than high-income countries, with a 30% absolute increase in 0- to 4-year-olds in middle-income than high-income countries (59% [95% CI 28-91%, I2 =99%] versus 29% [95% CI 16-41%, I2 =99%], respectively). ConclusionThis first meta-analysis producing estimates of EBV seroprevalence by age, provides crucial information to guide governments when choosing if to implement a vaccine for EBV. However, data variability and limited consistency of methodologies and EBV seroprevalence measurements hindered comprehensive meta-analyses across all WHO regions and countries. We provide an interim framework for the extrapolation of seroprevalence using country-specific income levels to aid vaccine rollout decisions. Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSThis study built on a previous systematic review evaluating the global literature to identify risk factors associated with EBV acquisition. The review searched three databases, (MEDLINE, Embase, and Web of Science), for studies investigating EBV risk factors (including age), on March 16 2017. No meta-analysis was performed, limiting the conclusions that could be drawn, but when data were grouped by country and WHO region it was revealed that EBV seroconversion tends to occur at younger ages in Asia versus Europe and North America. A substantial data gap was identified for countries in Africa and South America. What this study addsOur study documents more than double the number of publications on EBV seroprevalence by age globally and provides the first meta-analysis on the topic, which will be vital for governments seeking to deploy an EBV vaccine in their country. In the face of a dearth of data for many countries (particularly low- and middle-income countries, such as China, where EBV-associated nasopharyngeal carcinoma is endemic), we demonstrate how country income can be used to group studies and thus extrapolate to fill data gaps. How this study might affect research, practice or policyThe deployment strategy and cost-effectiveness case for an EBV vaccine will vary substantially among countries due to geographic variability in a) the burden of EBV-associated diseases and b) when infection is acquired. To inform deployment, it is critical to either have country-by-country data on the age at acquisition or a means to extrapolate from another appropriate setting. Our study informs policymakers on both points, by providing both meta-analysis estimates where possible and an interim framework for extrapolation of data among countries before new seroprevalence studies arise. This is particularly critical for low- and middle-income countries where data are sparse.