Predictors of Epstein-Barr virus serostatus and implications for vaccine policy: A systematic review of the literature

Abstract

Background: Epstein-Barr virus (EBV) is an important human pathogen; it infects >90% people globally and is linked to infectious mononucleosis and several types of cancer. Vaccines against EBV are in development. In this study we present the first systematic review of the literature on risk factors for EBV infection, and discuss how they differ between settings, in order to improve our understanding of EBV epidemiology and aid the design of effective vaccination strategies.

Methods: MEDLINE, Embase, and Web of Science were searched on 6^th March 2017 for observational studies of risk factors for EBV infection. Studies were excluded if they were published before 2008 to ensure relevance to the modern day, given the importance of influencing future vaccination policies. There were no language restrictions. After title, abstract and full text screening, followed by checking the reference lists of included studies to identify further studies, data were extracted into standardised spreadsheets and quality assessed. A narrative synthesis was undertaken.

Results: Seventy-seven papers met our inclusion criteria, including data from 31 countries. There was consistent evidence that EBV seroprevalence was associated with age, increasing throughout childhood and adolescence and remaining constant thereafter. EBV was generally acquired at younger ages in Asia than Europe/North America. There was also compelling evidence for an association between cytomegalovirus infection and EBV. Additional factors associated with EBV seroprevalence, albeit with less consistent evidence, included ethnicity, socioeconomic status, other chronic viral infections, and genetic variants of HLA and immune response genes.

Conclusions: Our study is the first systematic review to draw together the global literature on the risk factors for EBV infection and includes an evaluation of the quality of the published evidence. Across the literature, the factors examined are diverse. In Asia, early vaccination of infants would be required to prevent EBV infection. In contrast, in Western countries a vaccine could be deployed later, particularly if it has only a short duration of protection and the intention was to protect against infectious mononucleosis. There is a lack of high-quality data on the prevalence and age of EBV infection outside of Europe, North America and South-East Asia, which are essential for informing effective vaccination policies in these settings.

Figure 1

PRISMA flowchart of studies included in the systematic review.

Figure 2

The global distribution of study populations included in the literature review. The size of the blue dots is proportional to the total number of individuals included in studies from each country. The number inside the dot refers to the number of studies with participants in each country.

Figure 3

EBV seroprevalence by age in studies identified from the literature. Panel A. In participants up to 24 years of age. Panel B. In participants over 24 years of age. Panel C. In participants up to 24 years of age in Europe and North America. Panel D. In participants up to 24 years of age in Asia. Panel E. In participants up to 24 years of age in studies representative of their underlying populations in Europe and North America, (f) in participants up to 24 years of age in studies representative of their underlying populations in Europe and North America. Seroprevalence data categorised by age group was extracted from the literature and data points were plotted at the mid-point of each age group. Studies with only one data point above or below 24 years were excluded from the relevant graph. Studies were considered generalisable to the underlying population if it was a random sample of healthy individuals and the study population was representative of the local population.