Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom

Epstein-Barr Virus (EBV) is a ubiquitous gamma-herpesvirus with which ~ 95% of healthy adults are infected [1]. EBV is the commonest causative agent of Infectious Mononucleosis (IM), a triad of pharyngitis, lymphadenopathy and fever in the context of acute EBV infection [2]. EBV infection is also implicated in a range of haematological malignancies (Burkitt’s lymphoma, gastric lymphoma, and Non-Hodgkin lymphoma), and has been strongly associated with autoimmune diseases such as Multiple Sclerosis (MS).

EBV seroprevalence increases with age, and tends to be higher among females, non-Caucasian ethnic groups, and people living in socio-economically deprived households [3, 4]. Later age at EBV infection confers both a higher risk of IM and a higher risk of severe features [2]. Overall EBV seroprevalence rates among children and adolescents appear to be decreasing in some populations, implying that the population at risk of complicated primary EBV infection may be increasing [4‐6].

Various strands of evidence suggest a pathogenic role for EBV infection in MS: EBV seronegativity is exceptionally rare in people with MS, EBV seropositivity is higher in people with MS, higher anti-EBV antibody titres are associated with increased risk of MS, and prior IM increases the risk of subsequent MS [7‐9]. Understanding the epidemiology of EBV infection during childhood and adolescence is essential [10], for both maximising the efficacy and safety of vaccine studies [11], and in order to inform power calculations for future potential interventional studies [11].

Previous vaccine studies have demonstrated efficacy against symptomatic IM but not EBV seroconversion [12]; however multivalent vaccines are currently being developed with the aim of preventing seroconversion [13]. Alongside this, there remains an urgent need to better understand the current epidemiology of EBV transmission, and potential associations with both early and late seroconversion.

We therefore set out to update and establish current EBV seroprevalence across the UK, establish the potential effect of any change in the pattern of UK EBV seroprevalence on prevalence of hospital admissions with Infectious Mononucleosis (IM), and examine predictors of late EBV infection (IM) in a large primary care cohort. Finally, we used a small cohort of truly EBV-negative samples from adults to explore whether EBV seronegativity is associated with a reduced immune response to other vaccine-preventable and/or ubiquitous infections.

In this study we demonstrate the temporal trends in EBV seroprevalence during childhood and adolescence among healthy UK volunteers, and explore socio-demographic associations with IM (a marker of late infection). The seroprevalence estimates in all age bands in our study are higher than in other previous similar studies; additionally, we show that EBV seroprevalence differs between genders in adolescence (10–14.9 years), with male sex conferring a slightly lower risk of EBV seropositivity at this age. This corresponds to a gender imbalance among hospital admissions associated with a code indicating infectious mononucleosis in this age band. Supporting this finding is previous work demonstrating that the prevalence of EBV DNA in healthy tonsils increased with age for males (peak 77.4% for > 35 year-olds), but reached a peak at 79.3% for females from 15 to 24, and remained at that plateau [17]. The implication of these findings is a gender imbalance in EBV seroconversion hazard rates by age, as infectious mononucleosis rates are a function of the interaction between the population at risk (EBV naïve) and EBV-positive population pool [10].

An important finding of our work is the observation that EBV-seronegative individuals do not appear to have lower levels of circulating antibody to common vaccine antigens and pathogens. A major concern regarding EBV vaccines is disruption of the host-pathogen interaction with unintended deleterious consequences for host and population immunity. EBV achieves long-term immune evasion by transforming naive B cells into a resting memory B cell phenotype and activating latency programmes. Given this tropism, and the widespread prevalence of EBV, there is an evolutionary argument that humans have co-evolved with EBV due to a selective advantage offered by the virus. Specifically, it is possible that EBV infection promotes herd and individual immunity to a broad range of pathogens by expanding and maintaining the size of the memory B cell pool. Thus, there is a theoretical concern that vaccination against EBV may have unintended consequences for B cell memory at an individual and population level. Our pilot data is reassuring, and will need to be replicated on a larger scale in order to allay this theoretical concern.

We show that, as would be expected, the seroprevalence of EBV increases with age from 69.9% in the 1–4.9 age bracket to 96.0% among 20–25 year olds. Our results are consistent with previous studies on the determinants of EBV seropositivity, and fit with previous models of EBV infection and seroconversion [10]. Several studies in other populations have demonstrated a decline in age-adjusted seroprevalence of EBV over the past 15 years [4‐6]. In contrast, our study demonstrated consistently higher EBV seroprevalence among all age brackets compared to a comparable older study [18] – this may reflect a genuine increase in seroprevalence in the UK, differences in population sampling, or different sensitivity and specificity of the assays used (our study used VCA whereas previous studies have used EBNA). Reassuringly, our estimates closely mirror those from a recent random sampling of UK Biobank participants: among those aged 40–69 years, EBV seroprevalence was 94.7%¹.

We show that exposures associated with increased IM risk (i.e. late infection) include White ethnicity, normal/low body weight, lower deprivation, and never smoking, in keeping with international data [3, 4]. We found additional evidence of interaction between smoking, body weight, and ethnicity in determining IM risk. We cannot rule out that the exposures we identify as being associated with IM are in fact all proxies for lower levels of household crowding or other early life determinants. Our study used prevalent cases, which introduces the problems of reverse causation and confounding. The finding that effects differ between ethnicities is intriguing. These traits may be proxies for different exposures between different ethnicities (e.g. theoretically, being overweight could be a marker of high wealth in one group and deprivation in another). Alternatively, this may reflect a genuine biological effect whereby BMI and smoking interact with genetic background to influence IM risk.

The use of healthcare databases to study IM is challenging – coded diagnoses of IM are usually not linked to serological evidence, and certainly include non-EBV related infections. Others have used healthcare databases to examine IM incidence [10, 19], highlighting the role of transmission within families [19]. The observed similarities in gender variation in IM and seroconversion during teenage years between HES and serum data is compelling, as is the similarity in admission incidence by age between the UK and Denmark [19]. It must be noted that within the HES dataset the incidence of all diseases appears to be increasing due to improved coding; we have mitigated this to some degree by focussing on recent decades. However, the increase in incidence within the HES dataset is striking, with almost a 50% increase over 10 years.

Understanding the temporal trends and host determinants of EBV serostatus are essential for rational vaccine design and deployment. In principle, vaccination against EBV could help to reduce rates of EBV-associated malignancies and EBV-associated autoimmune diseases. Although there is still no effective vaccine available, several are in development, and phase 2 results from a recombinant gp350 vaccine suggested an effect on IM rates without affecting overall seroprevalence [12]. The population-level efficacy of such a vaccine depends crucially on the age at which it is administered, with earlier vaccines predicted to offer greater overall reductions in rates of IM and other EBV-related sequlae [20]. Our empirical data showing high seroprevalence even in the youngest age bracket support the modelling data, suggesting that, in terms of maximising efficacy, EBV vaccines should be delivered in the first few years of life.

In conclusion, our data suggest that, in the UK, EBV seroconversion is taking place earlier in life, that overall EBV seroprevalence remains very high (> 95% of 21–25 year olds), IM incidence is increasing, and there are several environmental exposures associated with IM risk (ethnicity, deprivation, smoking, and BMI). Furthermore, we provide preliminary evidence that EBV seronegative persons do not have lower levels of circulating antibodies to common pathogens and vaccine antigens, which mitigates some concerns around early life vaccination.