Modeling of EBV Infection and Antibody Responses in Kenyan Infants With Different Levels of Malaria Exposure Shows Maternal Antibody Decay is a Major Determinant of Early EBV Infection

Abstract

The combination of Epstein-Barr virus (EBV) infection and high malaria exposure are risk factors for endemic Burkitt lymphoma, and evidence suggests that infants in regions of high malaria exposure have earlier EBV infection and increased EBV reactivation. In this study we analyzed the longitudinal antibody response to EBV in Kenyan infants with different levels of malaria exposure. We found that high malaria exposure was associated with a faster decline of maternally derived immunoglobulin G antibody to both the EBV viral capsid antigen and EBV nuclear antigen, followed by a more rapid rise in antibody response to EBV antigens in children from the high-malaria-transmission region. We also observed the long-term persistence of anti-viral capsid antigen immunoglobulin M responses in children from the high-malaria region. More rapid decay of maternal antibodies was a major predictor of EBV infection outcome, because decay predicted time to EBV DNA detection, independent of high or low malaria exposure.Keywords. Epstein-Barr virus; P. falciparum malaria; Burkitt Lymphoma; antibody; immunity.Epstein-Barr virus (EBV) is a gammaherpesvirus causing infectious mononucleosis and also associated with a variety of cancers in humans [1]. In Africa, EBV is associated with endemic Burkitt lymphoma in the presence of Plasmodium falciparum malaria infection [2]. Previous studies in Africa have shown that most children seroconvert to EBV between 6 and 18 months of age [3][4][5] and that living in an area of high malaria transmission is associated with higher EBV load [4] and earlier time of the first EBV infection [5]. Moreover, the presence of P. falciparum infection is correlated with increased EBV load over time and with more frequent detectable EBV in children [5,6] and pregnant women [7]. High levels of antibody against the EBV viral capsid antigen (VCA) are associated with a higher risk of Burkitt lymphoma in both Ugandan [8,9] and Kenyan [10] children. High malaria exposure was also associated with impaired transfer of maternal VCA and EBV nuclear antigen 1 (EBNA1)-specific immunoglobulin (Ig) G from mother to infant [11], and later in life, higher level of EBV-specific IgG antibodies [12]. The measurement of antibodies specific for EBV VCA and EBNA1 have been used in numerous seroepidemiology studies to assess primary and persistent EBV infections (reviewed in [13]). Typically, anti-VCA IgG appears early after infection, with a delay to detection of anti-EBNA1 IgG. Both are then found at relatively stable levels throughout the life of the host. Anti-EBV early antigen diffuse complex (EAd) IgG has been used as a serological marker for evidence of viral reactivation, because its levels are generally much lower than levels of anti-VCA IgG, they decrease after primary infection (in contrast to VCA IgG), and are elevated during viral reactivation. The EBV Z-transactivation antigen (Zta) is an EBV immediate early protein. It has not been used in clinical settings to detect EBV reactivation to our knowledge, but we have found t...

Assessment of the Combined Effect of Epstein–Barr Virus and Plasmodium falciparum Infections on Endemic Burkitt Lymphoma Using a Multiplex Serological Approach

“…As expected, our data support a strong role of EBV in eBL, and a weak effect of malaria, but suggest that both infections might act jointly on eBL, as shown by the additive interaction between elevated IgGs against EBV and MSP-3. In agreement with this observation, two recent studies have reported that the key determinants of EBV primary infection kinetics in children are the degree of malaria exposure and maternal antibody decay ( 9 , 40 ).…”

“…High IgM levels against VCA-p18 usually indicate recent primary EBV infection, although it may persist for months or might reappear in EBV reactivation. The negative association of high IgM anti-VCA-p18 levels with eBL suggests that newly EBV-infected children might be at lesser risk of eBL compared with children exposed for a longer time, or might indicate that in a malaria endemic region the long-term persistence of anti-VCA IgM responses may be associated with a better control of EBV infection ( 40 ).…”

Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas

“…It was not surprising to find no correlation with EBV antibody titers using a single time point, because our past studies have demonstrated longitudinal variability in EBV antibody titers. 3,44 However, malaria antibody profiles have been used as an indicator of cumulative and recent past exposure in the absence of an active infection. 45 KIR licensing in malaria-exposed and eBL children favors inhibitory signals Figure 2F), we observed significantly higher expression for Kisumu and eBL children compared with Nandi children (P 5 .04 and .01, respectively).…”

Fc functional antibodies in humans with severe H7N9 and seasonal influenza

“…Our series of Fc-binding, hemagglutination inhibition (HI), and focus reduction assays (FRA) across the severe influenza infection cohorts allowed us to analyze the kinetics of the responses. To account for the limited series of samples and variable times after infection when the samples were taken from each subject, we modeled the peak of ADCC or NAb responses across data collected from all subjects at all time points tested (2-5 longitudinal samples per subject) based on standard rise and decay characteristics of Abs as previously described (34). The primary data used for modeling is shown in Supplemental Figures 6 and 7.…”

“…To analyze differences between influenza-specific Ab kinetics, we used a log linear regression as previously described (34). Ab responses increased exponentially until a certain time (T peak ), after which they decrease exponentially.…”