Impact of Epstein-Barr virus co-infection on natural acquired Plasmodium vivax antibody response
Authors: Dias Michelle H F , Guimarães Luiz F F , Barcelos Matheus G , Moreira Eduardo U M , do Nascimento Maria F A , de Souza Taís N , Pires Camilla V , Monteiro Talita A F , Middeldorp Jaap M , Soares Irene S , Ntumngia Francis B , Adams John H , Kano Flora S , Carvalho Luzia H 
Published: March 2022

AbstractBackgroundThe simultaneous infection of Plasmodium falciparum and Epstein-Barr virus (EBV) could promote the development of the aggressive endemic Burkitt’s Lymphoma (eBL) in children living in P. falciparum holoendemic areas. While it is well-established that eBL is not related to other human malaria parasites, the impact of EBV infection on the generation of human malaria immunity remains largely unexplored. Considering that this highly prevalent herpesvirus establishes a lifelong persistent infection on B-cells with possible influence on malaria immunity, we hypothesized that EBV co-infection could have impact on the naturally acquired antibody responses to P. vivax, the most widespread human malaria parasite.Methodology/Principal FindingsThe study design involved three cross-sectional surveys at six-month intervals (baseline, 6 and 12 months) among long-term P. vivax exposed adults living in the Amazon rainforest. The approach focused on a group of malaria-exposed individuals whose EBV-DNA (amplification of balf-5 gene) was persistently detected in the peripheral blood (PersVDNA, n=27), and an age-matched malaria-exposed group whose EBV-DNA could never be detected during the follow-up (NegVDNA, n=29). During the follow-up period, the serological detection of EBV antibodies to lytic/ latent viral antigens showed that IgG antibodies to viral capsid antigen (VCA-p18) were significantly different between groups (PersVDNA > NegVDNA). A panel of blood-stage P. vivax antigens covering a wide range of immunogenicity confirmed that in general PersVDNA group showed low levels of antibodies as compared with NegVDNA. Interestingly, more significant differences were observed to a novel DBPII immunogen, named DEKnull-2, which has been associated with long-term neutralizing antibody response. Differences between groups were less pronounced with blood-stage antigens (such as MSP1-19) whose levels can fluctuate according to malaria transmission.Conclusions/SignificanceIn a proof-of-concept study we provide evidence that a persistent detection of EBV DNA in peripheral blood of adults in a P. vivax semi-immune population may impact the long-term immune response to major malaria vaccine candidates.Author SummaryIn the Amazon rain forest, both Plasmodium vivax and Epstein-Barr virus (EBV) infections are common, yet the Burkitt’s lymphoma (BL) is rare, despite an association between endemic BL with chronic P. falciparum exposure. Nevertheless, the influence of EBV infection on malaria immunity remains undetermined. Here, we investigated for the first time whether continuous detection of EBV DNA in the peripheral blood of adults exposed to P. vivax could impact the antibody response to blood-stage malaria vaccine candidates. The methodological approach involved 12-month follow-up among P. vivax-exposed Amazonian classified as persistent EBV-DNA carriers (PersVDNA) and an age-matched group with no viral DNA detection (NegVDNA); groups were further differentiated based on profile of viral antibodies (mainly IgG VCA-p18). Collectively, our findings demonstrated that antibody levels against P. vivax antigens were in general lower in the PersVDNA group as compared with NegVDNA. More significant differences were observed to a novel vaccine candidate (DEKnull-2) whose antibody response were previously associated with broadly neutralizing P. vivax antibodies. Differences between groups were less pronounced with P. vivax antigens associated with seasonal changes in the antibody responses. In this conceptual study, we provide evidence that long-term detection of EBV in peripheral blood may impact immune response to major malaria vaccine candidates.