The persistence of naturally acquired antibodies and memory B cells specific to rhoptry proteins of Plasmodium vivax in patients from areas of low malaria transmission

Abstract

Background: Rhoptries are the large, paired, secretory organelles located at the apical tip of the malaria merozoite that are considered important for parasite invasion processes. Plasmodium vivax rhoptry proteins have been shown to induce humoral immunity during natural infections. Therefore, these proteins may be potential novel vaccine candidates. However, there is a lack of data on the duration of antibody and memory B cell (MBC) responses. Here, the longitudinal analysis of antibody and MBC responses to the P. vivax rhoptry proteins PvRALP1-Ecto and PvRhopH2 were monitored and analysed in individuals to determine their persistence.Methods: Thirty-nine samples from P. vivax-infected subjects (age 18-60 years) were recruited to explore the frequency and persistence of antibody and MBC responses against rhoptry proteins (PvRALP1-Ecto and PvRhopH2) using both cross-sectional and longitudinal cohort study designs. Antibody levels were determined by ELISA during clinical malaria, and at 3, 9 and 12 months post-infection. The frequency of MBC sub-sets and presence of rhoptryspecific MBCs in subjects 18 months after treatment were detected by flow cytometry and ELISPOT assay. Results:The seroprevalence of antibodies against PvRALP1-Ecto and PvRhopH2 proteins was found to be high during acute infection, with IgG1, IgG2 and IgG3 sub-classes predominant. However, these anti-rhoptry responses were short-lived and significantly decreased at 9 months post-infection. To relate the durability of these antibody responses to MBC persistence at post-infection, 18-month post-infection peripheral blood mononuclear cells (PBMCs) samples were taken to detect rhoptry-specific MBCs and frequency of MBC sub-sets, and correlate with antibody responses. These late post-infection samples revealed that rhoptry-specific MBCs were present in about 70% of total subjects. However, the persistence of specific MBCs was not correlated with antibody responses as the majority of malaria subjects who were positive for PvRALP1-Ecto-or PvRhopH2-specific MBCs were seronegative for the rhoptry antigens. The frequencies of classical MBCs were increased after infection, whereas those of activated and atypical MBCs were decreased, indicating that MBC responses could switch from activated or atypical MBCs to classical MBCs after parasite clearance, and were maintained in blood circulating at post-infection.

Heterogeneity in response to serological exposure markers of recent Plasmodium vivax infections in contrasting epidemiological contexts

“…The antibody longevity is maintained by memory B cells that upon re-exposure rapidly proliferate and differentiate into antibody secretory cells, greatly boosting antibody levels [34]. In settings of low transmission, P. vivax infections appear to induce long-lasting B cell PLOS NEGLECTED TROPICAL DISEASES PLOS NEGLECTED TROPICAL DISEASES memory but with corresponding relatively short-lived antibody responses [9,10], although long-lived antibody responses have also been reported [35]. Although it has not been rigorously investigated, in high transmission settings both memory and antibody responses appear to be long-lived [36].…”

“…Light microscopy (LM) and qPCR, although informative, are imperfect tools due to the poor sensitivity for detecting low density blood-stage infections LM and the inability to detect hypnozoite carriers (LM and qPCR). The antibody responses mounted to P. vivax can last weeks to several years after exposure [9,10], making them an ideal tool for assessing transmission history. Thus, by exploiting antibody longevity to assess recent exposure, we can use antibody levels to estimate the time since previous exposure and potentially detect hypnozoite carriers [11].…”

Heterogeneity in response to serological exposure markers of recentPlasmodium vivaxinfections in contrasting epidemiological contexts

“…The antibody longevity is maintained by memory B cells that upon re-exposure rapidly proliferate and differentiate into antibody secretory cells, greatly boosting antibody levels [33]. In settings of low transmission, P. vivax infections appear to induce long-lasting B cell memory but with corresponding relatively short-lived antibody responses [9,10], although long-lived antibody responses have also been reported [19] . In high transmission settings both memory and antibody responses appear to be long-lived.…”

“…Light microscopy and qPCR, although informative, are imperfect tools due to the poor sensitivity for detecting low density blood-stage infections (light microscopy) and the inability to detect hypnozoite carriers (light microscopy and qPCR). The antibody responses mounted to P. vivax can last weeks to several years after exposure [9, 10], making them an ideal tool for assessing transmission history. Thus, by exploiting antibody longevity to assess recent exposure, we can use antibody levels to estimate the time since previous exposure and potentially detect hypnozoite carriers [11].…”

Plasmodium vivax vaccine: What is the best way to go?

“…Several studies have investigated the relationship between the induction of specific antibodies and specific-MBC responses. In general, an increase in the number of plasma cells is observed during P. vivax acute infection, but the presence of long-lived MBCs was not consistently related to the antibody response (60)(61)(62)(63)(64)(65)(66).…”