Apical membrane protein 1‐specific antibody profile and temporal changes in peripheral blood B‐cell populations in Plasmodium vivax malaria

Abstract

Plasmodium falciparum‐specific antibodies tend to be short‐lived, but their cognate memory B cells (MBCs) circulate in the peripheral blood of exposed subjects for several months or years after the last infection. However, the time course of antigen‐specific antibodies and B‐cell responses to the relatively neglected parasite Plasmodium vivax remains largely unexplored. Here, we showed that uncomplicated vivax malaria elicits short‐lived antibodies but long‐lived MBC responses to a major blood‐stage P vivax antigen, apical membrane protein 1 (PvAMA‐1), in subjects exposed to declining malaria transmission in the Amazon Basin of Brazil. We found that atypical (CD19+CD10−CD21−CD27−) MBCs, which appear to share a common precursor with classical MBCs but are unable to differentiate into antibody‐secreting cells, significantly outnumbered classical MBCs by 5:1 in the peripheral blood of adult subjects currently or recently infected with P vivax and by 3:1 in healthy residents in the same endemic communities. We concluded that malaria can drive classical MBCs to differentiate into functionally impaired MBCs not only in subjects repeatedly exposed to P falciparum, but also in subjects living in areas with low levels of P vivax transmission in the Amazon, leading to an impaired B‐cell memory that may affect both naturally acquired and vaccine‐induced immunity.

Main B‐cell epitopes of PvAMA‐1 and PvMSP‐9 are targeted by naturally acquired antibodies and epitope‐specific memory cells in acute and convalescent phases of vivax malaria

“…Really, the frequencies of peripheral CD19 + B cells detected during acute phase and after recovery from infection were similar for subjects enrolled in our study. 47 Similarly, the idea that long-lived antibody response would only be possible after repeated malaria infections 23,72 is not compatible with the observations of this study, where subjects experiencing only one prior malaria episode too presented persistent levels of specific antibodies. Another hypothesis is that while prolonged antigenic stimulation appears to induce short-lived plasma cells, which die in situ after the clearance of infection, low exposition to the malaria parasites appears to induce long-lived plasma cells, who migrate to the bone marrow where they remain producing antibodies for a long time without additional antigenic stimulation or MBC activation.…”

“…However, as this phenomenon is observed especially in infected subjects (acute phase) and considering that both, infected and noninfected individuals, presenting antibody but not specific MBC were observed in our population, this hypothesis is not applicable to our data. Really, the frequencies of peripheral CD19 + B cells detected during acute phase and after recovery from infection were similar for subjects enrolled in our study . Similarly, the idea that long‐lived antibody response would only be possible after repeated malaria infections is not compatible with the observations of this study, where subjects experiencing only one prior malaria episode too presented persistent levels of specific antibodies.…”

“…Several studies that investigated the relation between specific antibodies and antimalarial immunity had been carried out in Brazil. However, only two of them focused on determining the occurrence and persistence of specific IgG and MBCs over time by using recombinant proteins as antigens . This first study, conducted with Brazilian subjects who were exposed to low levels of vivax malaria transmission, provides evidence that two peptides which contain B‐cell epitopes (PvAMA‐1 (S290‐K307) and PvMSP‐9 (E795‐A808) ) are recognized by naturally acquired antibodies and MBCs, which are detectable several months after clinical malaria episodes.…”

“…However, only two of them focused on determining the occurrence and persistence of specific IgG and MBCs over time by using recombinant proteins as antigens. 47,55 This first study, conducted with Brazilian subjects who were exposed to low levels of vivax malaria transmission, provides evidence that two peptides which contain B-cell epitopes (PvAMA-1 (S290-K307) and PvMSP-9 (E795-A808) ) are recognized by naturally acquired antibodies and MBCs, which are detectable several months after clinical malaria episodes. The high immunogenicity for both peptides has been previously demonstrated, 40,45 but there was no inference about the persistence of immune response over time for these antigens.…”

“…Venous blood samples were collected in heparinized tubes between May-August, 2013, and in February, 2014, as previously described. 47 Peripheral blood mononuclear cells (PBMCs) were separated by gradient centrifugation (Ficoll-Paque PLUS, GE Healthcare, United Kingdom) and cryopreserved in liquid nitrogen (−196°C). Blood and plasma samples were stored at −20°C and used for molecular diagnosis and enzyme-linked immunosorbent assay (ELISA) for antibody detection, respectively.…”