Antibodies to Plasmodium falciparum merozoite surface protein-1p19 malaria vaccine candidate induce antibody-dependent respiratory burst in human neutrophils

Abstract

BackgroundIdentification of plasmodial antigens targeted by protective immune mechanisms is important for malaria vaccine development. Among functional assays, the neutrophil antibody-dependent respiratory burst (ADRB) induced by opsonized Plasmodium falciparum merozoites has been correlated with acquired immunity to clinical malaria in endemic areas, but the target merozoite antigens are unknown. Here, the contribution of antibodies to the conserved C-terminal domain of the P. falciparum merozoite surface protein-1 (PfMSP1p19) in mediating ADRB was investigated in sera from individuals living in two Senegalese villages with differing malaria endemicity.MethodsAnti-PfMSP1p19 antibody levels in sera from 233 villagers were investigated and the involvement of anti-PfMSP1p19 antibodies in ADRB was explored in a subset of samples using (1) isogenic P. falciparum parasite clones expressing P. falciparum or Plasmodium chabaudi MSP1p19; (2) PfMSP1p19-coated plaque ADRB; and, (3) ADRB triggering using sera depleted from PfMSP1p19 antibodies by absorption onto the baculovirus recombinant antigen.ResultsADRB activity correlated with anti-PfMSP1p19 IgG levels (P < 10−3). A substantial contribution of PfMSP1p19 antibody responses to ADRB was confirmed (P < 10−4) in an age-adjusted linear regression model. PfMSP1p19 antibodies accounted for 33.1 % (range 7–54 %) and 33.2 % (range 0–70 %) of ADRB activity evaluated using isogenic merozoites (P < 10−3) and depleted sera (P = 0.0017), respectively. Coating of PfMSP1p19 on plates induced strong ADRB in anti-PfMSP1p19-positive sera.ConclusionThese data show that naturally acquired P. falciparum MSP1p19 antibodies are potent inducers of neutrophil ADRB and support the development of PfMSP1p19-based malaria vaccine using ADRB assay as a functional surrogate for protection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0935-5) contains supplementary material, which is available to authorized users.

Analysis of antibody responses to selected Plasmodium falciparum merozoite surface antigens in mild and cerebral malaria and associations with clinical outcomes

“…not children) individuals implicated and variable treatment before hospitalization. Importantly, these antigens were associated with anti-parasite functional activity based on antibody-dependent cellular effector mechanisms involving monocyte and polymorphonuclear neutrophils using the ADCI assay [8] for MSP3 [28] and the ADRB assay [33] for MSP1p19 [34]. These observations are in line with previous studies, underlining their strong association with natural protection.…”

“…As recently reported, the opsonic phagocytosis assay was shown to correlate with protective immunity [42,57] while the magnitude of the anti-merozoite antibody response correlated with the amount of reactive oxygen species production in the ADRB assay [37]. falciparum MSP1p19 constructs in in-vivo and in-vitro experiments [34,59] or transgenic deficient parasites for MSP1p19, MSP3, MSP6, MSPDBL1 [58]. These observations explain the efficacy of passive IgG transfer in curing malaria independently of the geographical origin of the IgG pools [8,9].…”

“…The ADRB activity was measured as described previously [33,34]. Briefly, polymorphonuclear (PMN) cells (pooled from six to seven healthy donors) were washed and suspended in PBS at 1-5 × 10 7 cells ml -1 .…”

Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity

“…Through opsonization of transgenic parasites, these antigens proved dispensable for opsonization as a whole, which may indicate that multiple targets of merozoite opsonization exist. MSP1-19 was recently demonstrated to significantly contribute to the neutrophil respiratory burst response to P. falciparum merozoites (27), which suggests that the antigenic targets of these related immune mechanisms are different. Antibodies to the conserved C-terminal SPAM domain of the MSP3-family can crossreact across the MSP3 family (28), and antibodies to SPAM domains from MSPDBL1 and MSPDBL2 were associated with protective immunity in this cohort (29).…”

“…The MSP3 family and MSP1-19 have been implicated as targets of opsonizing antibodies in neutrophil respiratory burst assays (27), in ADCI assays (28), or, more recently, in merozoite phagocytosis assays (11,29). Antibodies measured by enzyme-linked immunosorbent assay (ELISA) to the MSP3 family and MSP1-19 correlate with immunity from clinical malaria in this cohort (3,30), and MSP1-19 antibodies were strongly correlated with phagocytosis responses to all strains (see Fig.…”