Abstract
BackgroundEffective vaccines to combat malaria are urgently needed, but have proved elusive in the absence of validated correlates of natural immunity. Repeated blood stage infections induce antibodies considered to be the main arbiters of protection from pathology, but their essential functions have remained speculative.Methodology/Principal FindingsThis study evaluated antibody dependent respiratory burst (ADRB) activity in polymorphonuclear neutrophils (PMN) induced by Plasmodium falciparum merozoites and antibodies in the sera of two different African endemic populations, and investigated its association with naturally acquired clinical protection. Respiratory bursts by freshly isolated PMN were quantified by chemiluminescence readout in the presence of isoluminol, which preferentially detects extra-cellular reactive oxygen species (ROS). Using a standardized, high throughput protocol, 230 sera were analyzed from individuals of all age groups living in meso- (Ndiop) or holo-endemic (Dielmo) Senegalese villages, and enrolled in a cross-sectional prospective study with intensive follow-up. Statistical significance was determined using non-parametric tests and Poisson regression models. The most important finding was that PMN ADRB activity was correlated with acquired clinical protection from malaria in both high and low transmission areas (P = 0.006 and 0.036 respectively). Strikingly, individuals in Dielmo with dichotomized high ADRB indexes were seventeen fold less susceptible to malaria attacks (P = 0.006). Complementary results showed that ADRB activity was (i) dependent on intact merozoites and IgG opsonins, but not parasitized erythrocytes, or complement, (ii) correlated with merozoite specific cytophilic IgG1 and IgG3 antibody titers (P<0.001 for both), and (iii) stronger in antisera from a holo-endemic compared to a meso-endemic site (P = 0.002), and reduced in asymptomatic carriers (P<0.001).Conclusions/SignificanceThis work presents the first clearly demonstrated functional antibody immune correlate of clinical protection from Plasmodium falciparum malaria, and begs the question regarding the importance of ADRB by PMN for immune protection against malaria in vivo.
Highlights
There are 300–500 million clinical malaria cases annually, and 1–3 million deaths of primarily young African children [1]
Merozoites are visualized by confocal micrography as dense particles of 1–2 mm which are labeled by green immunofluorescence staining using a rabbit polyclonal antiserum raised to baculovirus recombinant P. falciparum MSP1p19
The insert at upper right shows immunofluorescence results using a control rabbit antiserum raised to insect cells infected with a baculovirusnull construct expressing no heterologous protein, indicating that the anti-MSP1p19 staining is highly specific and not due to possible contaminants present in the immunizing MSP1p19 antigen preparation
Summary
There are 300–500 million clinical malaria cases annually, and 1–3 million deaths of primarily young African children [1]. Merozoite surface proteins (MSPs) are considered relevant vaccine targets, because they mediate erythrocyte invasion, and are accessible to antibodies and complement. One postulated antibody function is to inhibit parasite growth by preventing erythrocyte invasion and/or by interfering with intra-erythrocytic development. The currently most widely accepted functional assays for antibodies to blood stage P. falciparum antigens measure inhibition of erythrocyte invasion and/ or parasite growth in vitro [6,7,8,9,10,11], but the relevance of these assays to clinical protection in humans has never been clearly established. Effective vaccines to combat malaria are urgently needed, but have proved elusive in the absence of validated correlates of natural immunity. Repeated blood stage infections induce antibodies considered to be the main arbiters of protection from pathology, but their essential functions have remained speculative
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