Effect of Plasmodium Infection during Pregnancy on Passive Neonatal Immunity against Tetanus Toxoid and Rotavirus.

Passive immunity acquired through transplacental IgG transport is essential to protect infants against pathogens as childhood vaccination programs begins. Diarrhea caused by rotavirus and neonatal tetanus are common and potentially fatal childhood infections that can be prevented by transplacental IgG. However, it is not known whether maternal infections in pregnancy can reduce the transfer of these antibodies to the fetus. This study evaluated the effect of submicroscopic Plasmodium infection during pregnancy on the transfer of maternal IgG antibodies against rotavirus (anti-RV) and tetanus toxoid (anti-TT) to newborns of pregnant women residing in Puerto Libertador and Tierralta, Colombia. Expression of different immune mediators and levels of IgG against rotavirus and tetanus toxoid were quantified in pregnant women with and without Plasmodium infection during pregnancy. Submicroscopic infection at the time of delivery was associated with a cord-to-maternal ratio (CMR) > 1 for anti-RV and < 1 for anti-TT IgG, as well as with an increase in the expression of immune mediators of inflammation (IFN-γ), anti-inflammation (IL-10, TGF-ß), and regulation (FoxP3, CTLA-4). When compared by species, these findings (CMR > 1 for anti-RV and < 1 for anti-TT IgG) were conserved in submicroscopic Plasmodium vivax infections at delivery. The impact of Plasmodium infections on neonatal susceptibility to other infections warrants further exploration.

Cross-Species Immune Recognition Between Plasmodium vivax Duffy Binding Protein Antibodies and the Plasmodium falciparum Surface Antigen VAR2CSA.

Background: In pregnancy, Plasmodium falciparum parasites express the surface antigen VAR2CSA, which mediates adherence of red blood cells to chondroitin sulfate A (CSA) in the placenta. VAR2CSA antibodies are generally acquired during infection in pregnancy and are associated with protection from placental malaria. We observed previously that men and children in Colombia also had antibodies to VAR2CSA, but the origin of these antibodies was unknown. Here, we tested whether infection with Plasmodium vivax is an alternative mechanism of acquisition of VAR2CSA antibodies. Methods: We analyzed sera from nonpregnant Colombians and Brazilians exposed to P. vivax and monoclonal antibodies raised against P. vivax Duffy binding protein (PvDBP). Cross-reactivity to VAR2CSA was characterized by enzyme-linked immunosorbent assay, immunofluorescence assay, and flow cytometry, and antibodies were tested for inhibition of parasite binding to CSA. Results: Over 50% of individuals had antibodies that recognized VAR2CSA. Affinity-purified PvDBP human antibodies and a PvDBP monoclonal antibody recognized VAR2CSA, showing that PvDBP can give rise to cross-reactive antibodies. Importantly, the monoclonal antibody inhibited parasite binding to CSA, which is the primary in vitro correlate of protection from placental malaria. Conclusions: These data suggest that PvDBP induces antibodies that functionally recognize VAR2CSA, revealing a novel mechanism of cross-species immune recognition to falciparum malaria.

Clinical Outcomes of Submicroscopic Infections and Correlates of Protection of VAR2CSA Antibodies in a Longitudinal Study of Pregnant Women in Colombia.

Malaria in pregnancy can cause serious adverse outcomes for the mother and the fetus. However, little is known about the effects of submicroscopic infections (SMIs) in pregnancy, particularly in areas where Plasmodium falciparum and Plasmodium vivax cocirculate. A cohort of 187 pregnant women living in Puerto Libertador in northwest Colombia was followed longitudinally from recruitment to delivery. Malaria was diagnosed by microscopy, reverse transcription-quantitative PCR (RT-qPCR), and placental histopathology. Gestational age, hemoglobin concentration, VAR2CSA-specific IgG levels, and adhesion-blocking antibodies were measured during pregnancy. Statistical analyses were performed to evaluate the impact of SMIs on birth weight and other delivery outcomes. Twenty-five percent of women (45/180) were positive for SMIs during pregnancy. Forty-seven percent of infections (21/45) were caused by P. falciparum, 33% were caused by P. vivax, and 20% were caused by mixed Plasmodium spp. Mixed infections of P. falciparum and P. vivax were associated with lower gestational age at delivery (P = 0.0033), while other outcomes were normal. Over 60% of women had antibodies to VAR2CSA, and there was no difference in antibody levels between those with and without SMIs. The anti-adhesion function of these antibodies was associated with protection from SMI-related anemia at delivery (P = 0.0086). SMIs occur frequently during pregnancy, and while mixed infections of both P. falciparum and P. vivax were not associated with a decrease in birth weight, they were associated with significant risk of preterm birth. We propose that the lack of adverse delivery outcomes is due to functional VAR2CSA antibodies that can protect pregnant women from SMI-related anemia.