Placental malaria (PM) is a major public health problem associated with severe maternal anemia, preeclampsia, pregnancy loss, low birthweight delivery and infant mortality. PM is caused by sequestration in the placenta of parasites that bind the receptor chondroitin sulfate A (CSA). Previous ex vivo experiments have shown that parasite binding to CSA can be inhibited by antibodies from multigravida women who acquired specific immunity to CSA-binding parasites, or by antibodies from animals immunized with antigens that mediate parasite binding to CSA. Highlighted in this year's summary are results from our publications: 1. Doritchamou et al. 2019. Infection and Immunity 20;87(7). Women become resistant to Plasmodium falciparum pregnancy malaria over successive pregnancies as they acquire antibodies to the CSA-binding infected erythrocytes (IE). Surface reactivity with two parasites forms selected for binding to CSA (FCR3 and NF54) and full-length recombinant VAR2CSA (FCR3 and NF54) were higher in multigravid women from both Tanzania and Mali compared to primigravidae residents of the same area (Doritchamou J, Duffy PE, et al, Infec & Immun). However, IgG reactivity of Malian women was higher to FCR3 variant compared to IgG reactivity in plasma of Tanzanian women and vice versa for reactivity with the NF54 form. Binding inhibition activity of multigravidae plasma was higher to NF54 IEs than FCR3 IEs, and higher opsonizing activity to FCR3 IEs than NF54 IEs. Further, anti-adhesion activity to the 2 IEs correlated with opsonizing activity in multigravidae but not in primigravidae. 2. Healy et al. 2019. Vaccine. Feb 4;37(6):763-770. We reported a consensus from an expert meeting convened at NIAID, NIH to deliberate on the rationale and design of malaria vaccine trials in pregnant women (Healy SA et al, Vaccine). The convened experts drafted a clinical development plan to test a malaria vaccine product during pregnancy, focused on PfSPZ Vaccine being developed by Sanaria Inc. that is currently in phase 2 testing. Following the expert recommendations, a pregnancy registry has been initiated in Ouelessebougou, Mali, to provide baseline information on maternal and fetal outcomes as a context for evaluating malaria vaccines in future. 3. Duffy et al. Future vaccines for use in pregnancy or before conception: Malaria. Book chapter in General concepts and vaccine specific background on maternal immunization. In press. We reviewed the impetus and rationale to test malaria vaccines in pregnant women. Pregnant women have never intentionally enrolled in a malaria vaccine trial, and no malaria vaccine has been licensed for use yet. We suggested that malaria vaccines may be given before conception or early in gestation to confer protective benefits throughout pregnancy, or pregnant women may be exposed to vaccines during mass vaccination programs envisioned for malaria elimination efforts. Because P. falciparum infection during pregnancy can be difficult to diagnose, and therefore vaccine trial endpoints require special considerations. In addition to our published work, we report unpublished progress accomplished this year: We completed preclinical studies to assess candidate placental malaria vaccines by measuring anti-adhesion activity and surface reactivity of rodent IgG induced by DNA vaccines. Candidate vaccines assessed in FY2019 corresponded to the C-terminus of VAR2CSA (DBL3-DBL6) that were tested by rodent vaccination using either single or multiple allelic forms. Surface reactivity to fresh parasite samples in Mali showed that IgG from rodents immunized with one allelic forms (7G8) was similar to IgG from animals vaccinated with 3 alleles (7G8, NF54 and HB3). An LMIV study supported by the European Vaccine Initiative tested VAR2CSA vaccine candidates that are currently in human trials for their immunogenicity in Aotus monkeys. The study included 2 clinical vaccine candidates (from our European collaborators) and 1 preclinical vaccine candidate (developed at LMIV). Aotus IgG responses were assessed after immunization, and then boosting of vaccine responses were measured after episodes of placental malaria. Overall, almost all Aotus monkeys immunized with the 2 clinical vaccine candidates developed strain-specific antibodies that reacted with IE surface of the homologous parasite strain, and some developed strain-specific anti-adhesion antibodies. Infection of pregnant Aotus monkeys with one of the parasite forms used for vaccination did not increase homologous or heterologous functional activity. In an important technological advance, 5 full-length (extracellular domain) VAR2CSA allelic forms initially expressed as recombinant protein in FY18 were produced at a large scale and used to vaccinate rodents in FY19. The resulting rodent IgG is currently under evaluation. Pregnancy registry: A pregnancy registry was initiated in order to establish rates of different pregnancy outcomes in Ouelessebougou, Mali as background information required to prepare for future vaccine trials involving pregnant women at the site. The 1st cohort of pregnant women enrolled at the time of their first antenatal clinic (ANC) visit which typically occurs mid-gestation. Enrollment and follow up of women were completed in February 2019. 1,854 women included in this cohort completed the study. Perinatal mortality (defined as miscarriage, stillbirth or early neonatal death) was 39/1000 births. Preterm delivery (PTD) rate was 47.2/1000 live births. Both pregnancy loss and PTD were more common in primigravidae than multigravidae. A manuscript describing these results is in preparation. The 2nd cohort for the pregnancy registry targeted non-pregnant women of child-bearing potential (WOCBP) and began enrollment in November 2018. In the enrollment period, 800 women joined the study and are currently being followed.
