Pregnancy Malaria Vaccine development

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

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 multigravid women who acquired specific immunity to CSA-binding parasites, or by antibodies from animals immunized with antigens that mediate parasite binding to CSA. From our publication this year, we report the following advances in FY2023: Doritchamou JYA, Renn JP, Hviid L, Duffy PE. A conformational epitope in placental malaria vaccine antigen VAR2CSA: what does it teach us? 2023. PLOS Pathogens. May 25: 19(5):e1011370. doi: 10.1371/journal.ppat.1011370. In this publication, we described evidence that residues located in the interdomain-1 fragment of VAR2CSA within the PAM1.4 binding epitope might be critical to broad reactivity of the antibody. Future investigation into broadly reactive anti-VAR2CSA antibodies may be important for the following: (1) identification of similar conformation epitopes targeted by broadly neutralizing antibodies; and (2) understanding different immune evasion mechanisms used by placenta-binding parasites through VAR2CSA polymorphism in critical epitopes. Duffy PE. Current approaches to malaria vaccines. 2022. Current Opinions in Microbiology. Nov 4. This review emphasized vaccine approaches and candidates currently in the clinic or likely to enter clinical testing soon, based on growing knowledge of parasite biology, host-parasite interactions, and immune mechanisms that are informing new concepts to improve on RTS,S and to target other parasite stages. The review included a section on placental malaria vaccines describing progress of recent clinical trials of VAR2CSA-based candidate antigens PRIMVAC and PAMVAC, and structural studies that account for their limited observed efficacy. Berhe, Doritchamou, Duffy. Malaria in Pregnancy (Frontiers in Trop Dis) in press. To prepare for safety and efficacy trials of vaccines to prevent malaria in pregnancy (MiP) and placental malaria, the incidence of adverse pregnancy outcomes including those caused by MiP should be documented at clinical sites. This review summarized reported key adverse pregnancy outcomes attributable to MiP, providing important baseline context to define measurable safety and efficacy endpoints for malaria vaccine trials in pregnancy. Gaoussou S, Attaher O, Swihart B, Traore M, Diarra S, Soumbounou IH, Ndiaye O, Issiaka D, Morrison R, Mahamar A, Duffy PE, Fried M. Pregnancy outcomes in a malaria-exposed Malian cohort of women of child-bearing age. 2022. Frontiers in Medicine-Obstetrics and Gynecology. Dec 8; 9:1061538. doi: 10.3389/fmed.2022.1061538 In Sub-Saharan Africa, majority of pregnant women make their first antenatal clinic visit during the second trimester, and that limits the ability to collect information on miscarriage rate. In this paper we described a cohort that included women of child-bearing age prior to becoming pregnant. Women were surveyed via monthly visits that included pregnancy tests. We describe that 12% of pregnancies resulted in miscarriage, with the majority occurring during the first trimester of pregnancy. We reported that age of >35 years and miscarriage in the previous pregnancy increased the risk miscarriage. We also described that malaria infection and being a primigravidae increased the risk of preterm delivery, consistent with our previous observation in a longitudinal cohort of pregnant women. Additional advances 1. In four Aotus monkeys immunized with full length VAR2CSA, antibodies were tested for functional anti-adhesion antibodies with clinical isolates collected from pregnant women. Plasma collected 2 weeks after the 2nd boost reduced parasite adhesion to CSA by more than 50% of 73%, 53%, 60% and 67% in samples from 4 immunized animals. 2. We established a proteomics analysis to map VAR2CSA epitopes using epitope excision method. Initial analysis was performed with 2 monoclonal antibodies to VAR2CSA. This method is now applied to plasma samples collected primigravid and multigravida women to identify epitopes preferentially recognized by multigravida women. This analysis will guide the development of a sub-unit vaccine based on VAR2CSA.