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 multigravida 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 FY2022: 1. Renn JP, Doritchamou JYA, Tentokam BCN, Morrison RD, Cowles MV, Burkhardt M, Ma R, Tolia NH, Fried M, Duffy PE. Allelic variants of full-length VAR2CSA, the placental malaria vaccine candidate, differ in antigenicity and receptor binding affinity. 2021. Communications Biology. Nov 19. Plasmodium falciparum-infected erythrocytes (IE) sequester in the placenta via surface protein VAR2CSA, which binds chondroitin sulfate A (CSA) expressed on the syncytiotrophoblast surface, causing placental malaria (PM) and severe adverse outcomes in mothers and their offspring. In this study, we produced deglycosylated (native-like) and glycosylated versions of seven recombinant full-length VAR2CSA ectodomains. Allelic and glycosylation variants of VAR2CSA differed in their affinity to CSA and their serum reactivities. Further, the gravidity-related increase in serum VAR2CSA reactivity (correlates with acquisition of protective immunity) was absent with the deglycosylated form of atypical M200101 VAR2CSA with an extended C-terminal region. Our findings indicate significant inter-allelic differences in adhesion and seroreactivity that may contribute to the heterogeneity of clinical presentations, which could have implications for vaccine design. 2. Doritchamou JYA, Renn JP, Jenkins B, Fried M, Duffy PE. A single full-length VAR2CSA ectodomain variant purifies broadly neutralizing antibodies against placental malaria isolates. 2022. eLife. Feb 1. Women become PM-resistant over successive pregnancies as they develop anti-adhesion and anti-VAR2CSA antibodies, supporting VAR2CSA as the leading PM-vaccine candidate. However, the first VAR2CSA subunit vaccines failed to induce broadly neutralizing antibody and it is known that naturally acquired antibodies target both variant-specific and conserved epitopes. It is crucial to determine whether effective vaccines will require incorporation of many or only a single VAR2CSA variants. In this study, IgG from multigravidae was sequentially purified on five full-length VAR2CSA ectodomain variants, thereby depleting IgG reactivity to each. The five VAR2CSA variants purified 0.7% of total IgG and yielded both strain-transcending and strain-specific reactivity to VAR2CSA and IE-surface antigen. In two independent antibody purification/depletion experiments with permutated order of VAR2CSA variants, IgG purified on the first VAR2CSA antigen displayed broad cross-reactivity to both recombinant and native VAR2CSA variants, and inhibited binding of all isolates to CSA. IgG remaining after depletion on all variants showed significantly reduced binding-inhibition activity compared to initial total IgG. These findings demonstrate a single VAR2CSA ectodomain variant displays conserved epitopes that are targeted by neutralizing (or binding-inhibitory) antibodies shared by multiple parasite strains, including maternal isolates. This suggests that a broadly effective PM-vaccine can be achieved with a limited number of VAR2CSA variants. 3. Keitany GJ, Jenkins BJ, Obiakor HT, Daniel S, Muehlenbachs A, Semblat JP, Doritchamou JYA, Desai SA, MacDonald NJ, Narum DL, Morrison R, Saveria T, Vignali M, Oleinikov AV, Fried M, Duffy PE. An invariant protein that co-localizes with VAR2CSA on Plasmodium falciparum-infected red cells binds to chondroitin sulfate A. 2021. Journal of Infectious Diseases. Oct 29. In pregnant women, VAR2CSA binds to chondroitin sulfate A (CSA) and mediates placental sequestration, making it the major placental malaria (PM) vaccine target. In this study, we characterized an invariant protein associated with PM called P. falciparum chondroitin sulfate A ligand (PfCSA-L) We found that recombinant PfCSA-L binds both placental CSA and VAR2CSA with nanomolar affinity, and is co-expressed on the IE surface with VAR2CSA. Unlike VAR2CSA, which is anchored by a transmembrane domain, PfCSA-L is peripherally associated with the outer surface of knobs through high-affinity protein-protein interactions with VAR2CSA. This suggests IE sequestration involves complexes of invariant and variant surface proteins, allowing parasites to maintain both diversity and function at the IE surface. PfCSA-L is a promising target for intervention because it is well-conserved, exposed on infected cells, and expressed and localized with VAR2CSA. 4. Sharma A, Jenkins B, Akue A, Lambert LE, Orr-Gonzalez S, Thomas III ML, Mahamar A, Diarra BS, Dicko A, Fried M, Duffy PE. Plasmodium falciparum in Aotus nancymaae: a new model for placental malaria. 2022. Journal of Infectious Diseases. Mar 15. Plasmodium falciparum IEs that display the variant surface antigen VAR2CSA bind chondroitin sulfate A (CSA) to sequester in placental intervillous spaces, causing severe sequelae for mother and offspring. This study established a novel placental malaria (PM) monkey model. Pregnant Aotus infected with CSA-binding Pf-CS2 parasites during 3rd trimester developed pronounced sequestration of late-stage parasites in placental intervillous spaces that express VAR2CSA and bind specifically to CSA. Similar to immune multigravid women, a monkey infected with Pf-CS2 parasites over successive pregnancies acquired antibodies against VAR2CSA, with potent functional activity that was boosted upon subsequent pregnancy infections. Aotus also developed functional antibodies after multiple acute PM episodes and subsequent VAR2CSA immunization. In summary, Pf infections in pregnant Aotus monkeys recapitulated all the prominent features of human PM infection and immunity; this model can be useful for basic mechanistic studies and preclinical studies to qualify candidate PM vaccines.