Progress and Insights Toward an Effective Placental Malaria Vaccine

In areas where Plasmodium falciparum transmission is endemic, clinical immunity against malaria is progressively acquired during childhood and adults are usually protected against the severe clinical consequences of the disease. Nevertheless, pregnant women, notably during their first pregnancies, are susceptible to placental malaria and the associated serious clinical outcomes. Placental malaria is characterized by the massive accumulation of P. falciparum infected erythrocytes and monocytes in the placental intervillous spaces leading to maternal anaemia, hypertension, stillbirth and low birth weight due to premature delivery, and foetal growth retardation. Remarkably, the prevalence of placental malaria sharply decreases with successive pregnancies. This protection is associated with the development of antibodies directed towards the surface of P. falciparum-infected erythrocytes from placental origin. Placental sequestration is mediated by the interaction between VAR2CSA, a member of the P. falciparum erythrocyte membrane protein 1 family expressed on the infected erythrocytes surface, and the placental receptor chondroitin sulfate A. VAR2CSA stands today as the leading candidate for a placental malaria vaccine. We recently reported the safety and immunogenicity of two VAR2CSA-derived placental malaria vaccines (PRIMVAC and PAMVAC), spanning the chondroitin sulfate A-binding region of VAR2CSA, in both malaria-naïve and P. falciparum-exposed non-pregnant women in two distinct Phase I clinical trials (ClinicalTrials.gov, NCT02658253 and NCT02647489). This review discusses recent advances in placental malaria vaccine development, with a focus on the recent clinical data, and discusses the next clinical steps to undertake in order to better comprehend vaccine-induced immunity and accelerate vaccine development.

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The Chondroitin Sulfate A-binding Site of the VAR2CSA Protein Involves Multiple N-terminal Domains

Journal of Biological Chemistry ◽

10.1074/jbc.m110.191510 ◽

2011 ◽

Vol 286 (18) ◽

pp. 15908-15917 ◽

Cited By ~ 54

Author(s):

Madeleine Dahlbäck ◽

Lars M. Jørgensen ◽

Morten A. Nielsen ◽

Thomas M. Clausen ◽

Sisse B. Ditlev ◽

...

Keyword(s):

Chondroitin Sulfate ◽

Binding Site ◽

Placental Malaria ◽

African Women ◽

Major Health Problem ◽

Major Health ◽

Malaria During Pregnancy ◽

High Parasite ◽

Similar Affinity ◽

Chondroitin Sulfate A

Malaria during pregnancy is a major health problem for African women. The disease is caused by Plasmodium falciparum malaria parasites, which accumulate in the placenta by adhering to chondroitin sulfate A (CSA). The interaction between infected erythrocytes and the placental receptor is mediated by a parasite expressed protein named VAR2CSA. A vaccine protecting pregnant women against placental malaria should induce antibodies inhibiting the interaction between VAR2CSA and CSA. Much effort has been put into defining the part of the 350 kDa VAR2CSA protein that is responsible for binding. It has been shown that full-length recombinant VAR2CSA binds specifically to CSA with high affinity, however to date no sub-fragment of VAR2CSA has been shown to interact with CSA with similar affinity or specificity. In this study, we used a biosensor technology to examine the binding properties of a panel of truncated VAR2CSA proteins. The experiments indicate that the core of the CSA-binding site is situated in three domains, DBL2X-CIDRPAM and a flanking domain, located in the N-terminal part of VAR2CSA. Furthermore, recombinant VAR2CSA subfragments containing this region elicit antibodies with high parasite adhesion blocking activity in animal immunization experiments.

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Effect of Sulfadoxine-Pyrimethamine doses for prevention of malaria during pregnancy in hypoendemic area in Tanzania

10.21203/rs.2.19381/v2 ◽

2020 ◽

Author(s):

Wigilya Padili Mikomangwa ◽

Omary Minzi ◽

Ritah Mutagonda ◽

Vito Baraka ◽

Eulambius M. Mlugu ◽

...

Keyword(s):

Pregnant Women ◽

Malaria Transmission ◽

Geometric Mean ◽

Placental Malaria ◽

Intermittent Preventive Treatment ◽

Premature Delivery ◽

Maternal Anaemia ◽

Malaria During Pregnancy ◽

Placental Blood ◽

Low Malaria Transmission

Abstract Background Malaria in pregnancy increases the risk of deleterious maternal and birth outcomes. The use of ≥3 doses of sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria (IPTp-SP) is recommended for preventing the consequences of malaria during pregnancy. This study assessed the effect of IPTp-SP for prevention of malaria during pregnancy in low transmission settings. Methods A cross-sectional study that involved consecutively selected 1,161 pregnant women was conducted at Mwananyamala regional referral hospital in Dar es Salaam. Assessment of the uptake of IPTp-SP was done by extracting information from antenatal clinic cards. Maternal venous blood, cord blood, placental blood and placental biopsy were collected for assessment of anaemia and malaria. High performance liquid chromatography with ultraviolet detection (HPLC-UV) was used to detect and quantify sulfadoxine (SDX). Dried blood spots (DBS) of placental blood were collected for determination of sub-microscopic malaria using polymerase chain reaction (PCR). Results In total, 397 (34.2%) pregnant women reported to have used sub-optimal doses (≤2) while 764(65.8%) used optimal doses (≥3) of IPTp-SP at the time of delivery. The prevalence of placental malaria as determined by histology was 3.6%. Submicroscopic placental malaria was detected in 1.4% of the study participants. Women with peripheral malaria had six times risk of maternal anaemia than those who were malaria negative (aOR, 5.83; 95% CI, 1.10-30.92; p = 0.04). The geometric mean plasma SDX concentration was 10.76± 2.51μg/mL. Sub-optimal IPTp-SP dose was not associated with placental malaria, premature delivery and fetal anaemia. The use of ≤2 doses of IPTp-SP increased the risk of maternal anaemia by 1.36 fold compared to ≥3 doses (aOR, 1.36; 95%CI, 1.04-1.79; p = 0.02). Conclusion The use of <2 doses of IPTp-SP increased the risk of maternal anaemia. However, sub-optimal doses (≤2 doses) were not associated with increased the risk of malaria parasitaemia, fetal anaemia and preterm delivery among pregnant women in low malaria transmission setting. The use of optimal doses (≥3doses) of IPTp-SP and complementary interventions should continue even in areas with low malaria transmission.

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Transcribed var Genes Associated with Placental Malaria in MalawianWomen

Infection and Immunity ◽

10.1128/iai.01978-05 ◽

2006 ◽

Vol 74 (8) ◽

pp. 4875-4883 ◽

Cited By ~ 65

Author(s):

Michael F. Duffy ◽

Aphrodite Caragounis ◽

Rintis Noviyanti ◽

Helen M. Kyriacou ◽

Ee Ken Choong ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Pregnant Women ◽

Reverse Transcription ◽

Malaria Vaccine ◽

Placental Malaria ◽

Var Genes ◽

Quantitative Reverse Transcription Pcr ◽

Reverse Transcription Pcr ◽

Malaria During Pregnancy

ABSTRACT Determining the diversity of PfEMP1 sequences expressed by Plasmodium falciparum-infected erythrocytes isolated from placentas is important for attempts to develop a pregnancy-specific malaria vaccine. The DBLγ and var2csa DBL3x domains of PfEMP1 molecules are believed to mediate placental sequestration of infected erythrocytes, so the sequences encoding these domains were amplified from the cDNAs of placental parasites by using degenerate oligonucleotides. The levels of specific var cDNAs were then determined by quantitative reverse transcription-PCR. Homologues of var2csa DBL3x were the predominant sequences amplified from the cDNAs of most placental but not most children's parasites. There was 56% identity between all placental var2csa sequences. Many different DBLγ domains were amplified from the cDNAs of placental and children's isolates. var2csa transcripts were the most abundant var transcripts of those tested in 11 of 12 placental isolates and 1 of 6 children's isolates. Gravidity did not affect the levels of var2csa transcripts. We concluded that placental malaria is frequently associated with transcription of var2csa but that other var genes are also expressed, and parasites expressing high levels of var2csa are not restricted to pregnant women. The diversity of var2csa sequences may be important for understanding immunity and for the development of vaccines for malaria during pregnancy.

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Malaria vaccine candidates displayed on novel virus-like particles are immunogenic and induce transmission-blocking activity

10.1101/597831 ◽

2019 ◽

Author(s):

Jo-Anne Chan ◽

David Wetzel ◽

Linda Reiling ◽

Kazutoyo Miura ◽

Damien Drew ◽

...

Keyword(s):

Malaria Vaccine ◽

Vaccine Development ◽

Transmission Blocking ◽

Vaccine Candidates ◽

Virus Like Particles ◽

Malaria Vaccines ◽

Membrane Feeding ◽

B Virus ◽

Vaccine Antigens ◽

Novel Virus

ABSTRACTThe development of effective malaria vaccines remains a global health priority. Currently, the most advanced vaccine, known as RTS,S, has only shown modest efficacy in clinical trials. Thus, the development of more efficacious vaccines by improving the formulation of RTS,S for increased efficacy or to interrupt malaria transmission are urgently needed. The RTS,S vaccine is based on the presentation of a fragment of the sporozoite antigen on the surface of virus-like particles (VLPs) based on human hepatitis B virus (HBV). In this study, we have developed and evaluated a novel VLP platform based on duck HBV (known as Metavax) for malaria vaccine development. This platform can incorporate large and complex proteins into VLPs and is produced in a Hansenula cell line compatible with cGMP vaccine production. Here, we have established the expression of leading P. falciparum malaria vaccine candidates as VLPs. This includes Pfs230 and Pfs25, which are candidate transmission-blocking vaccine antigens. We demonstrated that the VLPs effectively induce antibodies to malaria vaccine candidates with minimal induction of antibodies to the duck-HBV scaffold antigen. Antibodies to Pfs230 also recognised native protein on the surface of gametocytes, and antibodies to both Pfs230 and Pfs25 demonstrated transmission-reducing activity in standard membrane feeding assays. These results establish the potential utility of this VLP platform for malaria vaccines, which may be suitable for the development of multi-component vaccines that achieve high vaccine efficacy and transmission-blocking immunity.

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Antibodies to Escherichia coli-Expressed C-Terminal Domains of Plasmodium falciparum Variant Surface Antigen 2-Chondroitin Sulfate A (VAR2CSA) Inhibit Binding of CSA-Adherent Parasites to Placental Tissue

Infection and Immunity ◽

10.1128/iai.00978-12 ◽

2013 ◽

Vol 81 (4) ◽

pp. 1031-1039 ◽

Cited By ~ 8

Author(s):

Tracy Saveria ◽

Andrew V. Oleinikov ◽

Kathryn Wiliamson ◽

Richa Chaturvedi ◽

Joe Lograsso ◽

...

Keyword(s):

Escherichia Coli ◽

Plasmodium Falciparum ◽

Chondroitin Sulfate ◽

Surface Antigen ◽

Transmembrane Protein ◽

Placental Malaria ◽

Placental Tissue ◽

Content Type ◽

Variant Surface Antigen ◽

Chondroitin Sulfate A

ABSTRACTPlacental malaria (PM) is characterized by infected erythrocytes (IEs) that selectively bind to chondroitin sulfate A (CSA) and sequester in placental tissue. Variant surface antigen 2-CSA (VAR2CSA), aPlasmodium falciparumerythrocyte membrane protein 1 (PfEMP1) protein family member, is expressed on the surface of placental IEs and mediates adherence to CSA on the surface of syncytiotrophoblasts. This transmembrane protein contains 6 Duffy binding-like (DBL) domains which might contribute to the specific adhesive properties of IEs. Here, we use laboratory isolate 3D7 VAR2CSA DBL domains expressed inEscherichia colito generate antibodies specific for this protein. Flow cytometry results showed that antibodies generated against DBL4ε, DBL5ε, DBL6ε, and tandem double domains of DBL4-DBL5 and DBL5-DBL6 all bind to placental parasite isolates and to lab strains selected for CSA binding but do not bind to children's parasites. Antisera to DBL4ε and to DBL5ε inhibit maternal IE binding to placental tissue in a manner comparable to that for plasma collected from multigravid women. These antibodies also inhibit binding to CSA of several field isolates derived from pregnant women, while antibodies to double domains do not enhance the functional immune response. These data support DBL4ε and DBL5ε as vaccine candidates for pregnancy malaria and demonstrate thatE. coliis a feasible tool for the large-scale manufacture of a vaccine based on these VAR2CSA domains.

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Antibodies That Inhibit Binding of Plasmodium falciparum-Infected Erythrocytes to Chondroitin Sulfate A and to the C Terminus of Merozoite Surface Protein 1 Correlate with Reduced Placental Malaria in Cameroonian Women

Infection and Immunity ◽

10.1128/iai.72.3.1603-1607.2004 ◽

2004 ◽

Vol 72 (3) ◽

pp. 1603-1607 ◽

Cited By ~ 24

Author(s):

Diane Wallace Taylor ◽

Aniong Zhou ◽

Lauren E. Marsillio ◽

Lucy W. Thuita ◽

Efua B. Leke ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Chondroitin Sulfate ◽

Placental Malaria ◽

Surface Protein ◽

Merozoite Surface Protein ◽

Liver Stage ◽

Merozoite Surface Protein 1 ◽

Erythrocyte Surface ◽

Antibody Levels ◽

Chondroitin Sulfate A

ABSTRACT Plasmodium falciparum-infected erythrocytes often sequester in the placenta of pregnant women, producing placental malaria, a condition that can compromise the health of the developing fetus. Scientists are hopeful that a vaccine can be developed to prevent this condition. Immunological mechanisms responsible for eliminating parasites from the placenta remain unclear, but antibodies to the carboxyl-terminal 19-kDa segment of the merozoite surface protein 1 (MSP1-19), the ring-infected erythrocyte surface antigen (RESA), and an erythrocyte-surface ligand that binds chondroitin sulfate A (CSA-L) have been implicated. In addition, antibodies to sporozoite and liver-stage antigens could reduce initial parasite burdens. This study sought to determine if antibodies to the circumsporozoite protein (CSP), liver-stage antigen 1 (LSA1), RESA, MSP1-19, or CSA-L correlated with either the absence of placental parasites or low placental parasitemias. Using a frequency-matched case-control study design, we compared antibody levels in women (gravidity 1 to 11) with and without placental malaria. Results showed that women who were antibody negative for MSP1-19 were at a higher risk of having placental malaria than women with antibodies (P < 0.007). Furthermore, an association between high levels of antibodies that blocked the binding of infected erythrocytes to CSA and low placental parasitemias was observed (P = 0.02). On the other hand, women with high antibody levels at term to CSP, LSA1, and RESA were more likely to have placental malaria than antibody-negative women. Since antibodies to MSP1-19 and CSA-L were associated with reduced placental malaria, both antigens show promise for inclusion in a vaccine for women of child-bearing age.

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Down-selection of the VAR2CSA DBL1-2 expressed in E. coli as a lead antigen for placental malaria vaccine development

npj Vaccines ◽

10.1038/s41541-018-0064-6 ◽

2018 ◽

Vol 3 (1) ◽

Cited By ~ 8

Author(s):

Arnaud Chêne ◽

Stéphane Gangnard ◽

Célia Dechavanne ◽

Sebastien Dechavanne ◽

Anand Srivastava ◽

...

Keyword(s):

Malaria Vaccine ◽

Vaccine Development ◽

Placental Malaria ◽

E Coli ◽

Selection Of

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Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding

Nature Communications ◽

10.1038/s41467-021-23254-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kaituo Wang ◽

Robert Dagil ◽

Thomas Lavstsen ◽

Sandeep K. Misra ◽

Charlotte B. Spliid ◽

...

Keyword(s):

Chondroitin Sulfate ◽

Rational Design ◽

Immune Escape ◽

Binding Capacity ◽

Placental Malaria ◽

Structural Features ◽

Malaria Vaccines ◽

Mother And Child ◽

Binding Groove ◽

Dynamics Simulations

AbstractPlacental malaria can have severe consequences for both mother and child and effective vaccines are lacking. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Here, we report cryo-EM structures of the VAR2CSA ectodomain at up to 3.1 Å resolution revealing an overall V-shaped architecture and a complex domain organization. Notably, the surface displays a single significantly electropositive patch, compatible with binding of negatively charged CS. Using molecular docking and molecular dynamics simulations as well as comparative hydroxyl radical protein foot-printing of VAR2CSA in complex with placental CS, we identify the CS-binding groove, intersecting with the positively charged patch of the central VAR2CSA structure. We identify distinctive conserved structural features upholding the macro-molecular domain complex and CS binding capacity of VAR2CSA as well as divergent elements possibly allowing immune escape at or near the CS binding site. These observations will support rational design of second-generation placental malaria vaccines.

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Malaria vaccines: high-throughput tools for antigens discovery with potential for their development

Colombia Medica ◽

10.25100/cm.v44i2.1201 ◽

2013 ◽

pp. 121-128

Author(s):

Nora Céspedes ◽

Andrés Vallejo ◽

Myriam Arévalo-Herrera ◽

Sócrates Herrera

Keyword(s):

Malaria Vaccine ◽

Vaccine Development ◽

Plasmodium Species ◽

Cost Effective ◽

Control Measures ◽

Anopheles Mosquitoes ◽

Malaria Vaccines ◽

Large Numbers ◽

Immune Potential ◽

Selection Of

Malaria is a disease induced by parasites of the Plasmodium genus, which are transmitted by Anopheles mosquitoes and represents a great socio-economic burden worldwide. Plasmodium vivax is the second species of malaria worldwide, but it is the most prevalent in Latin America and other regions of the planet. It is currently considered that vaccines represent a cost-effective strategy for controlling transmissible diseases and could complement other malaria control measures; however, the chemical and immunological complexity of the parasite has hindered development of effective vaccines. Recent availability of several genomes of Plasmodium species, as well as bioinformatics tools are allowing the selection of large numbers of proteins and analysis of their immune potential. Herein, we review recently developed strategies for discovery of novel antigens with potential for malaria vaccine development.

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The Promise of a Malaria Vaccine—Are We Closer?

Annual Review of Microbiology ◽

10.1146/annurev-micro-090817-062427 ◽

2018 ◽

Vol 72 (1) ◽

pp. 273-292 ◽

Cited By ~ 14

Author(s):

Matthew B. Laurens

Keyword(s):

Malaria Vaccine ◽

Vaccine Development ◽

Phase 3 ◽

Target Populations ◽

The Past ◽

Malaria Vaccines ◽

Long Duration ◽

Implementation Studies ◽

Endemic Areas ◽

Pilot Implementation

Malaria vaccine development has rapidly advanced in the past decade. The very first phase 3 clinical trial of the RTS,S vaccine was completed with over 15,000 African infants and children, and pilot implementation studies are underway. Next-generation candidate vaccines using novel antigens, platforms, or approaches targeting different and/or multiple stages of the Plasmodium life cycle are being tested. Many candidates, in various stages of development, promise enhanced efficacy of long duration and broad protection against genetically diverse malaria strains, with a few studies under way in target populations in endemic areas. Malaria vaccines together with other interventions promise interruption and eventual elimination of malaria in endemic areas.

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