The case for PfEMP1-based vaccines to protect pregnant women against Plasmodium falciparum malaria

Expert Review of Vaccines

Volumn 10, Issue 10, 2011, Pages 1405-1414

  Hviid, Lars ^a,b  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b CSS Building 22 ^*  (Denmark)

Author keywords

malaria; PfEMP1; placenta; Plasmodium falciparum; pregnancy; vaccine; VAR2CSA

Indexed keywords

CD36 ANTIGEN; CHONDROITIN 4 SULFATE; DUFFY BINDING PROTEIN; ERYTHROCYTE MEMBRANE PROTEIN 1; HYALURONIC ACID; IMMUNOGLOBULIN G; MALARIA VACCINE; PROTEIN VAR2CSA; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; ANEMIA; ANTIBODY SPECIFICITY; BINDING AFFINITY; ERYTHROCYTE; ERYTHROCYTE ADHESIVENESS; HUMAN; IMMUNE RESPONSE; INFECTION SENSITIVITY; LOW BIRTH WEIGHT; MALARIA FALCIPARUM; PARASITEMIA; PLACENTA DISORDER; PLACENTAL TRANSFER; PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX; PREGNANCY OUTCOME; PREGNANT WOMAN; PREMATURE LABOR; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SYNCYTIOTROPHOBLAST; VACCINATION; VIRULENCE;

FEMALE; HUMANS; MALARIA VACCINES; MALARIA, FALCIPARUM; PREGNANCY; PREGNANCY COMPLICATIONS, PARASITIC; PROTOZOAN PROTEINS;

EID: 80054005258     PISSN: 14760584     EISSN: 17448395     Source Type: Journal    
DOI: 10.1586/erv.11.113     Document Type: Review

References (105)

1. Dellicour S, Tatem AJ, Guerra CA, Snow RW, Ter Kuile FO. Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study. PLoS Med. 7, e1000221 (2010).
2. Desai M, Ter Kuile FO, Nosten F et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect. Dis. 7, 93-104 (2007).
3. Nosten F, McGready R, Simpson JA et al. Effects of Plasmodium vivax malaria in pregnancy. Lancet 354, 546-549 (1999).
4. Poespoprodjo JR, Fobia W, Kenangalem E et al. Adverse pregnancy outcomes in an area where multidrug-resistant Plasmodium vivax and Plasmodium falciparum infections are endemic. Clin. Infect. Dis. 46, 1374-1381 (2008).
5. Tembo D, Montgomery J. Var gene expression and human Plasmodium pathogenesis. Future Microbiol. 203(5), 1185-1196 (2010).
6. Singh B, Sung LK, Matusop A et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet 363, 1017-1024 (2004).
7. Cox-Singh J, Davis TM, Lee KS et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin. Infect. Dis. 46, 165-171 (2008).
8. Korir CC, Galinski MR. Proteomic studies of Plasmodium knowlesi SICA variant antigens demonstrate their relationship with P. falciparum EMP1. Infect. Genet. Evol. 6, 75-79 (2006).
9. Hviid L. Naturally acquired immunity to Plasmodium falciparum malaria in Africa. Acta Trop. 95, 270-275 (2005).
10. Hviid L. The immuno-epidemiology of pregnancy-associated malaria: a variant surface antigen-specific perspective. Parasite Immunol. 26, 477-486 (2004).
11. Beeson JG, Amin N, Kanjala M, Rogerson SJ. Selective accumulation of mature asexual stages of Plasmodium falciparum-infected erythrocytes in the placenta. Infect. Immun. 70, 5412-5415 (2002).
12. Fried M, Duffy PE. Adherence of Plasmodium falciparum to chondroitin sulphate A in the human placenta. Science 272, 1502-1504 (1996).
13. Salanti A, Staalsoe T, Lavstsen T et al. Selective upregulation of a single distinctly structured var gene in CSA-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol. Microbiol. 49, 179-191 (2003).
14. Salanti A, Dahlbäck M, Turner L et al. Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. J. Exp. Med. 200, 1197-1203 (2004).
15. Smith JD, Deitsch KW. Pregnancy-associated malaria and the prospects for syndrome-specific antimalaria vaccines. J. Exp. Med. 200, 1093-1097 (2004).
16. Robert C, Pouvelle B, Meyer P et al. Chondroitin-4-sulphate (proteoglycan), a receptor for Plasmodium falciparum-infected erythrocyte adherence on brain microvascular endothelial cells. Res. Immunol. 146, 383-393 (1995).
17. Rogerson SJ, Chaiyaroj SC, Ng K, Reeder JC, Brown GV. Chondroitin sulfate A is a cell surface receptor for Plasmodium falciparum-infected erythrocytes. J. Exp. Med. 182, 15-20 (1995).
18. Flick K, Scholander C, Chen Q et al. Role of non-immune IgG bound to PfEMP1 in placental malaria. Science 293, 2098-2100 (2001).
19. Beeson JG, Rogerson SJ, Cooke BM et al. Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria. Nat. Med. 6, 86-90 (2000).
20. Rowe JA, Shafi J, Kai OK, Marsh K, Raza A. Nonimmune IgM, but not IgG binds to the surface of Plasmodium falciparum-infected erythrocytes and correlates with rosetting and severe malaria. Am. J. Trop. Med. Hyg. 66, 692-699 (2002).
21. Creasey A, Staalsoe T, Raza A, Arnot D, Rowe JA. Nonspecific Immunoglobulin M binding and chondroitin sulfate A binding are linked phenotypes of Plasmodium falciparum isolates implicated in malaria during pregnancy. Infect. Immun. 71, 4767-4771 (2003
22. Muthusamy A, Achur RN, Valiyaveettil M et al. Chondroitin sulfate proteoglycan but not hyaluronic acid is the receptor for the adherence of Plasmodium falciparum-infected erythrocytes in human placenta and IRBC adherence upregulates the receptor expression. Am. J. Pathol. 170, 1989-2000 (2007).
23. Beeson JG, Brown GV, Molyneux ME, Mhango C, Dzinjalamala F, Rogerson SJ. Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties. J. Infect. Dis. 180, 464-472 (1999).
24. Rogerson SJ, Beeson JG, Mhango CG, Dzinjalamala FK, Molyneux ME. Plasmodium falciparum rosette formation is uncommon in isolates from pregnant women. Infect. Immun. 68, 391-393 (2000).
25. Barfod L, Dobrilovic T, Magistrado P et al. CSA-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants. J. Immunol. 185, 7553-7561 (2010).
26. Rovira-Vallbona E, Dobano C, Bardaji A et al. Transcription of var genes other than var2csa in Plasmodium falciparum parasites infecting Mozambican pregnant women. J. Infect. Dis. 204, 27-35 (2011).
27. Maubert B, Guilbert LJ, Deloron P. Cytoadherence of Plasmodium falciparum to intercellular adhesion molecule 1 and chondroitin-4-sulfate expressed by the syncytiotrophoblast in the human placenta. Infect. Immun. 65, 1251-1257 (1997).
28. Fried M, Nosten F, Brockman A, Brabin BT, Duffy PE. Maternal antibodies block malaria. Nature 395, 851-852 (1998).
29. Ricke CH, Staalsoe T, Koram K et al. Plasma antibodies from malaria-exposed pregnant women recognize variant surface antigens on Plasmodium falciparum-infected erythrocytes in a parity-dependent manner and block parasite adhesion to chondroitin sulphate A. J. Immunol. 165, 3309-3316 (2000).
30. Staalsoe T, Megnekou R, Fievet N et al. Acquisition and decay of antibodies to pregnancy-associated variant antigens on the surface of Plasmodium falciparum infected erythrocytes that are associated with protection against placental parasitemia. J. Infect. Dis. 184, 618-626 (2001).
31. Duffy PE, Fried M. Antibodies that inhibit Plasmodium falciparum adhesion to chondroitin sulfate A are associated with increased birth weight and the gestational age of newborns. Infect. Immun. 71, 6620-6623 (2003).
32. Staalsoe T, Shulman CE, Bulmer JN, Kawuondo K, Marsh K, Hviid L. Variant surface antigen-specific IgG and protection against the clinical consequences of pregnancy-associated Plasmodium falciparum malaria. Lancet 363, 283-289 (2004).
33. Leech JH, Barnwell JW, Miller LH, Howard RJ. Identification of a strain-specific malarial antigen exposed on the surface of Plasmodium falciparum-infected erythrocytes. J. Exp. Med. 159, 1567-1575 (1984).
34. Baruch DI, Pasloske BL, Singh HB et al. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82, 77-87 (1995).
35. Smith JD, Chitnis CE, Craig AG et al. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82, 101-110 (1995).
36. Su X, Heatwole VM, Wertheimer SP et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82, 89-100 (1995).
37. Tuikue Ndam NG, Salanti A, Bertin G et al. High level of var2csa transcription by Plasmodium falciparum isolated from the placenta. J. Infect. Dis. 192, 331-335 (2005).
38. Duffy MF, Caragounis A, Noviyanti R et al. Transcribed var genes associated with placental malaria in Malawian women. Infect. Immun. 74, 4875-4883 (2006).
39. Francis SE, Malkov VA, Oleinikov AV et al. Six genes are preferentially transcribed by the circulating and sequestered forms of Plasmodium falciparum parasites that infect pregnant women. Infect. Immun. 75, 4838-4850 (2007).
40. Gardner MJ, Hall N, Fung E et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498-511 (2002).
41. Magistrado P, Salanti A, Tuikue Ndam NG et al. VAR2CSA expression on the surface of placenta-derived Plasmodium falciparum-infected erythrocytes. J. Infect. Dis. 198, 1071-1074 (2008).
42. Buffet PA, Gamain B, Scheidig C et al. Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: a receptor for human placental infection. Proc. Natl Acad. Sci. USA 96, 12743-12748 (1999).
43. Reeder JC, Cowman AF, Davern KM et al. The adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane protein 1. Proc. Natl Acad. Sci. USA 96, 5198-5202 (1999).
44. Degen R, Weiss N, Beck HP. Plasmodium falciparum: cloned and expressed CIDR domains of PfEMP1 bind to chondroitin sulfate A. Exp. Parasitol. 95, 113-121 (2000).
45. Khattab A, Kun J, Deloron P, Kremsner PG, Klinkert M-Q. Variants of Plasmodium falciparum erythrocyte membrane protein 1 expressed by different placental parasites are closely related and adhere to chondroitin sulfate A. J. Infect. Dis. 183, 1165-1169 (2001).
46. Resende M, Ditlev SB, Nielsen MA et al. Chondroitin sulphate A (CSA)-binding of single recombinant Duffy-binding-like domains is not restricted to Plasmodium falciparum erythrocyte membrane protein 1 expressed by CSA-binding parasites. Int. J. Parasitol. 39, 1195-1204 (2009).
47. Khunrae P, Dahlbäck M, Nielsen MA et al. Full-length recombinant Plasmodium falciparum VAR2CSA binds specifically to CSPG and induces potent parasite adhesion-blocking antibodies. J. Mol. Biol. 397, 826-834 (2010).
48. Srivastava A, Gangnard S, Round A et al. Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific, high-affinity binding to CSA. Proc. Natl Acad. Sci. USA 107, 4884-4889 (2010).
49. Viebig NK, Gamain B, Scheidig C et al. A single member of the Plasmodium falciparum var multigene family determines cytoadhesion to the placental receptor chondroitin sulphate A. EMBO Reports 6, 775-781 (2005).
50. Duffy MF, Maier AG, Byrne TJ et al. VAR2CSA is the principal ligand for chondroitin sulfate A in two allogeneic isolates of Plasmodium falciparum. Mol. Biochem. Parasitol. 148, 117-124 (2006).
51. Viebig NK, Levin E, Dechavanne S et al. Disruption of var2csa gene impairs placental malaria associated adhesion phenotype. PLoS ONE 2, e910 (2007).
52. Barfod L, Bernasconi N, Dahlbäck M et al. Human pregnancy-associated malaria-specific B cells target polymorphic, conformational epitopes in VAR2CSA. Mol. Microbiol. 63, 335-347 (2007).
53. Bigey P, Gnidehou S, Doritchamou J et al. The NTS-DBL2X region of VAR2CSA induces cross-reactive antibodies that inhibit adhesion of several Plasmodium falciparum isolates to chondroitin sulfate A. J. Infect. Dis. 204, 1125-1133 (2011).
54. Dahlbäck M, Jørgensen LM, Nielsen MA et al. The chondroitin sulphate A-binding site of the VAR2CSA protein involves multiple N-terminal domains. J. Biol. Chem. 286, 15908-15917 (2011).
55. Srivastava A, Gangnard S, Dechavanne S et al. Var2CSA minimal CSA binding region is located within the N-terminal region. PLoS ONE 6, e20270 (2011).
56. Higgins MK. The structure of a chondroitin sulfate-binding domain important in placental malaria. J. Biol. Chem. 283, 21842-21846 (2008).
57. Singh K, Gittis AG, Nguyen P, Gowda DC, Miller LH, Garboczi DN. Structure of the DBL3x domain of pregnancy-associated malaria protein VAR2CSA complexed with chondroitin sulfate A. Nat. Struct. Mol. Biol. 15, 932-938 (2008).
58. Singh K, Gitti RK, Diouf A et al. Subdomain 3 of Plasmodium falciparum VAR2CSA DBL3X is identified as a minimal chondroitin sulfate A binding region. J. Biol. Chem. 285, 24855-24862 (2010).
59. Gowda AS, Madhunapantula SV, Achur RN, Valiyaveettil M, Bhavanandan VP, Gowda DC. Structural basis for the adherence of Plasmodium falciparum-infected erythrocytes to chondroitin 4-sulfate and design of novel photoactivable reagents for the identification of parasite adhesive proteins. J. Biol. Chem. 282, 916-928 (2007).
60. Fried M, Wendler JP, Mutabingwa TK, Duffy PE. Mass spectrometric analysis of Plasmodium falciparum erythrocyte membrane protein-1 variants expressed by placental malaria parasites. Proteomics 4, 1086-1093 (2004).
61. Fried M, Hixson KK, Anderson L, Ogata Y, Mutabingwa TK, Duffy PE. The distinct proteome of placental malaria parasites. Mol. Biochem. Parasitol. 155, 57-65 (2007).
62. Lasonder E, Ishihama Y, Andersen JS et al. Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrometry. Nature 419, 537-542 (2002).
63. Tuikue Ndam N, Bischoff E, Proux C et al. Plasmodium falciparum transcriptome analysis reveals pregnancy malaria associated gene expression. PLoS ONE 3, e1855 (2008).
64. Tuikue Ndam NG, Salanti A, Le-Hesran J-Y et al. Dynamics of anti-VAR2CSA immunoglobulin G response in a cohort of Senegalese pregnant women. J. Infect. Dis. 193, 713-720 (2006).
65. Pouvelle B, Buffet PA, Lepolard C, Scherf A, Gysin J. Cytoadhesion of Plasmodium falciparum ring-stage-infected erythrocytes. Nat. Med. 6, 1264-1268 (2000).
66. Douki LJB, Sterkers Y, Lepolard C et al. Adhesion of normal and Plasmodium falciparum ring-infected erythrocytes to endothelial cells and the placenta involves the rhoptry-derived ring surface protein-2. Blood 101, 5025-5032 (2003).
67. Brabin BJ. An analysis of malaria in pregnancy in Africa. Bull. World Health Organ. 61, 1005-1016 (1983).
68. Steketee RW, Nahlen BL, Parise ME, Menendez C. The burden of malaria in pregnancy in malaria-endemic areas. Am. J. Trop. Med. Hyg. 64, 28-35 (2001).
69. Lindsay S, Ansell J, Selman C, Cox V, Hamilton K, Walraven G. Effect of pregnancy on exposure to malaria mosquitoes. Lancet 355, 1972 (2000).
70. Ansell J, Hamilton KA, Pinder M, Walraven GE, Lindsay SW. Short-range attractiveness of pregnant women to Anopheles gambiae mosquitoes. Trans. R. Soc. Trop. Med. Hyg. 96, 113-116 (2002).
71. Guilbert LJ. There is a bias against type 1 (inflammatory) cytokine expression and function in pregnancy. J. Repr. Immunol. 32, 105-110 (1996).
72. Cottrell G, Mary JY, Barro D, Cot M. The importance of the period of malarial infection during pregnancy on birth weight in tropical Africa. Am. J. Trop. Med. Hyg. 76, 849-854 (2007).
73. Huynh BT, Fievet N, Gbaguidi G et al. Influence of the timing of malaria infection during pregnancy on birth weight and on maternal anemia in Benin. Am. J. Trop. Med. Hyg. 85, 214-220 (2011).
74. Brabin BJ, Romagosa C, Abdelgalil S et al. The sick placenta - the role of malaria. Placenta 25, 359-378 (2004).
75. Giobbia M, Tonon E, Zanatta A, Cesaris L, Vaglia A. Late recrudescence of Plasmodium falciparum malaria in a pregnant woman: a case report. Int. J. Infect. Dis. 9, 234-235 (2005).
76. Poilane I, Jeantils V, Carbillon L. Découverte fortuite de paludisme à Plasmodium falciparum au cours de la grossesse: à propos de deux cas. Gynecol. Obstet. Fertil. 37, 824-826 (2009).
77. Menéndez C, Moorthy VS, Reed Z, Bardají A, Alonso P, Brown GV. Development of vaccines to prevent malaria in pregnant women: WHO MALVAC meeting report. Expert Rev. Vaccines 10(9), 1271-1280 (2011).
78. Nguyen-Dinh P, Steketee RW, Greenberg AE, Wirima JJ, Mulenda O, Williams SB. Rapid spontaneous postpartum clearance of Plasmodium falciparum parasitaemia in African women. Lancet 2, 751-752 (1988).
79. Ofori MF, Staalsoe T, Bam V et al. Expression of variant surface antigens by Plasmodium falciparum parasites in the peripheral blood of clinically immune pregnant women indicates ongoing placental infection. Infect. Immun. 71, 1584-1586 (2003).
80. Bottero J, Briand V, Agbowai C, Doritchamou J, Massougbodji A, Cot M. Spontaneous postpartum clearance of Plasmodium falciparum parasitemia in pregnant women, Benin. Am. J. Trop. Med. Hyg. 84, 267-269 (2011).
81. Kamwendo DD, Dzinjalamala FK, Snounou G et al. Plasmodium falciparum: PCR detection and genotyping of isolates from peripheral, placental, and cord blood of pregnant Malawian women and their infants. Trans. R. Soc. Trop. Med. Hyg. 96, 145-149 (2002).
82. Tuikue Ndam NG, Fievet N, Bertin G, Cottrell G, Gaye A, Deloron P. Variable adhesion abilities and overlapping antigenic properties in placental Plasmodium falciparum isolates. J. Infect. Dis. 190, 2001-2009 (2004).
83. Cox SE, Staalsoe T, Arthur P et al. Maternal vitamin A supplementation and immunity to malaria in pregnancy in Ghanaian primigravids. Trop. Med Int. Health 10, 1286-1297 (2005).
84. Ataide R, Hasang W, Wilson DW et al. Using an improved phagocytosis assay to evaluate the effect of HIV on specific antibodies to pregnancy-associated malaria. PLoS ONE 5, e10807 (2010).
85. Serra-Casas E, Menendez C, Bardaji A et al. The effect of intermittent preventive treatment during pregnancy on malarial antibodies depends on HIV status and is not associated with poor delivery outcomes. J. Infect. Dis. 201, 123-131 (2010).
86. Cox SE, Staalsoe T, Arthur P et al. Rapid acquisition of isolate-specific antibodies to chondroitin sulphate A-adherent Plasmodium falciparum isolates in Ghanaian primigravidae. Infect. Immun. 73, 2841-2847 (2005).
87. Nielsen MA, Pinto VV, Resende M et al. Induction of adhesion-inhibitory antibodies against placental Plasmodium falciparum parasites by using single domains of VAR2CSA. Infect. Immun. 77, 2482-2487 (2009).
88. Magistrado PA, Minja D, Doritchamou J et al. High efficacy of anti DBL4e- VAR2CSA antibodies in inhibition of CSA-binding Plasmodium falciparum-infected erythrocytes from pregnant women. Vaccine 29, 437-443 (2010).
89. Barfod L, Dalgaard MB, Pleman ST, Ofori MF, Pleass RJ, Hviid L. Evasion of immunity to Plasmodium falciparum malaria by IgM masking of protective IgG epitopes in infected erythrocyte surface-exposed PfEMP1. Proc. Natl Acad. Sci. USA 108, 12485-12490 (2011).
90. O'Neill-Dunne I, Achur RN, Agbor-Enoh ST et al. Gravidity-dependent production of antibodies that inhibit binding of Plasmodium falciparum-infected erythrocytes to placental chondroitin sulfate proteoglycan during pregnancy. Infect. Immun. 69, 7487-7492 (2001).
91. Brolin KJ, Ribacke U, Nilsson S et al. Simultaneous transcription of duplicated var2csa gene copies in individual Plasmodium falciparum parasites. Genome Biol. 10, R117 (2009).
92. Sander AF, Salanti A, Lavstsen T et al. Multiple var2csa-type PfEMP1 genes located at different chromosomal loci occur in many Plasmodium falciparum isolates. PLoS ONE 4, e6667 (2009).
93. Sander AF, Salanti A, Lavstsen T et al. Positive selection of Plasmodium falciparum parasites with multiple var2csa-type PfEMP1 genes during the course of infection in pregnant women. J. Infect. Dis. 203, 1679-1685 (2011).
94. Rask TS, Hansen DA, Theander TG, Pedersen AG, Lavstsen T. Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes - divide and conquer. PLoS Comput. Biol. 6, e1000983 (2010).
95. Trimnell AR, Kraemer SM, Mukherjee S et al. Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria. Mol. Biochem. Parasitol. 148, 169-180 (2006).
96. Dahlbäck M, Rask TS, Andersen PH et al. Epitope mapping and topographic analysis of VAR2CSA DBL3X involved in Plasmodium falciparum placental sequestration. PLoS Pathog. 2, e124 (2006).
97. Hommel M, Elliott SR, Soma V et al. Evaluating the antigenic diversity of placental binding Plasmodium falciparum variants and the antibody repertoire among pregnant women. Infect. Immun. 78, 1963-1978 (2010).
98. Elliott SR, Duffy MF, Byrne TJ et al. Cross-reactive surface epitopes on chondroitin sulfate A- adherent Plasmodium falciparum-infected erythrocytes are associated with transcription of var2csa. Infect. Immun. 73, 2848-2856 (2005).
99. Andersen P, Nielsen MA, Resende M et al. Structural insights into epitopes in the pregnancy-associated malaria protein VAR2CSA. PLoS Pathog. 4, e42 (2008).
100. Soerli J, Barfod L, Lavstsen T, Bernasconi NL, Lanzavecchia A, Hviid L. Human monoclonal IgG selection of Plasmodium falciparum for the expression of placental malaria-specific variant surface antigens. Parasite Immunol. 31, 341-346 (2009).
101. Avril M, Cartwright MM, Hathaway MJ et al. Immunization with VAR2CSA-DBL5 recombinant protein elicits broadly cross-reactive antibodies to placental-type Plasmodium falciparum infected erythrocytes. Infect. Immun. 78, 2248-2256 (2010).
102. Fernandez P, Petres S, Mecheri S, Gysin J, Scherf A. Strain-transcendent immune response to recombinant Var2CSA DBL5-e domain block P. falciparum adhesion to placenta-derived BeWo cells under flow conditions. PLoS ONE 5(9), e12558 (2010).
103. Gnidehou S, Jessen L, Gangnard S et al. Insight into antigenic diversity of VAR2CSA-DBL5e domain from multiple Plasmodium falciparum placental isolates. PLoS ONE 5, e13105 (2010).
104. Avril M, Hathaway MJ, Srivastava A et al. Antibodies to a full-length VAR2CSA immunogen are broadly strain-transcendent but do not cross-inhibit different placental-type parasite isolates. PLoS ONE 6, e16622 (2011).
105. Rogerson SJ, Hviid L, Duffy PE, Leke RFG, Taylor DW. Malaria in pregnancy: pathogenesis and immunity. Lancet Infect. Dis. 7, 105-117 (2007).