Volume 92, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



The erythrocyte membrane protein 1 (PfEMP1) family mediates parasite sequestration in small capillaries through tissue-specific cytoadherence. The best characterized of these proteins is VAR2CSA, which is expressed on the surface of infected erythrocytes that bind to chondroitin sulfate in the placental matrix. Antibodies to VAR2CSA prevent placental cytoadherence and protect against placental malaria. The size and complexity of the VAR2CSA protein pose challenges for vaccine development, but smaller constitutive domains may be suitable for subunit vaccine development. A protein microarray was printed to include five overlapping fragments of the 3D7 VAR2CSA extracellular region. Malian women with a history of at least one pregnancy had antibody recognition of four of these fragments and had stronger reactivity against the two distal fragments than did nulliparous women, children, and men from Mali, suggesting that the C-terminal extracellular VAR2CSA domains are a potential focus of protective immunity. With carefully chosen sera from longitudinal studies of pregnant women, this approach has the potential to identify seroreactive VAR2CSA domains associated with protective immunity against pregnancy-associated malaria.

[open-access] This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Rowe JA, Claessens A, Corrigan RA, Arman M, , 2009. Adhesion of Plasmodium falciparum-infected erythrocytes to human cells: molecular mechanisms and therapeutic implications. Expert Rev Mol Med 11: e16.[Crossref] [Google Scholar]
  2. Fried M, Duffy PE, , 1996. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science 272: 15021504.[Crossref] [Google Scholar]
  3. Salanti A, Staalsoe T, Lavstsen T, Jensen AT, Sowa MP, Arnot DE, Hviid L, Theander TG, , 2003. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol Microbiol 49: 179191.[Crossref] [Google Scholar]
  4. Salanti A, Dahlback M, Turner L, Nielsen MA, Barfod L, Magistrado P, Jensen AT, Lavstsen T, Ofori MF, Marsh K, Hviid L, Theander TG, , 2004. Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. J Exp Med 200: 11971203.[Crossref] [Google Scholar]
  5. Duffy PE, Fried M, , 2003. 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: 66206623.[Crossref] [Google Scholar]
  6. Brolin KJ, Persson KE, Wahlgren M, Rogerson SJ, Chen Q, , 2010. Differential recognition of P. falciparum VAR2CSA domains by naturally acquired antibodies in pregnant women from a malaria endemic area. PLoS ONE 5: e9230.[Crossref] [Google Scholar]
  7. Oleinikov AV, Rossnagle E, Francis S, Mutabingwa TK, Fried M, Duffy PE, , 2007. Effects of sex, parity, and sequence variation on seroreactivity to candidate pregnancy malaria vaccine antigens. J Infect Dis 196: 155164.[Crossref] [Google Scholar]
  8. Bordbar B, Tuikue-Ndam N, Bigey P, Doritchamou J, Scherman D, Deloron P, , 2012. Identification of Id1-DBL2X of VAR2CSA as a key domain inducing highly inhibitory and cross-reactive antibodies. Vaccine 30: 13431348.[Crossref] [Google Scholar]
  9. Clausen TM, Christoffersen S, Dahlback M, Langkilde AE, Jensen KE, Resende M, Agerbaek MO, Andersen D, Berisha B, Ditlev SB, Pinto VV, Nielsen MA, Theander TG, Larsen S, Salanti A, , 2012. Structural and functional insight into how the Plasmodium falciparum VAR2CSA protein mediates binding to chondroitin sulfate A in placental malaria. J Biol Chem 287: 2333223345.[Crossref] [Google Scholar]
  10. Srivastava A, Gangnard S, Dechavanne S, Amirat F, Lewit BA, Bentley GA, Gamain B, , 2011. Var2CSA minimal CSA binding region is located within the N-terminal region. PLoS ONE 6: e20270.[Crossref] [Google Scholar]
  11. Thera MA, Doumbo OK, Coulibaly D, Diallo DA, Sagara I, Dicko A, Diemert DJ, Heppner DG, Jr Stewart VA, Angov E, Soisson L, Leach A, Tucker K, Lyke KE, Plowe CV, , 2006. Safety and allele-specific immunogenicity of a malaria vaccine in Malian adults: results of a phase I randomized trial. PLoS Clin Trials 1: e34.[Crossref] [Google Scholar]
  12. Thera MA, Doumbo OK, Coulibaly D, Diallo DA, Kone AK, Guindo AB, Traore K, Dicko A, Sagara I, Sissoko MS, Baby M, Sissoko M, Diarra I, Niangaly A, Dolo A, Daou M, Diawara SI, Heppner DG, Stewart VA, Angov E, Bergmann-Leitner ES, Lanar DE, Dutta S, Soisson L, Diggs CL, Leach A, Owusu A, Dubois MC, Cohen J, Nixon JN, Gregson A, Takala SL, Lyke KE, Plowe CV, , 2008. Safety and immunogenicity of an AMA-1 malaria vaccine in Malian adults: results of a phase 1 randomized controlled trial. PLoS ONE 3: e1465.[Crossref] [Google Scholar]
  13. Thera MA, Doumbo OK, Coulibaly D, Laurens MB, Ouattara A, Kone AK, Guindo AB, Traore K, Traore I, Kouriba B, Diallo DA, Diarra I, Daou M, Dolo A, Tolo Y, Sissoko MS, Niangaly A, Sissoko M, Takala-Harrison S, Lyke KE, Wu Y, Blackwelder WC, Godeaux O, Vekemans J, Dubois MC, Ballou WR, Cohen J, Thompson D, Dube T, Soisson L, Diggs CL, House B, Lanar DE, Dutta S, Heppner DG, Jr Plowe CV, , 2011. A field trial to assess a blood-stage malaria vaccine. N Engl J Med 365: 10041013.[Crossref] [Google Scholar]
  14. Rask TS, Hansen DA, Theander TG, Gorm PA, Lavstsen T, , 2010. Plasmodium falciparum erythrocyte membrane protein 1 diversity in seven genomes—divide and conquer. PLOS Comput Biol 6: pii.e1000933.[Crossref] [Google Scholar]
  15. Davies DH, Liang X, Hernandez JE, Randall A, Hirst S, Mu Y, Romero KM, Nguyen TT, Kalantari-Dehaghi M, Crotty S, Baldi P, Villarreal LP, Felgner PL, , 2005. Profiling the humoral immune response to infection by using proteome microarrays: high-throughput vaccine and diagnostic antigen discovery. Proc Natl Acad Sci USA 102: 547552.[Crossref] [Google Scholar]
  16. Doolan DL, Mu Y, Unal B, Sundaresh S, Hirst S, Valdez C, Randall A, Molina D, Liang X, Freilich DA, Oloo JA, Blair PL, Aguiar JC, Baldi P, Davies DH, Felgner PL, , 2008. Profiling humoral immune responses to P. falciparum infection with protein microarrays. Proteomics 8: 46804694.[Crossref] [Google Scholar]
  17. Travassos MA, Niangaly A, Bailey JA, Ouattara A, Coulibaly D, Laurens MB, Pablo J, Jasinskas A, Nakajima-Sasaki R, Berry AA, Takala-Harrison S, Kouriba B, Rowe JA, Lyke KE, Doumbo OK, Thera MA, Felgner PL, Plowe CV, , 2013. Seroreactivity to Plasmodium falciparum erythrocyte membrane protein 1 intracellular domain in malaria-exposed children and adults. J Infect Dis 208: 15141519.[Crossref] [Google Scholar]
  18. Crompton PD, Kayala MA, Traore B, Kayentao K, Ongoiba A, Weiss GE, Molina DM, Burk CR, Waisberg M, Jasinskas A, Tan X, Doumbo S, Doumtabe D, Kone Y, Narum DL, Liang X, Doumbo OK, Miller LH, Doolan DL, Baldi P, Felgner PL, Pierce SK, , 2010. A prospective analysis of the Ab response to Plasmodium falciparum before and after a malaria season by protein microarray. Proc Natl Acad Sci USA 107: 69586963.[Crossref] [Google Scholar]
  19. Tuikue Ndam NG, Salanti A, Le-Hesran JY, Cottrell G, Fievet N, Turner L, Sow S, Dangou JM, Theander T, Deloron P, , 2006. Dynamics of anti-VAR2CSA immunoglobulin G response in a cohort of Senegalese pregnant women. J Infect Dis 193: 713720.[Crossref] [Google Scholar]
  20. Brolin KJ, Persson KE, Wahlgren M, Rogerson SJ, Chen Q, , 2010. Differential recognition of P. falciparum VAR2CSA domains by naturally acquired antibodies in pregnant women from a malaria endemic area. PLoS ONE 5: e9230.[Crossref] [Google Scholar]
  21. Oleinikov AV, Voronkova VV, Frye IT, Amos E, Morrison R, Fried M, Duffy PE, , 2012. A plasma survey using 38 PfEMP1 domains reveals frequent recognition of the Plasmodium falciparum antigen VAR2CSA among young Tanzanian children. PLoS ONE 7: e31011.[Crossref] [Google Scholar]
  22. Gnidehou S, Doritchamou J, Arango EM, Cabrera A, Arroyo MI, Kain KC, Ndam NT, Maestre A, Yanow SK, , 2014. Functional antibodies against VAR2CSA in nonpregnant populations from Colombia exposed to Plasmodium falciparum and Plasmodium vivax . Infect Immun 82: 25652573.[Crossref] [Google Scholar]
  23. Tutterrow YL, Avril M, Singh K, Long CA, Leke RJ, Sama G, Salanti A, Smith JD, Leke RG, Taylor DW, , 2012. High levels of antibodies to multiple domains and strains of VAR2CSA correlate with the absence of placental malaria in Cameroonian women living in an area of high Plasmodium falciparum transmission. Infect Immun 80: 14791490.[Crossref] [Google Scholar]
  24. Babakhanyan A, Leke RG, Salanti A, Bobbili N, Gwanmesia P, Leke RJ, Quakyi IA, Chen JJ, Taylor DW, , 2014. The antibody response of pregnant Cameroonian women to VAR2CSA ID1-ID2a, a small recombinant protein containing the CSA-binding site. PLoS ONE 9: e88173.[Crossref] [Google Scholar]
  25. Barry AE, Trieu A, Fowkes FJ, Pablo J, Kalantari-Dehaghi M, Jasinskas A, Tan X, Kayala MA, Tavul L, Siba PM, Day KP, Baldi P, Felgner PL, Doolan DL, , 2011. The stability and complexity of antibody responses to the major surface antigen of Plasmodium falciparum are associated with age in a malaria endemic area. Mol Cell Proteomics 10: M111.008326.[Crossref] [Google Scholar]
  26. Mayor A, Rovira-Vallbona E, Srivastava A, Sharma SK, Pati SS, Puyol L, Quinto L, Bassat Q, Machevo S, Mandomando I, Chauhan VS, Alonso PL, Chitnis CE, , 2009. Functional and immunological characterization of a Duffy binding-like alpha domain from Plasmodium falciparum erythrocyte membrane protein 1 that mediates rosetting. Infect Immun 77: 38573863.[Crossref] [Google Scholar]
  27. Oguariri RM, Borrmann S, Klinkert MQ, Kremsner PG, Kun JF, , 2001. High prevalence of human antibodies to recombinant Duffy binding-like alpha domains of the Plasmodium falciparum-infected erythrocyte membrane protein 1 in semi-immune adults compared to that in nonimmune children. Infect Immun 69: 76037609.[Crossref] [Google Scholar]
  28. Bailey JA, Pablo J, Niangaly A, Travassos MA, Ouattara A, Coulibaly D, Laurens MB, Takala-Harrison SL, Lyke KE, Skinner J, Berry AA, Jasinskas A, Nakajima-Sasaki R, Kouriba B, Thera MA, Felgner PL, Doumbo OK, Plowe CV, , 2015. Seroreactivity to a large panel of field-derived Plasmodium falciparum blood stage antigen variants reflects seasonal and lifetime acquired immunity to malaria. Am J Trop Med Hyg 92: 912.[Crossref] [Google Scholar]

Data & Media loading...

  • Received : 21 Aug 2014
  • Accepted : 03 Mar 2015
  • Published online : 03 Jun 2015

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error