Genetic diversity of VAR2CSA ID1-DBL2Xb in worldwide Plasmodium falciparum populations: impact on vaccine design for placental malaria.
In placental malaria (PM), sequestration of infected erythrocytes in the placenta is mediated by an interaction between VAR2CSA, a Plasmodium falciparum protein expressed on erythrocytes, and chondroitin sulfate A (CSA) on syncytiotrophoblasts. Recent works have identified ID1-DBL2Xb as the minimal CSA-binding region within VAR2CSA able to induce strong protective immunity, making it the leading candidate for the development of a vaccine against PM. Assessing the existence of population differences in the distribution of ID1-DBL2Xb polymorphisms is of paramount importance to determine whether geographic diversity must be considered when designing a candidate vaccine based on this fragment. In this study, we examined patterns of sequence variation of ID1-DBL2Xb in a large collection of P. falciparum field isolates (n=247) from different malaria-endemic areas, including Africa (Benin, Senegal, Cameroon and Madagascar), Asia (Cambodia), Oceania (Papua New Guinea), and Latin America (Peru). Detection of variants and estimation of their allele frequencies were performed using next-generation sequencing of DNA pools. A considerable amount of variation was detected along the whole gene segment, suggesting that several allelic variants may need to be included in a candidate vaccine to achieve broad population coverage. However, most sequence variants were common and extensively shared among worldwide parasite populations, demonstrating long term persistence of those polymorphisms, probably maintained through balancing selection. Therefore, a vaccine mixture including such stable antigen variants will be putatively applicable and efficacious in all world regions where malaria occurs. Despite similarity in ID1-DBL2Xb allele repertoire across geographic areas, several peaks of strong population differentiation were observed at specific polymorphic loci, pointing out putative targets of humoral immunity subject to positive immune selection.
PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France; Institut de Recherche Pour le Développement (IRD), UMR216 Mère et enfant face aux infections tropicales, Paris, France.
Bita
B
Bordbar
PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France; Institut de Recherche Pour le Développement (IRD), UMR216 Mère et enfant face aux infections tropicales, Paris, France; Centre d'Étude et de Recherche sur le Paludisme Associé à la Grossesse et à l'Enfance (CERPAGE), Cotonou, Benin.
Nicaise
N
Tuikue Ndam
PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France; Institut de Recherche Pour le Développement (IRD), UMR216 Mère et enfant face aux infections tropicales, Paris, France.
Emmanuelle
E
Renard
PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France; Institut de Recherche Pour le Développement (IRD), UMR216 Mère et enfant face aux infections tropicales, Paris, France.
Sayeh
S
Jafari-Guemouri
Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
Livingstone
L
Tavul
Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Charlie
C
Jennison
PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France; Institut de Recherche Pour le Développement (IRD), UMR216 Mère et enfant face aux infections tropicales, Paris, France.
Sédami
S
Gnidehou
PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France; Institut de Recherche Pour le Développement (IRD), UMR216 Mère et enfant face aux infections tropicales, Paris, France.
Rachida
R
Tahar
Instituto de Medicina Tropical "Alexander Von Humboldt", Universidad Peruana Cayetano Heredia, Lima, Peru.
Dionicia
D
Gamboa
Instituto de Medicina Tropical "Alexander Von Humboldt", Universidad Peruana Cayetano Heredia, Lima, Peru.
Jorge
J
Bendezu
Unité d'Epidémiologie Moléculaire, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
Didier
D
Menard
Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Alyssa E
AE
Barry
PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France; Institut de Recherche Pour le Développement (IRD), UMR216 Mère et enfant face aux infections tropicales, Paris, France.
Philippe
P
Deloron
PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France; Institut de Recherche Pour le Développement (IRD), UMR216 Mère et enfant face aux infections tropicales, Paris, France. Electronic address: audrey.sabbagh@ird.fr.
Audrey
A
Sabbagh
D000293:Adolescent; D000328:Adult; D000940:Antigenic Variation / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics* / Q000276:immunology; D016054:DNA, Protozoan / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000276:immunology / Q000469:parasitology*; D058974:Phylogeography; D010920:Placenta / Q000276:immunology / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000145:classification / Q000276:immunology / Q000302:isolation & purification* / Q000378:metabolism*; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000276:immunology / Q000469:parasitology*; D017422:Sequence Analysis, DNA; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology; D055815:Young Adult
D000953:Antigens, Protozoan; D016054:DNA, Protozoan; C512601:VAR2CSA protein, Plasmodium falciparum; D014765:Viral Vaccines
Genetic structure; Next-generation sequencing; Plasmodium falciparum; Pregnancy-associated malaria; VAR2CSA; Vaccine