Differential adhesion-inhibitory patterns of antibodies raised against two major variants of the NTS-DBL2X region of VAR2CSA.
BACKGROUND
VAR2CSA is a large polymorphic Plasmodium falciparum protein expressed on infected erythrocytes (IE) that allows their binding in the placenta, thus precipitating placental malaria (PM). The N-terminal part of VAR2CSA that contains the binding site to placental chondroitin sulfate A (CSA) is currently recognized as the most attractive region for vaccine development. An ultimate challenge is to define epitopes in this region that induce a broad cross-reactive adhesion inhibitory antibody response.


METHODS
Based on phylogenetic data that identified a dimorphic sequence motif in the VAR2CSA DBL2X, we raised antibodies against the NTS-DBL2X constructs containing one sequence or the other (3D7 and FCR3) and tested their functional properties on P. falciparum isolates from pregnant women and on laboratory-adapted strains.


RESULTS
The CSA binding inhibitory capacity of the antibodies induced varied from one parasite isolate to another (range, 10%–100%), but the combined analysis of individual activity highlighted a broader functionality that increased the total number of isolates inhibited. Interestingly, the differential inhibitory effect of the antibodies observed on field isolates resulted in significant inhibition of all field isolates tested, suggesting that optimal inhibitory spectrum on field isolates from pregnant women might be achieved with antibodies targeting limited variants of the N-terminal VAR2CSA.


CONCLUSIONS
Our findings indicate that the NTS-DBL2X region of VAR2CSA can elicit strain-transcending anti-adhesion antibodies and suggest that the combination of the two major variants used here could represent the basis for an effective bivalent VAR2CSA-based vaccine.
PRES Sorbonne Paris Cité, Faculté de Pharmacie, Université Paris Descartes, France; Institut de Recherche pour le Développement, UMR216 Mère et enfant face aux infections tropicales, Paris, France; Centre d'Etude et de Recherche sur le paludisme associé à la Grossesse et à l'Enfance, Université d'Abomey-Calavi, Cotonou, Benin.
Justin
J
Doritchamou
Pascal
P
Bigey
Morten Agertoug
MA
Nielsen
Sédami
S
Gnidehou
Sem
S
Ezinmegnon
Aurore
A
Burgain
Achille
A
Massougbodji
Philippe
P
Deloron
Ali
A
Salanti
Nicaise Tuikue
NT
Ndam
D000328:Adult; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology*; D002448:Cell Adhesion / Q000187:drug effects*; D004912:Erythrocytes / Q000469:parasitology* / Q000502:physiology*; D005260:Female; D006801:Humans; D010963:Plasmodium falciparum / Q000276:immunology* / Q000502:physiology*; D011247:Pregnancy; D011817:Rabbits; D055815:Young Adult
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; C512601:VAR2CSA protein, Plasmodium falciparum
BSA; CSA; CSPG; DBL; DSM; Duffy binding-like; IE; IPTp; Id; MFI; Malaria; N-terminal sequence; NTS; PBS; PM; PfEMP1; Pfalciparum-infected erythrocytes; Plasmodium falciparum; Plasmodium falciparum erythrocyte membrane protein 1; Pregnancy; VAR2CSA; Vaccine; bovine serum albumin; chondroitin sulfate A; chondroitin sulfate proteoglycan; dimorphic sequence motif; inter-domain; intermittent preventive treatment during pregnancy; median fluorescence intensity; phosphate buffered saline; placental malaria