Genetic variation in the Plasmodium falciparum circumsporozoite protein in India and its relevance to RTS,S malaria vaccine.
RTS,S is the most advanced malaria vaccine candidate, currently under phase-III clinical trials in Africa. This Plasmodium falciparum vaccine contains part of the central repeat region and the complete C-terminal T cell epitope region (Th2R and Th3R) of the circumsporozoite protein (CSP). Since naturally occurring polymorphisms at the vaccine candidate loci are critical determinants of the protective efficacy of the vaccines, it is imperative to investigate these polymorphisms in field isolates. In this study we have investigated the genetic diversity at the central repeat, C-terminal T cell epitope (Th2R and Th3R) and N-terminal T cell epitope regions of the CSP, in P. falciparum isolates from Madhya Pradesh state of India. These isolates were collected through a 5-year prospective study aimed to develop a well-characterized field-site for the future evaluation of malaria vaccine in India. Our results revealed that the central repeat (63 haplotypes, n = 161) and C-terminal Th2R/Th3R epitope (24 haplotypes, n = 179) regions were highly polymorphic, whereas N-terminal non-repeat region was less polymorphic (5 haplotypes, n = 161) in this population. We did not find any evidence of the role of positive natural selection in maintaining the genetic diversity at the Th2R/Th3R regions of CSP. Comparative analysis of the Th2R/Th3R sequences from this study to the global isolates (n = 1160) retrieved from the GenBank database revealed two important points. First, the majority of the sequences (~61%, n = 179) from this study were identical to the Dd2/Indochina type, which is also the predominant Th2R/Th3R haplotype in Asia (~59%, n = 974). Second, the Th2R/Th3R sequences in Asia, South America and Africa are geographically distinct with little allele sharing between continents. In conclusion, this study provides an insight on the existing polymorphisms in the CSP in a parasite population from India that could potentially influence the efficacy of RTS,S vaccine in this region.
Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India.
Mohammad
M
Zeeshan
Mohammad Tauqeer
MT
Alam
Sumiti
S
Vinayak
Hema
H
Bora
Rupesh Kumar
RK
Tyagi
Mohd Shoeb
MS
Alam
Vandana
V
Choudhary
Pooja
P
Mittra
Vanshika
V
Lumb
Praveen Kumar
PK
Bharti
Venkatachalam
V
Udhayakumar
Neeru
N
Singh
Vidhan
V
Jain
Pushpendra Pal
PP
Singh
Yagya Dutta
YD
Sharma
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005843:Geography; D006239:Haplotypes; D006801:Humans; D007194:India / Q000453:epidemiology; D017780:Malaria Vaccines / Q000235:genetics* / Q000276:immunology; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000276:immunology / Q000469:parasitology; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D015800:Protozoan Proteins / Q000145:classification / Q000235:genetics* / Q000276:immunology; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
D018984:Epitopes, T-Lymphocyte; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan