Genetic Variation in the Plasmodium falciparum Circumsporozoite Protein in India and Its Relevance to RTS,S Malaria Vaccine

Zeeshan, Mohammad; Alam, Mohammad Tauqeer; Vinayak, Sumiti; Bora, Hema; Tyagi, Rupesh Kumar; Alam, Mohd Shoeb; Choudhary, Vandana; Mittra, Pooja; Lumb, Vanshika; Bharti, Praveen K.; Udhayakumar, Venkatachalam; Singh, Neeru; Jain, Vidhan; Singh, Pushpendra; Sharma, Yagya D.

doi:10.1371/journal.pone.0043430

Cited by 58 publications

(81 citation statements)

References 55 publications

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“…Genetic polymorphism is a major problem in malaria vaccine development. The Pfs48/45 gene is less polymorphic in comparison to other erythrocytic and pre-erythrocytic stage specific antigens353637 with a minimum number of amino acid substitutions38. These observations suggest that this transmission blocking antigen is conserved at the protein level, making it a good candidate for multistage, multivalent vaccine.…”

Section: Potential Of Tbv Candidatesmentioning

confidence: 96%

Strategies & recent development of transmission-blocking vaccines against Plasmodium falciparum

et al. 2016

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Transmission blocking malaria vaccines are aimed to block the development and maturity of sexual stages of parasite within mosquitoes. The vaccine candidate antigens (Pfs25, Pfs48/45, Pfs230) that have shown transmission blocking immunity in model systems are in different stages of development. These antigens are immunogenic with limited genetic diversity. Pfs25 is a leading candidate and currently in phase I clinical trial. Efforts are now focused on the cost-effective production of potent antigens using safe adjuvants and optimization of vaccine delivery system that are capable of inducing strong immune responses. This review addresses the potential usefulness, development strategies, challenges, clinical trials and current status of Plasmodium falciparum sexual stage malaria vaccine candidate antigens for the development of transmission-blocking vaccines.

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Section: Potential Of Tbv Candidatesmentioning

confidence: 96%

Strategies & recent development of transmission-blocking vaccines against Plasmodium falciparum

et al. 2016

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“…The C-terminal region contains the thrombospondin-like type 1 repeat domain [15] overlapping the Th2R and Th3R T epitope regions [16]. While the RTS,S vaccine contains aa 207–395 [17], and therefore lacks the N-terminal region [18], the Ad-C vaccine is full length except for a deletion of 16 repeats (64 aa) between 209–272 (leaving 26 repeats intact), and the insertion of a 23 aa tail at the C-terminus, derived from the 3’-noncoding bovine growth hormone polyadenylation sequence [7,8].…”

Section: Introductionmentioning

confidence: 99%

Identification of minimal human MHC-restricted CD8+ T-cell epitopes within the Plasmodium falciparum circumsporozoite protein (CSP)

Kim

Ganeshan

Huang

et al. 2013

Malar J

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BackgroundPlasmodium falciparum circumsporozoite protein (CSP) is a leading malaria vaccine candidate antigen, known to elicit protective antibody responses in humans (RTS,S vaccine). Recently, a DNA prime / adenovirus (Ad) vector boost vaccine encoding CSP and a second P. falciparum antigen, apical membrane antigen-1, also elicited sterile protection, but in this case associated with interferon gamma ELISpot and CD8+ T cell but not antibody responses. The finding that CSP delivered by an appropriate vaccine platform likely elicits protective cell-mediated immunity provided a rationale for identifying class I-restricted epitopes within this leading vaccine candidate antigen.MethodsLimited samples of peripheral blood mononuclear cells from clinical trials of the Ad vaccine were used to identify CD8+ T cell epitopes within pools of overlapping 15mer peptides spanning portions of CSP that stimulated recall responses. Computerized algorithms (NetMHC) predicted 17 minimal class I-restricted 9-10mer epitopes within fifteen 15mers positive in ELISpot assay using PBMC from 10 HLA-matched study subjects. Four additional epitopes were subsequently predicted using NetMHC, matched to other study subjects without initial 15mer ELISpot screening. Nine of the putative epitopes were synthesized and tested by ELISpot assay, and six of these nine were further tested for CD8+ T cell responses by ELISpot CD4+ and CD8+ T cell-depletion and flow cytometry assays for evidence of CD8+ T cell dependence.ResultsEach of the nine putative epitopes, all sequence-conserved, recalled responses from HLA-matched CSP-immunized research subjects. Four shorter sequences contained within these sequences were identified using NetMHC predictions and may have contributed to recall responses. Five (9-10mer) epitopes were confirmed to be targets of CD8+ T cell responses using ELISpot depletion and ICS assays. Two 9mers among these nine epitopes were each restricted by two HLA supertypes (A01/B07; A01A24/A24) and one 9mer was restricted by three HLA supertypes (A01A24/A24/B27) indicating that some CSP class I-restricted epitopes, like DR epitopes, may be HLA-promiscuous.ConclusionsThis study identified nine and confirmed five novel class I epitopes restricted by six HLA supertypes, suggesting that an adenovirus-vectored CSP vaccine would be immunogenic and potentially protective in genetically diverse populations.

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“…The circumsporozoite protein ( csp ) gene, which is known to be critical for plasmodia sporozoite motility and hepatocyte invasion ( 23 ), has been shown to be variable in length and is a sequence of the tandemly repeated peptide units in P. falciparum ( 24 , 25 ), P. vivax ( 26 , 27 ), and P. malariae isolates from Central Africa ( 28 ). The vast antigenic variation observed in P. falciparum as a result of immune selection pressure can influence the capacity of mosquito transmission and the effectiveness of malaria vaccine ( 29 ). In this study, we sought to determine the prevalence of infection and age distribution of persons with asymptomatic and symptomatic P. malariae infection in western Kenya, the genetic affinity between P. malariae isolates from East Africa and other regions, and the level of csp gene diversity among P. malariae and the significance of this diversity.…”

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confidence: 99%

Plasmodium malariaePrevalence andcspGene Diversity, Kenya, 2014 and 2015

Lo¹,

Nguyen²,

Nguyen³

et al. 2017

Emerg. Infect. Dis.

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In Africa, control programs that target primarily Plasmodium falciparum are inadequate for eliminating malaria. To learn more about prevalence and genetic variability of P. malariae in Africa, we examined blood samples from 663 asymptomatic and 245 symptomatic persons from western Kenya during June–August of 2014 and 2015. P. malariae accounted for 5.3% (35/663) of asymptomatic infections and 3.3% (8/245) of clinical cases. Among asymptomatic persons, 71% (32/45) of P. malariae infections detected by PCR were undetected by microscopy. The low sensitivity of microscopy probably results from the significantly lower parasitemia of P. malariae. Analyses of P. malariae circumsporozoite protein gene sequences revealed high genetic diversity among P. malariae in Africa, but no clear differentiation among geographic populations was observed. Our findings suggest that P. malariae should be included in the malaria elimination strategy in Africa and highlight the need for sensitive and field-applicable methods to identify P. malariae in malaria-endemic areas.

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Genetic Variation in the Plasmodium falciparum Circumsporozoite Protein in India and Its Relevance to RTS,S Malaria Vaccine

Cited by 58 publications

References 55 publications

Strategies & recent development of transmission-blocking vaccines against Plasmodium falciparum

Strategies & recent development of transmission-blocking vaccines against Plasmodium falciparum

Identification of minimal human MHC-restricted CD8+ T-cell epitopes within the Plasmodium falciparum circumsporozoite protein (CSP)

Plasmodium malariaePrevalence andcspGene Diversity, Kenya, 2014 and 2015

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