Genetic polymorphism and natural selection of circumsporozoite surface protein in  Plasmodium falciparum  field isolates from Myanmar

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Abstract

Background

Plasmodium falciparum circumsporozoite protein (PfCSP) is one of the most extensively studied malaria vaccine candidates, but the genetic polymorphism of PfCSP within and among the global P. falciparum population raises concerns regarding the efficacy of a PfCSP-based vaccine efficacy. In this study, genetic diversity and natural selection of PfCSP in Myanmar as well as global P. falciparum were comprehensively analysed.

Methods

Blood samples were collected from 51 P. falciparum infected Myanmar patients. Fifty-one full-length PfCSP genes were amplified from the blood samples through a nested polymerase chain reaction, cloned into a TA cloning vector, and then sequenced. Polymorphic characteristics and natural selection of Myanmar PfCSP were analysed using the DNASTAR, MEGA6, and DnaSP programs. Polymorphic diversity and natural selection in publicly available global PfCSP were also analysed.

Results

The N-terminal and C-terminal non-repeat regions of Myanmar PfCSP showed limited genetic variations. A comparative analysis of the two regions in global PfCSP displayed similar patterns of low genetic diversity in global population, but substantial geographic differentiation was also observed. The most notable polymorphisms identified in the N-terminal region of global PfCSP were A98G and 19-amino acid length insertion in global population with different frequencies. Major polymorphic characters in the C-terminal region of Myanmar and global PfCSP were found in the Th2R and Th3R regions, where natural selection and recombination occurred. The central repeat region of Myanmar PfCSP was highly polymorphic, with differing numbers of repetitive repeat sequences NANP and NVDP. The numbers of the NANP repeats varied among global PfCSP, with the highest number of repeats seen in Asian and Oceanian PfCSP. Haplotype network analysis of global PfCSP revealed that global PfCSP clustered into 103 different haplotypes with geographically-separated populations.

Conclusion

Myanmar and global PfCSP displayed genetic diversity. N-terminal and C-terminal non-repeat regions were relatively conserved, but the central repeat region displayed high levels of genetic polymorphism in Myanmar and global PfCSP. The observed geographic pattern of genetic differentiation and the points of evidence for natural selection and recombination suggest that the functional consequences of the polymorphism should be considered for developing a vaccine based on PfCSP.

Electronic supplementary material

The online version of this article (10.1186/s12936-018-2513-0) contains supplementary material, which is available to authorized users.

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Most cited references 27

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A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants.

Didier Lapierre, Hermann Sorgho, Erik Jongert … (2012)

The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).

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Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

Magnus Manske, Olivo Miotto, Susana Campino … (2012)

Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. 1,2 Here we describe methods for large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short term culture. Analysis of 86,158 exonic SNPs that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.

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Nested PCR analysis of Plasmodium parasites.

Georges Snounou, Balbir Kumar Singh (2002)

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Author and article information

Contributors

Byoung-Kuk Na: bkna@gnu.ac.kr

Journal

Journal ID (nlm-ta): Malar J

Journal ID (iso-abbrev): Malar. J

Title: Malaria Journal

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2875

Publication date (Electronic): 12 October 2018

Publication date PMC-release: 12 October 2018

Publication date Collection: 2018

Volume: 17

Electronic Location Identifier: 361

Affiliations

[1 ]ISNI 0000 0001 0661 1492, GRID grid.256681.e, Department of Parasitology and Tropical Medicine and Institute of Health Sciences, , Gyeongsang National University College of Medicine, ; Jinju, 52727 Republic of Korea

[2 ]ISNI 0000 0001 0661 1492, GRID grid.256681.e, BK21Plus Team for Anti-aging Biotechnology and Industry, Department of Convergence Medical Science, , Gyeongsang National University, ; Jinju, 52727 Republic of Korea

[3 ]Department of Medical Research Pyin Oo Lwin Branch, Pyin Oo Lwin, Myanmar

[4 ]ISNI 0000 0001 2364 8385, GRID grid.202119.9, Department of Tropical Medicine and Inha Research Institute for Medical Sciences, , Inha University College of Medicine, ; Incheon, 22212 Republic of Korea

[5 ]ISNI 0000 0004 0532 3933, GRID grid.251916.8, Department of Microbiology, , Ajou University College of Medicine, ; Suwon, 16499 Republic of Korea

Article

Publisher ID: 2513

DOI: 10.1186/s12936-018-2513-0

PMC ID: 6186114

PubMed ID: 30314440

SO-VID: 11e2ff47-b5de-417c-9534-582487fe01f2

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 August 2018

Date accepted : 8 October 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100011512, National Research Foundation;

Award ID: NRF-2015K1A3A9A01034893

Award ID: NRF-2017M3A9B8069530

Award Recipient : Tong-Soo Kim Byoung-Kuk Na

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: plasmodium falciparum,circumsporozoite protein,genetic polymorphism,natural selection,myanmar

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: plasmodium falciparum, circumsporozoite protein, genetic polymorphism, natural selection, myanmar

Genetic polymorphism and natural selection of circumsporozoite surface protein in Plasmodium falciparum field isolates from Myanmar

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Most cited references 27

A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants.

Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

Nested PCR analysis of Plasmodium parasites.

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