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Protein interaction analysis of Plasmodium falciparum circumsporozoite protein variants with human immunoproteins explains RTS,S vaccine efficacy in Ghana

View ORCID ProfileCheikh Cambel Dieng, View ORCID ProfileColby T. Ford, View ORCID ProfileAnita Lerch, Dickson Donu, Jennifer Huynh, Kovidh Vegesna, View ORCID ProfileJun-tao Guo, View ORCID ProfileDaniel A. Janies, View ORCID ProfileLinda Amoah, View ORCID ProfileYaw Afrane, View ORCID ProfileEugenia Lo
doi: https://doi.org/10.1101/2021.12.29.474460
Cheikh Cambel Dieng
1Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC,USA
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  • ORCID record for Cheikh Cambel Dieng
  • For correspondence: cdieng@uncc.edu colby.ford@uncc.edu eugenia.lo@uncc.edu
Colby T. Ford
2Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
3School of Data Science, University of North Carolina at Charlotte, Charlotte, NC USA
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  • For correspondence: cdieng@uncc.edu colby.ford@uncc.edu eugenia.lo@uncc.edu
Anita Lerch
4Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
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Dickson Donu
5Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
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Jennifer Huynh
1Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC,USA
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Kovidh Vegesna
3School of Data Science, University of North Carolina at Charlotte, Charlotte, NC USA
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Jun-tao Guo
2Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
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  • ORCID record for Jun-tao Guo
Daniel A. Janies
2Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA
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  • ORCID record for Daniel A. Janies
Linda Amoah
5Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
6West Africa Center for Cell Biology of Infectious Pathogens, University of Ghana, Accra, Ghana
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  • ORCID record for Linda Amoah
Yaw Afrane
7Department of Microbiology, University of Ghana Medical School, Accra, Ghana
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Eugenia Lo
1Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC,USA
3School of Data Science, University of North Carolina at Charlotte, Charlotte, NC USA
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  • ORCID record for Eugenia Lo
  • For correspondence: cdieng@uncc.edu colby.ford@uncc.edu eugenia.lo@uncc.edu
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Abstract

Background The world’s first malaria vaccine RTS,S provides only partial protection against Plasmodium falciparum infections. The explanation for such low efficacy is unclear. This study examined the associations of parasite genetic variations with binding affinity to human immunological proteins including human leukocyte antigen (HLA) and T cell receptors (TCR) involved in RTS,S-induced immune responses.

Methods Multiplicity of infections was determined by amplicon deep sequencing of merozoite surface protein 1 (PfMSP1). Genetic variations in the C-terminal of circumsporozoite protein (PfMSP1) gene were examined across 88 samples of P. falciparum collected from high and low transmission settings of Ghana. Binding interactions of PfMSP1 variants and HLA/TCR were analyzed using NetChop and HADDOCK predictions. Anti-CSP IgG levels were measured by ELISA in a subset of 10 samples.

Findings High polyclonality was detected among P. falciparum infections. A total 27 CSP haplotypes were detected among samples. A significant correlation was detected between the CSP and MSP multiplicity of infection (MOI). No clear clustering of haplotypes was observed by geographic regions. The number of genetic differences in PfCSP between 3D7 and non-3D7 variants does not influence binding interactions to HLA/T cells nor anti-CSP IgG levels. Nevertheless, PfCSP peptide length significantly affects its molecular weight and binding affinity to the HLA.

Interpretations The presence of multiple non-3D7 strains among P. falciparum infections in Ghana impact the effectiveness of RTS,S. Longer PfCSP peptides may elicit a stronger immune response and should be considered in future version RTS,S. The molecular mechanisms of RTS,S cell-mediated immune responses related to longer CSP peptides warrants further investigations.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/colbyford/Ghana_CSP_Haplotypes

  • https://www.ncbi.nlm.nih.gov/bioproject/PRJNA783000/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 30, 2021.
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Protein interaction analysis of Plasmodium falciparum circumsporozoite protein variants with human immunoproteins explains RTS,S vaccine efficacy in Ghana
Cheikh Cambel Dieng, Colby T. Ford, Anita Lerch, Dickson Donu, Jennifer Huynh, Kovidh Vegesna, Jun-tao Guo, Daniel A. Janies, Linda Amoah, Yaw Afrane, Eugenia Lo
bioRxiv 2021.12.29.474460; doi: https://doi.org/10.1101/2021.12.29.474460
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Protein interaction analysis of Plasmodium falciparum circumsporozoite protein variants with human immunoproteins explains RTS,S vaccine efficacy in Ghana
Cheikh Cambel Dieng, Colby T. Ford, Anita Lerch, Dickson Donu, Jennifer Huynh, Kovidh Vegesna, Jun-tao Guo, Daniel A. Janies, Linda Amoah, Yaw Afrane, Eugenia Lo
bioRxiv 2021.12.29.474460; doi: https://doi.org/10.1101/2021.12.29.474460

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