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dc.contributor.authorMoser, K.A.
dc.contributor.authorDwivedi, A.
dc.contributor.authorStucke, E.M.
dc.contributor.authorCrabtree, J.
dc.contributor.authorDara, A.
dc.contributor.authorShah, Z.
dc.contributor.authorAdams, M.
dc.contributor.authorMunro, J.B.
dc.contributor.authorOuattara, A.
dc.contributor.authorSparklin, B.C.
dc.contributor.authorDunning, Hotopp, J.C.
dc.contributor.authorLyke, K.E.
dc.contributor.authorSadzewicz, L.
dc.contributor.authorTallon, L.J.
dc.contributor.authorNyunt, M.M.
dc.contributor.authorLaufer, M.K.
dc.contributor.authorTravassos, M.A.
dc.contributor.authorTakala-Harrison, S.
dc.contributor.authorFraser, C.M.
dc.contributor.authorPlowe, C.V.
dc.contributor.authorSilva, J.C.
dc.contributor.authorDrábek, E.F.
dc.date.accessioned2020-02-04T17:04:33Z
dc.date.available2020-02-04T17:04:33Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85077677898&doi=10.1186%2fs13073-019-0708-9&partnerID=40&md5=8046505b99a44f880d22a0915fc977cb
dc.identifier.urihttp://hdl.handle.net/10713/11678
dc.description.abstractBackground: Plasmodium falciparum (Pf) whole-organism sporozoite vaccines have been shown to provide significant protection against controlled human malaria infection (CHMI) in clinical trials. Initial CHMI studies showed significantly higher durable protection against homologous than heterologous strains, suggesting the presence of strain-specific vaccine-induced protection. However, interpretation of these results and understanding of their relevance to vaccine efficacy have been hampered by the lack of knowledge on genetic differences between vaccine and CHMI strains, and how these strains are related to parasites in malaria endemic regions. Methods: Whole genome sequencing using long-read (Pacific Biosciences) and short-read (Illumina) sequencing platforms was conducted to generate de novo genome assemblies for the vaccine strain, NF54, and for strains used in heterologous CHMI (7G8 from Brazil, NF166.C8 from Guinea, and NF135.C10 from Cambodia). The assemblies were used to characterize sequences in each strain relative to the reference 3D7 (a clone of NF54) genome. Strains were compared to each other and to a collection of clinical isolates (sequenced as part of this study or from public repositories) from South America, sub-Saharan Africa, and Southeast Asia. Results: While few variants were detected between 3D7 and NF54, we identified tens of thousands of variants between NF54 and the three heterologous strains. These variants include SNPs, indels, and small structural variants that fall in regulatory and immunologically important regions, including transcription factors (such as PfAP2-L and PfAP2-G) and pre-erythrocytic antigens that may be key for sporozoite vaccine-induced protection. Additionally, these variants directly contributed to diversity in immunologically important regions of the genomes as detected through in silico CD8+ T cell epitope predictions. Of all heterologous strains, NF135.C10 had the highest number of unique predicted epitope sequences when compared to NF54. Comparison to global clinical isolates revealed that these four strains are representative of their geographic origin despite long-term culture adaptation; of note, NF135.C10 is from an admixed population, and not part of recently formed subpopulations resistant to artemisinin-based therapies present in the Greater Mekong Sub-region. Conclusions: These results will assist in the interpretation of vaccine efficacy of whole-organism vaccines against homologous and heterologous CHMI. Copyright 2020 The Author(s).en_US
dc.description.sponsorshipNational Institutes of Health (NIH) awards U19 AI110820, R01 AI141900, R01 AI125579; National Human Genome Research Institute, NHGRI: 1ZIAHG200398; Howard Hughes Medical Institute, HHMI; Small Business Innovation Research, SBIR; Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq; National Institute of Allergy and Infectious Diseases, NIAID: 2R44AI058375, U19 AI089683, 5R44AI055229-09A1; Armed Forces Health Surveillance Branch, AFHSB: U19 AI089681, WR1576, WR2017en_US
dc.description.urihttps://doi.org/10.1186/s13073-019-0708-9en_US
dc.language.isoen_USen_US
dc.publisherBioMed Central Ltd.en_US
dc.relation.ispartofGenome Medicine
dc.subjectGenome assemblyen_US
dc.subjectMalariaen_US
dc.subjectP. falciparumen_US
dc.subjectPfSPZ vaccineen_US
dc.subjectWhole-sporozoite vaccineen_US
dc.titleStrains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potentialen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/s13073-019-0708-9
dc.identifier.pmid31915075


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