Strains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potential.
Genome assembly
Malaria
P. falciparum
PfSPZ vaccine
Whole-sporozoite vaccine
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
08 01 2020
08 01 2020
Historique:
received:
26
06
2019
accepted:
19
12
2019
entrez:
10
1
2020
pubmed:
10
1
2020
medline:
5
1
2021
Statut:
epublish
Résumé
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. 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. 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 These results will assist in the interpretation of vaccine efficacy of whole-organism vaccines against homologous and heterologous CHMI.
Sections du résumé
BACKGROUND
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
CONCLUSIONS
These results will assist in the interpretation of vaccine efficacy of whole-organism vaccines against homologous and heterologous CHMI.
Identifiants
pubmed: 31915075
doi: 10.1186/s13073-019-0708-9
pii: 10.1186/s13073-019-0708-9
pmc: PMC6950926
doi:
Substances chimiques
Malaria Vaccines
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
6Subventions
Organisme : NIAID NIH HHS
ID : R01 AI125579
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM055036
Pays : United States
Organisme : NIAID NIH HHS
ID : R44 AI058375
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI110820
Pays : United States
Organisme : NIAID NIH HHS
ID : R44 AI055229
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI141900
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI089681
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI089683
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA HG200398
Pays : United States
Organisme : NHGRI NIH HHS
ID : 1ZIAHG200398
Pays : United States
Organisme : NHLBI NIH HHS
ID : F31 HL147471
Pays : United States
Organisme : NHLBI NIH HHS
ID : K01 HL140285
Pays : United States
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