Safety, infectivity and immunogenicity of a genetically attenuated blood-stage malaria vaccine.
Antimalarials
/ therapeutic use
Artemether
/ therapeutic use
Artemether, Lumefantrine Drug Combination
/ therapeutic use
Australia
Humans
Malaria
/ drug therapy
Malaria Vaccines
/ adverse effects
Malaria, Falciparum
/ drug therapy
Male
Plasmodium falciparum
/ genetics
Protozoan Proteins
/ genetics
Vaccine Development
Vaccines, Attenuated
/ adverse effects
Genetically attenuated
KAHRP
Malaria
PfEMP1
Plasmodium falciparum
Vaccine
Journal
BMC medicine
ISSN: 1741-7015
Titre abrégé: BMC Med
Pays: England
ID NLM: 101190723
Informations de publication
Date de publication:
22 11 2021
22 11 2021
Historique:
received:
06
07
2021
accepted:
30
09
2021
entrez:
22
11
2021
pubmed:
23
11
2021
medline:
27
1
2022
Statut:
epublish
Résumé
There is a clear need for novel approaches to malaria vaccine development. We aimed to develop a genetically attenuated blood-stage vaccine and test its safety, infectivity, and immunogenicity in healthy volunteers. Our approach was to target the gene encoding the knob-associated histidine-rich protein (KAHRP), which is responsible for the assembly of knob structures at the infected erythrocyte surface. Knobs are required for correct display of the polymorphic adhesion ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1), a key virulence determinant encoded by a repertoire of var genes. The gene encoding KAHRP was deleted from P. falciparum 3D7 and a master cell bank was produced in accordance with Good Manufacturing Practice. Eight malaria naïve males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 × 10 None of the subjects who were administered with 1800 or 1.8 × 10 This study represents the first clinical investigation of a genetically attenuated blood-stage human malaria vaccine. A P. falciparum 3D7 kahrp- strain was tested in vivo and found to be immunogenic but can lead to patent parasitemia at high doses. Australian New Zealand Clinical Trials Registry (number: ACTRN12617000824369 ; date: 06 June 2017).
Sections du résumé
BACKGROUND
There is a clear need for novel approaches to malaria vaccine development. We aimed to develop a genetically attenuated blood-stage vaccine and test its safety, infectivity, and immunogenicity in healthy volunteers. Our approach was to target the gene encoding the knob-associated histidine-rich protein (KAHRP), which is responsible for the assembly of knob structures at the infected erythrocyte surface. Knobs are required for correct display of the polymorphic adhesion ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1), a key virulence determinant encoded by a repertoire of var genes.
METHODS
The gene encoding KAHRP was deleted from P. falciparum 3D7 and a master cell bank was produced in accordance with Good Manufacturing Practice. Eight malaria naïve males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 × 10
RESULTS
None of the subjects who were administered with 1800 or 1.8 × 10
CONCLUSIONS
This study represents the first clinical investigation of a genetically attenuated blood-stage human malaria vaccine. A P. falciparum 3D7 kahrp- strain was tested in vivo and found to be immunogenic but can lead to patent parasitemia at high doses.
TRIAL REGISTRATION
Australian New Zealand Clinical Trials Registry (number: ACTRN12617000824369 ; date: 06 June 2017).
Identifiants
pubmed: 34802442
doi: 10.1186/s12916-021-02150-x
pii: 10.1186/s12916-021-02150-x
pmc: PMC8606250
doi:
Substances chimiques
Antimalarials
0
Artemether, Lumefantrine Drug Combination
0
Malaria Vaccines
0
Protozoan Proteins
0
Vaccines, Attenuated
0
Artemether
C7D6T3H22J
Types de publication
Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
293Informations de copyright
© 2021. The Author(s).
Références
Malar J. 2011 Feb 28;10:48
pubmed: 21352599
Front Immunol. 2020 Oct 29;11:594653
pubmed: 33193447
EMBO Mol Med. 2019 Feb;11(2):
pubmed: 30610112
Clin Infect Dis. 2020 Dec 17;71(10):e657-e664
pubmed: 32239164
Genome Res. 2012 Mar;22(3):568-76
pubmed: 22300766
Lancet. 2015 Jul 4;386(9988):31-45
pubmed: 25913272
Cell Host Microbe. 2007 Aug 16;2(2):130-8
pubmed: 18005727
Mol Microbiol. 2007 Jun;64(6):1486-98
pubmed: 17555435
NPJ Vaccines. 2020 Jun 9;5(1):48
pubmed: 32566259
Malar J. 2018 Aug 6;17(1):283
pubmed: 30081913
PLoS Pathog. 2016 Apr 12;12(4):e1005538
pubmed: 27070311
Immunol Rev. 2020 Jan;293(1):70-87
pubmed: 31674682
Sci Transl Med. 2017 Jan 4;9(371):
pubmed: 28053159
Chem Immunol. 2002;80:144-62
pubmed: 12058637
Mol Microbiol. 2003 Mar;47(5):1265-78
pubmed: 12603733
Nature. 1997 Jul 17;388(6639):292-5
pubmed: 9230440
mBio. 2020 Mar 17;11(2):
pubmed: 32184257
Sci Adv. 2019 Sep 25;5(9):eaax4489
pubmed: 31579826
Cell Rep. 2016 Oct 4;17(2):399-412
pubmed: 27705789
Science. 2011 Oct 28;334(6055):475-80
pubmed: 21903775
Clin Transl Immunology. 2018 Jan 12;7(1):e1003
pubmed: 29484181
Infect Immun. 2006 Aug;74(8):4875-83
pubmed: 16861676
PLoS One. 2011;6(8):e21914
pubmed: 21887214
J Infect Dis. 2020 Mar 2;221(6):963-972
pubmed: 31679015
Antimicrob Agents Chemother. 2019 Dec 20;64(1):
pubmed: 31685476
Lancet Infect Dis. 2017 Jun;17(6):626-635
pubmed: 28363636
Nucleic Acids Res. 2009 Jan;37(Database issue):D539-43
pubmed: 18957442
Genome Res. 2014 Dec;24(12):2022-32
pubmed: 25236618
J Antimicrob Chemother. 2016 Sep;71(9):2620-7
pubmed: 27272721
PLoS Med. 2020 Aug 21;17(8):e1003203
pubmed: 32822347
Malar J. 2021 Feb 16;20(1):93
pubmed: 33593375
Sci Adv. 2020 Jan 17;6(3):eaay7243
pubmed: 32010773
Genome Res. 2017 Dec;27(12):2050-2060
pubmed: 29097403
Sci Transl Med. 2020 May 20;12(544):
pubmed: 32434846
Blood. 1989 Dec;74(8):2603-18
pubmed: 2479423
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
BMC Med. 2018 Oct 8;16(1):184
pubmed: 30293531
PLoS Biol. 2018 Mar 12;16(3):e2004328
pubmed: 29529020
J Mol Biol. 2009 Jun 12;389(3):453-69
pubmed: 19389407
J Clin Invest. 2020 Jun 1;130(6):2920-2927
pubmed: 32045385
Parasite Immunol. 1995 Sep;17(9):493-501
pubmed: 8552419
Infect Immun. 1985 Mar;47(3):760-6
pubmed: 3882566
Vaccine. 2015 Dec 22;33(52):7469-75
pubmed: 26428451
Cell. 1997 Apr 18;89(2):287-96
pubmed: 9108483
Cell Host Microbe. 2018 Jul 11;24(1):43-56
pubmed: 30001524
Nucleic Acids Res. 2011 Oct;39(19):e132
pubmed: 21813454
PLoS One. 2014 Oct 31;9(10):e111518
pubmed: 25360558
JCI Insight. 2017 Aug 3;2(15):
pubmed: 28768914
Sci Transl Med. 2020 May 20;12(544):
pubmed: 32434847
Antimicrob Agents Chemother. 2019 Mar 27;63(4):
pubmed: 30858218
Cell. 1995 Jul 14;82(1):89-100
pubmed: 7606788
J Infect Dis. 2020 Mar 2;221(6):948-955
pubmed: 30852586
Hum Vaccin. 2010 Jan;6(1):114-23
pubmed: 19946204