Early whole blood transcriptional responses to radiation-attenuated Plasmodium falciparum sporozoite vaccination in malaria naïve and malaria pre-exposed adult volunteers.
Antibodies, Protozoan
/ blood
Clinical Trials as Topic
Humans
Malaria Vaccines
/ administration & dosage
Malaria, Falciparum
/ prevention & control
Plasmodium falciparum
/ genetics
Protozoan Proteins
/ genetics
Sporozoites
/ genetics
Transcription, Genetic
Vaccines, Attenuated
/ administration & dosage
Journal
Malaria journal
ISSN: 1475-2875
Titre abrégé: Malar J
Pays: England
ID NLM: 101139802
Informations de publication
Date de publication:
09 Jul 2021
09 Jul 2021
Historique:
received:
21
03
2021
accepted:
29
06
2021
entrez:
10
7
2021
pubmed:
11
7
2021
medline:
21
10
2021
Statut:
epublish
Résumé
Vaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity. However, the mechanisms underlying this protection remain unclear. In this work, two recent radiation-attenuated sporozoite vaccination studies were used to identify potential transcriptional correlates of vaccination-induced protection. Longitudinal whole blood RNAseq transcriptome responses to immunization with radiation-attenuated P. falciparum sporozoites were analysed and compared across malaria-naïve adult participants (IMRAS) and malaria-experienced adult participants (BSPZV1). Parasite dose and method of delivery differed between trials, and immunization regimens were designed to achieve incomplete protective efficacy. Observed protective efficacy was 55% in IMRAS and 20% in BSPZV1. Study vaccine dosings were chosen to elicit both protected and non-protected subjects, so that protection-associated responses could be identified. Analysis of comparable time points up to 1 week after the first vaccination revealed a shared cross-study transcriptional response programme, despite large differences in number and magnitude of differentially expressed genes between trials. A time-dependent regulatory programme of coherent blood transcriptional modular responses was observed, involving induction of inflammatory responses 1-3 days post-vaccination, with cell cycle responses apparent by day 7 in protected individuals from both trials. Additionally, strongly increased induction of inflammation and interferon-associated responses was seen in non-protected IMRAS participants. All individuals, except for non-protected BSPZV1 participants, showed robust upregulation of cell-cycle associated transcriptional responses post vaccination. In summary, despite stark differences between the two studies, including route of vaccination and status of malaria exposure, responses were identified that were associated with protection after PfRAS vaccination. These comprised a moderate early interferon response peaking 2 days post vaccination, followed by a later proliferative cell cycle response steadily increasing over the first 7 days post vaccination. Non-protection is associated with deviations from this model, observed in this study with over-induction of early interferon responses in IMRAS and failure to mount a cell cycle response in BSPZV1.
Sections du résumé
BACKGROUND
BACKGROUND
Vaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity. However, the mechanisms underlying this protection remain unclear. In this work, two recent radiation-attenuated sporozoite vaccination studies were used to identify potential transcriptional correlates of vaccination-induced protection.
METHODS
METHODS
Longitudinal whole blood RNAseq transcriptome responses to immunization with radiation-attenuated P. falciparum sporozoites were analysed and compared across malaria-naïve adult participants (IMRAS) and malaria-experienced adult participants (BSPZV1). Parasite dose and method of delivery differed between trials, and immunization regimens were designed to achieve incomplete protective efficacy. Observed protective efficacy was 55% in IMRAS and 20% in BSPZV1. Study vaccine dosings were chosen to elicit both protected and non-protected subjects, so that protection-associated responses could be identified.
RESULTS
RESULTS
Analysis of comparable time points up to 1 week after the first vaccination revealed a shared cross-study transcriptional response programme, despite large differences in number and magnitude of differentially expressed genes between trials. A time-dependent regulatory programme of coherent blood transcriptional modular responses was observed, involving induction of inflammatory responses 1-3 days post-vaccination, with cell cycle responses apparent by day 7 in protected individuals from both trials. Additionally, strongly increased induction of inflammation and interferon-associated responses was seen in non-protected IMRAS participants. All individuals, except for non-protected BSPZV1 participants, showed robust upregulation of cell-cycle associated transcriptional responses post vaccination.
CONCLUSIONS
CONCLUSIONS
In summary, despite stark differences between the two studies, including route of vaccination and status of malaria exposure, responses were identified that were associated with protection after PfRAS vaccination. These comprised a moderate early interferon response peaking 2 days post vaccination, followed by a later proliferative cell cycle response steadily increasing over the first 7 days post vaccination. Non-protection is associated with deviations from this model, observed in this study with over-induction of early interferon responses in IMRAS and failure to mount a cell cycle response in BSPZV1.
Identifiants
pubmed: 34243763
doi: 10.1186/s12936-021-03839-3
pii: 10.1186/s12936-021-03839-3
pmc: PMC8267772
doi:
Substances chimiques
Antibodies, Protozoan
0
Malaria Vaccines
0
Protozoan Proteins
0
Vaccines, Attenuated
0
circumsporozoite protein, Protozoan
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
308Subventions
Organisme : NIAID NIH HHS
ID : U19 AI128914
Pays : United States
Organisme : National Institute of Allergy and Infectious Diseases (US)
ID : U19AI128914
Organisme : Bill and Melinda Gates Foundation
ID : OPP1034596
Informations de copyright
© 2021. The Author(s).
Références
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Am J Trop Med Hyg. 2001 Sep;65(3):197-203
pubmed: 11561704
Nature. 1967 Oct 14;216(5111):160-2
pubmed: 6057225
PLoS One. 2020 Jun 17;15(6):e0233840
pubmed: 32555601
PLoS Negl Trop Dis. 2018 May 17;12(5):e0006439
pubmed: 29771921
Trans R Soc Trop Med Hyg. 1974;68(3):258-9
pubmed: 4608063
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Nat Immunol. 2014 Feb;15(2):195-204
pubmed: 24336226
Am J Trop Med Hyg. 2001 Sep;65(3):167-70
pubmed: 11561697
Vaccine. 2015 Nov 27;33 Suppl 4:D13-23
pubmed: 26324116
Nat Med. 2016 Jun;22(6):614-23
pubmed: 27158907
Cell Host Microbe. 2019 Apr 10;25(4):565-577.e6
pubmed: 30905437
Clin Infect Dis. 2013 Jul;57(1):40-7
pubmed: 23487390
Nat Rev Microbiol. 2010 Apr;8(4):272-80
pubmed: 20208550
Lancet Infect Dis. 2017 May;17(5):498-509
pubmed: 28216244
J Exp Med. 2003 Jan 20;197(2):143-51
pubmed: 12538654
PLoS Comput Biol. 2012;8(10):e1002729
pubmed: 23093922
Am J Trop Med Hyg. 2002 Mar;66(3):310-3
pubmed: 12139226
Am J Med Sci. 1973 Sep;266(3):169-77
pubmed: 4583408
Cell Rep. 2016 Dec 20;17(12):3193-3205
pubmed: 28009289
Am J Trop Med Hyg. 2018 Aug;99(2):338-349
pubmed: 29943719
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Nat Immunol. 2018 Nov;19(11):1199-1211
pubmed: 30333613
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
N Engl J Med. 2009 Jul 30;361(5):455-67
pubmed: 19641202
Genome Biol. 2014 Feb 03;15(2):R29
pubmed: 24485249
Immunity. 2008 Jul 18;29(1):150-64
pubmed: 18631455
Nat Commun. 2019 Sep 2;10(1):3950
pubmed: 31477704
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Nat Immunol. 2008 Jul;9(7):725-32
pubmed: 18563083
J Clin Invest. 2008 Apr;118(4):1266-76
pubmed: 18382739
Lancet. 2015 Jul 4;386(9988):31-45
pubmed: 25913272
Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):2425-2430
pubmed: 28193898
Sci Rep. 2019 Jun 10;9(1):8386
pubmed: 31182757