Expression of genes associated with immunoproteasome processing of major histocompatibility complex peptides is indicative of protection with adjuvanted RTS,S malaria vaccine.
BACKGROUND
Patterns of expressed genes in the peripheral blood mononuclear cells of persons who were receiving RTS,S/AS01 or RTS,S/AS02 malaria vaccine and were undergoing experimental challenge with mosquito-borne falciparum malaria were examined to identify markers associated with protection.


METHODS
Thirty-nine vaccine recipients were assessed at study entry; on the day of the third vaccination; at 24 h, 72 h, and 2 weeks after vaccination; and on day 5 after challenge. Of 39 vaccine recipients, 13 were protected and 26 were not. Eleven vaccine recipients exhibited delayed onset of parasitemia. All infectivity control subjects developed parasitemia. Prediction analysis of microarrays identified genes corresponding with protection. Gene set enrichment analysis identified sets of genes associated with protection after the third vaccination and before challenge.


RESULTS
After the third vaccination and before challenge, differential expression of genes in the immunoproteasome pathway distinguished protected and nonprotected persons. At 5 days after challenge, differential expression of genes associated with programmed cell death distinguished between subjects protected and not protected from malaria blood-stage infection.


CONCLUSIONS
The up-regulation of genes associated with the efficient processing of major histocompatibility complex peptides suggests a potential role of the vaccine in conferring major histocompatibility complex class 1-mediated protection and may represent a useful surrogate marker of vaccine efficacy without the need for challenge.
Vahey
Maryanne T
MT
The Walter Reed Army Institute of Research, Silver Spring, Maryland 20403, USA. maryanne.vahey@us.army.mil
Wang
Zhining
Z
Kester
Kent E
KE
Cummings
James
J
Heppner
D Gray
DG
Nau
Martin E
ME
Ofori-Anyinam
Opokua
O
Cohen
Joe
J
Coche
Thierry
T
Ballou
W Ripley
WR
Ockenhouse
Christian F
CF
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000276:immunology*
D000276:Adjuvants, Immunologic; D051017:Apoptosis Regulatory Proteins; D017780:Malaria Vaccines; D046988:Proteasome Endopeptidase Complex