Expression of genes associated with immunoproteasome processing of major histocompatibility complex peptides is indicative of protection with adjuvanted RTS,S malaria vaccine

• Published in: The Journal of infectious diseases Vol. 201; no. 4; pp. 580 - 589
• Main Authors: Vahey, Maryanne T., Wang, Zhining, Kester, Kent E., Cummings, James, Heppner, D. Gray, Nau, Martin E., Ofori-Anyinam, Opokua, Cohen, Joe, Coche, Thierry, Ballou, W. Ripley, Ockenhouse, Christian F.
• Format: Journal Article
• Language: English
• Published: Oxford The University of Chicago Press 15.02.2010; University of Chicago Press; Oxford University Press
• Subjects: Adjuvants, Immunologic - administration & dosage; Antigen Presentation - genetics; Antigen Presentation - immunology; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - immunology; Applied microbiology; Biological and medical sciences; Cells, Cultured; Computational Biology - methods; Datasets; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling - methods; Gene expression regulation; Genes; Human protozoal diseases; Humans; Infectious diseases; Leukocytes, Mononuclear - immunology; Major Histocompatibility Complex - genetics; Major Histocompatibility Complex - immunology; Malaria; Malaria vaccine; Malaria Vaccines - administration & dosage; Malaria Vaccines - immunology; Male; Medical sciences; Microbiology; Oligonucleotide Array Sequence Analysis - methods; Parasitemia; PARASITES; Parasitic diseases; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - immunology; Protozoal diseases; Regulator genes; Up regulation; Vaccination; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Infection; Protozoal disease; Malaria; Peptides; Immunological adjuvant; Major histocompatibility system; Vaccine; Parasitosis; Gene expression
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/650310

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.