RTS,S malaria vaccine efficacy and immunogenicity during Plasmodium falciparum challenge is associated with HLA genotype

C M Nielsen, J Vekemans, M Lievens, K E Kester, J A Regules, C F Ockenhouse, C M Nielsen, J Vekemans, M Lievens, K E Kester, J A Regules, C F Ockenhouse

Abstract

Although RTS,S remains the most advanced malaria vaccine, the factors influencing differences in vaccine immunogenicity or efficacy between individuals or populations are still poorly characterised. The analyses of genetic determinants of immunogenicity have previously been restricted by relatively small sample sizes from individual trials. Here we combine data from six Phase II RTS,S trials and evaluate the relationship between HLA allele groups and RTS,S-mediated protection in controlled human malaria infections (CHMI), using multivariate logistic or linear regression. We observed significant associations between three allele groups (HLA-A∗01, HLA-B∗08, and HLA-DRB1∗15/∗16) and protection, while another three allele groups (HLA-A∗03, HLA-B∗53, and HLA-DRB1∗07) were significantly associated with lack of protection. It is noteworthy that these 'protective' allele groups are thought to be at a lower prevalence in sub-Saharan African populations than in the UK or USA where these Phase II trials occurred. Taken together, the analyses presented here give an indication that HLA genotype may influence RTS,S-mediated protective efficacy against malaria infection.

Keywords: Antibody; HLA; Malaria; Protection; RTS,S.

Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
Allele groups significantly associated with protection in controlled human malaria infection (CHMI) are not associated with delays to parasitemia. The percentage of vaccinees who are protected in CHMI following vaccination (i.e. have not been diagnosed with malaria) is plotted against days since malaria challenge, comparing donors positive or negative for HLA-A*01 (A), HLA-A*03 (B), HLA-B*08 (C), HLA-B*53 (D), HLA-DRB1*15/*16 (E), and HLA-DRB1*07 (F) allele groups. The number of donors positive or negative for each allele group (n) out of a possible 222 subjects is given in the figure legends.

References

    1. WHO. World Malaria Report 2015. 2015.
    1. RTS,S Clinical Trials Partnership Efficacy and safety of RTS, S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015;386(9988):31–45.
    1. European Medicines Agency. Summary of opinion: Mosquirix. EMA/CHMP/464758/2015. .
    1. Regules J.A., Cicatelli S.B., Bennett J.W., Paolino K.M., Twomey P.S., Moon J.E. Fractional third and fourth dose of RTS, S/AS01 malaria candidate vaccine: a phase 2a controlled human malaria infection and immunogenicity study. J Infect Dis. 2016
    1. Posteraro B., Pastorino R., Di Giannantonio P., Ianuale C., Amore R., Ricciardi W. The link between genetic variation and variability in vaccine responses: systematic review and meta-analyses. Vaccine. 2014;32(15):1661–1669.
    1. Li Z.K., Nie J.J., Li J., Zhuang H. The effect of HLA on immunological response to hepatitis B vaccine in healthy people: a meta-analysis. Vaccine. 2013;31(40):4355–4361.
    1. Ovsyannikova I.G., Pankratz V.S., Vierkant R.A., Pajewski N.M., Quinn C.P., Kaslow R.A. Human leukocyte antigens and cellular immune responses to anthrax vaccine adsorbed. Infect Immun. 2013;81(7):2584–2591.
    1. Moss A.J., Gaughran F.P., Karasu A., Gilbert A.S., Mann A.J., Gelder C.M. Correlation between human leukocyte antigen class II alleles and HAI titers detected post-influenza vaccination. PLOS One. 2013;8(8):e71376.
    1. Wu T.W., Chu C.C., Ho T.Y., Chang Liao H.W., Lin S.K., Lin M. Responses to booster hepatitis B vaccination are significantly correlated with genotypes of human leukocyte antigen (HLA)-DPB1 in neonatally vaccinated adolescents. Hum Genet. 2013;132(10):1131–1139.
    1. Wu T.W., Chu C.C., Liao H.W., Lin S.K., Ho T.Y., Lin M. HLA-DPB1 and anti-HBs titer kinetics in hepatitis B booster recipients who completed primary hepatitis B vaccination during infancy. Genes Immun. 2014;15(1):47–53.
    1. Moorthy V.S., Ballou W.R. Immunological mechanisms underlying protection mediated by RTS, S: a review of the available data. Malar J. 2009;8:312.
    1. Schwenk R., Lumsden J.M., Rein L.E., Juompan L., Kester K.E., Heppner D.G. Immunization with the RTS, S/AS malaria vaccine induces IFN-gamma(+)CD4 T cells that recognize only discrete regions of the circumsporozoite protein and these specificities are maintained following booster immunizations and challenge. Vaccine. 2011;29(48):8847–8854.
    1. Sedegah M., Kim Y., Ganeshan H., Huang J., Belmonte M., Abot E. Identification of minimal human MHC-restricted CD8+ T-cell epitopes within the Plasmodium falciparum circumsporozoite protein (CSP) Malar J. 2013;12:185.
    1. Bongfen S.E., Torgler R., Romero J.F., Renia L., Corradin G. Plasmodium berghei-infected primary hepatocytes process and present the circumsporozoite protein to specific CD8+ T cells in vitro. J Immunol. 2007;178(11):7054–7063.
    1. Kester K.E., McKinney D.A., Tornieporth N., Ockenhouse C.F., Heppner D.G., Jr., Hall T. A phase I/IIa safety, immunogenicity, and efficacy bridging randomized study of a two-dose regimen of liquid and lyophilized formulations of the candidate malaria vaccine RTS, S/AS02A in malaria-naive adults. Vaccine. 2007;25(29):5359–5366.
    1. Kester K.E., Cummings J.F., Ockenhouse C.F., Nielsen R., Hall B.T., Gordon D.M. Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS, S/AS02 in malaria-naive adults at the Walter Reed Army Institute of Research. Vaccine. 2008;26(18):2191–2202.
    1. Kester K.E., Cummings J.F., Ofori-Anyinam O., Ockenhouse C.F., Krzych U., Moris P. Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS, S/AS01B and RTS, S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection. J Inf Dis. 2009;200(3):337–346.
    1. Ockenhouse C.F., Regules J., Tosh D., Cowden J., Kathcart A., Cummings J. Ad35.CS.01-RTS, S/AS01 heterologous prime boost vaccine efficacy against sporozoite challenge in healthy malaria-naive adults. PLOS One. 2015;10(7)
    1. Rampling T., Ewer K.J., Bowyer G., Bliss C.M., Edwards N.J., Wright D. Safety and high level efficacy of the combination malaria vaccine regimen of RTS, S/AS01B with chimpanzee adenovirus 63 and modified vaccinia ankara vectored vaccines expressing ME-TRAP. J Infect Dis. 2016;214(5):772–781.
    1. Laurens M.B., Duncan C.J., Epstein J.E., Hill A.V., Komisar J.L., Lyke K.E. A consultation on the optimization of controlled human malaria infection by mosquito bite for evaluation of candidate malaria vaccines. Vaccine. 2012;30(36):5302–5304.
    1. Rothman K.J. No adjustments are needed for multiple comparisons. Epidemiology. 1990;1(1):43–46.
    1. Price P., Witt C., Allcock R., Sayer D., Garlepp M., Kok C.C. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev. 1999;167:257–274.
    1. Maiers M., Gragert L., Klitz W. High-resolution HLA alleles and haplotypes in the United States population. Human Immunol. 2007;68(9):779–788.
    1. Hill A.V., Allsopp C.E., Kwiatkowski D., Anstey N.M., Twumasi P., Rowe P.A. Common west African HLA antigens are associated with protection from severe malaria. Nature. 1991;352(6336):595–600.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir