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

doi:10.1016/j.vaccine.2018.01.069

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.

Highlights

Malaria caused by the Plasmodium falciparum parasite caused 438,000 deaths in 2015 and remains one of the major causes of mortality in children under five-years old in sub-Saharan Africa [1]
95% confidence interval (CI), and p value refer to comparison of proportion of subjects protected between subjects positive and negative for an allele group using logistic regression and adjusting for trial, adjuvant, and schedule
95% confidence interval (CI), and p value refer to comparison of proportion of subjects protected between subjects positive and negative for an allele group using logistic regression and adjusting for trial, adjuvant, schedule, and other allele groups previously associated with protection or non-protection

Summary

Introduction

Malaria caused by the Plasmodium falciparum parasite caused 438,000 deaths in 2015 and remains one of the major causes of mortality in children under five-years old in sub-Saharan Africa [1]. RTS,S is a candidate malaria vaccine antigen including a carboxy-terminal segment of the P. falciparum circumsporozoite (CS) protein fused to the hepatitis B surface antigen (HBsAg). When simultaneously expressed in yeast cells together with free HBsAg, these antigens assemble into particulate structures. The RTS,S antigen is formulated with the AS01E adjuvant system which contains the immunostimulants MPL, QS21, and liposomes. RTS,S/AS01 has been tested in a Phase III trial [2] and received a positive opinion from the European Medicines Agency [3], but further evaluation is ongoing and the underlying mechanisms of action are still not well understood [4].

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