Immune escape and immune camouflage may reduce the efficacy of RTS, S vaccine in Malawi. Issue 2 (1st February 2020)

• Record Type: Journal Article
• Authors: Khan, Sundos; Parrillo, Matthew; Gutierrez, Andres H.; Terry, Frances E.; Moise, Leonard; Martin, William D.; De Groot, Anne S.
• Is Part Of: Human vaccines & immunotherapeutics. Volume 16:Issue 2(2020)
• Page Start: 214
• Page End: 227
• Publication Date: 2020-02-01
• Subjects: Malaria -- RTS -- S vaccine -- T-cell epitopes -- circumsporozoite protein (CSP) -- immune escape -- immune camouflage -- immunoinformatics -- EpiMatrix -- EpiCC -- JanusMatrix; Vaccines -- Periodicals; 615.372
• DOI: 10.1080/21645515.2018.1560772
• Languages: English
• ISSNs: 2164-5515

Abstract

ABSTRACT: The RTS, S/AS01 malaria vaccine will undergo a pilot vaccination study in sub-Saharan Africa beginning in 2019. RTS, S/AS01 Phase III trials reported an efficacy of 28.3% (children 5–17 months) and 18.3% (infants 6–12 weeks), with substantial variability across study sites. We postulated that the relatively low efficacy of the RTS, S vaccine and variability across sites may be due to lack of T-cell epitopes in the vaccine antigen, and due to the HLA distribution of the vaccinated population, and/or due to 'immune camouflage', an immune escape mechanism. To examine these hypotheses, we used immunoinformatics tools to compare T helper epitopes contained in RTS, S vaccine antigens with Plasmodium falciparum circumsporozoite protein (CSP) variants isolated from infected individuals in Malawi. The prevalence of epitopes restricted by specific HLA-DRB1 alleles was inversely associated with prevalence of the HLA-DRB1 allele in the Malawi study population, suggesting immune escape. In addition, T-cell epitopes in the CSP of strains circulating in Malawi were more often restricted by low-frequency HLA-DRB1 alleles in the population. Furthermore, T-cell epitopes that were highly conserved across CSP variants in Malawi possessed TCR-facing residues that were highly conserved in the human proteome, potentially reducing T-cell help through tolerance. The CSP component of the RTS, S vaccine also exhibited a low degree of T-cell epitope relatedness to circulating variants. These results suggest that RTS, S vaccine efficacy may be impacted by low T-cell epitope content, reduced presentation of T-cell epitopes by prevalent HLA-DRB1, high potential for human-cross-reactivity, and limited conservation with the CSP of circulating malaria strains.