Identification and characterisation of the genetic determinants of variable response to antigens from infectious agents

Despite the success of vaccines in routine use worldwide, there are substantial challenges hampering our ability to develop vaccines against extant diseases including malaria and tuberculosis. Novel approaches are urgently required to help us understand immunological correlates of protection against disease and facilitate our understanding of the impact of human genetic variation on the success of diverse vaccines. To identify host genetic factors responsible for variation in antibody responses against vaccine antigens delivered routinely to infants worldwide I performed a genome-wide association study (GWAS) involving 2,499 infants recruited from three diverse sites across Africa. I identified strong genetic associations between variants in the class II major histocompatibility complex (MHC) locus and responses against five antigens: pertussis toxin (PT), filamentous haemagglutinin (FHA) and pertactin; diphtheria toxin (DT); and hepatitis B surface antigen. To characterise these associations at the gene and allelic level I developed a large, high-resolution (6-digit ‘G’) population-specific human leukocyte antigen (HLA) imputation reference panel including 697 individuals from the vaccine GWAS typed at 11 genes, highlighting the diversity of HLA across the African continent. Using this panel I imputed HLA into the remaining GWAS dataset to fine-map the associations to specific HLA alleles, amino acid and single nucleotide polymorphism sites; some of which were found to be African specific. I then used these HLA association findings observed with PT response to correlate, through genetics, this trait with susceptibility to whooping cough in an independently recruited and analysed set of cohorts from the UK. I further used these genetic correlations to demonstrate the relevance of levels of PT-specific circulating follicular helper T-cells and TRBV29-1 T-cell receptor gene expression levels in the development of this protective immune response against PT. By using HLA-peptide binding studies I also demonstrate the diversity of mechanisms that are involved in HLA-disease association, showing that the breadth and affinity of DT-peptide binding are increased with HLA-DRB1 alleles associated with increased DT antibody responses. Taken together, these data represent the first comprehensive genetic association study of multiple vaccine responses undertaken in African infants. These results highlight the importance of human genetics in modulating protective responses against vaccine antigens and demonstrate how such associations can be harnessed to understand biological mechanisms of protective efficacy in greater detail that may in turn facilitate future vaccine development.