Genetics determinants of vaccine responses

Vaccines have had a profound influence on human health with no other health intervention rivalling their impact on the morbidity and mortality associated with infectious disease. However, the magnitude and persistence of vaccine immunity varies considerably between individuals, a phenomenon that is not well understood. Recent studies have used contemporary technologies to correlate variations in the genome and transcriptome to complex phenotypic traits, and these approaches have started to provide fresh insight into the intrinsic factors determining the generation and persistence of vaccine-induced immunity. This thesis aimed to describe the relationship between genomic and transcriptomic variations, and the immunogenicity of childhood immunisations. Candidate gene and genome-wide genotyping was conducted to evaluate the influence of genetic variants on vaccine-induced immunity following childhood immunisation. Furthermore, contemporary methodologies were used to assess non-coding and coding gene transcript profiles following vaccination, to further dissect the molecular systems involved in vaccine responses. Key findings from this thesis include the description of the first genome-wide association studies into the persistence of immunity to three routine childhood immunisations: capsular group C meningococcal (MenC) conjugate vaccine, Haemophilus influenzae type b (Hib) conjugate vaccine and tetanus toxoid (TT) vaccine. Genome-wide genotyping was completed on over 2000 participants, with an additional 1000 participants genotyped at selected genetic markers. Genome-wide significant associations (p<5×10−8) were described between single- nucleotide polymorphisms (SNPs) in two genes, CNTN6 and ENKUR, and the persistence of serological immunity to MenC following immunisation of children 6-15 years of age. In addition, genome-wide significant associations were described between SNPs within an intergenic region of chromosome 10 and the persistence of TT-specific IgG concentrations following childhood immunisations. Furthermore, a number of variants in loci with putative involvement in the immune system such as FOXP1, the human leukocyte antigen locus and the lambda light chain immunoglobulin locus, were shown to have suggestive associations (p<1×10−5) with the persistence of vaccine-induced serological immunity. The fundamental challenge will be to describe functional mechanisms associated with these findings, and to translate these into innovative and pragmatic strategies to develop new and more effective vaccines.