Exonic Single Nucleotide Polymorphisms within TLR3 Associated with Infant Responses to Serogroup C Meningococcal Conjugate Vaccine D. O’Connor a , M.D. Snape a , T.M. John a , C.E. Moore b , A.V.S. Hill c and A.J. Pollard a a Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, UK; b Nuffield Department of Clinical Medicine, University of Oxford, UK; c Wellcome Trust Centre for Human Genetics, Oxford, UK. The introduction of the serogroup C meningococcal (MenC) conjugate vaccination has successfully controlled the burden of disease associated with this serogroup in many countries. However, considerable inter-individual variation is observed in immune re- sponses to MenC vaccine, and little is understood of the determinants of this variabil- ity. Previously, we reported an association between single nucleotide polymorphisms (SNPs) in TLR3 and CD44 and the persistence of MenC vaccine immunity. Here we further examine polymorphisms within these two candidate genes and immune responses to MenC vaccination. Specific-IgG concentrations and serum bactericidal assay (SBA) titres were measured one month after a primary course of MenC vaccination in 318 in- fants. Tagging SNPs (TagSNPs) within TLR3 and CD44 were genotyped and regional imputations carried out to screen these genes for variations associated with immunologi- cal responses to MenC vaccination. This study reports an association between an exonic variant (rs3775290, P = 0.025) in TLR3 and MenC IgG concentrations, as well as an association between three SNPs in CD44 (rs3794109, P = 0.021; rs3794110, P = 0.022; rs112762, P=0.049) and MenC SBA titres. These data replicate our previous findings of an association between SNPs in the TLR3 and CD44, and present novel findings implicating exonic variants in these genes with MenC vaccine responses. Introduction Neisseria meningitidis is a Gram-negative diplo- coccus and a major cause of invasive bacterial in- fection worldwide, with peak disease incidence oc- curring in children aged under two years of age [1, 2]. Thirteen serogroups of meningococci have been described based on distinct capsular anti- genicities; however, the majority of invasive dis- ease worldwide is attributable to serogroups: A, B, C, W, X, and Y [3]. Prior to the introduc- tion of the MenC conjugate vaccine, serogroups B and C were the major cause of invasive meningo- coccal disease in Europe and the Americas [4]. Following the introduction of the MenC conju- gate vaccine a drastic decline in serogroup C dis- ease was observed [5–7]. However, the magni- tude and persistence of immunity following MenC vaccination varies considerably between individu- als, a phenomenon which is characteristic of vac- cine responses, but is not well understood [8, 9]. This heterogeneity is particularly noteworthy in the young where responses wane rapidly, such that most older children’s sera lose bactericidal activ- ity following infant MenC vaccination [9]. Conse- quently, the United Kingdom has recently intro- duced an adolescent booster dose of MenC vac- cination to provide protection into early adult- hood [10]. A number of factors including: age, sex, nu- trition, smoking, ultraviolet light exposure, and infectious disease have been implicated in de- termining quantitative measures of vaccine in- duced immunity [11]. Importantly, twin stud- ies have shown vaccine responses to be highly heritable (36 to 89%), highlighting the impor- tance of genetic variation in shaping vaccine im- munity [12–16]. Despite the evident heritability of vaccine responses the particular factors involved remain largely uncharacterized. We previously re- ported SNPs within TLR3 and CD44 that asso- ciated with the persistence of MenC IgG concen- trations in 905 vaccinated teenagers and 351 in- fants/children [17]. Here we further assess the in- fluence of variations within TLR3 and CD44 on the magnitude of responses to MenC conjugate vaccination in infancy. 1