TLR genetic variation is associated with Rotavirus–specific IgA seroconversion in South African Black infants after two doses of Rotarix vaccine

Live oral rotavirus vaccines have significantly reduced rotavirus-related diarrheal morbidity and mortality globally, but low efficacy of these vaccines is observed in low–income countries where disease burden is highest. The biological basis of rotavirus vaccine failure remains unknown but likely includes both microbial and host factors. We investigated associations between 19 candidate SNPs in the TLR3, TLR7, TLR8, DDX58 and IFIH1 genes that play a role in innate immunity, and seroconversion in Black South African infants after vaccination with Rotarix at 6 and 14 weeks of age. Rotavirus-specific IgA antibody titre was measured by ELISA before each vaccine dose and four weeks after the second dose, and seroconversion was defined as a four-fold or greater increase in IgA antibody titre at 18 weeks of age when compared to pre-vaccine titres. A total of 95/138 individuals seroconverted (68.8%) and seroconversion was significantly affected by birthweight (P = 0.010), pre-vaccine IgA and IgG titres (P = 0.0002 and P = 0.007 respectively). rs2159377 SNP in TLR8 was significantly associated with seroconversion in a univariate allelic model (P = 0.015) and was borderline significant in a multivariable logistic regression adjusted for birthweight and pre-vaccine titres (P = 0.071), although these values did not remain significant after Bonferroni correction. A haplotype of six SNPs on the X chromosome across TLR7 and TLR8, including rs179008 and rs5935438 minor alleles, was significantly associated with seroconversion in a univariate model (P = 0.042), but not in a multivariable model or after Bonferroni correction. Epistatic interaction between rs5743305 in TLR3 and rs55789327 in DDX58 was significantly associated with seroconversion (P = 0.034) but a genetic risk score constructed from all 19 minor alleles was not. Our results suggest that TLR variants may influence IgA antibody production and seroconversion to Rotarix vaccine in South Africans. Host genetic variation contributes to the varying immunogenicity of live oral rotavirus vaccines.