Protective vaccine responses to nine distinct serogroups of Dichelobacter nodosus (serogroups A-I) can be readily measured by serogroup-specific K-agglutinating antibody titres. On the basis of a large quantitative genetic experiment (1200 progeny from 129 sire groups), it was shown that variation in antibody responses following vaccination with a multi-valent pilus antigen D. nodosus vaccine (serogroups A-I) is, in part, under genetic control and thus heritable. Based on the genetic relationships between antibody responses to all nine antigens, results suggested that both genes for a broad-based and genes for serogroup-specific response contributed to genetic variation in vaccine response. Furthermore, preliminary data in 389 progeny showed that polymorphism within the ovine major histocompatibility (MHC) based on serological classification accounted for a significant proportion of the variation in vaccine responses. In subsequent experimentation, we examined the importance of genetic polymorphism within the ovine MHC, and the possibility of genes outside the MHC for their involvement in antigen-specific and broad-based vaccine response. Within two large half sib families(131, and 143 progeny), four MHC haplotypes were investigated and found to be associated with differential antibody responses to six out of eight distinct vaccine-antigens presented to the host in a multi-valent vaccine. The model used here shows how well characterised immunogens, quantitative genetic experimentation, and molecular gene mapping tools can be used to unravel genetic differences in host responses to commercial vaccines.