© 2019 The Author(s) Vaccines have revolutionized public health, preventing millions of deaths each year, particularly in childhood. Yet, there is considerable variability in the magnitude and persistence of vaccine-induced immunity. Maintenance of specific antibody is essential for continuity of vaccine-induced serological protection. We conducted a genome-wide association study into the persistence of immunity to three childhood vaccines: capsular group C meningococcal (MenC), Haemophilus influenzae type b, and tetanus toxoid (TT)vaccines. We detail associations between variants in a locus containing a family of signal-regulatory proteins and the persistence MenC immunity. We postulate a regulatory role for the lead SNP, with supporting epigenetic and expression quantitative trait loci data. Furthermore, we define associations between SNPs in the human leukocyte antigen (HLA)locus and the persistence of TT-specific immunity. Moreover, we describe four classical HLA alleles, HLA DRB1∗0301, HLA DQB1∗0201, HLA DQB1∗0602, and HLA DRB1∗1501, associated with TT-specific immunity, independent of the lead SNP association.