The highly efficacious human papillomavirus (HPV)
vaccines contain virus-like particles (VLP) representing genotypes HPV16 and HPV18, which together account for approximately 70% of
cervical cancer cases.
Vaccine-type protection is thought to be mediated by high titer, type-specific
neutralizing antibodies. The
vaccines also confer a degree of cross-protection against some genetically-related types from the Alpha-9 (HPV16-like: HPV31, HPV33, HPV35, HPV52, HPV58) and Alpha-7 (HPV18-like: HPV39, HPV45, HPV59, HPV68) species groups. Cross-protection is coincident with the detection of low titer serum responses against non-
vaccine types by vaccinees. Such
antibodies may be the effectors of cross-protection or their detection may be useful as a correlate or surrogate. This study evaluated whether cross-neutralization of HPV types from the Alpha-9 species group is mediated by
antibodies with a predominantly type-restricted specificity for HPV16 that nevertheless exhibit low affinity interactions with non-
vaccine types, or by antibody specificities that demonstrate similar recognition of
vaccine and non-
vaccine types but are present at very low levels.
Antibodies generated following Cervarix® vaccination of 13-14 year old girls were evaluated by pseudovirus neutralization, VLP ELISA and by enrichment of target
antigen specificity using VLP-immobilized beads. Two-dimensional hierarchical clustering of serology data demonstrated that the antibody specificity profile generated by VLP ELISA was both quantitatively and qualitatively different from the
neutralizing antibody specificity profile. Target-specific antibody enrichment demonstrated that cross-neutralization of non-
vaccine types was due to a minority of
antibodies rather than by the weak interactions of a predominantly type-restricted HPV16 antibody specificity. Furthermore, cross-neutralization of non-
vaccine types appeared to be mediated by multiple antibody specificities, recognizing single and multiple non-
vaccine types, and whose specificities were not predictable from examination of the serum
neutralizing antibody profile. These data contribute to our understanding of the antibody specificities elicited following HPV vaccination and have potential implications for
vaccine-induced cross-protection.