Phylogenetic Considerations in Designing a Broadly Protective Multimeric L2 Vaccine

Abstract

While the oncogenic human papillomavirus (HPV) types with the greatest medical impact are clustered within the α9 and α7 species, a significant fraction of cervical cancers are caused by α5, α6, and α11 viruses. Benign genital warts are caused principally by the α10 viruses HPV6 and HPV11. In an effort to achieve broad protection against both cervical cancer- and genital wart-associated types, we produced at high levels in bacteria a multimeric protein (α11-88x8) fusing eight polypeptides corresponding to a protective domain comprising L2 residues ∼11 to 88 derived from HPV6 (α10), HPV16 (α9), HPV18 (α7), HPV31 (α9), HPV39 (α7), HPV51 (α5), HPV56 (α6), and HPV73 (α11) and a truncated derivative with the last three units deleted (α11-88x5). Mice were immunized three times with α11-88x8 or α11-88x5 adjuvanted with alum or the licensed HPV vaccines and challenged intravaginally with HPV6, HPV16, HPV26, HPV31, HPV33, HPV35, HPV45, HPV51, HPV56, HPV58, or HPV59 pseudovirions. The α11-88x5 and α11-88x8 vaccines induced similarly robust protection against each HPV type tested and indistinguishable HPV16-neutralizing antibody titers. Passive transfer of α11-88x8 antisera was protective. Further, rabbit antisera to α11-88x8 and α11-88x5 similarly neutralized native HPV18 virions. These findings suggest that immunologic competition between units is not a significant issue and that it is not necessary to include a unit of L2 derived from each species to achieve broader protection against diverse medically significant HPV types than is achieved with the licensed HPV vaccines.