Phylogenetic Considerations in Designing a Broadly Protective Multimeric L2 Vaccine

While the oncogenic human papillomavirus (HPV) types with the greatest medical impact are clustered within the alpha 9 and alpha 7 species, a significant fraction of cervical cancers are caused by alpha 5, alpha 6, and alpha 11 viruses. Benign genital warts are caused principally by the alpha 10 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 (alpha 11-88x8) fusing eight polypeptides corresponding to a protective domain comprising L2 residues alpha 11 to 88 derived from HPV6 (alpha 10), HPV16 (alpha 9), HPV18 (alpha 7), HPV31 (alpha 9), HPV39 (alpha 7), HPV51 (alpha 5), HPV56 (alpha 6), and HPV73 (alpha 11) and a truncated derivative with the last three units deleted (alpha 11-88x5). Mice were immunized three times with alpha 11-88x8 or alpha 11-88x5 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 alpha 11-88x5 and alpha 11-88x8 vaccines induced similarly robust protection against each HPV type tested and indistinguishable HPV16-neutralizing antibody titers. Passive transfer of alpha 11-88x8 antisera was protective. Further, rabbit antisera to alpha 11-88x8 and alpha 11-88x5 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.