Human papilloma virus (HPV)-16 and -18 are responsible for approximately 70% of invasive
cervical cancers worldwide. Other oncogenic HPV types account for almost all the remainder. Importantly, HPV-45 and -31 account for approximately 10%. HPV-18 and -45, along with HPV-16, are found in over 90% of endocervical
adenocarcinomas. HPV-45 is the third most frequent HPV type in cervical
carcinoma and
adenocarcinoma. The AS04-adjuvanted
vaccine Cervarix was developed against HPV-16 and -18 focusing on preventing
cervical cancer by inducing durable protection against new
infection. In clinical trials, it shows evidence of cross-protection against other important oncogenic HPV types using a range of clinicopathological and virological endpoints. The current evidence suggesting the cross-protective effect comes from its overall impact on precancerous lesions and on 12-month or more persistent oncogenic
HPV infection, together with specific evidence of protection against incident and new
persistent infection lasting 6 months or more with individual HPV types. The use of virological endpoints for such studies is discussed, in particular for cross-protection evaluation, in view of the lower frequency of many important oncogenic HPV types other than HPV-16 or -18 in precancerous lesions and the frequent presence of multiple
HPV infections. Both of these factors complicate the interpretation of type-specific,
vaccine-induced protection against
cervical intraepithelial neoplasia (CIN) lesions, in which other HPV
DNA types are found along with HPV-16 and -18. The observed high level of overall protection against clinicopathological lesions, including CIN2+ in the vaccinated subjects (regardless of their HPV
DNA status), predicts a potentially broader impact of the
vaccine in the prevention of HPV-related precancers that goes beyond HPV-16 and -18. The prevention of
persistent infections by individual types such as HPV-45 provides specific information on the protection against that type, using an alternative endpoint that relates to both precancer and
cancer development. Together with sustained protection against HPV-16 and -18, protection against HPV-45 could offer an additional effect on invasive
cervical cancer and may have an important impact on endocervical
adenocarcinoma, which is not effectively prevented by screening and is becoming increasingly important in young women.