Developing an HPV vaccine to prevent cervical cancer and genital warts

doi:10.1016/j.vaccine.2007.01.013

Vaccine

Volume 25, Issue 16, 20 April 2007, Pages 3001-3006

https://doi.org/10.1016/j.vaccine.2007.01.013 Get rights and content

Abstract

The challenges of the journey from target identification through development of a prophylactic quadrivalent human papillomavirus (HPV) vaccine have been met in Gardasil^®. Cervical cancer is the second leading cause of cancer-related death in women worldwide. Approximately 70% of cervical cancer is caused by infection with HPV types 16 and 18 and ∼90% of genital warts are caused by HPV types 6 and 11. The quadrivalent HPV vaccine was generated by expression of the major capsid protein (L1) of HPV types 16, 18, 6 and 11 in yeast. L1 proteins self assemble into pentamer structures and these pentamer structures come together to form virus-like particles (VLPs). The VLPs are antigenically indistinguishable from HPV virions. The VLPs contain no viral DNA and therefore the vaccine is non-infectious. Gardasil^® is composed of VLPs of HPV types 16, 18, 6 and 11 conjugated to a proprietary amorphous aluminum hydroxyphosphate sulfate adjuvant. The results of a rigorous clinical program have demonstrated that the vaccine is safe and highly efficacious in preventing dysplasias, cervical intraepithelial neoplasias (CIN 1–3) the precursors of cervical cancer and external genital lesions caused by vaccine-HPV types. In conclusion, Gardasil^® addresses a major medical need, that is, reduction of HPV-related disease including cervical cancer as a safe, immunogenic, and highly efficacious vaccine.

Section snippets

Rationale and design of the quadrivalent HPV vaccine

Human papillomavirus (HPV) related morbidity and mortality from cytologic abnormalities of the cervix, surrounding genitalia and cervical cancer occur with high frequency. Cervical cancer has been shown to be caused by HPV infection in over 99% of cases [1]. There are over 100 HPV types with 30–40 types associated with anogenital disease. Approximately two-thirds of these are considered “high-risk” for oncogenic progression whereas the remaining one-third are considered “low-risk”. Cervical

Immunogenicity

Ideally, a prophylactic vaccine would be highly immunogenic and stable at a low dose providing the subject with maximal response and limiting any adverse experiences. In the development and storage of VLPs it was found that under certain conditions and concentrations, VLP aggregation might occur. To provide optimal stabilization of HPV VLPs in solution required the presence of both non-ionic surfactants and sufficient levels of salt. PS80 was incorporated into the VLP storage buffer in addition

Efficacy and immune memory

We have demonstrated that we can produce a highly immunogenic quadrivalent HPV vaccine, the question now is whether the vaccine is in fact efficacious and what might the duration of protection be? Prior to initiating the Phase III clinical trials for Gardasil^® the question of which clinical endpoint should be monitored, was addressed. Clearly the most significant HPV-related disease endpoint is cervical cancer, however, progression to cervical cancer can take many years. Ethically, it is not a

Conclusions

A quadrivalent HPV 16, 18, 6 and 11 VLP vaccine has been effectively produced. It can be produced consistently at large scale and is stable. It has been packaged and delivered safely to thousands of subjects. Through the use of highly sensitive and specific HPV immunoassays and HPV genotyping assays it has been demonstrated that the vaccine is immunogenic and highly efficacious. The duration of efficacy of the vaccine is not known; however, it appears to be at least 5 years. Pharmacovigilance

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Developing an HPV vaccine to prevent cervical cancer and genital warts

Abstract

Section snippets

Rationale and design of the quadrivalent HPV vaccine

Immunogenicity

Efficacy and immune memory

Conclusions

Gynecol Oncol

Lancet Infect Dis

Otolaryngol Clin North Am

Otolaryngol Clin North Am

Virology

Virology

Gene

Protein Expr Purif

Vaccine

Vaccine

Vaccine

J Pharm Sci

Vaccine

Vaccine

Vaccine

Virology

Virology

Lancet Oncol

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide

J Pathol

Cofactors with human papillomavirus in a population-based study of vulvar cancer

J Natl Cancer Inst

On the etiology of anal squamous carcinoma

Dan Med Bull

External genital warts: diagnosis, treatment, and prevention

Clin Infect Dis