Vaccine Research and Development
Because of the role that papillomavirus plays in causing cervical and other types of cancer, there has been a lot of research into the development of a vaccine against some strains of HPV. HPV-16 is present in 50 percent of cervical cancers and high-grade cervical intraepithelial neoplasias, and in 25 percent of low-grade intraepithelial neoplasias. Theoretically, a preventative vaccine could drastically reduce the prevalence of cervical cancer by reducing the number of individuals infected with HPV. Although primary prevention of all HPV infections may be impossible to achieve, secondary prevention (elimination of low-grade lesions before they progress to invasive cancer) is a more realistic goal. Among the hurdles yet to be overcome are the type-specificity of neutralizing antibodies (current vaccine formulas that generate immunity to HPV-16 will be less effective against other oncogenic HPV types) and the lack of a rapid, inexpensive serologic test to identify incident infections. However, progress in the field has been exceptionally rapid, and motivation is high. The majority of current cervical cancer deaths occur in developing countries that lack the resources for widespread cytologic screening through Pap smears. Thus, the potential public health benefit of an effective HPV vaccine would be hard to overstate.
In a study published in the New England Journal of Medicine in November of 2002, the results from a multi-center, randomized clinical trial of a preventative vaccine against HPV 16 were reported and proved very promising. Over 2000 women from the ages of 16 to 23 who were not infected with HPV 16 were given three doses of a placebo or HPV-16 virus-like-particle vaccine at day 0, month 2, and month 6. They were then followed for almost a year and a half to determine the incidence of HPV 16. The incidence of persistent HPV-16 infection was 3.8 per 100 women-years at risk in the placebo group and 0 per 100 women-years at risk in the vaccine group. In other words, the vaccine was 100% efficacious. In addition, the only cases of cervical intraepithelial neoplasia that were found occurred among the placebo recipients. This reduction in HPV-16-related cervical intraepithelial neoplasia may eventually reduce the incidence of cervical cancer.
Merck currently has a quadrivalent HPV vaccine, which protects against HPV 6, 11, 16, and 18, in phase III clinical trials. 16 and 18 are the two most common cancer-causing strains, while 6 and 11 are most commonly associated with genital warts. Interestingly, while including 6 and 11 in the vaccine increases the duration of clinical trials, they are necessary to include because people are more likely to be vaccinated in order to receive visible results, especially in the case of men, who cannot develop cervical cancer.
The results from these trials are very promising thus far. None of the women who received the vaccine have contracted HPV. The trials will continue to follow these women to see if the initial protection offered by the vaccine has long-term potential. Limitations of this vaccine include that it only protect against four strains of HPV. It also is not a therapeutic vaccine; that is, it does not prevent against a person who is already infected with HPV from developing HPV-related cancer. Finally, it is not yet known how long the immunity will last.
Research into the development of a therapeutic vaccine is also ongoing. A new study, published in Cancer Immunology and Immunotherapy, reported on the results from a phase I/II trial of the effectiveness of a HPV-16 E7 protein-based vaccine in women with oncogenic HPV-positive cervical intraepithelial neoplasia. All of the vaccinated patients, but not the placebo, showed significant immune response to the vaccine, justifying further analysis of this vaccine. Another study recently published in Virology used a recombinant Kunjin virus vector with a CTL epitope of HPV 16 E7 protein. This vector system was shown to be efficacious in inducing protective immunity against HPV 16 E7-expressing tumors in mice. A third study in the Journal of Virology tested a therapeutic vaccine in mice that used the HPV 16 E5 protein.
Vaccination against HPV could have incredible benefits for developing countries, where the screening tests for infection to prevent cervical cancer are virtually nonexistent. One study looked at the feasibility of developing an oral vaccine, which would be particularly beneficial in countries that lack adequate production and delivery infrastructure for vaccines. The study showed that HPV L1 proteins can be expressed in genetically engineered plants and that these proteins elicit an immune response against the viral-like particles that could possibly provide protective humoral immunity to HPV.
Information on further research into both therapeutic and prophylactic vaccines can be found in the section on new and hot research.