It has been estimated that over 20 million people in the United States are currently infected with the Human Papillomavirus (HPV), and 50-75% of sexually active men and women will become infected with the virus at some point in their lives. Since HPV infections are associated with the development of various malignancies, including cervical, anal, perianal, vulvar, vaginal, penile, and oropharyngeal cancers, it is not surprising that the recent work on developing an HPV vaccine has generated so much interest [1, 2]. This presentation (HPV Vaccines) from November 10, 2003 focused on the various types of vaccines that are under investigation and their mechanisms of action.
Included at the end of the presentation is a brief review of the New England Journal of Medicine article published in November of 2002 regarding the potential success of a prophylactic HPV-16 vaccine. Such prophylactic vaccines contain HPV subunits that induce neutralizing antibodies prior to a host encountering an HPV infection. This study demonstrated that the administration of the HPV-16 vaccine could reduce the incidence of HPV-16 infection and HPV-16-related cervical intraepithelial neoplasia (CIN) .
Since the above presentation, similar findings were noted in a randomized, double-blind, placebo-controlled study published in November of 2004 in Lancet. This study randomized 1,113 women between the ages of 15-25 years to receive either a placebo vaccine or a bivalent HPV-16/18 L1 virus-like particle vaccine (HPV 16 and 18 are the two most significant oncogenic HPV subtypes and together they are associated with 70% of cervical cancers). With follow-up at 27 months, the vaccine was demonstrated to be 95.1% effective against persistent cervical infections and 92.9% effective against cytological abnormalities associated with infections of HPV 16 and 18 .
In a double-blind, placebo-controlled study published in May of 2005 in Lancet Oncology , 552 women were randomized to assess the efficacy of a prophylactic quadrivalent L1 virus-like particle vaccine targeting HPV types 16 and 18, as well as HPV types 6 and 11, which are associated with 90% of genital warts. With follow-up at 36 months, compared to the placebo group, the combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 was decreased by about 90% in the 277 patients that received the vaccine .
In addition to prophylactic HPV vaccines, there is great interest in the development of v accines directed against HPV-infected cells for treatment. These therapeutic vaccines are designed to augment the host cell-mediated immunologic response and enhance the specific, directed T-cell mediated response, resulting in the downregulation of viral reproduction or viral clearance .
In a study published in September of 2003 in Cancer Research , 18 women with HPV 16-associated high-grade vulval intraepithelial neoplasia (VIN) were vaccinated with TA-HPV, a recombinant vaccinia virus encoding modified HPV 16 and 18 E6 and E7. Thirteen patients showed an increased HPV 16-specific immune response following immunization, and 8 patients achieved a =50% reduction in lesion diameter. Viral load was reduced or cleared in six of the eight lesion responders and in six of 10 nonresponders. Additionally, clinical responders were found to have significantly higher levels of pre-vaccination, lesion-associated CD4(+), CD8(+), and CD1a(+)-immune cells compared to the nonresponders .
In November of 2003, Clinical Cancer Research published a study of 12 women with high-grade HPV-associated vulval or vaginal intraepithelial neoplasias who were immunized with a recombinant TA-HPV modified vaccine, similar to the vaccine used in the above study. Ten patients achieved a decreased in lesion size, and five patients experienced a =50% reduction in lesion diameter .
Most recently, published in July of 2004 in Cancer Immunology, Immunotherapy , researchers tested the immunogenicity of a fusion protein (PD-E7) comprised of a mutated HPV-16 E7 linked to part of the Haemophilus influenzae protein D. This vaccine was given to seven patients with HPV-associated CIN. Two patients achieved a disappearance of their cervical lesion, and most patients experienced systemic specific immune responses, with five patients achieving significantly increased IFN-gamma CD8+ cell responses .
Although the results of clinical trials investigating HPV vaccines have been promising, several limitations need to be overcome before cervical cancer can potentially be eradicated worldwide. Currently, trial vaccines have restricted valency and thus cover only a few HPV subtypes. Such vaccines could potentially cause an epidemiological shift of HPV-induced disease towards the currently less frequent types and variants. HPV vaccines are also very expensive, and the cost-effectiveness of immunizing males is currently being debated. Additionally, widespread education about HPV and its role in the pathogenesis of cervical cancer needs to be instituted in order to help overcome the societal stigmas associated with sexually transmitted diseases and the public health measures aimed at preventing them .