Abstract LE01: DISTINGUISHED LECTURE ON TARGETS FOR CANCER PREVENTION: Prevention of cervical cancer in current and future generations by HPV vaccination and other approaches

Abstracts: Frontiers in Cancer Prevention Research 2008 LE01 Cervical infection by a sub-set of human papillomaviruses (HPV) is the primary cause of virtually all cases of cervical cancer, which worldwide is the second most common cause of cancer deaths in women. Approximately 50% of these cancers are attributable to infection by HPV16, and another 15-20% are caused by HPV18. The remaining cases are attributable to about a dozen other HPV types. HPVs also cause a variable proportion of other malignancies, including vulvar, vaginal, penile, anal, and oropharyngeal cancer. When these cancers are associated with HPV infection, HPV16 accounts for an even higher proportion than for cervical cancer, and HPV18 is found in most of the others. The HPVs that cause these cancers are usually transmitted by sexual exposure. Genital HPV infection is extremely common, and many women are exposed to HPV soon after initiating sexual activity. It is estimated that the lifetime risk of acquiring genital HPV infection is at least a 75%. Most infections are self-limited, and regression is associated with developing a degree of type-specific resistance to reinfection. However, those infections that persist, especially with HPV16 and HPV18, place a woman at risk of cervical precancer and invasive cancer. The viral oncogenes, E6 and E7, continue to be expressed in tumors and contribute to their maintenance. Until recently, the main approach to cervical cancer prevention has been secondary prevention by pap smear screening. However, identification of HPV as the causative agent of cervical cancer has led to two etiology-based advances. One is the use of HPV-based screening. The other is primary prevention through development of prophylactic HPV vaccines, which is the main topic of this presentation. The current vaccines are based on the observation that the L1 main structural protein of the HPV virion can self-assemble into empty virus-like particles (VLPs) which, because they contain the conformationally-dependent neutralization epitopes of L1, can induce high levels of neutralizing antibodies. Preclinical studies showed that passive transfer of immune IgG could protect animals against high dose experimental infection, implying that neutralizing antibodies are the main mechanism for protection. Two pharmaceutical companies have developed commercial versions of the VLP vaccine. The one manufactured by GlaxoSmithKline (GSK) is a bivalent vaccine composed of VLPs from HPV16 and HPV18, while the one from Merck is a quadravalent vaccine composed of VLPs from HPV6 and HPV11 (which together account for about 90% of genital warts) in addition to VLPs from HPV16 and HPV18. The Merck vaccine is licensed in the United States (for females 9-26 years old), the European Union, and other countries, while the GSK vaccine is licensed in Europe and other countries, but has not yet been licensed in the US. In fully immunized women, clinical efficacy trials carried out by the companies have shown that both vaccines induce almost complete protection against incident persistent genital infection attributable to the HPV types targeted by the vaccine and their associated lesions, including high-grade cervical dysplasia and, for the Merck vaccine, genital warts. Both vaccines also confer some degree of cross-protection against incident infection by closely related HPV types, but neither vaccine appears to alter the natural history of prevalent infection. The type-restricted nature of the protection implies that ~30% of potentially cancer-causing infections will not be prevented by the vaccine. Protection has been shown to last at least several years, but it remains possible that protection may wane over time, and booster vaccination could then be needed. Males have shown a similar immune response to the vaccine, but efficacy data in males have not yet been reported. The CDC Advisory Committee on Immunization Practices (ACIP) has recommended that the main target group for the vaccine should be young adolescent girls, 11-12, because the vaccine is most cost-effective if given before sexual activity has been initiated. The ACIP has also recommended catch-up vaccination for women up to age 26. The high rate of incident infection that develops in young sexually active women implies that the vaccine is likely to prevent fewer serious infections the longer the interval between initiation of sexual activity and subsequent administration of the vaccine. Efforts to maximize the overall reduction in cervical cancer will require coordination between vaccination and screening. A potential advantage of HPV-based screening is that its increased sensitivity compared with cytology might make it easier to safely increase the interval for screening compared with cytology. In countries with low resources, if less expensive high quality screening methods become available, lives may be saved sooner by screening and treating precancer in the current generation of women, compared with vaccination, which will be of benefit primarily to the next generation of women. In addition to the current vaccines, it would be beneficial to develop second generation vaccines that can protect against a broader spectrum of serious HPV infections, are less expensive to produce and deliver, and require fewer doses. The companies will try to broaden protection by increasing the valency of the vaccine via the incoroporation of VLPs from other HPV types. This is a logical approach, but the manufacturing complexities could mean that such new vaccines will be expensive. In collaboration with Richard Roden at Johns Hopkins University, we are taking an alternate approach, which is to develop a vaccine based on the observation that the L2 minor capsid protein contains cross-neutralization epitopes that can induce neutralizing activity against a broad range of HPV types. Although L2 is less immunogenic than VLPs, this vaccine approach can prevent infection in preclinical models. It has not yet been tested in humans. An L2-based vaccine could be produced in bacteria and should be substantially less expensive to manufacture than VLPs. We are also investigating the mechanisms by which HPVs infect cells and the mechanisms that underlie the efficacy of the neutralizing antibodies induced by the vaccines. To explore these issues, we have recently developed a mouse cervico-vaginal challenge model in which the mouse genital tract can be infected with what we call HPV pseudoviruses; the virions of the pseudoviruses are composed of authentic HPV capsids that, instead of encapsidating the HPV genome, have encapsidated a genome that expresses a reporter protein, which can be used as a marker of successful infection. The pseudoviruses appear to faithfully mimic the early steps of actual HPV infection. A noteworthy observation made in the mouse model is that the intact genital mucosa, including the cervix, is resistant to virion binding and, therefore, to infection. However, disruption of mucosal integrity, by gentle abrasion with a cytobrush or a detergent (nonoxynol-9), leads to the virions efficiently binding to the basement membrane, rather than to cells. Expression of the reporter protein from the pseudovirus is seen in keratinocytes 1-3 days after exposure of the genital tract to the pseudovirus. These results imply that disruption of mucosal integrity is essential for HPV infection, that the disruption enables the virus to bind to the basement membrane, and that it binds to the keratinocytes in the epithelium only after it has bound to the basement membrane. The importance of the disruption of mucosal integrity to the infectious process makes it likely that in immunized individuals, infection is prevented because there is exudation of systemic neutralizing antibodies at these potential sites of infection. This hypothesis is currently being tested. Citation Information: Cancer Prev Res 2008;1(7 Suppl):LE01.