Dean's Newsletter

Archive of previous newsletters

HPV Vaccine for the Prevention of Cervical Cancer

February 04, 2005

Earlier this week, Marjorie Hunter, Esq., Director of our Technology Transfer Office, informed me of an important milestone that would occur later in the week: two drug companies would sign royalty agreements regarding an important technology developed at the University of Rochester School of Medicine and Dentistry. This technology, initiated by three scientists in the Infectious Disease Unit of the Department of Medicine—Robert Rose, Ph.D., Richard Reichman, M.D. and William Bonnez, M.D.—involves the use of virus-like particles (VLPs) to produce a vaccine against human papillomavirus (HPV), the cause of genital warts, cervical cancer and other cancers. Indeed, Glaxo-Smith-Kline (GSK) and Merck have now both signed contracts agreeing to royalty payments in connection with sales of this vaccine.

The commercialization of the intellectual property embodied in this invention represents an important dimension of our research mission. Not only will this work lead to fundamentally new ways of preventing cervical cancer, but it will generate substantial revenues that will further our research mission, add jobs to the local economy, and promote collaboration with industry.

Is such research less "pure" because it has led to commercial use? Not at all! In fact, it follows the mandate of the third goal set forth in the NIH mission statement: "Expand the knowledge base in medical and associated sciences in order to enhance the Nation's economic well being and ensure a continued return on the public investment in research." The Bayh-Dole Act of 1980 (named for co-sponsors, Senators Birch Bayh and Robert Dole) made technology transfer part of the government mandate for institutions receiving federal funding. In the academic health sector, technology transfer is essentially the process of bringing new medical technologies to the marketplace. The Bayh-Dole Act encourages universities and commercial federal contractors to retain title to inventions that are conceived in the performance of a federal grant. Some of the key objectives of the Act are to promote the commercialization and public availability of inventions arising out of federally supported research and to promote collaboration between nonprofits (e.g., universities) and commercial concerns. Most universities now apply the objectives of this Act to all research, regardless of funding source. Indeed, the initial VLP work of Drs. Rose, Reichman, and Bonnez used non-federal sources of funds. Universities license intellectual property to companies that have the resources and interest to develop, produce and market the technology. In return, universities receive payments--licensing fees, equity, and/or royalties on revenues of the products that were licensed.

This will be another "newsletter trilogy." For the remainder of this newsletter, I will provide some additional background on the HPV vaccine and its extraordinary clinical and public health implications. Next week, I will try to acquaint you with the faculty members responsible for this towering achievement—the biographical stories behind the story. And finally, in the following week, I will provide an overview of the activities in our Technology Transfer Office and newly-formed Office of Corporate Alliance, which supports the part of our research mission that seeks to bring our scientific discoveries to the bedside and to the marketplace through licensing agreements and start-up companies.

Following the introduction of Pap smears in the 1950's, the incidence of cervical cancer declined by more than 2/3 in the United States. One woman in 70, however, will still develop this disease in her lifetime. Approximately 12,000 women in the U.S. are diagnosed with cervical cancer each year, and 4,500 will die despite 50 years of screening programs, colposcopy, precursor ablation and now HPV testing. The global disease burden of cervical cancer is much greater—470,000 new cases and 230,000 deaths every year; almost 80% of the cases occur in developing countries, where in many regions it is the most common cancer among women. Cervical cancer is the leading cause of lost life-years in women in south central Asia, Latin America and sub-Saharan Africa.

In the last two decades, it became recognized that human papillomaviruses (HPVs) are causatively linked to a wide range of genital tract neoplasms. HPVs are small DNA viruses that infect cutaneous and mucosal stratified epithelia. HPV types 6 (HPV6) and, very closely related, 11 (HPV11) cause condylomata acuminata (anogenital warts) and are also present in benign lesions of the lower genital tract, while HPV16 and HPV18 are common in premalignant and malignant lesions of the cervical squamous epithelium. Molecular studies show that DNA from these high-risk HPV types are detected in virtually all cases of cervical cancers with highly sensitive PCR.

Once it became known that a virus was the cause of cervical cancer, there was tremendous interest in the possibility of producing a vaccine against the offending HPV types. This was not possible for a variety of technical reasons, however, until a method was developed to produce virus-like particles (VLPs) that could confer immunity against HPV infection. As reported by Rose, Reichman, and Bonnez in two papers in the early 1990s (Rose RC et al. J Virol 1993;67:1936-44, Rose RC et al. J Gen Virol 1994;75:2075-79.), this was accomplished by expressing the L1 capsid protein of HPV11 in Sf-9 cells with a recombinant baculovirus vector. VLPs were detected by electron microscopy in the nucleus and cytoplasm of the infected cells. These VLPs were demonstrated to be quite similar to native HPV11 in their morphologic and immunologic characteristics, could be used to elicit a neutralizing antibody response, and could substitute faithfully for native virions in the development of HPV-serodiagnostic immunoassays.

This work was largely done as Dr. Rose's PhD thesis in the Department of Microbiology and Immunology under Dr. Reichman's mentorship. While most PhD theses sit on a shelf, the two landmark papers cited above led to the patenting of the technology for HPV vaccine development using virus-like particles. This was licensed initially to a small pharmaceutical company, who then sold the license to GSK. Several other groups filed patents for similar discoveries at around the same time (1993), but the work of Rose, Reichman and Bonnez is considered by most observers to be the strongest, due to use of the correct (L1) capsid protein and the demonstration that their VLPs detected antibodies in human sera also induced a neutralizing antibody response in human subjects.

Although cervical cancer is the main target for the HPV vaccine, there are other cancers whose prevention is likely to benefit from the vaccine now in development. There is good evidence that high-risk anogenital (also called mucosal) HPVs are responsible for incipient and invasive squamous cell carcinomas of the anus, as well as subsets of vulvar, vaginal, and penile cancers. These viruses may also play a causal role in some oro- and nasopharyngeal squamous cell cancers.

HPV vaccines are currently in Phase 3 trials. Two large-scale clinical trials have demonstrated near-perfect efficacy of the vaccine in preventing infection with HPV 16/18 (Koutsky LA et al, N Engl J Med 2002;347:1645-51 and Harper DM et al, Lancet 2004;364:1757-65). It is expected that the first vaccines will be marketed in the first half of 2006.

This exciting story truly captures the potential of translational science. From the fundamental work that led to creation of VLPs that could confer immunity against HPV infection, to the production of a vaccine, to clinical trials demonstrating vaccine efficacy, we now have the prospect of vaccination against HPV on an international scale to avert, or at least significantly reduce, a major cause of morbidity and mortality.

David S. Guzick, MD, PhD
Dean, School of Medicine and Dentistry