NIH Technology Licensed to Merck for HPV Vaccine

A new cancer vaccine developed by Merck makes use of a novel disease prevention strategy to protect against cervical cancer. The vaccine is based on research conducted at the NIH. Cervical cancer is the second most common form of cancer deaths in women worldwide. Each year roughly 233,000 women die from cervical cancer. In the US, 9710 women are diagnosed annually and 3,700 die from it.

Gardasil®, the new Merck vaccine, as well as a new vaccine in development by GlaxoSmithKline (GSK), could dramatically reduce that number.

Unlike many forms of cancer, cervical cancer is not strongly associated with a genetic predisposition. Rather it is attributed to infection by Human Papilloma Virus (HPV). HPV is associated with almost all cases of cervical cancer. HPV is a highly prevalent sexually transmitted disease (STD) and is the most common STD in the US. By age 50 approximately 80% of females have acquired the virus. HPV also causes benign genital warts. There are approximately 32 million cases of genital warts each year. Currently there are no effective therapeutic interventions for HPV infection. A pap smear can detect HPV induced pre-cancerous lesions which can then be surgically removed. However routine screening opportunities are not as affordable for women in poorer countries. As a result, the mortality rate from cervical cancer is much higher in these countries.

There are over 100 strains of HPV, many of which exhibit no symptoms and clear up on their own. But some strains are cause for particular concern, especially HPV16 and HPV18, which cause approximately 70% of cervical cancer world wide. HPV6 and HPV11, although generally considered to be nononcogenic, cause approximately 90% of genital warts. Gardasil® prevents infection against these four forms of HPV, in effect; preventing the majority of HPV related illnesses.

The underlying technology for the vaccine originated in the laboratories of Drs. John Schiller and Douglas Lowy of the NIH National Cancer Institute. Drs. Schiller and Lowy commenced their research on the molecular biology of HPV nearly 20 years ago. Among their numerous findings, they discovered that the major outer coat protein of the virus, called L1, could self assemble into non-infectious virus-like particles (VLPs) that closely resemble the native outer shell of the actual virus.

The principle behind the vaccine is that exposure to VLPs triggers the immune system to produce protective antibodies. If an individual is exposed to HPV after receiving the vaccine, the immune system already contains the antibodies necessary to prevent virus infection. The antibodies primarily function by preventing the virus from binding to the cell which is necessary in order for the virus to reproduce and thrive.

The catch is that for induction of HPV neutralizing antibodies the L1 must be in the same conformation as in the intact virus. Unlike some other viral vaccines, inactivated virus produced in cultured cells was not a viable option because the viruses could not be produced in sufficient quantities in vitro. Also, the inactivated virions would still contain the viral oncogenes, which would preclude use in healthy young people, the primary target population. Schiller and Lowy demonstrated that large quantities of VLPs could be produced in insect cells infected with L1 recombinant baculovirus. Critically, they also showed in animal models that the L1 VLPs were able to induce high titers of neutralizing antibodies, comparable to those induced by authentic virions. Furthermore, they and their colleagues demonstrated that L1 VLP vaccination could protect animals from experimental challenge with high dose virus of the corresponding animal papillomavirus types and that human and animal papillomavirus L1 behaved similarly in the ability to assemble into VLP.

Working with the NCI technology transfer office, the NIH Office of Technology Transfer (OTT) oversaw the patenting of the VLPs. OTT then sought a suitable company with the necessary resources to formulate the vaccine and to conduct clinical trials. The technology was licensed to Merck, the maker of Gardasil®. In October 2005 Merck announced the results of it clinical trials. It was one of the most successful vaccine clinical trials ever. The phase II and phase III studies evaluated the effects of Gardasil® on 20,541 women between the ages of 16 and 26. The women were followed for up to 5 years. Remarkably, none of the women receiving Gardasil® developed precancerous cervical lesions caused by the HPV types in the vaccine. Gardasil® also had a 99% efficacy in preventing genital warts by the types targeted by the vaccine. Moreover, there is evidence that Gardasil® is effective at treatment of preexisting HPV infection. Merck applied for priority FDA review for the vaccine in December of 2005. GlaxoSmithKline, another licensee of the NIH VLP technology, is conducting efficacy trials of a VLP vaccine targeting HPV16 and HPV18. GSK applied for regulatory approval in Europe in March 2006, and is expected to apply for US FDA approval by the end of 2006.

On June 8th 2006, the FDA gave its final approval for Gardasil®. Gardasil® is currently approved for females ages 9 to 26. The vaccine is administered 3 times over a period of 6 months. Although not currently recommended for males, the FDA may in the future approve such use.

Merck is developing a patient assistance program for adults who are uninsured or who cannot afford the vaccine. Merck is seeking approval for Gardasil® in other countries around the world and is working with the global nonprofit health group PATH, with support from the Bill and Melinda Gates Foundation, to explore opportunities for distributing the vaccine in developing countries (see the full story).

Gardasil® marks a tremendous step forward in the prevention of STDs and cancer. Most treatments in the field of cancer aim to cure the disease, but this one is designed to prevent it. It is not only an achievement for cervical cancer but is a remarkable advance in the field of cancer vaccines and an extraordinary proof of principle. According to NCI Acting Director John E. Niederhuber, M.D., “This vaccine opens a new era in cancer prevention.” Women who receive Gardasil® will still need to receive routine screenings for cervical cancer as protection is strain restricted and 30% of cervical cancer cases are attributed to other HPV strains. There are currently over 100 cancer vaccines being developed by drug companies, although few are likely to be as efficacious as Gardasil®. The majority are not preventative like Gardasil® but, instead, help to boost the immune system of individuals who have already developed the disease. Hopefully, Gardasil® will pave the way for the development of other preventative cancer vaccines.