A Potato that Proffers Protection Against Papilloma

Scientists are bellying up to the challenge of creating an edible vaccine to confer protection against human papilloma virus (HPV), one of the most common sexually transmitted diseases and the cause of virtually all cases of cervical cancer in women.

Potatoes produced and tested by scientists at the University of Rochester, Cornell University and Tulane University provoked an immune response in mice that munched on the transgenic spuds. When enhanced with a substance derived from E.coli to boost their effectiveness, the potatoes provoked the immune system in the same way thought to be necessary to protect humans from the virus.

It's another step on the path of creating not only a vaccine to protect against a common sexually transmitted disease, but a vaccine that would make needles needless.

"The beauty of an oral vaccine is that you don't need a needle. In most cases you don't even need a doctor," says virologist Robert Rose, Ph.D., one of the vaccine's creators at the University of Rochester. "You don't need sterile injection equipment or highly skilled medical personnel who know how to inject a vaccine; you just need to put a couple of drops on someone's tongue. Part of the reason that polio has been virtually stamped out is because of the development of an oral vaccine.

"We're designing a vaccine in a way that it could be readily delivered in developing countries, where it is most urgently needed," Rose says.

The work is the latest in a series of steps to create edible vaccines for a cornucopia of diseases. Bananas, potatoes, tobacco and apples are among the crops being tested for the production of vaccines for diseases like hepatitis B, rotavirus, respiratory syncytial virus, and even tooth decay. At the forefront of the budding technology have been Hugh Mason and Charles Arntzen, formerly of Cornell's Boyce Thompson Institute for Plant Biology and now at Arizona State University.

Making the HPV vaccine edible is the latest twist in HPV research at the University that spans more than a decade. In the early 1990s a Rochester team isolated the genetic sequence that creates the protein envelope surrounding the HPV virus. Using that DNA sequence, scientists created virus-like particles, or VLPs, that are not infectious but simply look like viral particles. The team, which included Richard Reichman, M.D., William Bonnez, M.D., and Rose, soon learned that immunization with VLPs could block infection, suggesting the particles might be useful for a vaccine.

They focused on HPV's shape because oftentimes shape or appearance alone is enough to provoke the body's cells to attack, the key to any vaccine. Its distinctive appearance subjects the newcomer to the immune system's ire, much like a fan showing up to a Yankees game in a Boston Red Sox jersey is "greeted" by hometown fans.

Using the VLPs, five years ago the Rochester researchers initiated the first test in humans of a vaccine against HPV. Initial studies showed that the vaccine is safe and provokes an immune response in people. Since then, the researchers led by Rose have been the first to demonstrate in mice an HPV oral vaccine that spurs an immune reaction, and the first to show that an edible vaccine in mice provokes an immune reaction.

The VLP technology was licensed to MedImmune and is now being co-developed with SB Biologicals, a division of GlaxoSmithKline, which is continuing its tests. That vaccine is one of several HPV vaccines under development by companies worldwide. Currently there is no HPV vaccine available; prevention is accomplished mainly by limiting the number of sexual partners and by practicing safe sex.

While pharmaceutical companies continue testing HPV vaccines, researchers at the University have been exploring new methods to make the vaccine more effective and convenient to use. Rose began collaborating with Cornell experts in transgenic plants -- plants that have additional genetic sequences as part of their makeup. The Cornell team inserted into potatoes the DNA that encodes for VLPs; as the plant grows, its leaves and fruit contain VLPs.

Scientists fed the potatoes to mice, testing different combinations of potatoes and other compounds. Mice that ate a small amount of the transgenic potato each week for four weeks, and received a tiny booster of purified VLPs plus some E.coli, had antibodies against HPV.

The thought of using a substance from the intestinal bacteria E.coli as part of an edible vaccine might turn the stomach, but it's a well known and safe "adjuvant" that boosts the effectiveness of vaccines, Rose says. The substance puts the immune system on alert, making the body more likely to mount a powerful immune response when it does find an "invader" like a VLP or HPV. It's not uncommon for scientists to search for an adjuvant to boost the response of an oral vaccine, which is generally weaker than an injection.

While potatoes have been popular among researchers so far, Rose and colleagues have their eyes on bananas. That's because a product that is widely eaten when raw is preferable as part of a vaccine, since proteins are often destroyed by cooking.

"The banana is the goal set by my colleagues, Drs. Charles Arntzen and Hugh Mason, who are now pursuing this work at Arizona State University," says Rose. "The banana is a universally accepted food that is tasty and can be eaten uncooked. The crop could be grown locally in the developing world, where huge numbers of people are at risk for HPV.

"This won't be something where people can just go and pick a banana and eat it and be vaccinated," Rose says. "Any vaccine has to be prepared and administered in a controlled manner. The crop would be grown, evaluated, processed, and prepared into measured doses."

Rose's work to develop needle-free ways to immunize people against HPV has been supported by the National Cancer Institute, which is funding a new effort to make an oral vaccine reliably so it can be tested in people. NCI is funding the work through a program designed to move especially promising technologies along rapidly. Rose's team also recently found that the VLP vaccine may be effective as a skin patch, perhaps offering another needle-free method of vaccinating against cervical cancer.

Doctors estimate that more than 20 million people in the United States alone have HPV. In some age groups, such as sexually active women under age 30, experts believe that as many as 40 percent of women are infected; for unknown reasons, most people never develop symptoms, while others develop genital warts, and some women die from cervical cancer caused by the disease.

The disease causes about 1 million people in the United States to develop genital warts each year; in addition, in the U.S. roughly 13,000 new cases of cervical cancer occur each year, and about 5,000 women die of the disease. Worldwide about half a million cases of cervical cancer occur annually, with about 230,000 deaths; in some developing nations, it's the most common cause of death from cancer among women.

The work was presented last month at the Fifth Annual Conference on Vaccine Research by Rose, who is an assistant professor of Medicine, Microbiology and Immunology, as well as a scientist in the David H. Smith Center for Vaccine Biology and Immunology. Heribert Warzecha of Cornell, John Clements of Tulane, and technician Christopher Lane at the University of Rochester contributed to the effort.