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Vanderbilt receives $20 million to develop new vaccines for rotavirus, RSV and more.

By Paul Govern
January 2011

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When Edward Jenner developed the smallpox vaccine and invented vaccination late in the 18th century, he had no way of understanding the underlying biological mechanisms. It was more a matter of, how about we give you a little cowpox and see if that makes you resistant to the much more virulent smallpox.

Even today, vaccine development tends to be more experimental, less rational than other drug development.

“You don’t have to understand much at the beginning. An interesting little secret in the vaccine world is that for a vast majority of vaccines we don’t really know exactly how they work. We don’t need to know. We only know that they somehow mimic mechanisms of protection that work normally,” said James Crowe Jr., M.D., director of the newly launched Vanderbilt Vaccine Center.

Vaccines deliver medical intelligence into the body, instructing the immune system about how to recognize and prepare defenses against attempted colonization by enemy invaders, usually a virus or bacterium. Typical vaccines introduce a weakened form of a pathogen or an inactivated partial pathogen, easy targets designed in most cases to spur production of protective blood proteins called antibodies.

The immune system remembers the target as alien and if actual infection should later occur, the patient is prepared with both an early warning system and a ready means of defense.

Antibodies may break up or otherwise inactivate pathogens themselves or they may simply tag pathogens for destruction by other components of the immune system. Strictly speaking, antibodies attack antigens, that is, some unique feature — a protein, a sugar, a lipid — that conveniently marks out a microbe as alien.

“I think I’m into antibodies the way some collectors are into orchids,” said Crowe, professor of Pediatrics, Cancer Research, and Microbiology and Immunology.

James Crowe's passion is deeply rooted in his experiences on medical missions in Africa, where he saw firsthand the devastation infectious diseases can cause.  Photo by Susan Urmy.

James Crowe's passion is deeply rooted in his experiences on medical missions in Africa, where he saw firsthand the devastation infectious diseases can cause. Photo by Susan Urmy.

Unlike most proteins, antibodies are made not from single genes but from three or four genes working in concert, genes that have the rare distinction of being permitted to mutate rapidly, allowing huge diversity of gene products. A single antigen usually meets with hundreds of different single-purpose antibodies.

“You could invent a wholly new substance and the immune system would make antibodies for it,” Crowe said.

Vaccine development begins by questioning what works naturally, what protects an animal or human from disease. It’s about mimicry.

“That’s really the theme in all vaccine development: what part of the immune system protects, and then how do you mimic the way an infection induces that? If you delete part of an animal’s immune system and the infection is still prevented or cleared, that missing part isn’t essential, but if infection proceeds, it suggests the deleted part is very important,” Crowe said. “Then we can go in depth, trying to figure out, for example, which antibody is protecting. And with those antibodies in our hand in the lab we can ask how they work. That’s when the intellectual fun part occurs — we know they work, but how do they work?”

Sometime there’s no immunity to emulate. “Things like HIV stump us because there is no effective immunity after natural infection to mimic,” Crowe said.

Creating New Vaccines
With more than $20 million of currently committed research funding, Crowe’s new center brings together all vaccine-related activity and signals a new emphasis on creating new vaccines at Vanderbilt University Medical Center. The center has an important institutional partner in Buenos Aires, the INFANT Foundation, headed by Vanderbilt faculty member Fernando Polack, M.D. Researchers at the center are studying the diarrhea-causing rotavirus and viruses that cause dengue fever, and they’ve also begun dreaming of a universal, one-time vaccine for influenza.

Crowe is well along in developing a new vaccine for respiratory syncytial virus (RSV), an endemic early childhood infection that figures as the leading single cause of pediatric hospitalization, sending 2 percent to 3 percent of children to the hospital at least once with bronchiolitis.

A surface protein called the F protein is the crucial antigen in RSV. Crowe and colleagues have taken the gene that encodes this protein and inserted it in the Venezuelan equine encephalitis virus, or rather in a version of the virus that’s been stripped of a number of its genes (by colleagues at the University of North Carolina), rendering it harmless but leaving intact its ability to move from cell to cell. The harmless zombified virus provides transport for the RSV antigen, and all indications are that this will induce resistance to human RSV.

Crowe hopes to begin human testing within a year, but it can take 25 years to complete a new vaccine. Once you have a new vaccine that works in animals, you purify the substance and pay around $1 million to any one of a number of outfits that are in the business of checking new vaccines thoroughly for germs, toxins and cancer-causing activity. Then come multiple phases of mandated human testing: an initial placebo-controlled safety test in a score of healthy adults, followed by a safety and efficacy test in about 500 people (more precise dosages get set at this stage), followed by a more definitive efficacy test in 50,000 to 70,000 people. Provided you’re dealing with a reasonably common infectious disease, with a test group this large you learn quickly how well a vaccine works. After licensing and implementation, regulators may ask the drug maker to follow reports of adverse events, amounting to an extra stage of safety testing. Meanwhile, the Centers for Disease Control and Prevention (CDC) routinely gathers and analyzes vaccine adverse event reports and supports vaccine safety research.

Microbiologists and immunologists want to know fundamentally how things work, and tend to consider vaccines too applied of a discipline. Even those who do choose to develop vaccines can become “enamored with complexity and with new tools, and get bogged down in that complexity,” Crowe said. “But the point is we just need to find something that works against disease. I think a lot of people have forgotten the end goal.”

In it for the Right Reasons
Lack of commercial interest amounts to another damper on vaccine development. As Crowe notes, vaccines are by far the most successful, most life-saving medical interventions ever devised, providing more benefit than all the world’s hospitals and all other drugs combined. But there was a period not long ago when the entire world vaccine market fetched less revenue than the stomach antacid Tagamet. “If you’re a drug company, would you rather sell a one-time vaccine or something that people have to take every day? This isn’t a great financial area. People don’t do it for the money.”

Crowe does see a funding bright spot: the Gates Foundation’s emphasis on the developing world is encouraging vaccine development for diseases like TB, malaria and HIV. Meanwhile, people in the rich world have become “weird about the cost of vaccine. These vaccines are cheap, typically $50 to $80 for life-long protection, yet people balk. It’s patently ridiculous. If a vaccine prevents me from being in an iron lung or dying, and it’s $50, who wouldn’t use it?”

In the clinic, once risks and benefits are explained, “most people are reasonable about vaccines,” Crowe said, “but there’s been increasing public visibility of the anti-vaccine movement. I have run into a number of people who are just fundamentally against vaccines without a rational reason for this position. I’ve personally not been effective in talking to them.”

After a 1998 paper in The Lancet suggested a link between the MMR vaccine and autism, pediatricians in England and elsewhere saw refusal of the vaccine shoot up. The media picked up the story and the resulting controversy left many doctors around the world unsure about the safety of the vaccine. A lot of ink has been spilled over this controversy. MMR coverage in England fell from 92 percent in 1995–1996 to 80 percent in 2003–2004. Fortunately, since 2005, vaccination rates have been recovering in that country. No link between the MMR vaccine and autism has turned up in the numerous studies touched off by the Lancet paper. It eventually came out that the original paper’s lead author, gastroenterologist Andrew Wakefield, was at the time developing a competitor vaccine. The Lancet published a partial retraction in 2004, followed by a complete retraction in February 2010.

Building Trust
Among parents who refuse vaccine for their children, vaccine safety concerns tend to be matched with comparatively low concern about the dangers of vaccine-preventable illness. So say the authors of a May 9, 2009, article in the New England Journal of Medicine, “Vaccine refusal, mandatory immunization, and the risks of vaccine-preventable diseases.” Some statistics from the article: in the U.S. between 1991 and 2004, the mean state-level rate of nonmedical exemptions for vaccination increased from 0.98 to 1.48 percent; based on nationwide surveillance (1985 through 1992), children with exemptions were 35 times as likely to contract measles as nonexempt children; non-medical exemption rates are often geographically clustered, and in one state (Michigan) the odds ratio for the likelihood that a census tract included in a pertussis cluster would also be included in an exemptions cluster was 2.7.

“Vaccines are one of our most important medical advances. Prevention is much preferable to treatment of infectious diseases. But if the public fails to be immunized the diseases of the past can come back again,” said Kathryn Edwards, M.D., professor of Pediatrics and a principal investigator with the Vanderbilt Vaccine Research Program (VVRP). The VVRP evaluates new vaccines, mounts safety studies of recommended vaccines and serves as one of six sites in the Center for Immunization Safety Assessment Network, funded by the CDC to assess reports of suspected adverse patient reactions to vaccine. (Providers can call the VVRP at (615) 322-8792 to submit reports.)

Kathryn Edwards, M.D., stresses the need to improve communication to establish trust in vaccines. Photo by Susan Urmy.

Kathryn Edwards, M.D., stresses the need to improve communication to establish trust in vaccines. Photo by Susan Urmy.

“In trying to inform the public regarding the vaccine safety debate, it’s important that we not simply hold to the line that vaccines never cause adverse events, because sometimes they do,” Edwards said. “We need to improve our methods of communication with parents. We need to arm them with the facts about vaccine. We need to tell them what reactions can be seen with vaccines and how we might reduce them. We need to train young investigators who are interested in assessing and communicating the safety of vaccine.”

Elizabeth Williams, M.D., one of the young investigators working with Edwards, is designing materials that pediatricians can use to aid discussion of vaccine safety with parents.

“One of the real challenges of vaccines is trust in them, the safety aspect,” Edwards said. “No matter how exciting and scientific and sexy a new vaccine is, if people are afraid of it, no one is going to get it.”

It was in association with compulsory vaccination that the term “conscientious objector” first entered the law (in late 19th century England). Today the Amish and some other communities in Tennessee choose not to immunize. Pediatricians at Vanderbilt periodically see a child with meningitis “who gets brain damaged because he didn’t get the vaccine,” Crowe said.

“It only takes a small community for bad things to happen. If a high school falls below 95 percent immunity to measles, at some point there will be a measles case. These germs find unvaccinated people.”

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