We live in fear of a potentially devastating release of the virus by terrorists because our current smallpox vaccine, though very effective in providing immunity, relies on using the live vaccinia (once called "cowpox") virus that is itself deadly dangerous to small percentage of the people that would be vaccinated. Though mass vaccination would make us safe from this greatest of all bioterrors, the risks and the real cost in human lives has kept us from taking this step.
Arizona State University virologist Bertram Jacobs thinks he may have a way to end the worry. Jacobs has received a $5.5 million, five-year grant from the National Institutes of Health's Biodefense Partnership program to develop and test a modified smallpox vaccine that is expected to be identical in effectiveness to the current vaccine while being "treatable" for dangerous reactions.
Jacobs' partners in the grant are Dr. Jeffrey Jacobson at New York's Beth Israel Hospital and NYU; Dr. Alfred Prince, Dr. Mohamed Tarek Shata and Linda Andrus at the New York Blood Center; and Virax Holdings Limited, an Australian biomedical corporation. ASU will develop the modified vaccinia virus and do preliminary animal testing; Virax will create a clinical-grade vaccine from ASU stocks; the New York Blood Center and Beth Israel Hospital will do further animal testing and then human clinical trials.
The project aims to sidestep a problem that has prevented weaker, less dangerous vaccinia strains from being used as smallpox vaccines: they can not be tested for effectiveness because smallpox no longer exists in human populations and exposing humans to it for testing is too dangerous and morally unacceptable.
"The problem with making a safer vaccine is that you have to prove that it works, and you can't do that, because smallpox isn't out there anymore to use a vaccine against," Jacobs said. "What we're talking about is a vaccine that, when you don't treat it, is identical to the vaccine that we know works. All we've added is the capability of treating it."
Working with a strain that is known to be highly effective against smallpox, Jacobs' team aims to add genes to the virus that will give it a hidden weakness: susceptibility to a common, widely tolerated antibiotic or anti-viral drug. The modifications will not change the virus's effectiveness in immunizing against smallpox, but will give doctors a sure and effective way to treat it in rare cases where it causes serious illness.
"The current vaccine works, we know that, but some people come down with complications, and when they do, there's not much you can do to treat them," Jacobs explained.
"We know enough about the molecular biology of vaccinia virus that we think we can create a 'backdoor' to the virus - make it sensitive to some very common drug so that if someone comes up with a complication, you can treat it. It's a way of putting a leash on a virus that is really useful but can sometimes get out of control," he said.
Among the drugs that the team is examining as a potential vaccinia "leash" are tetracycline, a commonly used antibiotic, and acyclovir, a widely tolerated drug used to control the herpes simplex virus.
"If we can engineer the virus to be sensitive to one of these drugs, we can treat with a drug that is currently taken every day by millions of people with virtually no complications," Jacobs noted.
A long-time vaccinia researcher, Jacobs is enthusiastic about the project because he believes it represents the best opportunity for a vaccine that will be acceptable for non-crisis use in large populations. If all goes well, the grant calls for the vaccine to be through clinical trials and ready for government approval in five years, thus effectively ending the danger of smallpox being used as a weapon of bioterror.
Jacobs points out that the research may also be important for other medical research involving live viruses, including gene therapy and the use of viruses in combating bacterial infections.
"This is a way of putting a leash on a virus, and it provides a solution to a big problem in viral research," he said. "For example, we're very interested in trying to treat cancer patients with vaccinia virus - using the virus to kill cancer cells. It would be really nice to have a leash on it, so that if something goes wrong we can treat the virus infection.
"I think it will be much easier to get treatments like this in clinical trials if we have a treatable strain of virus."
Source: Bertram Jacobs, 480-965- 4684.