A Vexing Fact about Vaccines

By David Shook Confronted by mounting anthrax scares in Washington and New York, the federal government is moving to ramp up production of vaccines to protect Americans from germ warfare. But will the anthrax vaccine really be effective? Will some recipients experience negative side effects? Truth is, nobody can be really sure. And the same problem exists for vaccines targeting smallpox, the plague, and other biological terrors.

In the late 1940s and early '50s, military scientists conducted what appears to be the only U.S. test of the anthrax vaccine's effectiveness in humans. The results were sketchy. Scientists inoculated workers in four Northeast textile mills -- where exposure to goat hair, a common carrier of anthrax, was routine. The tests used the anthrax vaccine still stockpiled today, and a total of 26 anthrax cases were reported during the study, including three infections in people who had been inoculated.

DR. JENNER'S ADVANTAGE. The postwar trial hints at some of the challenges in producing vaccines for public use against biological weapons. Anthrax hasn't been a real public-health problem for 50 years. These days, finding groups of people at high risk of anthrax infection is impossible. Improvements in protecting textile workers from animal bacteria have rendered anthrax a minuscule threat. At the same time, no one is sure what new or refined strains of anthrax, small pox, and other biological weapons have been developed.

Medical researchers face a tough scientific dilemma. Ethically, it isn't an option to immunize people and then infect them with anthrax to test the vaccine's effectiveness. So it may never be clear whether the vaccine really does the job unless there's a major attack on people already vaccinated.

It was much easier for Edward Jenner, who observed that exposure to the common cowpox virus prevented smallpox and who proved his theory in England in 1797 by repeatedly injecting the smallpox virus into the arm of his gardener, Joseph Merret. The servant "received no injury from exposure to the contagion," Jenner recorded in his medical paper on the vaccine.

ADVERSE REACTIONS. These days, as a microbiologist who works at a major U.S. university and has studied anthrax bluntly puts it: "How do you know the anthrax vaccine really works? Nobody can answer that at this point."

It's also unclear whether the vaccine would pass muster with the U.S. Food & Drug Administration and the Centers for Disease Control if produced on a massive scale for public use. Only military personnel have received the vaccine, and of those, more than 40% of recipients reported adverse reactions.

This month's anthrax attacks could kick off a new paradigm in vaccine development (see BW Online, 10/18/01, "Vaccines Are Our Best Shot"). But keep in mind that the FDA has never approved a drug or vaccine based solely on its effectiveness in animals and test tubes. Yet that's exactly the dilemma public-health officials now face with the smallpox vaccine, which has not been used since the world eradicated the virus 25 years ago.

MODERN METHODS. "There's no smallpox left in nature, and there won't be unless somebody introduces it again," says Dr. Lance Gordon, CEO of Vaxgen and the inventor of a vaccine for infant bacterial meningitis. So it will be impossible to do the classic vaccine test on high-risk groups, he says. "You're certainly not going to start challenging people with the disease to see if the vaccine still works."

Gordon is the former CEO of Acambis, the British company holding the federal government's only contract to manufacture smallpox vaccine. The new vaccine will be based on the same vaccinia virus strain that was used in the U.S. for routine immunization against smallpox prior to the global eradication of the disease in the '70s. Acambis, which declined to comment, will harvest vaccinia from large-scale cell cultures, using modern methods for making live-viral vaccines. The company also will be responsible for full clinical testing, which will have to be licensed by the FDA for prevention of infection -- probably within two to three years.

With anthrax, Gordon says, it may be possible to test vaccinated volunteers with the less-lethal cutaneous form of the bacteria to check for immunity. But even such a lower-risk test would be controversial. And the results might be compromised if the volunteers are given antibiotics as a safety net. If the volunteers fail to develop symptoms, it may be impossible to tell with any degree of certainty if it was defeated by the vaccine or the antibiotics.

SCARCE EVIDENCE. Gordon's company, Vaxgen, offers a good example of how vaccines for more common diseases are being developed today. Vaxgen is developing an AIDS vaccine that scientists can test on high-risk groups in Third World countries, where AIDS is pandemic. Over time, researchers can draw scientifically valid conclusions about how well the vaccine is protecting people.

"Generally, you can correlate a higher count of antibodies or T-cells in the body with lower incidences of infection," says Dr. Sharon Seiler, a biotech analyst for Punk, Ziegal, & Co. "The higher counts indicate a positive immune response to the vaccine."

But that type of evidence is impossible to gather for anthrax, plague, smallpox, and a host of other biological agents that don't have updated vaccines. "Typically, the first step is to treat and look for the body to mount an immune response based on the treatment, but that may not be possible [with anthrax]," warns Dr. Stuart Levy, CEO of Paratek Pharmaceuticals, a Boston company developing new anti-infective medicines.

"A PRIORITY." Because of this unknown factor for some vaccines, the FDA is weighing the possibility of approving new protective treatments for bioterrorism based solely on animal tests -- a move it has been pondering since 1999. The possibility of a change in policy can be expected to get a boost in the wake of the anthrax attacks. Says an FDA spokeswoman: "I'm certain it's a priority now."

This is a brave, new world for science and for public-health officials. Any vaccine produced on a mass scale for public use may never be proven 100% effective until an actual attack. And inoculations could result in negative reactions. But if nothing else, the knowledge that vaccines are available might provide some peace of mind to an anxious nation. Shook covers biotechnology for BW Online