By Justin Gillis
Washington Post Staff Writer
Monday, November 14, 2005
New vaccine technologies are emerging that offer a fresh chance to devise a strategy against smallpox, the most fearsome potential weapon in the bioterror arsenal.
Two companies are reporting rapid progress in developing a new vaccine designed to be safer than the standard one, and a third company, with no government support, is developing yet another new vaccine. That vaccine could offer significant advantages if terrorists were to unleash the smallpox germ in several cities at once, requiring the vaccination of huge numbers of people.
The government stumbled badly in its campaign after Sept. 11, 2001, to vaccinate health care workers who would respond to a smallpox attack. It has since spent millions to fund development of a new, safer vaccine and has already decided to order enough to protect at least 10 million people. It could buy far more if money becomes available.
Progress on safer vaccines is a success for U.S. policymakers, but it also confronts them with vexing new questions about which vaccines to buy, how many doses to buy, whether to resume a failed program to inoculate some people in advance of an attack and how to deploy the vaccines rapidly if smallpox is unleashed by terrorists.
The government is preparing to tackle the strategic questions over the next few months. "Right at the present moment, we're setting up a committee to really look at this with a very hard eye," said D.A. Henderson, a Baltimore doctor who advises the government and who is often called the world's premier expert on smallpox. "There are major changes that have occurred that force us to reexamine what we're going to do."
After the terrorist and anthrax attacks of late 2001, concern about the unrelated smallpox virus reached a fever pitch. Anthrax is deadly, but it does not spread from person to person; smallpox does, and an attack could theoretically kill millions. For a population of nearly 300 million, the country had only 15 million doses of vaccine.
Since then, the government has pulled off a huge feat by stockpiling enough vaccine for every American, but the campaign stalled after President Bush announced a plan to inoculate as many 10.5 million doctors, nurses, police, firefighters and other workers ahead of time so they could respond to an attack.
Many health workers, not fully convinced of the threat and worried about the safety of the standard vaccine, refused inoculation. In the end, only 40,000 health workers were vaccinated. After unexpected heart problems emerged in some vaccine recipients, plans to offer shots to the public were shelved. Early this year, an expert panel excoriated the administration for what it described as poor strategy and communication in devising the smallpox plan.
Now, experts contend, the development of safer vaccines offers a chance to start over, though in some ways the issue of what to do has only grown more complicated. The Department of Health and Human Services acknowledged, for instance, that with no smallpox cases in the world, it can never be certain how the new vaccines would perform in an epidemic. It will have to base its plans on rough information, including animal tests.
"You cannot answer all the questions -- it's not possible," said Noreen A. Hynes, head of an office that helps coordinate development of bioterror countermeasures at HHS.
Smallpox killed hundreds of millions of people in recorded history, more than any other infectious disease. It was eradicated in 1977 after a worldwide campaign that Henderson led. Routine vaccination stopped. But by the late 1990s, doctors realized that their very success against the disease had turned it into a potentially potent weapon.
Studies have suggested that a quarter of the U.S. population has some lingering immunity from childhood smallpox vaccination, but the rest -- 223 million people -- are believed vulnerable. Virtually no one younger than 37 has been vaccinated.
The smallpox virus resides in only two official repositories, in the United States and Russia, but there are fears that some countries kept hidden stocks and that terrorists or rogue states could get their hands on the germ.
The standard vaccine is relatively dangerous compared with most modern vaccines and was killing several babies a year in the United States when vaccination stopped in 1972. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, in Bethesda, called the vaccine "the gold standard" given its track record of eradicating smallpox. "Unfortunately, it's a gold standard that has some significant side effects -- rare but significant," he said.
Some groups are at particular risk of vaccine complications: infants, pregnant women, cancer survivors, AIDS patients, organ-transplant recipients, anyone who has ever had the skin disease eczema and some others. These people would be discouraged from receiving the standard vaccine under most circumstances, and so would anyone living in a household with them -- a large swath of the population. It was this concern that prompted the push for safer vaccines.
All smallpox vaccines contain a weakened virus, called vaccinia virus, that is closely related to smallpox but much less likely to cause illness. The virus in the standard vaccine reproduces in the body, which elicits a powerful immune response that can ward off later smallpox infection, but it does sicken some people, causing a catastrophic brain infection in a few cases. Another, unexpected side effect turned up when the government sought to vaccinate medical personnel in 2003: heart inflammation in adults who had not previously been vaccinated. It is unclear how serious a problem that would be if the vaccine were used widely.
One newer type of vaccine, the one that has been the focus of most publicly funded research, essentially trades potency for safety. This vaccine is known as modified vaccinia Ankara, or MVA. A version was first developed in Germany in the 1970s; it does not reproduce in the body and appears less likely to cause illness in vulnerable people.
But because it is weaker, people need a higher dose and may need two shots several weeks apart for full protection. That could limit the usefulness of the vaccine in an emergency and may constitute an argument for using it ahead of time in some people.
There is also evidence that the side effects of the standard vaccine in healthy people could be ameliorated if they got a shot of MVA a few weeks before a regular inoculation. Potentially, such a strategy could alleviate some safety concerns that prompted many doctors and nurses to refuse smallpox vaccination.
Two companies -- Acambis PLC, with joint headquarters in Cambridge, England, and Cambridge, Mass., and Bavarian Nordic A/S, with headquarters in Kvistgard, Denmark -- have received federal grants to develop MVA, and they are battling each other to supply it to the government. Their vaccines have undergone extensive tests, though full side effects are not known yet.
Health and Human Services has issued bidding documents asking for at least 20 million doses of MVA -- enough for a minimum of 10 million people -- and has said it may eventually buy an additional 60 million doses. The final decision may depend in part on price. The Acambis and Bavarian Nordic proposals are not yet public, but most experts think MVA will cost 10 to 20 times as much as the standard vaccine, which runs about $3 per dose.
Bavarian Nordic, seeking an expanded market, has argued that the government should consider replacing its entire vaccine stockpile with the newer product, a decision that could cost billions of dollars.
"What would the public say if smallpox is released, 20 million people get the safe vaccine, and everyone else gets the unsafe vaccine?" said Paul Chaplin, executive vice president for research at Bavarian Nordic. "Which line would you and your family like to be in?"
The government must consider yet another factor. With no public funds, VaxGen Inc. of Brisbane, Calif., is developing a Japanese vaccine that reproduces in the body, and thus elicits strong immunity with one dose, but appears less likely to cause life-threatening brain infections in children than the standard vaccine.
The company has already completed some human research. "We are generating the data to show the product is intrinsically safe," said Lance K. Gordon, president and chief executive of VaxGen.
VaxGen's product is expected to be far cheaper than MVA and, as a one-dose vaccine, potentially more useful in an emergency. But buying a significant amount would further complicate the strategic issues about how to use the various vaccines.
It is expected to be at least a year or two before significant quantities of new vaccine arrive in federal stockpiles. Experts said that gives the government time to devise a new strategy and to consult with the state health departments and medical personnel that resisted the government's original vaccination plan.
"I think the medical community has to take a serious look at this," said Michael T. Osterholm, head of the Center for Infectious Disease Research and Policy at the University of Minnesota. "Anybody who thinks smallpox is off the table also doesn't think a single jet can bring down a skyscraper."