Next Step in Smallpox Effort: Drug for Vaccine Side Effects

By DONALD G. McNEIL Jr. and LAWRENCE K. ALTMAN

ARIETTA, Ga. — It may not be obvious, but as he reclines in a suburban Atlanta plasma center with a needle in one arm and a fresh smallpox vaccine scar on the other, Michael Kuring is on the front line of the war on terrorism.

"I dare any parent — my kids have not been vaccinated — I dare any parent to look at the consequences of what could happen, and not get involved," said Mr. Kuring, who sees it as his patriotic duty to roll up his sleeve twice a week and let his antibody-rich blood drain through a plasma-extraction machine. "You almost can't not answer the call."

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For this former soldier turned Staples Office Supply account manager, the front is on an obscure but crucial salient of the war.

The Bush administration, which is considering whether to vaccinate millions of Americans against smallpox, cannot go forward until it produces enough antidote to the vaccine's side effects.

Smallpox vaccine — made from vaccinia, a cousin to smallpox that is grown in cows — is among the most dangerous of vaccines. It often produces temporary fevers and sore, swollen arms. In a small but unpredictable number of cases, however, the vaccinia pox itself runs wild and leaves its victims scarred, blinded or sometimes even dead.

The only tested antidote is vaccinia immune globulin, or VIG, but until this month, the nation had only 600 to 700 doses.

That is where people like Mr. Kuring come in: the antidote must be made from the blood of people vaccinated in the last two months, while a flood tide of newly minted antibodies is coursing through their veins.

Until recently, there were only a handful of potential donors.

Routine smallpox vaccinations for children stopped in 1972, and the military stopped in the late 1980's, so the only ones with current vaccinations were laboratory technicians working with the world's remaining stocks of smallpox or related viruses.

Now, after hastily signing up two companies to make more, the government, which may vaccinate up to 500,000 health workers and 500,000 people in the military, is opening up this bottleneck a bit.

By year's end, the government should have about 5,000 doses of VIG in hand.

Theoretically, that would be enough to allow at least 40 million people to be vaccinated.

Making enough to vaccinate all 280 million Americans safely could take two years, based on the most pessimistic estimates of need. But no one knows exactly how much is needed because experts do not know how many bad reactions will occur or how effective efforts will be to screen out the people most likely to have them — pregnant women, people with compromised immune systems, people with a history of eczema or other rashes.

In 1968, two separate studies found one life-threatening reaction per 67,000 vaccinations and one per 20,000. But in 1968, far fewer Americans had immune systems weakened by AIDS, cancer chemotherapy or organ transplants, and eczema was less common.

The military's supplier said it was told to assume one serious reaction per 8,000 vaccinations. Asked about that, Dr. Raymond A. Strikas, an epidemiologist working on smallpox vaccination protocols for the Centers for Disease Control and Prevention, said, "Given the uncertainties here, that may not be a bad estimate."

VIG is no miracle drug. It was invented in the 1950's and never tested in rigorous clinical studies. Case surveys from the 1960's suggest that it can cut deaths from severe vaccination eczema by two-thirds and stop the spread of new sores. But it seemed to have no effect on vaccinia necrosum, in which tissue around the site dies in ever-enlarging circles. The condition, rare in the 1960's, can kill immuno-suppressed people, whose numbers have grown sharply.

VIG also seemed not to help brain inflammation complications.

But the government wants more because "you don't have anything else," said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases.

Dr. Fauci said the government was investigating cidofovir, a drug licensed for use against another virus. But it would be reserved for the most severe cases if VIG failed. Cidofovir is toxic and untested against vaccinia in humans.

The two companies that received rush VIG orders were the DynPort Vaccine Company of Frederick, Md., which has a longstanding contract to supply vaccines for smallpox, botulism, plague, anthrax and tularemia to the military, and the Cangene Corporation of Winnipeg, Canada, which makes antibody products that protect babies with dangerous Rh mismatches, pregnant women exposed to chickenpox and people exposed to anthrax and hepatitis B.

DynPort had a head start, and has not yet needed to recruit donors because it has a large stockpile of frozen plasma from soldiers vaccinated years ago, said Dr. David Smith, DynPort's principal scientist.

The plasma is tested for H.I.V., hepatitis and other pathogens, and is then "fractionated" using a combination of ethanol and salt concentrations to yield a few drops of antibodies, which are proteins.

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DynPort has already produced enough VIG to treat 660 severe reactions, Dr. Smith said. Dr. David Clanton, a DynPort senior scientist, said the company had tested its new antidote on volunteers and found that even a dose five times as great as normal produced "no adverse effects."

Cangene, by contrast, has a bigger contract but a less urgent time frame. It is to produce up to 100,000 doses for the United States civilian population over five years. Lacking a pool of frozen plasma, it is seeking about 10,000 volunteers like Mr. Kuring to be inoculated for smallpox and then bled twice a week for two months. Plasma is spun off their blood and their red cells are returned to them.

The plasma goes to Winnipeg, where Cangene uses a newer chromatography process, pouring it through layers of beads that filter out everything but the antibodies. Other purification steps are added, including solvents that destroy the lipid shells of viruses like H.I.V. or West Nile.

Now that the company has contracts affecting the war on terrorism, it has "big-time security from a Canadian viewpoint," said John Langstaff, Cangene's president. He declined to let any part of his operation be photographed.

To find all those donors, Cangene subcontracts several "specialty plasma" companies. The Serologicals Corporation, a 32-year-old company with headquarters in Norcross, Ga., is the biggest, with 13 clinics in 7 states drawing blood from people "stimulated" with injections to produce antibodies to rabies, hepatitis, mononucleosis or herpes.

So far, it has found 1,300 VIG donors through advertising and word of mouth. All donors must have been vaccinated against smallpox as children, and have the scars as proof. They are screened for all diseases that disqualify blood donors, and for skin problems.

No donors have yet had bad reactions, said Dr. Barbara Slade, medical director of Serologicals.

Each is paid $100 a week, but four donors interviewed in Marietta said money was not a factor. Mr. Kuring, Ralph McKinstry, Albert Casanova, all veterans, and Kathy Eagye, who has a master's degree in public health, said they wanted to help protect others. Ms. Eagye, however, did confess that she so feared a smallpox attack that she volunteered partly to get revaccinated.

Because touching the vaccination site or the bandage can infect someone else with the vaccinia virus, potential donors cannot live with anyone at high risk for complications — anyone pregnant, under 1 year old, with unexplained rashes or with a weakened immune system.

Mr. Kuring, who first became a specialty plasma donor after a friend's child died of an Rh factor reaction, said he was very careful not to let his three children touch his new vaccination site. "For the two weeks till it healed, I let my wife snuggle with them and put them to sleep," he said.

That does not mean that scientists can anticipate every worry.

"I have two dogs, and I love them," Mr. McKinstry said. "I was concerned, so I asked. I was told it shouldn't affect them at all."

Listening to this conversation, Dr. Slade mused: "Hmm, dogs. . . . I never thought about that one. I don't see any reason why they wouldn't be O.K."

The donors are given waterproof bandages and, to change them, must wear latex gloves, bag them and return them to the plasma center.

"Easy," said Mr. Casanova. "It's pretty much a no-brainer to change a bandage."