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http://www.nytimes.com/2002/06/04/health/04VACC.html

Experts Searching for Ways to Fill the Vaccine Gap

By LESLIE BERGER

ithin blocks of Dr. Max Van Gilder's bustling pediatric office near Central Park in Manhattan, patients and their parents can readily find bubble bath from France, chocolates from Belgium and fresh melon from South America. But for months now, Dr. Van Gilder's youngest patients have had to wait for their shots against diseases like measles and diphtheria and to come back to his office once they were available.

"I never know on a given day which vaccines I'm going to be able to give children and which ones I'll run out of and won't be able to get," Dr. Van Gilder said. "It's very frustrating and very time consuming."

At the Southwest Community Health Center in Santa Rosa, Calif., Dr. Panna Lossy has been similarly frustrated by a sporadic supply of vaccines. She also worries about whether her patients' parents, most of them laborers from Mexico, will be able to come back for the delayed inoculations.

Across the country, whether in private practices treating privileged children or public clinics helping the neediest, a shortage of American-made vaccines has been disrupting the normal schedule of inoculations for 8 of the 11 preventable childhood diseases since last year. No outbreaks have been attributed to the inconsistent supplies, and enough vaccine has been available for the crucial first doses.

But experts say the shortages are sobering, underscoring the shrinking number of companies making vaccines and a tangle of legal and financial issues that may be choking supplies.

"We've got a complex system of regulations that have served us well but now may be serving as barriers," said Dr. Louis Z. Cooper, president of the American Academy of Pediatrics. "The system needs significant upgrading."

The General Accounting Office, the investigative arm of Congress, is studying why the shortages happened and how others might be prevented. A report is expected in July. Experts convened by the Centers for Disease Control and Prevention and the National Vaccine Advisory Committee are also preparing recommendations.

Better stockpiles, a national authority to oversee vaccine development and financial incentives for pharmaceutical companies to stay in the market, like tax breaks or higher prices, are among the possible solutions, said Dr. Walter A. Orenstein, director of the C.D.C.'s National Immunization Program.

"This is the worst shortage that I can remember," said Dr. Orenstein, who has been in his field for more than 25 years. In the mid-1980's, he noted, lawsuits alleging neurological damage from the vaccine against diphtheria, tetanus and pertussis, or whooping cough, led to a brief shortage.

This time, no single cause is to blame. The problem has involved three companies and five products, including some longtime staples of preventative medicine: the vaccine against diphtheria, tetanus and pertussis, now known as DTaP; the Td booster shot for tetanus and diphtheria that is given to teenagers and adults; M.M.R. for measles, mumps and rubella; the varicella, or chickenpox, vaccine; and a relatively new vaccine called Prevnar that protects against seven strains of pneumococcal bacteria.

Dr. Lossy and others said they were bracing for complications in school enrollment but so far the problems have been most apparent in day care centers and preschools, whose infants and toddlers are in the heaviest inoculation period.

At the Church of the Covenant Day Care Center in Cleveland, Carolyn Pfeiffer, the director, said she had given 30-day extensions to many families unable to get vaccines on schedule. The shortages have seemed worse recently, and private physicians are referring parents to county clinics, which seem to get supplies faster.

"These are working parents," Ms. Pfeiffer noted. "To get to the doctor, they have to take off work, and when you can't get the shot, you have to turn around and take another day off."

Parents involved in the early childhood program of the Jewish Community Association of Austin are keenly aware of the shortages and seem to be helping one another avoid long delays. "A lot of our parents are doctors and they treat each other," said Bill Carver, the director.

"It's kind of ironic that just when we're getting stricter on enforcement of vaccines and we know how well they're working that we're having a shortage," he said. For now, the C.D.C. has issued a new schedule for inoculations that defers shots to stretch limited supplies. The agency has also recommended that doctors keep lists of patients needing delayed vaccines and call the patients once supplies are available.

Residual immunity probably accounts for the absence of serious problems in the recent shortages, Dr. Cooper said. But as evidence of the thin line against disease, he cited recent outbreaks of measles in Britain, where fears of a link between the M.M.R. vaccine and autism, largely discredited, have caused a drop in inoculations.

"We've never had higher immunization levels or lower numbers of cases of vaccine-preventable diseases, so we've been able to coast on the high levels," Dr. Cooper said. "But we don't have a lot of margin of safety."

In New York, Ned Levinsohn had to bring his son Adam, 6 1/2 months old, back to Dr. Van Gilder's office one extra time for shots of DTaP and Prevnar that were not available on schedule. Adam's six-month checkup then had to be delayed for spacing between doses.

"I was concerned, and then the doctor assured me that as long as he's on schedule now and stays on schedule that he's fine," said Mr. Levinsohn, a copywriter who works from home.

Problems with the supplies began in January 2001 when Wyeth Pharmaceuticals announced plans to stop production of its tetanus and diphtheria vaccines after 50 years. That left two manufacturers, Aventis Pasteur and Glaxo SmithKline for DTaP. Moreover, Aventis was left as the sole maker of the Td booster.

But those vaccines by Aventis needed to be completely reformulated to meet new standards — a joint recommendation in 1999 by the Public Health Service and the American Academy of Pediatrics to avoid using a mercury-containing preservative called thimerosal. (Glaxo SmithKline did not use thimerosal in its DTaP vaccine so the new advisory did not affect its production.)

Yield dropped drastically as Aventis sought clearance from the Food and Drug Administration to switch from the multidose vials containing thimerosal to single-dose vials without it. Production was further delayed because the single-shot vials require more liquid to ensure that a full dose is drawn up into the injection needle.

"The thimerosal notice took effect in the middle of 1999, and we got F.D.A. approval in March 2001, two months after Wyeth discontinued their product," said Len Lavenda, an Aventis spokesman. Aventis is also seeking F.D.A. approval for a DTaP vaccine made by an affiliated Canadian company.

Wyeth's decision to stop making DTaP and the tetanus booster stemmed in part from its development of Prevnar, also known PCV-7, Natalie de Vane, a spokeswoman, said. Introduced in February 2000, Prevnar protects against infections as diverse as earaches and meningitis, and it was immediately popular. But as demand exploded, a disruption in the filling stage slowed production. Wyeth hopes supplies will return to normal by year's end.

Still another pharmaceutical firm, Merck & Company, experienced its own production delays that led to shortages of the M.M.R. and chickenpox vaccines. Merck, the country's sole maker of those vaccines, operates one vaccine-filling plant in West Point, Pa., and twice shut down that site for repairs in August and September.

The first closing lasted about a week and followed a routine F.D.A. inspection. The second closing, for a planned renovation, lasted about a month. Production resumed in late October, a company spokesman said, but supplies are not expected to return to normal until this summer.

Even under ideal circumstances, vaccines are tricky to make and can take almost a year to get from the lab to the doctor's office. Unlike synthetic drugs, they are grown from live organisms — bacteria and viruses — an unpredictable process.

The time it takes to make vaccines, the cost of meeting government standards and the limited number of doses given in a lifetime — compared with the long-term use of many prescription drugs — all contribute to smaller profits for vaccine makers. Over time, the pool of licensed vaccine makers in the United States has dropped to four major companies from more than two dozen in 1967, according to government reports cited by Mr. Lavenda and others.

"It's no secret that the economics of vaccine manufacturing are not as attractive as the economics of pharmaceuticals manufacturing," Mr. Lavenda said.
 

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