Why doesn’t the world’s sole superpower have dependable supplies of all vaccines for its citizens?
At his Atlanta pediatric practice, Philip Weiss, MD, insists on a 100 percent vaccination rate for his patients. He advises parents hesitant about vaccinating their child to find another pediatrician. He has his staff continually order vaccines so that they have a constant supply on hand. And he recently discarded $26,000 of one vaccine because he feared it had been improperly stored.
Weiss isn't heroic when it comes to vaccines; most conscientious pediatricians do the same. But since 1999, Weiss and fellow pediatricians all over the country have not always been able to vaccinate children on their regular schedules. The reason: vaccine shortages. A few months ago, his practice ran out of Prevnar, a vaccine that prevents meningitis, and varicella vaccine, which guards against chickenpox. Children due for the vaccines simply had to wait. Most parents weren’t concerned, Weiss notes. "The vaccines have done such a good job of reducing the diseases" that most people don't consider missing one to be a real risk, he says.
It's a contemporary public health irony: vaccines have been so successful in ridding the United States of killers like smallpox, polio, and measles that society has forgotten how essential they are to staving off infectious diseases. In the last couple of decades, while the public's attention has been focused elsewhere, the U.S. vaccine infrastructure has weakened considerably and has become a dangerously fragile system that cannot always guarantee the adequate, timely supply of standard childhood and flu vaccines.
Hard numbers are difficult to come by, but regulatory agencies, doctors, and public health experts are seeing shortages across the spectrum. The DTaP vaccine, a combination drug that guards against diphtheria, tetanus, and pertussis (whooping cough) in children, has been in short supply since January 2000, and until recently met only about three-quarters of demand, according to the Centers for Disease Control and Prevention (CDC). Influenza vaccines for adults were dangerously scarce during the winters of 2000 and 2001.
There have been recent shortages of three of the most important childhood vaccines: the varicella vaccine; MMR, the combination vaccine to prevent measles, mumps, and rubella; and the pneumococcal conjugate vaccine (PCV), which guards against pneumonia, meningitis, and ear infections. Tetanus vaccine was in such short supply that what had been a routine booster given in a doctor’s office became an after-the-fact prophylactic administered only in emergency rooms. (By late July, the CDC had announced that the DTaP and MMR supplies, which had been experiencing shortages since 1998, were sufficient for physicians to resume normal vaccination schedules. PCV is, however, still in short supply.)
As director of the School’s Center for Immunization Research, Professor Donald Burke, MD, is one of the most persistent voices in the vaccine discussion. Before joining the School in 1997, Burke spent 23 years working on disease control and prevention and vaccine development for the U.S. Army. "Almost all of us who work in public health think access to safe and effective vaccines should be a right in the United States," Burke says. That's why, he says, the current situation is so distressing. According to Burke, of the 23 basic vaccines routinely given in the United States, three have been withdrawn from the market, four have experienced delayed supply, three are manufactured at a capacity that cannot meet possible demand, and seven have a single manufacturer, leaving just six vaccines with multiple manufacturers and a stable supply to meet demand.
The events of last fall have turned public attention toward the need for better vaccine production, specifically to protect against bioterrorism. After five people died and more than a dozen were made ill by anthrax-laced letters sent to politicians and media organizations, there was outcry for stepped-up production of anthrax vaccine for civilian use, which previously had been limited to the military. Officials also feared that smallpox and other deadly viruses could become tools of bioterrorism.
Burke's interest isn't limited to such threats. Like other public health scientists, Burke is concerned about the status of standard vaccines, such as childhood and flu shots; about what he calls "global vaccines," including traveler's immunizations and military-developed vaccines to prevent diseases that are not prevalent in the United States; as well as about the bioterrorism vaccines, such as smallpox and anthrax. For the past five years, Burke has organized and taught in the School's seminar in Vaccine Science and Policy, a yearlong class that educates students about all aspects of the vaccine issue: the science, finances, politics, policy—and history.
Controlling "The Diseases of Man"
In the two centuries since Edward Jenner discovered that inoculating a patient with a small dose of the cowpox virus would provide immunity to the dreaded smallpox virus, vaccines have saved millions of lives around the world and eased endless suffering. Parents in the United States today need no longer fear whooping cough, measles, and polio—childhood diseases that only a generation ago posed a formidable threat. Thanks to vaccinations, most children today have built up immunities to a host of other potential killers. According to the World Health Organization, "nine major diseases of man have been controlled to a greater or lesser extent through the use of vaccines." Burke estimates that the vaccines preventing smallpox, diphtheria, pertussis, measles, tetanus, and hepatitis B save more than 12 million lives a year worldwide.
But in the United States, our reliance on vaccination as the most cost-effective public health measure ever belies the tenuous nature of today's vaccine manufacturing and distribution systems. The current instability is largely due to an ever-decreasing number of major manufacturers. Kathryn Zoon, PhD, director of the branch of the U.S. Food and Drug Administration (FDA) that oversees vaccines, recently told Science magazine that in 1967, the "FDA had licensed vaccines made by 26 different manufacturers. By 1980, the number had fallen to 17. Today it stands at 12, of which only four are large pharmaceutical companies."
Contraction within the vaccine industry is an American phenomenon; in developing countries the industry is expanding. David Webster, president of the Webster Consulting Group and former marketing director for a U.S. division of Aventis, one of the world’s largest drug manufacturers, estimates that Russia has as many as 20 manufacturers of one childhood vaccine.
Why, then, has vaccine production lost its luster for U.S. manufacturers? Don’t current "universal" vaccination efforts guarantee large markets? And doesn’t the government create huge new markets for vaccines it endorses, such as the pneumococcal vaccine now required of all schoolchildren?
The scenario is hardly so straightforward. According to Burke, as they are currently manufactured and marketed, vaccines are subject to conflicting pressures at all stages of their development and distribution. From the outset, Burke notes, vaccines are troublesome. Unlike synthetic drugs, produced the same way every time, vaccines cannot be reduced to a formula because they require the use of biological organisms, viruses, and bacteria. These living things often do not behave as scientists and pharmaceutical companies would like. In 2000, for example, the influenza strain being cultivated for adult flu vaccines grew surprisingly slowly, causing manufacturers to miss deadlines and creating a shortage.
Because vaccines are created from living organisms, and because they are given to presumably healthy people, for whom any side effect is generally viewed as unacceptable, the FDA closely regulates their production—more strictly than it does other drugs, according to an FDA spokesperson. Due to these factors and others, pharmaceutical companies must build unique facilities to produce vaccines; Burke puts the typical start-up cost for manufacturing a vaccine—"including building a plant, perfecting manufacturing techniques, and training employees"—at $300 million to $400 million.
What's more, manufacturers must regularly upgrade their vaccine facilities to meet FDA requirements. The 2000 influenza vaccine shortage may have been exacerbated by the FDA's citing of two of the four vaccine manufacturers for quality-control violations; one company soon eliminated its flu vaccine program.
Indeed, a mere blip in production can cause serious vaccine shortages. In 1999, for example, the CDC required manufacturers to stop their use of thimerosal, a mercury-based antibacterial compound used as a preservative in childhood vaccines. According to the CDC's Curtis Allan, the request caused problems on the production line, where a change from the 10-dose vial possible with thimerosal to the one-dose vial necessary in the absence of a preservative meant a "lesser yield of the vaccine"—and contributed to that year's shortage of DTaP.
The FDA has also increased the number of clinical trials necessary for a vaccine to win approval; the hepatitis B vaccine won approval in 1986 after tests on just 549 patients. Today one pharmaceutical company has tested its influenza vaccine on 24,000 patients and still hasn’t received FDA approval.
The FDA defends its demands for more clinical trials by pointing to the unique nature of vaccines and the possibility of "vaccine-adverse events," which can range from fever and skin rash to shock and convulsions, and even death, as in the case of the rotavirus vaccine, which was blamed for deadly bowel obstructions in infants in 1999. An FDA spokesperson says, "The FDA has found it increasingly important to have sound science. You need to have scientific data to show efficacy and safety. In order to do that, you have to do clinical trials. They take a long time, they're expensive, but [pharmaceutical companies] need to assure us and assure the public" that each individual vaccine is safe and effective.
Despite such rigorous testing, vaccines still carry risks, and the consequences of those risks can cripple a manufacturer. In 1986, lawsuits against manufacturers of DTP (a precursor to the DTaP vaccine) reached an all-time high, and Congress passed the National Childhood Vaccine Injury Act of 1986, establishing the National Vaccine Injury Compensation Program. The program operates as a "no-fault" insurer, compensating those purportedly injured by childhood vaccines, without involving pharmaceutical companies in litigation. But that legislation only protects the manufacturers of childhood vaccines; companies producing adult vaccines still risk potentially costly injury claims.Once a vaccine is manufactured, it hardly rewards the pharmaceutical company for the effort: Vaccines are dramatically less profitable than other drugs. In March, Science reported that GlaxoSmithKline, the world’s largest vaccine manufacturer, enjoyed worldwide vaccine sales of $4.3 billion. Contrast that figure with the profits of one drug, the cholesterol-lowering Lipitor, which grosses $6 billion a year. According to IMS Health, a pharmaceutical intelligence service, vaccines comprise only 1 to 2 percent of global pharmaceutical sales.
Vaccine experts blame the low profit margins on a number of factors. For starters, the American public has come to see vaccines as something of an entitlement. Notes Neal Halsey, MD, director of the School's Institute for Vaccine Safety and professor in International Health, "We have the psychology that vaccines are very cheap." As a society, he says, we don't want to pay a fair price for prevention unless we detect a direct threat. Most diseases currently vaccinated against—the annual winter flu or childhood diseases such as measles, mumps, and rubella—either seem old-fashioned and unlikely to occur on an epidemic level, or strike the public as inconveniences that are easily survived.
Many critics within industry, however, lay the biggest share of blame at the feet of the U.S. government, which is America’s primary purchaser of vaccines—the result of Congress’s 1993 creation of the Vaccines for Children program. Under this program, which was established to improve vaccination rates among the poor, the government purchases more than half of the childhood vaccines used in the United States. Such purchasing capacity gives the federal government extraordinary negotiating power over price. The government asks for—and gets—deep discounts on many vaccines. Vaccine makers and their lobbyists argue that governmental price caps act as a big disincentive to producing vaccines that historically have been high-volume, low-profit items anyway. (Unlike antidepressants or cholesterol-lowering medicines, which are taken for years and have an ever-expanding target population, vaccines are administered on a rigid schedule and for only a limited number of doses.) Consider: In 1987, the CDC paid about $11 for a dose of MMR; today the price is only $15.50.
On a global level, the World Health Organization (WHO) operates in much the same way as the federal government does within the United States. According to Phil Russell, MD, senior advisor in the Office of Public Health Preparedness at HHS and a professor emeritus in the School's Department of International Health, the WHO's dual roles as regulator and customer wreak havoc with the vaccine market. "They want to vaccinate the most children possible and get the most vaccines at the cheapest price. They dominate the vaccine field and purchasing policy," Russell says. "All of it comes down to a necessity to fully understand the economics of the issue and understand the responsibility of the dominant purchasers."
To be fair, the price caps negotiated by the U.S. government have applied to existing vaccines only (such as MMR and DTaP), not to newer vaccines (like the chickenpox vaccine) still under patent. Manufacturers of the diphtheria-tetanus vaccine, for instance, can expect to be paid only 15 cents a dose by the federal government, whereas the new pneumococcal vaccine goes for $58.75, according to the March 15 issue of Science.
But at least one pharmaceutical company says that profit has never been the sole motivation for manufacturing vaccines. "A lot of companies have gotten out of the business of making vaccines, but Merck has been in the vaccine business for 100 years, going back to smallpox," says Joyce Buford, public affairs director for Merck's vaccine division. "We have a public health commitment to disease prevention. It's important that companies make the vaccines that they have the expertise to make."
Fixing a Fragile System
Given complications at every stage of the development process, the fragility of the vaccine system won't likely respond to a single solution. Still, experts are nearly unanimous on the need to sweeten the economic incentive for producing vaccines.
"It's quite clear that federal policy has to change from the intent of buying most vaccines at a discount to paying a fair value, fair price. We need to create an incentive for industry, not just price but assurance of market share," the HHS' Russell says. "We have to come back to some basic understanding of how valuable vaccines are to us, and how we translate that knowledge of value into a market."
Burke imagines that the federal government may need to take a greater role in the business of vaccines, from the NIH and the military contributing more to research and development to greater financial support for vaccine production. He says that one proposed solution would be "construction of government-owned facilities, which would be turned over to industry so that upfront investment on the part of industry wouldn’t be so great."
Burke says regulations may need to change as well. In terms of the development process, he says animal testing could be used when human testing is not feasible, and he believes that it may take legislation to get pharmaceutical companies to look past the liability issues inherent in creating new vaccines that will reach such a wide audience.
Burke also advocates changes in who watches over the vaccine system. "There is no central point of responsibility except at the presidential level," he notes. "Authority is distributed across HHS, National Institutes of Health, committees that report to the secretary of HHS, and the Centers for Disease Control, while others also involve the Department of Defense. We need to establish authority and accountability. We need a mechanism to ensure national vaccine accountability."
Ultimately, though, Burke stresses that there is no single "fix" to the current vaccine shortages. When the CDC recently announced that by the end of the year it expects to have enough doses of smallpox vaccine for every American, it was a quick answer for a top priority in bioterrorism preparedness. It was not, however, the comprehensive answer needed for the chronic vaccine shortages. Long-term solutions for fixing the nation’s vaccine infrastructure will require the public and the U.S. government to muster a similar sense of urgency.
"Nobody bitched about the price we’re paying for smallpox vaccine. Whatever we need, we’ll pay," Russell says. "We know how valuable fighter aircraft are to our defense and we pay the cost for them. If we want the next generation of anthrax vaccine, we're going to have to pay a reasonable price for it. We have to address the whole economic basis and figure out how valuable vaccines are to our society."