Our last posting told how the flu vaccine came to be produced in chicken eggs (1). In short, in 1931, at a time when virologists were still searching for fruitful means to cultivate viruses outside of a live laboratory animal, Ernest Goodpasture and Alice Woodruff developed a procedure to grow fowlpox virus in fertile (embryonated) chicken eggs. Soon afterwards, their egg-based virus cultivation method was applied to generate vaccines against smallpox and yellow fever. Then, in 1941, Thomas Francis used fertile chicken eggs to produce the first influenza vaccine.
Remarkably, even today, in the era of recombinant DNA and proteomics, this seemingly quaint procedure is still the preferred means for producing the standard trivalent flu vaccine. Yet, this tried and true method is not without its pitfalls.
Circumstances involving the egg-based method led to a severe flu vaccine shortage in the United States during the winter of 2004/2005. American officials were initially alerted to the coming shortfall in early October 2004, when the Chiron Corporation of Emoryville, CA, announced that its influenza vaccine, which was manufactured in its factory in Liverpool, U.K., would not be available in the United States for the approaching 2004/2005 influenza season. British regulators suspended Chiron’s license for three months because its Liverpool factory had not used appropriate vaccine production procedures, resulting in some of its 50,000,000 vaccine doses being contaminated with Serratia marcescens; a bacterium that can be dangerous, especially if injected into a frail or elderly person.
Before the crisis at Chiron, the United States was expecting to obtain about one-half of its 100,000,000 doses of influenza vaccine from that company, with the rest coming from the Pennsylvania plant of the French company, Aventis Pasteur. Thus, the projected supply of vaccine in the United States would be reduced by about half.
As the shortfall materialized, federal and state health officials tried to distribute the limited number of vaccine doses to individuals most at risk, such as the elderly and those with compromised immune systems. Nevertheless, there were incidents in which crowds of elderly and infirm people waited for hours at clinics and health centers for the vaccine, only to learn that there was none to be had. One New York City clinic actually called in the police to stop a riot by mostly elderly people. Even the Memorial Sloan-Kettering Cancer Center, which is one America’s leading cancer facilities, with many desperately ill and elderly patients, did not have flu vaccine. And thousands of callers to New York City’s flu line, or to 911, could not get through or were told that the vaccine was in extremely short supply. In Connecticut, there were reports of vaccine sellers engaging in price gouging.
What happened at Chiron was as follows. The company bought its aging Liverpool factory in 2003 because it saw a good business opportunity when two American vaccine producers announced they were dropping out of the vaccine business. But signs that there might be trouble at Chiron’s Liverpool operation surfaced in June 2003, when an inspection by the U.S. Food and Drug Administration (FDA) discovered bacterial contamination in early production stages of the 2003/2004 vaccine, although not in the final product after sterilization. The FDA was satisfied with Chiron’s efforts to solve the problem and, believing that the trouble had been resolved, it let the Liverpool plant continue to operate.
Then, in August 2004, with production of the 2004/2005 flu vaccine underway, the company announced that its own routine testing revealed bacterial contamination in actual lots of the vaccine. Chiron attempted to get to the bottom of the issue, while keeping the FDA abreast of its progress via weekly conference calls. Chiron then assured the FDA that the contamination was limited only to the first lots of the vaccine and that it expected to begin shipping to the USA within a month’s time.
However, the final blow to Chiron’s efforts came on October 5, when British regulators visited the factory and determined that it was not operating according to regulations that assure good manufacturing practice. The British suspended Chiron’s license and announced that Chiron’s flu vaccine was contaminated with Serratia marcescens. Chiron’s California headquarters received news of the debacle at 3 a.m. the next morning and immediately called American officials in Washington, who were stunned by the news.
Why was it not possible to rectify the situation in time for the 2004/2005 winter flu season? First, each year’s supply of the egg-based flu vaccine is mass-produced in millions of hen’s eggs. In fact, Chiron used 100,000 eggs per day at the peak of production. Moreover, these eggs have to be ordered months in advance. Thus, it is virtually impossible to suddenly come up with a fresh supply if something should go awry.
Additionally, because influenza virus strains undergo antigenic changes from one year to the next, the vaccine needs to be reformulated each and every year. Consequently, and importantly, unlike vaccines against other viruses, the flu vaccine cannot be stockpiled for use in later years. Any doses left over from any year necessarily go to waste.
Because of the above, and because demand for the flu vaccine varies somewhat unpredictably from year to year, manufacturing the flu vaccine poses particular economic risks to producers. Indeed, a spokesperson for Wyeth said that his company terminated production of its FluShield vaccine in 2002 because it was able to sell only half of the 20 million doses that it manufactured every year, forcing it to throw out the remaining 10 million doses. And, the company would have been required to make a huge investment to upgrade its facilities to meet new federal regulations. Since Wyeth expected little if any profits from manufacturing its flu vaccine, it chose to give up that undertaking.
A spokesman for the FDA responded to Wyeth’s dilemma, saying that if companies could not measure up to its standards, or chose not to, it might be better for them to pull out of the vaccine business. While the FDA’s position seems somewhat unsympathetic to the concerns of the manufacturer, it remains the case that safety must not be compromised.
On the other hand, a main factor that led to the vaccine shortfall of 2004/2005 was that the United States had put all its eggs in only two metaphorical baskets; Chiron and Aventis Pasteur. If there had been more vaccine producers, then the vaccine supply would not have been as susceptible to disruption when one producer could not meet demand.
Some public health experts claimed that government policies actually discouraged companies from developing and producing vaccines. They argued that low profits to vaccine producers, and their exposure to legal liabilities, brought on a situation in which there were literally only a handful of companies engaged in vaccine production. A 2004 report the by the U.S. National Academy of Sciences noted that as recently as the 1970s, twenty-five companies made vaccines for the United States, whereas in 2004 there were only five.
Another factor leading to the crisis of 2004 was that Chiron, and other U.S. vaccine manufacturers, began to move their operations to lower-cost locations overseas, in order to maintain a profit margin. This made it considerably more difficult for the FDA to carry out rigorous inspections of facilities. As noted above, the FDA relied on assurances from Chiron that it was adequately addressing safety issues at its Liverpool plant. But, it was the first-hand inspection by British regulators that later caught Chiron.
Some public health experts called for the government to step in and play a significantly greater role in ensuring vaccine production, rather than relying on the pharmaceutical companies and the free market. Suggestions included having the government subsidize vaccine manufacturers, or guarantee to purchase a fixed number of vaccine doses, irrespective of whether they are used, and perhaps put in place a policy that might protect vaccine producers from legal liability if they have fulfilled all of the accepted standards for vaccine testing and production.
In an earlier posting, I discussed the factors that might influence public response to particular virus outbreaks and epidemics (2). It is interesting to consider the course of public reaction to the 2004 flu vaccine shortage from that perspective. At first, when there were insufficient doses of the flu vaccine to go around, there was widespread panic, even rioting. Then, as a relatively few extra units of vaccine began to trickle in from other sources, demand for the vaccine dramatically decreased. Indeed, there actually was a surplus!
Whereas only two companies made flu vaccines for the U.S. market in 2004, now there are seven. In addition, more varieties of flu vaccine are now available; special formulations for the elderly, for people allergic to eggs, vaccines that protect against four strains of flu instead of three, and a vaccine administered as a nasal spray. Nonetheless, all of these options are still produced in chicken eggs. However, some companies are now turning to other technologies. For instance, Novartis’ Flucelvax is produced in cultured dog cells. Importantly, Novartis’ methodology is supposed to enable the company to respond to an emerging pandemic in weeks, rather than months. Other companies are exploring using genetic material. Yet, most of the U.S. flu vaccine supply is still grown in chicken eggs, and much of that is made in other countries, leaving the FDA with less control over quality and supply.
For a time in 2009 it appeared that demand for flu vaccine would once again vastly exceed supply. In that instance, increased demand was triggered by fears of an impending swine flu pandemic, which ultimately proved to be much less severe than originally feared. Reminiscent of the recent 24-hour cable news coverage of the 2014 West African Ebola outbreak (2), nonstop TV updates of new swine flu cases in 2009 created the false impression that a killer pandemic was sweeping through the country.
1. Ernest Goodpasture and the Egg in the Flu Vaccine, posted on the blog November 25, 2014.
2. The American Public’s Response to the 2014 West African Ebola Outbreak, posted on the blog August 11, 2014