Thanks, Chiron!

November 2004

Thanks, Chiron — you may have just done us a huge favor!

No, the title was not designed to be sarcastic, nor facetious. It is simply a statement of my opinion, and my fervent hope. Despite all the short-term problems and the hours some high-risk people have waited in line, the Chiron debacle may yet have at least one very beneficial result: Few events could have so dramatized the tenuous and “fragile” nature of the U.S. vaccine industry. Similarly, few events could have so forcefully brought home just how ill prepared we really are for an influenza pandemic at the present time.

Despite years of dire warnings from the CDC and the National Vaccine Advisory Committee, as well as more than one report from the Institute of Medicine, in reality little has been accomplished to date to reform the vaccine industry in the United States. Will the very well publicized problems in Chiron’s influenza vaccine production facility in Liverpool, England, and the sudden unexpected loss of almost 50% of the expected U.S. supply of influenza vaccine this year galvanize government and the industry to begin to address the challenges in a meaningful way? That would, of course, be the best possible scenario and the silver lining for this particular black cloud.

No room for error

These problems have been years in the making — about a quarter century or more. Attempts to use this particular debacle as political fodder in the current presidential campaign are patently ridiculous and should be so identified. Multiple administrations and many Congresses have shared in the federal inaction to bring about the present state of affairs. What were many vaccine producers 30 years ago are down to a mere handful today, and in all too many instances, only one or two. As could easily have been predicted, vaccine shortages have become commonplace. There is simply no room for error when one is wholly dependent on only one, or at the most, two, manufacturers. How did these problems develop? Those answers are well known, too. The two biggest concerns: liability issues and the simple fact that vaccines are not big money earners for the industry. Why tie up huge production facilities, for example, for influenza vaccine production, when there is far more money to be made developing and producing many kinds of drugs (no longer including antibiotics!)? The federal Vaccines for Children program, despite its profoundly beneficial effect in making childhood vaccines more widely available, also has one very serious economic downside: It has made the federal government (CDC) the major purchaser of a number of childhood vaccines at the lowest possible contract price, thus further limiting financial returns for the producer.

Liability issues were partially addressed by the 1988 legislation creating the Vaccine Injury Compensation Fund, but that has not gone far enough to attract many new players into vaccine development and production, nor has it appeared to decrease the number of lawsuits filed against manufacturers. The “deep pockets” approach of many trial lawyers seems still to rule the day, and the manufacturers are clearly perceived as having the deepest pockets.

Chiron has been less than totally reassuring that its contamination problems will be fully resolved in time for next year’s vaccine production. This may not be totally surprising, given the almost full-year time lag from ordering embryonated eggs to actual release of trivalent vaccine in an egg-based production cycle.

So what about next year’s influenza vaccine, absent a pandemic crisis? There has been much discussion in the media about possible importation of vaccine, but that seems of little realistic likelihood for this year yet. Next year, however, especially if Chiron is unable to produce vaccine, that should be a more realistic possibility. It seems unlikely that Aventis Pasteur would be able to bring about a major increase in their production, but it might be possible to import vaccine from Canada and from manufacturers in Europe, eg GlaxoSmithKline. To import vaccine next year, however, will still require prompt and, perhaps, innovative regulatory action within the Center for Biologics Research, the vaccine regulatory authority within the FDA.

Consider now where the Chiron default leaves us in terms of pandemic preparedness, in both national and global terms. At the global level, Chiron’s problems are already having an impact, and Klaus Stohr, the WHO influenza chief, has called for a conference in Geneva of all national experts and vaccine producers on Nov. 11 to assess the current situation and chart a course for the future.

The federal plan

At the national level, the federal Influenza Pandemic Preparedness Plan was finally released for public comment late last summer, and at a minimum at least provides a framework for thinking through the problems that we face. As far as vaccine production is concerned, the prevailing assumption has been that a pandemic vaccine would be monovalent, and that if the United States could produce 100 million doses of a trivalent vaccine containing 45 mg total of three viral hemagglutinins, then we could make 300 million doses of monovalent vaccine, each containing 15 mg of hemagglutinin of the putative pandemic strain. This would theoretically be sufficient to immunize almost everyone in the United States, even if two doses were recommended for some.

The Chiron experience has shown us just how fallacious these assumptions may be. Even if Chiron were able to produce vaccine, the output of this facility, located in Liverpool, could be “nationalized” by a simple executive order within the United Kingdom, if they chose to do so for any reason. Other problems: the most likely pandemic candidate for the past several years has been a highly pathogenic avian influenza virus, which is itself lethal to embryonated eggs; hence, a tissue-culture-based vaccine production technology must be developed, tested, approved by regulatory authorities and ready to go if/when it is needed.

The mortality rate of the approximately 35 human cases of H5N1 influenza that have occurred in Southeast Asia this year has been a shocking 70%. Even granting a substantial underreporting bias, a pandemic due to this strain could still be a disaster of epic proportions. Can the United States afford to think only of its own needs when it comes to vaccine production? One hopes that would not be the case. Thus, ways to “stretch” influenza vaccine, most likely with adjuvants, need to be re-explored and evaluated, and this must be done at the earliest possible time.

It’s my impression, having attended a conference in Lisbon, Portugal, on global influenza vaccines last spring, that our European colleagues are well ahead of us in pandemic planning, at least in terms of vaccine production. They have already “harmonized” production and licensure regulations among EU member nations and have learned to think globally, rather than nationally.

So thanks, Chiron, for focusing us on the problems and challenging us to action.

For more information:

• Readers interested in the IDSA’s response to the U.S. Pandemic Influenza Preparedness Plan are urged to read it on the IDSA Web site at www.idsociety.org.