Our Best Shot

Scarcity sometimes even with seasonal flu vaccine

Two months following the Katrina disaster, President Bush proposed a multibillion-dollar spending plan to address the pandemic, allotting much-needed funds to boost antiviral stockpiles and give domestic vaccine production a shot in the arm to improve vaccine technology.²²⁹⁷ In an unclassified Congressional briefing, Gregory A. Poland of the Mayo Clinic and the Infectious Diseases Society of America said, “We and the entire world remain unprepared for what could arguably be the most horrific disaster in modern history.” He emphasized, “The key to our survival, in my opinion, and to the continuity of government is vaccination.²²⁹⁸

Officials understand that waiting for the pandemic strain to arise before starting vaccine production would mean a six- to eight-month delay and untold numbers of deaths. Instead of waiting, many experts have advocated making a human vaccine to the current bird-adapted H5N1 in hopes that the current strain will be sufficiently similar to the virus that eventually “goes human” for the vaccine to afford at least some protection. The vaccine industry has not been quick to act on this recommendation. In 2004, the editorial board of science journal Nature Medicine asked, “Why have we waited so long to develop a human vaccine against avian flu despite evidence—dating back to 1997—of human infection?”²²⁹⁹ A year earlier, after another man in Hong Kong died from H5N1, Robert Webster put it flatly: “We’ve had H5N1 since 1997, yet we don’t have a vaccine on the shelf. That is a black eye for WHO and the system. What the hell have we been doing?”²³⁰⁰

Despite years of lost lead time, in August 2005, the development of an H5N1 vaccine was announced. The New York Times ran an exclusive in its Sunday edition trumpeting, “Avian Flu Vaccine Called Effective in Human Testing.” The story of a human H5N1 vaccine was picked up by the Associated Press and echoed with titles like “Vaccine Appears to Ward Off Bird Flu.”²³⁰¹ These feel-good, “hope is on the way” stories may have led to a nationwide collective sigh of relief. Unfortunately, the story was effectively retracted days later²³⁰² as details emerged.²³⁰³

The announcement was based on a small clinical study showing that healthy volunteers injected with a vaccine made from a single Southeast Asian strain of H5N1 (not the one that escaped from China into Russia and winged its way to Western Europe) did seem to make antibodies against the virus. Unfortunately, this response does not necessarily translate into protection from disease. Other experimental influenza vaccines have similarly raised antibodies but paradoxically led to increased severity of disease and mortality in vaccinated animals in laboratories.²³⁰⁴ Even if this vaccine is effective in reducing mortality from the avian strain utilized and the imminent human pandemic virus, the researchers discovered that the dose required to elicit the immune response was so huge as to make global production impractical.²³⁰⁵ To Osterholm, the results suggest that the world is even less prepared than previously thought.²³⁰⁶ “You know how you creep, then you walk, then you run?” Osterholm asked. “We’re still on our knees.”²³⁰⁷

Annual flu vaccines typically only require a single shot of 15 micrograms (µg) of killed virus protein, since people already have a low level of pre-existing immunity to similar strains from past flu seasons.²³⁰⁸ Essentially no one, though, has any natural immunity to H5 viruses.²³⁰⁹ The researchers reported that a massive vaccination dose—two separate injections of 90µg—would be required. Twelve times the standard dose of regular flu vaccine means 12 times fewer vaccine doses can be produced. “Needing two doses of 90µg is the worst-case scenario,” noted a leading virologist. “You are not going to get very far with that.”²³¹⁰

The U.S. production capacity for seasonal flu vaccines is 180 million doses. Two doses of 90 µg would mean that if the entire U.S. production system was devoted entirely to making pandemic vaccine, it could only produce enough to protect 15 million people, barely 5% of the U.S. population.²³¹¹ Globally, the situation is worse. At the concentration required, the world’s vaccine producers straining at full capacity could only cover about 1% of the planet’s population. “There is now a tremendous anxiety among scientists—including me—about this,” said Professor Peter Dunnill, chairman of the Advanced Centre for Biochemical Engineering at University College, London. “Instead of providing protection for up to a billion people across the world, we will be lucky to get enough doses to vaccinate a few dozen million.”²³¹² A WHO official asked, “Who’s going to get the limited antivirals and vaccines that do become available? And how do we live with people who don’t? What do we say to them?”²³¹³ As one researcher described it in Science, “It’s a vaccine for the happy few.”²³¹⁴

“The good news is, we do have a vaccine,” Secretary Leavitt told CBS News’ The Early Show.²³¹⁵ “It doesn’t matter if we have a vaccine now or not,” Osterholm exclaimed in a telephone interview. “We can’t make it.”²³¹⁶ It’s not enough to produce a vaccine; it must be mass produced.²³¹⁷ Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, describes the “critical issue now” as, “Can we make enough vaccine, given the well-known inability of the vaccine industry to make enough vaccine?”²³¹⁸ “For those of us who do this and think about it every day, all day,” Fauci continued, “even if we could and wanted to and made the decision—this is what we need—the capacity’s not there.”²³¹⁹ This begs the question, why not? Why aren’t there more dedicated factories? Why does the vaccine distribution system allegedly remain “broken, both technically and financially?”²³²⁰ Why is the manufacturing process—as an expert summed up in a word—“lousy?”²³²¹

Two-time Pulitzer Prize-winning journalists Donald L. Barlett and James B. Steele have been called by the Washington Journalism Review “almost certainly the best team in the history of investigative reporting.”²³²² They took on these questions for the seasonal flu shots in a New York Times editorial and laid blame on the privatization of vaccine production. “Preventing a flu epidemic that could kill thousands,” they wrote, “is not nearly as profitable as making pills for something like erectile dysfunction.”²³²³ Bringing a vaccine to market may cost drug companies close to $1 billion;²³²⁴ that’s how much money Viagra alone brings in every year.²³²⁵ Ideally vaccines are “one shot deals,” unlike medications more profitably taken long-term.²³²⁶ “It’s basically the corporate model working,” said a flu expert at the University of Michigan. “You put your money where the blockbusters are.”²³²⁷

Industry insiders agree. David Fedson, a former director of medical affairs for a major vaccine manufacturer, notes, “We have a toxic mixture in America of a corporate culture that is inappropriate for producing vaccines for national security and a political culture that is unwilling to accept government responsibility for ensuring it is achieved.” “Our corporate culture demands a 15–25% annual net return on sales,” he said, “which life-saving commodity products such as vaccines never attain.”²³²⁸

Lacking adequate domestic vaccine production, Americans may find themselves at the end of the line when the pandemic breaks.²³²⁹ The few U.S. vaccine manufacturers produce most of their vaccine overseas in countries that could nationalize production facilities and claim first dibs.²³³⁰ We acted in much the same way in 1976; anticipating a swine flu pandemic, the United States refused to share any of its vaccine.²³³¹ “It is sheer folly,” one doctor wrote, “to expect overseas sourcing [of a vaccine] as an option.”²³³²

The rest of the world would be left even worse off. At present, 90% of production capacity for all influenza vaccines is concentrated in European and North American countries that account for only 10% of the world’s population.²³³³ “If there is an epidemic of bird flu and people start dying in the proportion people believe, I don’t think goodwill is going to be an issue,” said a former chairman of the Food and Drug Administration’s vaccine advisory committee. “It’s going to be every man for himself.”²³³⁴

Acknowledging a “compelling national interest for a vaccine manufacturing capacity to exist,” the Bush administration’s answer is to provide incentives and subsidies “ranging from liability insurance to better profit margins” for the pharmaceutical giants that produce vaccines.²³³⁵ “Otherwise,” Secretary Leavitt explains, “they have competing demands for their capital that make more sense for them to pursue.”²³³⁶ The potential saving of millions of lives is evidently not a “compelling national interest.” Nature’s senior reporter comments: “When the military knows it needs a fighter aircraft, it doesn’t offer incentives to Lockheed Martin or Boeing. It pays them through procurement to develop the weapon to the specifications it wants.”²³³⁷

Scientists are currently working on a way to decrease the required dose of H5N1 vaccine by adding a chemical adjuvant—a substance that nonspecifically irritates the immune system and may boost the immune response to the vaccine.²³³⁸ Said one vaccine expert:

It is possible we could improve dosage levels, but legal disputes over manufacturing rights, problems of scaling up manufacturing, arguments about who owns vaccines made in a given country and many other problems will also affect vaccine manufacture. We will be lucky to get enough vaccine to protect the public against avian flu in the next five years. We should therefore be quite clear: the chances of stopping a flu pandemic before 2010 are going to be extremely slim.²³³⁹

Others are pushing for more radical solutions. “The current vaccine system is not going to work,” says Professor Dunnill. “We need a new approach.”²³⁴⁰ That new approach is cell-culture, rather than egg-based, vaccine production. One artifact of the current system is that when viruses are grown in eggs for certain types of vaccines, the viruses may adapt to the infection of eggs, rather than the infection of humans. Growing the virus directly in cultures of human cells precludes this possibility.²³⁴¹ Also, according to the director of the FDA’s Center for Biologics Evaluation and Review, growing vaccine virus in culture not only eliminates the need for hundreds of millions of fertile chicken eggs, but is expected to increase the flexibility, yield, and speed of vaccine production.²³⁴² President Bush’s 2006 veto on stem cell research, though, may hinder research on cell culture-based vaccines,²³⁴³ some of which—like Sabin’s famous polio vaccine—use fetal tissue.²³⁴⁴

Efforts to upgrade and expand domestic vaccine production continue in the United States, but are expected to take years to have an effect.²³⁴⁵ Asked if it was too late to prepare for the coming pandemic, vaccine industry insider Fedson replied, “It’s always too late, and it’s never too soon. But we’ve got to start somewhere.”²³⁴⁶