Because people will have had no prior exposure to a pandemic strain of influenza, everyone will need two doses: a primer and then a booster about four weeks later. So even those first in line for vaccines are unlikely to develop immunity until at least seven or eight months following the start of a pandemic.
And there will undoubtedly be a line. Total worldwide production of flu vaccine amounts to roughly 300 million doses a year. Most of that is made in Europe; only two plants operate in the U.S. Last winter, when contamination shut down a Chiron facility in Britain, Sanofi Pasteur and MedImmune pulled out all stops on their American lines--and produced 61 million doses. The CDC recommends annual flu immunization for high-risk groups that in the U.S. include some 185 million people.
Sanofi now runs its plant at full bore 365 days a year. In July it broke ground for a new facility in Pennsylvania that will double its output--in 2009. Even in the face of an emergency, "it would be very hard to compress that timeline," says James T. Matthews, who sits on Sanofi's pandemic-planning working group. He says it would not be feasible to convert factories for other kinds of vaccines over to make flu shots.
Pascale Wortley of the CDC's National Immunization Program raises another concern. Pandemics typically overlap with the normal flu season, she notes, and flu vaccine plants can make only one strain at a time. Sanofi spokesman Len Lavenda agrees that "we could face a Sophie's choice: whether to stop producing the annual vaccine in order to start producing the pandemic vaccine."
MedImmune aims to scale up production of its inhalable vaccine from about two million doses a year to 40 million doses by 2007. But Gellin cautions that it might be too risky to distribute live vaccine derived from a pandemic strain. There is a small chance, he says, that the virus in the vaccine could exchange genes with a "normal" flu virus in a person and generate an even more dangerous strain of influenza.
Because delays and shortages in producing vaccine against a pandemic are unavoidable, one of the most important functions of national pandemic plans is to push political leaders to decide in advance which groups will be the first to receive vaccine and how the government will enforce its rationing. The U.S. national vaccine advisory committee recommended in July that the first shots to roll off the lines should go to key government leaders, medical caregivers, workers in flu vaccine and drug factories, pregnant women, and those infants, elderly and ill people who are already in the high-priority group for annual flu shots. That top tier includes about 46 million Americans.
Among CDC planners, Wortley says, "there is a strong feeling that we ought to say beforehand that the government will purchase some amount of vaccine to guarantee equitable distribution." Australia, Britain, France and other European governments are working out advance contracts with vaccine producers to do just that. The U.S., so far, has not.
In principle, governments could work around these supply difficulties by stockpiling vaccine. They would have to continually update their stocks as new strains of influenza threatened to go global; even doing so, the reserves would probably always be a step or two behind the disease. Nevertheless, Wortley says, "it makes sense to have H5N1 vaccine on hand, because even if it is not an exact match, it probably would afford some amount of protection" if the H5N1 strain evolved to cause a pandemic.
To that end, the U.S. National Institute of Allergy and Infectious Diseases (NIAID) last year distributed an H5N1 seed virus created from a victim in Vietnam by scientists at St. Jude Children's Research Hospital in Memphis. The HHS then placed an order with Sanofi for two million doses of vaccine against that strain. Human trials began in March, and "the preliminary results from the clinical trial indicate that the vaccine would be protective," says NIAID director Anthony S. Fauci. "HHS Secretary Michael Leavitt is trying to negotiate to get up to 20 million doses," he adds. (Leavitt announced in September that HHS had increased its H5N1 vaccine order by $100 million.) According to Gel-lin, current vaccine producers could contribute at most 15 million to 20 million doses a year to the U.S. stockpile.
Those numbers are probably over-optimistic, however. The trial tested four different concentrations of antigen. A typical annual flu shot has 45 micrograms of protein and covers three strains of influenza. Officials had expected that 30 micrograms of H5N1 antigen--two shots, with 15 micrograms in each--would be enough to induce immunity. But the preliminary trial results suggest that 180 micrograms of antigen are needed to immunize one person.
An order for 20 million conventional doses may thus actually yield only enough H5N1 vaccine for about 3.3 million people. The true number could be even lower, because H5 strains grow poorly in eggs, so each batch yields less of the active antigen than usual. This grim picture may brighten, however, when NIAID analyzes the final results from the trial. It may also be possible to extend vaccine supplies with the use of adjuvants (substances added to vaccines to increase the immune response they induce) or new immunization approaches, such as injecting the vaccine into the skin rather than into muscle.
Caching large amounts of prepandemic vaccine, though not impossible, is clearly a challenge. Vaccines expire after a few years. At current production rates, a stockpile would never grow to the 228 million doses needed to cover the three highest priority groups, let alone to the roughly 600 million doses that would be needed to vaccinate everyone in the U.S. Other nations face similar limitations.
The primary reason that capacity is so tight, Matthews explains, is that vaccine makers aim only to meet the demand for annual immunizations when making business decisions. "We really don't see the pandemic itself as a market opportunity," he says.
To raise manufacturers' interest, "we need to offer a number of incentives, ranging from liability insurance to better profit margins to guaranteed purchases," Fauci acknowledges. Long-term solutions, Gellin predicts, may come from new technologies that allow vaccines to be made more efficiently, to be scaled up more rapidly, to be effective at much lower doses and perhaps to work equally well on all strains of influenza.
Rapid Response: Could a Pandemic Be Stopped?
As recently as 1999, WHO had a simple definition for when a flu pandemic began: with confirmation that a new virus was spreading between people in at least one country. Thereafter, stopping the flu's lightning-fast expansion was unthinkable--or so it then seemed. But because of recent advances in the state of disease surveillance and antiviral drugs, the latest version of WHO's guidelines recognizes a period on the cusp of the pandemic when a flu virus ready to burst on the world might instead be intercepted and restrained, if not stamped out.
Computer models and common sense indicate that a containment effort would have to be exceptionally swift and efficient. Flu moves with extraordinary speed because it has such a short incubation period--just two days after infection by the virus, a person may start showing symptoms and shedding virus particles that can infect others. Some people may become infectious a day before their symptoms appear. In contrast, people infected by the SARS coronavirus that emerged from China in 2003 took as long as 10 days to become infectious, giving health workers ample time to trace and isolate their contacts before they, too, could spread the disease.
Contact tracing and isolation alone could never contain flu, public health experts say. But computer-simulation results published in August showed when up to 30 million doses of antiviral drugs and a low-efficacy vaccine were added to the interventions a chance emerged to thwart a potential pandemic.
Conditions would have to be nearly ideal. Modeling a population of 85 million based on the demographics and geography of Thailand, Neil M. Ferguson of Imperial College London found that health workers would have at most 30 days from the start of person-to-person viral transmission to deploy antivirals as both treatment and preventives wherever outbreaks were detected.
But even after seeing the model results earlier this year, WHO officials expressed doubt that surveillance in parts of Asia is reliable enough to catch a budding epidemic in time. In practice, confirmation of some human H5N1 cases has taken more than 20 days, WHO flu chief Stˆhr warned a gathering of experts in Washington, D.C., this past April. That leaves just a narrow window in which to deliver the drugs to remote areas and dispense them to as many as one million people.
Partial immunity in the population could buy more time, however, according to Ira M. Longini, Jr., of Emory University. He, too, modeled intervention with antivirals in a smaller community based on Thai demographic data, with outcomes similar to Ferguson's. But Longini added scenarios in which people had been vaccinated in advance. He assumed that an existing vaccine, such as the H5N1 prototype version some countries have already developed, would not perfectly match a new variant of the virus, so his model's vaccinees were only 30 percent less likely to be infected. Still, their reduced susceptibility made containing even a highly infectious flu strain possible in simulations. NIAID director Fauci has said that the U.S. and other nations with H5N1 vaccine are still considering whether to direct it toward prevention in the region where a human-adapted version of that virus is most likely to emerge--even if that means less would remain for their own citizens. "If we're smart, we would," Longini says.
Based on patterns of past pandemics, experts expect that once a new strain breaks loose, it will circle the globe in two or three waves, each potentially lasting several months but peaking in individual communities about five weeks after its arrival. The waves could be separated by as long as a season: if the first hit in springtime, the second might not begin until late summer or early fall. Because meaningful amounts of vaccine tailored to the pandemic strain will not emerge from factories for some six months, government planners are especially concerned with bracing for the first wave.
Once a pandemic goes global, responses will vary locally as individual countries with differing resources make choices based on political priorities as much as on science. Prophylactic use of antivirals is an option for a handful of countries able to afford drug stockpiles, though not a very practical one. No nation has enough of the drugs at present to protect a significant fraction of its population for months. Moreover, such prolonged use has never been tested and could cause unforeseen problems. For these reasons, the U.K. declared this past July that it would use its pandemic stockpile primarily for treating patients rather than for protecting the uninfected. The U.S., Canada and several other countries are still working out their priorities for who will receive antivirals and when.
For most countries there will be no choice: what the WHO calls nonpharmaceutical interventions will have to be their primary defense. Although the effectiveness of such measures has not been extensively researched, the WHO gathered flu specialists in Geneva in March 2004 to try to determine which actions medical evidence does support. Screening incoming travelers for flu symptoms, for instance, "lacks proven health benefit," the group concluded, although they acknowledged that countries might do it anyway to promote public confidence. Similarly, they were skeptical that public fever screening, fever hotlines or fever clinics would do much to slow the spread of the disease.
The experts recommended surgical masks for flu patients and health workers exposed to those patients. For the healthy, hand washing offers more protection than wearing masks in public, because people can be exposed to the virus at home, at work and by touching contaminated surfaces--including the surface of a mask.