Nov 15, 2007 (CIDRAP News) – This in-depth article investigates the prospects for development of vaccines to head off the threat of an influenza pandemic posed by the H5N1 avian influenza virus. Its seven parts put advances in vaccine technology in perspective by illuminating the formidable barriers to producing an effective and widely usable vaccine in a short time frame.
Part 1: Flu research: a legacy of neglect
Part 2: Vaccine production capacity falls far short
Part 3: H5N1 poses major immunologic challenges
Part 4: The promise and problems of adjuvants
Part 5: What role for prepandemic vaccination?
Part 6: Looking to novel vaccine technologies
Part 7: Time for a vaccine 'Manhattan Project'?
Oct 25, 2007 (CIDRAP News) – It has been 10 years since the H5N1 strain of avian influenza first grabbed international attention by causing the death of a Hong Kong 3-year-old, the novel virus's first known human casualty (see Bibliography: CDC 1997). In the decade since, the virus has torn across the globe, causing 332 known human illnesses and 204 deaths in 12 countries, according to the World Health Organization (WHO), as well as the deaths or preventive slaughter of hundreds of millions of birds.
In that time, avian flu and the potential human pandemic it could cause have waxed and waned in public attention. Scientific attention to the H5N1 threat, though, has never wavered. Much of that attention has focused on finding a vaccine against H5N1, "the single most important public health tool for decreasing the morbidity, mortality and economic effects of pandemic influenza," according to Dr. Gregory Poland, director of the Mayo Clinic's Vaccine Research Group in Rochester, Minn. (see Bibliography: Poland 2006).
But after almost a decade of research, a safe, effective, affordable, and abundant vaccine against H5N1 flu remains disappointingly out of reach. The search for a human avian-flu vaccine that could be developed and delivered in time to short-circuit a pandemic has been dogged by multiple obstacles across many sectors. They include patchy scientific knowledge, sparse government funding, thin manufacturing and packaging capability, and restrictive regulatory structures—along with the wily immunology of the H5N1 virus itself.
Despite recent encouraging news from several clinical trials, the scientific—and financial and political—hurdles to producing a widely deployable vaccine remain dauntingly high. As the WHO admitted in its Global Pandemic Influenza Action Plan, published last year, "At the present time, if an influenza pandemic were to occur, the potential vaccine supply would fall several billion doses short of the amount needed to provide protection to the global population" (see Bibliography: WHO 2006).
A chronic low priority
The search for a pandemic vaccine was hobbled from the start by the relatively low priority placed on influenza research before the 1997 Hong Kong outbreak. Almost 80 years had passed since the 1918 pandemic, an outbreak that was globally traumatic but was largely, and strangely, overlooked by historians of the period (see Bibliography: Crosby 1989). For most, "pandemic" would have evoked not the estimated 100 million dead of 1918 but the approximately 1 million worldwide deaths in 1968-69, the mildest pandemic since modern records began—or the failed pandemic alarm sounded in 1976 after swine flu cases were discovered in Fort Dix, N.J., and the rash of adverse events triggered by the emergency vaccination campaign that followed.
As a public health threat, flu had faded from federal, commercial, and thus public attention. A 1985 Institute of Medicine (IOM) report, "New Vaccine Development" (updated in 2000 as "Vaccines for the 21st Century") urged fresh focus on flu-vaccine research but, coming as concern over AIDS began to crest, attracted no additional investment to flu (see Bibliography: IOM 1985, IOM 2000). Consumption of seasonal flu vaccine was relatively low: Americans received 54.9 million doses in 1995, according to data from the Centers for Disease Control and Prevention (CDC), and an additional 16.6 million were returned unused to manufacturers (see Bibliography: Santoli 2007). Lacking a strong public appetite for seasonal flu vaccine, and thus a reliable market, flu-vaccine manufacturers saw no reason to improve on the cumbersome egg-based production technology that had been used since the 1950s.
"Influenza has not been treated with the degree of medical attention that the disease warrants," Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), warned in a 2006 commentary (see Bibliography: Fauci 2006). "There is not an adequate baseline of preparedness in the United States to deal with the potential of pandemic influenza."
Gaps in the knowledge base
Recent assessments by US and European experts have conceded that flu research still lags. A blue-ribbon panel convened last year by the NIAID recommended in a June 2007 report that "eight specific aspects of influenza research in which there are substantial gaps in knowledge" receive immediate attention. The areas included clinical and immune responses to flu, flu epidemiology, animal models for flu research, antivirals, diagnostic assays, and, notably, vaccines, of which the group said: "Development of improved influenza vaccines is a key priority for the control of both seasonal and pandemic influenza" (see Bibliography: NIH 2007).
Echoing that report, the European Centre for Disease Prevention and Control's technical advisory groups on human H5N1 vaccines warned in August that 10 essential research questions must be answered before a vaccine can be achieved. The questions' very basic nature—How much antigen should a vaccine contain? How many doses should be given? How long does vaccine protection last?—suggest how far flu-vaccine science has yet to go (see Bibliography: European Centre for Disease Prevention and Control 2007: Technical report).
Funding: A starvation diet
The historical low profile of flu research translated into a chronic lack of investment. For most of the past decade, as well as many years before that, the field was starved for money. In 2001—after the 1997 outbreak, but before H5N1 began its global spread—the NIH's entire flu-research budget was $20.6 million, with $14.9 million of that in NIAID activities (see Bibliography: NIAID 2007). Funding stayed stagnant until the White House issued the National Strategy for Pandemic Influenza in November 2005 and called for $7.1 billion to be appropriated for flu. As of February, when the fiscal year 2007 budget was finalized, $5.3 billion had been appropriated overall, and NIH's flu research budget had been raised to $222 million (see Bibliography: NIH 2007).
Those appropriations have gone to fund a wide array of pandemic-preparation tasks, from improving state and local planning to supporting antiviral research (see Bibliography: Trust for America's Health 2007). Strictly within the vaccine realm, funds have been divided among research, production, and purchase of existing vaccines for the national stockpile. As of May 2007, Congress had given the Department of Health and Human Services (HHS) $5.6 billion for pandemic preparedness; HHS has allocated $3.2 billion of that to expanding vaccine capacity. So far the agency has committed $1.5 billion of those funds, including $1 billion for research into alternative production methods such as cell culture, $147 million for research on low-dose vaccines, and $133 million for retrofitting existing plants to improve manufacturing capacity (see Bibliography: HHS 2007; Trust for America's Health 2007).
"We are finally starting to do the right thing, because money is being put in," Poland said, "but we are late. We are really playing catch-up" (see Bibliography: Poland 2007).
For the two years since federal money began flowing, scientific and public health groups have begged the administration to allocate more. In November 2005, May 2006, and again in April and June 2007, the Working Group on Pandemic Influenza Preparedness—an umbrella organization for 15 medical and science societies—unsuccessfully urged members of Congress to increase funding for the whole panoply of pandemic preparation, including vaccine research and development (see Bibliography: Working Group for Pandemic Influenza Preparedness 2005, 2006, 2007).
US leads other countries
Late though the United States may have been in funding vaccine research, it nonetheless outshines other countries. "Government officials in the five Western European countries where influenza vaccine production facilities are located . . . have provided virtually no public funding to support H5N1 vaccine trials," David Fedson, MD, wrote this summer in the Journal of Public Health Policy. "Germany is the sole exception, providing modest support for a trial of one company's vaccine" (see Bibliography: Fedson and Dunnill 2007: Commentary). Fedson is a retired academic and vaccine-industry executive who has published critical analyses of pandemic-vaccine planning in a number of journals.
There is widespread fear in the research community that the money is simply not enough.
"The political inertia is surprising, particularly as politicians, if and when a pandemic eventuates, will be asked why, despite repeated warnings, they did not take appropriate action in time," Lars Haaheim of the University of Bergen said in a stinging May article in Influenza and Other Respiratory Diseases. "With very few exceptions, the academia, research establishments and vaccine industry [have] had to settle for meagre and sometimes no public support at all" (see Bibliography: Haaheim 2007).
The difficult reality is that, even if influenza science were perfect and research funding were abundant, achieving a widely deployable pandemic vaccine is currently out of reach. Chief among the reasons: The world lacks the manufacturing capacity to make enough vaccine to matter.
Food and Drug Administration (FDA) planners have accepted that, absent rapid changes in current flu-vaccine manufacturing techniques, delivering the earliest doses of a vaccine tuned to a newly emerged pandemic strain would take a minimum of 4 months (see Bibliography: Goodman 2006). A vaccine-industry scenario, described in August in the journal BioPharm International, goes out 6 months: 3 to 4 months to generate a seed strain, 4 to 6 weeks of manufacturing set-up, and 18 weeks of production, including 2 to 3 weeks of quality assurance and regulatory approval—all adding up to a vaccine product that would arrive roughly in time for the pandemic's second wave but long after the first patients had recovered or died (see Bibliography: Thomas 2007).
But the more difficult obstacle is not the time needed to produce vaccine—which newer technologies such as cell culture could shorten to some degree—but the amount of vaccine needed. Despite years of work, the grave mismatch between predicted demand and likely supply has yet to be solved.
The World Health Organization's (WHO's) own best-case analysis, published in the agency's 2006 "Global Pandemic Influenza Action Plan to Increase Vaccine Supply," and updated in an Oct. 23, 2007, press release,breaks down the situation this way. In 2006,global manufacturing capacity for seasonal flu vaccine was 350 million doses per year of trivalent vaccine (comprising one 15-microgram [mcg] dose of each ofthree flu strains' antigens). This year, according to the WHO, capacity could rise as high as 565 million doses, a total that incorporates both actual capacity increases achieved by manufacturers and theoretical capacity that would be created if manufacturing lines ran around the clock for the entire calendar year—something they do not do for seasonal flu-vaccine production. Given that a pandemic vaccine would be aimed at a single strain rather than three, global capacity could thusrise as high as 1.5 billion doses. But a pandemic vaccine would need to be given twice, because, unlike with seasonal flu, there would have been no prior exposure to the novel strain. So absent the use of adjuvants to stretch limited antigen supplies, industry could produce at best enough vaccine for 750 million people, far short of the amount needed to cover the world's 6.7 billion inhabitants (see Bibliography: WHO 2006: Global influenza action plan; WHO 2007: Projected supply of pandemic influenza vaccine; Palkonyay 2007).
A vaccine embargo?
The WHO analysis hides a number of highly optimistic assumptions, including zero glitches in production and 100% cooperation by regulators. But the greatest assumption may be that the newly produced pandemic vaccine would be distributed equitably to all comers around the globe. It is more likely that vaccine would never leave the countries where it is produced.
Seven hundred and fifty million "is fewer than the number of people that live in the nine countries that produce 85% of the world's supply of flu vaccine," said David Fedson, MD, a retired academic and vaccine-industry executive who has published critical analyses of pandemic-vaccine planning. "Which means that, if you live outside of a vaccine-producing country—whether that means Indonesia or Sweden or Spain—you get nothing" (see Bibliography: Fedson 2007: Author interview).
The nine countries—France, Germany, Italy, The Netherlands, Switzerland, the United Kingdom, the United States, Canada, and Australia—trade vaccine across borders but are unlikely to keep doing so in a pandemic, he added: "In 2000, a total of six western European companies distributed 66 million doses of vaccine to 18 western European countries. Only 42% of these doses were distributed within the countries that produced them; the remaining 58% were exported to other western European countries. For the rest of the world, about 40% of the doses used in central and eastern Europe, 60% of the doses used in the western Pacific and Southeast Asia, and virtually 100% of the doses used in Latin America, the eastern Mediterranean, and Africa were imported from one or more of the nine vaccine-producing developed countries"(see Bibliography: Fedson 2003).
In one example of the supply-demand mismatch, the United States plans to secure enough pandemic vaccine to deliver two doses to all 300 million of its residents (see Bibliography: FDA 2007: Committee meeting transcript). But current US manufacturing capacity tops out at 150 million 15-mcg doses, a total that is expected to rise to 250 million when a new Sanofi Pasteur plant comes online in 2008 (see Bibliography: Sanofi Pasteur 2007), but that still falls far short of the number the federal government hopes to deploy. And those hoped-for 600 million doses do not include the 40 million destined for the US pandemic stockpile that must be replaced periodically as flu strains mutate or the vaccine expires (see Bibliography: Riley 2007).
The role of seasonal flu vaccine demand
The WHO action plan avers that manufacturers will significantly expand production capacity by 2012, largely because demand for seasonal flu vaccine will rise—but it offers no evidence that demand can be stimulated to levels that will persuade manufacturers to invest (see Bibliography: WHO 2006: Global pandemic influenza action plan). In the United States, for instance, the amount of vaccine manufactured has risen nearly every year, but so too has the amount returned to manufacturers unused. In the 2006-07 season, manufacturers selling to the US market delivered 120.9 million doses, the highest on record; they received back 18.4 million unused doses, also a record (see Bibliography: Santoli 2007).
The WHO plan asks countries that do not now use seasonal flu vaccine to launch new seasonal vaccination campaigns as a way of stimulating demand. It also asks countries with existing vaccination programs to increase vaccine use, so that 75% of those for whom vaccination is recommended are taking the shot. Both recommendations may be unrealistic: The United States, which uses more vaccine than any other nation, has never reached 75% uptake even among groups that are urged to take the shot because they are at high risk for flu complications. In the 2005-06 flu season, according to CDC data published in September, the highest acceptance of seasonal flu shots—69.3%—was among adults older than 64, who are considered "high risk" because of their age. Fifty- to 64-year-olds who are at high risk because of chronic medical conditions had a vaccination rate of 48.4%; only 32.3% of those in the same age range who had no high-risk conditions took the flu shot, and only 18.3% of healthy adults between 18 and 50 did so (see Bibliography: CDC 2007).
"I have never believed that boosting seasonal flu-vaccine demand was the way to prepare for pandemic flu," said Michael Osterholm, PhD, MPH, director of the University of Minnesota Center for Infectious Disease Research and Policy (CIDRAP), which publishes CIDRAP News, and of the National Institutes of Health (NIH)–funded Minnesota Center of Excellence for Influenza Research and Surveillance. "That economic model doesn't work on its own and it has no scalability to provide flu vaccine for the rest of the world" (see Bibliography: Osterholm 2007).
Little incentive to build
Many experts have warned that the only way to expand flu-vaccine manufacturing capacity is to get governments to pay for it. In its 2004 "Consultation on priority public health interventions before and during an influenza pandemic," the WHO cautioned: "Industry has little incentive to build additional manufacturing capacity, which requires very large long-term investments for an event that occurs only rarely and unpredictably." (See Bibliography: WHO 2004) Last year, Britain's Royal Society added bluntly: "It is not commercially viable for the vaccine industry to commit the necessary resources to scale up production in advance of a pandemic when there is no existing market, the threat of a pandemic may be years away and the risk in any single year may be considered to be low" (see Bibliography: Royal Society 2006).
Creating enough vaccine-manufacturing capacity to protect the world's population is not cheap. The price tag is likely to be at least $2 billion and could rise to $9 billion, according to a WHO estimate (see Bibliography: WHO 2006: Global pandemic influenza action plan). Experts within the vaccine industry say that expecting manufacturers to make the investment asks companies to spend against their own best interest. "In the US market alone by the year 2010 there could be a surplus capacity resulting from 'building for demand' for pandemic preparedness but 'suboptimal utilization' based on significantly lesser demand for seasonal vaccines," an engineer and two strategists from the Danish biotech firm NNE PharmaPlan wrote in the industry journal BioPharm International. "In Europe, Asia and the rest of the world, planned future capacities for 'pandemic preparedness' would have to address how potential surplus capacities can be effectively used in markets where there is little or no demand for seasonal vaccines" (see Bibliography: Thomas 2007).
The United States has already experienced the aftermath of vaccine companies' feeling overextended. Between 1998 and 2002, two of the four companies that then supplied seasonal flu vaccine left the market, citing losses on investment and increased regulatory demands. In the 2000-01 and 2003-04 flu seasons, the country experienced significant shortages of flu vaccine, with long lines, panic buying, price-gouging, and subsequent congressional investigations (see Bibliography: GAO 2001, 2004; Grady 2004).
The same scenario could happen again. "The U.S. will have a serious problem if the pandemic doesn't strike in the next couple of years, because interest will decline and demand will go down again," said Hedwig Kresse, an associate analyst for infectious diseases with the British-based market analysts Datamonitor. "Governments will have to guarantee a certain sales volume to keep [manufacturers] in the market and to keep these capacities up" (see Bibliography: Kresse 2007).
While the US government has taken initial steps to support manufacturers—witness the $133 million given to two manufacturers this past summer to retrofit existing plants and the $1 billion awarded for cell-culture research—much more is needed (see Bibliography: HHS 2006, 2007).
"If we really want to have surge capacity for pandemic vaccine, we have to invest in it like we do our oil reserves, or military reserve capacity," Osterholm said. "The facilities may sit for years before they are utilized. But the analogy is having an airport fire department in case of a plane crash: You hope never to use it, but you invest as though it were a possibility" (see Bibliography: Osterholm 2007).
To be useful, those investments must be made well in advance of when vaccine is needed: The WHO estimates that building and licensing a new vaccine production line takes up to 5 years (see Bibliography: WHO 2004).
What about vials and syringes?
While vaccine manufacturers are likely grateful for the HHS funding, others in the industry say the investment is incomplete—because it does nothing to expand capacity for critical downstream tasks such as bottling and administering completed vaccine.
The "fill-finish" sector—which puts bulk manufactured vaccine into vials or syringes—is not being asked to prepare for any excess capacity, said Jack Lysfjord, vice-president for pharmaceutical consulting in the Valicare division of Robert Bosch Packaging Technology Inc., in Brooklyn Park, Minn., a leading manufacturer of production and fill-finish equipment. "We are talking to some companies, but we are not hearing that they plan to buy twice as much from us in the next five years," he said. "If they want to expand, they should be starting production now" because building an automated filling line can take 2 years (see Bibliography: Bosch 2007).
The same frustration is evident at BD (formerly Becton, Dickinson and Co.), the dominant company in syringe manufacturing.
"Everyone understands that if you don't have vaccine you are dead in the water, but what has not been dealt with is that, if you don't have the syringes and needles, the vaccine doesn't do you any good," said George Goldman, senior director for hypodermics at BD Medical Surgical Systems in Franklin Lakes, N.J. "Six hundred million devices, which is what in theory would be required to vaccinate the US population twice, is a very large volume if you plan for it and an even larger volume if you produce them in a reactive mode. We do not believe the industry is capable of producing that kind of volume in any short period of time under the best of circumstances" (see Bibliography: BD 2007).
Manufacturing 600 million syringes would take 2 years if manufacturers used only their existing excess capacity, Goldman said, and creating a new manufacturing line takes approximately a year.
"We have been working at the federal, state, even the local level to try to make sure this issue is visible," he said. "To date, the results have been underwhelming."
The companies that occupy the end of the vaccine-production process are also experiencing anxiety—on their own behalf and for the pharmaceutical manufacturers who feed product to them—that their operations will be disrupted by the start of a pandemic if they are brought into the process too late.
As a foreign-owned company, with its US unit in Minnesota andheadquarters and manufacturing plants in Europe, Bosch feels this acutely. Much of the fill-finish equipment sold out of its US plant undergoes preliminary assembly in Germany, and many of the manufacturers for whom Bosch makes equipment rely on pharmaceutical ingredients or production components sourced from around the world.
"You have to think about every part of the components," Lysfjord said. "The machines, the plants, the chemicals; the stopper, the glass, the aluminum overcast for the top of the vial; the labels. You're not aware of how well-connected the system is until it breaks, and it is going to break big-time."
Many of the difficulties facing achievement of a pandemic influenza vaccine could not have been anticipated before the pandemic threat arose: They are intrinsic to the H5N1 virus itself.
Some are obvious. Because all flu viruses mutate rapidly, antigenic drift and division into clades, or subgroups, has already rendered some early vaccine candidates less potent against circulating strains (see Bibliography: Smith 2006, Riley 2007). Because this flu virus is highly pathogenic, it must be handled initially in one of a relatively small number of high-biosecurity laboratories (see Bibliography: WHO 2004) and also requires the use of reverse genetics to create a seed strain that will reproduce in eggs. Reverse genetics and the stringent pre-release testing that follows add a minimum of 6 weeks to the vaccine production process (see Bibliography: Wood 2007: Reference viruses). And absent regulatory changes, the resulting seed strain could be considered a genetically modified organism under European Union rules or a select agent under US law, further restricting the laboratories, personnel, and manufacturers who could work with it from then on (see Bibliography: Stephenson 2006: Development and evaluation).
Reverse genetics may be responsible for a phenomenon noted by several researchers: H5N1 does not reproduce well in vitro, a potentially major obstacle for vaccine production because it would greatly lengthen the manufacturing timeline. "Most manufacturers report that yields of antigen from reverse genetics–derived H5N1 viruses are 30-40% of the average of seasonal influenza viruses, reducing the quantity of antigen available for vaccine formulation," Iain Stephenson of University Hospital-Leicester and colleagues wrote last year in Lancet Infectious Diseases (see Bibliography: Stephenson 2006: Development of vaccines).
Vaccines show poor immunogenicity
Furthermore, when candidate vaccines have been produced from them, H5N1 and similar viruses have not done a good job of provoking an immune response. This was noted as early as 1998, when an early attempt to create a vaccine in the wake of the 1997 Hong Kong outbreak used an antigenically similar H5N3 strain—only to find it was poorly immunogenic even at the highest concentration of two 30-microgram (mcg) doses (see Bibliography: Nicholson 2001). There were similarly poor results in 2006 and 2007 trials that used an H5N1 strain isolated from Vietnam in 2004 and modified by reverse genetics (see Bibliography: Bresson 2006, Leroux-Roels 2007): Even at the highest dosage given (two 30-mcg doses), neither trial induced levels of immune protection that would be acceptable to the Food and Drug Administration (FDA) or the European Union's Committee for Medicinal Products for Human Use (CHMP).
But the best example of H5N1's poor immunogenicity is the 2006 trial that led to the first FDA licensing of an H5N1 vaccine. The trial, which used the same modified 2004 Vietnam strain as the others, achieved acceptable levels of protection only at the highest amounts given, two doses of 90 mcg each, or 12 times the 15-mcg dose that induces immunity in a seasonal vaccine (see Bibliography: Treanor 2006: Safety and immunogenicity of an inactivated subvirion influenza A [H5N1] vaccine). Even at that dosage, only 54% or 58% of the subjects (by two different measures) exhibited antibody titers that matched FDA and CHMP regulations, compared with the 70% to 90% usually achieved with seasonal vaccine (see Bibliography: CDC 2005).
The trial's investigators acknowledged that the extraordinarily high dose necessary to protect was an unsatisfying result, saying, "The need for a vaccine with a total dose of 180 mcg would pose a considerable barrier to rapid production of a supply that would be adequate to meet the world's requirements should a pandemic occur" (see Bibliography: Treanor 2006: Safety and immunogenicity). Experts who reviewed the data during FDA deliberations on licensure agreed, signaling that they hoped for improved results as research advances. "There are numerous vaccines under development that are potentially better, if you will, than this vaccine. This is an interim vaccine," Norman Baylor, PhD, director of the FDA's Office of Vaccines Research and Review, said during the FDA hearing (see Bibliography: FDA 2007: Committee meeting transcript).
The amount of antigen needed in that vaccine concerns researchers several times over. It is so high that the vaccine would stress the manufacturing system if put into broad production, although regulators at the licensure hearings said the vaccine is intended only for federal stockpiling and not for commercial sale. In addition, they fear the high dose—which at 180 mcg total is four times the total seasonal trivalent dose—could provoke an unusual rate of adverse reactions (see Bibliography: FDA 2007: Committee meeting transcript).
(Regulators may be quietly bracing for adverse publicity as well. Testimony at the same FDA committee meeting indicated that, because of limitations on fill/finish capacity, the 90-mcg vaccine being manufactured for the US stockpile will be packaged in multi-dose vials which, to guard against contamination, will contain the still-controversial preservative thimerosal.)
Immunity hard to measure
The 2006 trial's unsatisfying results highlighted a chronic concern in flu-vaccine research: the lack of reliable correlates of immunity for pandemic vaccines. Given the lack of a vaccine, moderate antiviral resistance, and a case-fatality rate of more than 60%, humans cannot ethically be experimentally exposed to the H5N1 virus. Yet none of the animal models—mice, ferrets, or the recently proposed guinea pigs (see Bibliography: Lowen 2006)—is a perfect substitute. Hence the research community relies instead on measures of human antibody response that are neither uniform across laboratories nor universally agreed to by regulatory bodies.
"I think this is our biggest scientific issue—that we are not sure what the appropriate surrogate for protection is, given the fact we have no ability to challenge [expose humans] and are not likely to," said flu epidemiologist Dr. Arnold Monto of the University of Michigan (see Bibliography: Monto 2007).
In the United States, the FDA-accepted surrogate for immunity in flu-vaccine trials is a hemagglutination-inhibition (HI) antibody assay that returns a post-vaccination titer of more than 1:40 for 70% of those vaccinated (see Bibliography: FDA 2007: Guidance for industry: clinical data needed to support the licensure of seasonal inactivated influenza vaccines). But that measure is known to be imperfect even for seasonal flu: Patients with higher titers have contracted flu, while those with lower post-vaccination titers have apparently been protected (see Bibliography: Poland 2006). Additionally, the HI test appears in the lab to be less sensitive to H5 antibodies than it is to the seasonal strains H1 and H3; a second test, virus microneutralization, appears more sensitive but also has no agreed-upon clinical correlates (see Bibliography: Stephenson 2004). Researchers have resorted to using a 1:40 result as the best available measure of immunologic response, while conceding that it may not indicate actual degrees of protection.
"It's important to understand that this choice of a 1:40 endpoint is not validated in any way as an actual assessment of protection against H5 in humans," Dr. John Treanor of the University of Rochester, principal investigator for the trial that produced the licensed H5 vaccine, said at the FDA licensure hearings. "It might be just as valid to choose a 1:20 or a 1:80 or a 1:10 endpoint. But it's really more a convenient way in order to discriminate responses between groups" (see Bibliography: FDA 2007: Committee meeting transcript).
Unfortunately, HI titer results vary wildly. In two studies, European labs performing the same test for seasonal flu strains returned results that varied from 16- to 128-fold, and for H5N1, labs have achieved different results depending on the source and age of the animal cells used in the assay (see Bibliography: Wood 2007: International standards). The WHO is pursuing international agreement on a standard for H5N1 tests, similar to standards achieved earlier for measles, polio, rubella, and other infectious diseases.
But the problem with finding correlates of immunity goes further. The HI test may not return reliable results for vaccines that provoke types of immunity other than antibody response. That makes it an unreliable measure for the effectiveness of two promising alternative classes of vaccines: live-attenuated vaccines, which have the potential to generate immunity against multiple strains of flu, and inactivated adjuvanted vaccines (those containing a chemical immune-system stimulant), which could help solve the supply bottleneck by allowing much smaller amounts of antigen to be dispensed in each vaccine dose (see Bibliography: Subbarao 2007, Wood 2007: Author interview).
Adjuvanted vaccines appear to hold the greatest promise for solving the grave supply-demand imbalance in pandemic influenza vaccine development. They come with obstacles—immunologic, regulatory, and commercial—but they also have generated more excitement than any other type of vaccine thus far.
In an example of the hope being hung on adjuvants, the WHO last week issued a statement declaring that the pandemic vaccine supply is "sharply" increasing and forecasting that annual manufacturing capacity will rise to 4.5 billion two-dose courses by 2010 (see Bibliography: WHO 2007: Projected supply). The forecast is based on the expectation that flu vaccines made in 2010 will include an adjuvant permitting the use of just one-eighth of current vaccines' antigen content. (Adjuvants are chemicals that are incorporated in some vaccines to improveresponse to the vaccines' active ingredient. Adjuvants make it possible to reduce the dose of antigen in a vaccine without dampening the immune response.)
"We have H5N1 to thank for opening up the flu research field, which was absolutely creeping along," said Dr. Arnold Monto, a flu epidemiologist at the University of Michigan, who has long research experience with live-attenuated vaccine. "We've always known that flu vaccine was good, but not great—not a 21st century vaccine with 95% protection—but there was a feeling that it was good enough. But H5N1 changed the risk-benefit ratio so that we are willing for instance to work with adjuvants, which may have theoretical risks but certainly may well afford tangible benefits. We're going to learn a whole lot about the immunology of protection that we haven't learned in the past" (see Bibliography: Monto 2007).
While adjuvants hold the greatest promise for dose-sparing, they also provoke trepidation because they are by definition immune-system activators.While many have been tested over the years, few have entered the market, because they proved too reactogenic to be acceptable to consumers or safe. Only one set of adjuvants, aluminum salts or alum (aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate), is licensed in the United States. Aluminum adjuvants and MF59, an oil-in-water emulsion that contains squalene (an oil found in some fish oils), are licensed in Europe (see Bibliography: Petrovsky 2007).
No adjuvanted flu vaccine is licensed in the United States—a notable oversight since federal health authorities urged such a vaccine be investigated as a preparedness measure after the pandemic of 1957 (see Bibliography: Strikas 2005). Fifty years later, the need to seek regulatory approval for novel components in adjuvanted pandemic vaccines could prove a barrier to rapid market entry of formulas that look promising.
Adjuvants old and new
Early hopes for an adjuvanted H5N1 vaccine focused on alum, because it is well-understood and widely licensed, but those formulas have proved disappointing. A phase 1 study of alum-adjuvanted vaccine made by the Chinese company Sinovac Biotech achieved acceptable levels of protection using two doses of only 10 micrograms (mcg) of flu antigen—but that formula was based on an inactivated whole virus, a flu-vaccine type that is licensed in the European Union but not currently used in the United States (see Bibliography: Lin 2006).
Two other alum-adjuvanted vaccines that used whole viruseshave shown some promise for antigen sparing. At a February 2007World Health Organization (WHO) meeting, Norbert Hehme of GlaxoSmithKline Biologicals reported that a regimen of two 15-mcg doses met EU criteria for immune response (see Bibliography: Hehme 2007). And in May, Hungarian investigators reported that they had achieved an acceptable immune response in a small study using a formula (based on a seasonal vaccine already licensed in the EU) containing a single dose of only 6 mcg (see Bibliography: Vajo 2007). Two alum-adjuvanted vaccines that used the split-virus formulation common in the United States have reported levels of immune response acceptable to regulators at two doses of 45 mcg (see Bibliography: Keitel 2007) or 30 mcg (see Bibliography: Bresson 2006). But those levels of antigen are so high that deployment of those vaccines would not allow significant dose-sparing.
The most provocative news in dose-sparing has come in the past several months. In August, scientists working with a GlaxoSmithKline formula published a trial of a two-dose regimen of an inactivated split-virus vaccine adjuvanted with a proprietary oil-in-water emulsion; after the second injection, even the lowest dose of 3.8 mcg exceeded EU criteria for immune response (see Bibliography: Leroux-Roels 2007). And in September, Sanofi Pasteur reported in a press release that an inactivated vaccine adjuvanted with the company's own proprietary formula induced EU-accepted levels of protection after two doses of 1.9 mcg.
Regulatory barriers loom
Like many other aspects of pandemic planning, adjuvants' ability to solve some of the challenges of preparedness will depend on how rapidly a pandemic arrives. That is because the most promising vaccines rely on formulas that have not yet been licensed in the United States. The Food and Drug Administration (FDA) has indicated that pandemic vaccines made in the same manner as an already-licensed seasonal vaccine may be treated only as a "strain change," in an accelerated approval process by which components are swapped out of existing seasonal flu vaccines each spring. But since there are no adjuvanted seasonal flu vaccines currently licensed in the United States, antigen-sparing pandemic vaccines may require a full Biologics License Application—the complete portfolio of testing and data, on both the product and the manufacturing facility, that is demanded of any new drug submitted for licensure and can take years to assemble (see Bibliography: FDA 2007: Guidance for industry: clinical data needed to support the licensure of pandemic influenza vaccines).
Moreover, at the moment both the FDA and the European Union's drug agency consider adjuvants to be a component of vaccines, not a product separate from vaccines—implying that adjuvants can be brought forward only as part of a precise antigen dose/adjuvant combination that must be tested for safety and efficacy, probably in a "non-inferiority" trial against the same antigen dose without adjuvant, and then submitted for licensure (see Bibliography: European Agency for the Evaluation of Medicinal Products 2005; FDA 2007: Guidance for industry: clinical data needed to support the licensure of seasonal inactivated influenza vaccines).
"We have not taken the position that an adjuvant can be thought of as a stand-alone product," Dr. Pamela MacInnes of the National Institutes of Health said at an FDA advisory committee meeting last February. "It's a product that has antigen in combination with an adjuvant that comes forward for licensure" (see Bibliography: FDA 2007: Committee meeting transcript).
Mixing and matching
There is currently no regulatory pathway by which adjuvants may be submitted for approval as products by themselves—or may be paired with a separately manufactured antigen, perhaps one produced by another company. Regulators acknowledge that could stand in the way of, for instance, converting the already-manufactured vaccine in the national stockpile (which was purchased under the 90-mcg-dose license granted Sanofi Pasteur earlier this year but is held in bulk) to an adjuvanted vaccine that could be stretched much further.
"There probably are more concerns about an antigen made with one manufacturing process and an antigen made with another manufacturing process and whether when those are mixed with ideal adjuvant X in two potentially different circumstances or time points, that could raise a bunch of issues about formulation, stability, immunogenicity, safety," Dr. Jesse Goodman, director of the FDA's Center for Biologics Evaluation and Research, said at the FDA meeting (see Bibliography: FDA 2007: Committee meeting transcript).
The US Department of Health and Human Services (HHS) issued $132.5 million in contracts in January 2007 to three companies—GlaxoSmithKline, Iomai, and Novartis—to study antigen technology, including the possibility of mixing and matching adjuvants with separately manufactured antigens (see Bibliography: GSK 2007; Iomai 2007; Novartis 2007: Novartis receives US government contract). Manufacturers have welcomed the government interest because negotiating combinations of components from different companies is fraught with antitrust and intellectual-property pitfalls.
"I have heard a lot of people say they expect problems with adjuvanted vaccines," said Hedwig Kresse, an associate analyst for infectious diseases with the British-based market analysts Datamonitor. "It is a technology that definitely has some potential, but there are a lot of issues that need to be addressed first" (see Bibliography: Kresse 2007).
Experiments with vaccine adjuvants have raised some hope of removing one of the great stumbling blocks to pandemic influenza preparedness: the impossibility of making a vaccine that protects against a pandemic virus before that virus actually emerges.
A number of the studies that have shown adjuvants may be able to stretch the vaccine supply also demonstrated a secondary benefit: The formulas protected not only against the H5N1 flu strain on which they were based, but against other H5N1 strains as well, a phenomenon called cross-reactive protection (see Bibliography: Nicholson2001, Stephenson 2005, Govorkova 2006, Hehme 2007, Hoffenbach 2007). Most recently, the GlaxoSmithKline-backed team that described an acceptable immune response after two adjuvanted 3.8-microgram (mcg) doses found that three fourths of their subjects were protected not only against the clade 1 Vietnam virus on which the vaccine was based, but against a drifted clade 2 virus from Indonesia as well (see Bibliography: Leroux-Roels 2007).
The findings are not completely understood, though researchers agree that they make biological sense. Adjuvants stimulate the immune system in some manner that is broader than and different from the body’s reaction to the antigen packaged with them. The discovery that adjuvanted flu vaccines may invoke cross-reactivity has generated tremendous excitement—because that could allow production of at least partially protective vaccines well in advance of a pandemic’s beginning.
A tough ethical problem
But the next logical step—that if vaccines can be formulated without waiting for a pandemic, they could be administered before a pandemic began—is a much tougher one to take, and policy makers are approaching it with great caution.The scientific, logistical, and especially ethical questions raised by prepandemic vaccination are grave.
Any vaccination that took place before a pandemic was detected would offer uncertain amounts of both benefit and risk. The vaccine might be cross-protective against a future pandemic—but the lag time to the pandemic’s emergence might be so long that the vaccination would seem pointless. As well, the vaccine might cause a greater-than-expected rate of adverse events, causing both direct harm to recipients and indirect damage to government credibility—results that would be particularly difficult to tolerate if vaccination proved unnecessary because the pandemic did not arrive. Those risks are not theoretical: They have been demonstrated in the United States twice in recent history, in the abortive 2002 smallpox vaccination campaign and the 1976 swine-flu campaign (see Bibliography: Kotalik 2005), which has haunted US flu decision-making ever since.
The danger demonstrated by both those campaigns, of causing adverse events while protecting against a disease that might never arise, has been noted in World Health Organization (WHO) policies as well. "Possible high-risk shortcuts in response to a potential emergency would be difficult to justify prior to the actual occurrence of the emergency," the agency said after the June 2006 meeting of its Global Advisory Committee on Vaccine Safety. "Effectiveness of pandemic vaccines will not be known before the pandemic and possibly only after it is over" (see Bibliography: WHO 2006: Global Advisory Committee on Vaccine Safety, 6-7 June 2006).
Yet the potential benefits of prepandemic vaccination are so alluring that governments have begun gingerly to lay groundwork for its consideration, despite the obvious difficulties of putting the idea into practice.
"Extraordinary threats call for consideration of innovative strategies that, in less-threatening circumstances, might be dismissed," Bruce Gellin and Ben Schwartz of the Department of Health and Human Services' National Vaccine Program Office wrote 2 years ago. "Although it has been assumed that pandemic vaccine cannot be stockpiled or that vaccination cannot occur before the start of a pandemic, might these approaches actually be possible? . . . Would receipt of a vaccine prepared before the pandemic be effective in providing some protection or in priming recipients so a single subsequent dose of vaccine would be protective?" (see Bibliography: Schwartz 2005).
The prime-boost strategy
The most likely and biologically plausible use of prepandemic vaccination would be as the first half of a "prime-boost" series. People would still be given the two doses of vaccine necessary to provoke immunity in a naïve individual. But the doses would be based on different vaccine strains—the first an early best guess, the second tuned to the pandemic strain—and could be given not weeks but months or years apart if the science supported it.
At the moment, however, the science is thin. Much of the support for priming has come from animal studies (see Bibliography: Lipatov 2005, Govorkova 2006, Kreijtz 2007) or via computer modeling (see Bibliography: Longini 2005, Ferguson 2006, Germann 2006). A few small studies in humans have shown promising results. In one, serum from 15 volunteers who received three doses over 16 months of an adjuvanted vaccine based on a 1997 H5N3 isolate showed significant antibody response against H5N1 strains isolated years later (see Bibliography: Stephenson 2005). In another, 37 participants who had been given a baculovirus-grown, clade 3 H5 vaccine in 1998 were boosted with a single dose of the unadjuvanted 90-mcg Sanofi vaccine in 2005, and showed much higher antibody responses than participants who had not been primed but received one or two doses of the 90-mcg vaccine (see Bibliography: Treanor 2007: Immune responses). And researchers at a conference earlier this year reported that some of the participants in the phase 3 trial of the 90-mcg Sanofi vaccine were boosted with a third dose 6 months after their second dose and showed a significant rise in antibody levels that lasted for 6 months (see Bibliography: Zangwill 2007).
Hurdles are many
So many steps separate those early results from an agreed-upon policy that would allow for prepandemic vaccines—in an annual flu shot or stockpiled until the WHO declares a pandemic imminent—that it is unrealistic to expect them to be created any time soon. The scientific questions alone are significant and novel.
"I think priming should be done, but I am not sure how it should be done," said Dr. John Wood, principal scientist in the division of virology at the United Kingdom's National Institute for Biological Standards and Control. "What we don't know is how low you can go to actually prime people. It may be that you can go much lower than where we can detect antibody. That is a regulatory headache, because you have to demonstrate that you are doing something, but there is a potential there" (see Bibliography: Wood 2007: author interview).
To achieve prepandemic vaccines, researchers would have to ascertain the right dose and dose interval, determine how long priming lasts, and solve the puzzle of measuring primed immunity. Further, regulatory authorities would have to determine the trial design that could deliver those answers, the public discussion that would be necessary for prepandemic vaccines to be accepted, and the safety data that would need to be gathered once the vaccines went into use (see Bibliography: Goodman 2007).
Recognizing those hurdles, the European Centre for Disease Prevention and Control said in August that while it welcomes the development of prepandemic vaccines, it would not support administering them until a WHO declaration of pandemic phase 5 or 6, meaning significant human-to-human transmission is occurring or a pandemic is under way (see Bibliography: ECDC 2007: "Pre-pandemic" vaccines might offer protection but uncertainties remain).
Frustration with the slow pace of pandemic-vaccine achievement has spurred second looks at both old and new technologies, such as using whole influenza viruses instead of fragments or growing flu viruses in cultures of mammalian cells instead of in eggs.
Such approaches may yield cross-protection against various H5N1 strains, shorten the production timeline, or increase the amount of vaccine that can be produced. As with the inactivated subvirion or split-virus vaccines, however, much of the research into new types of vaccines and forms of delivery is in its early stages, and the vaccines could be years away from marketability. Few of them pass the real-world tests specified recently by David Fedson, MD, in the Permanente Journal. Fedson, a retired vaccine-industry executive who has analyzed pandemic vaccine planning, wrote that the vaccines must be "scientifically promising," they must be "licensed or near licensure," and "the global industrial capacity to produce them must be large and already in place" (see Bibliography: Fedson 2007: New approaches).
Among older and known technologies, the lure of cross-reactive protection has spurred a second look at inactivated whole-virus and live-attenuated flu vaccines. Some whole-virus trials have returned encouraging results. But in the past, whole-virus vaccines' much higher rate of adverse reactions has kept them out of commercial use in the United States. As a result, "if whole-virus vaccines are confirmed to be more immunogenic than subvirion vaccines, this will pose challenges to manufacturers and regulators, since it will require substantial changes to existing licensed production processes," Iain Stephenson of University Hospital-Leicester and colleagues observed in Lancet Infectious Diseases (see Bibliography: Stephenson 2006: Development of vaccines against influenza H5).
Pros and cons of live vaccines
Live-attenuated vaccine has been the Cinderella of the seasonal flu vaccine world, struggling for market share since it was introduced in 2003 by MedImmune (now part of AstraZeneca). Even during flu-shot shortages, its acceptability was hampered by restrictive FDA indications limiting its use to 5- to 49-year-olds, as well as a formula that required physicians to keep it frozen (see Bibliography: Rosenwald 2007). The vaccine was relaunched this year with a new formula that requires only refrigeration, along with a broadened indication permitting use in children as young as 2 years old, backed by research showing that it protected young children better than a shot (see Bibliography: Belshe 2007).
Because they contain live virus, live-attenuated vaccines provoke multiple types of immunity. In studies they have been shown to protect against both the strains from which vaccine candidates were derived and against drifted (slightly mutated) strains as well—characteristics that make them highly appealing to pandemic planners (see Bibliography: Belshe 2004). They also grow in eggs at a much higher volume than inactivated vaccines (see Bibliography: Monto 2007). But their live-virus content is responsible for the vaccines' greatest potential danger: the possibility that they might lead to reassortment between the vaccine virus and circulating flu strains.
"Although such an event may not be of concern in the face of widespread disease from a pandemic strain of influenza, it would clearly be an unfavorable outcome if the threatened pandemic did not materialize," Catherine Luke and Kanta Subbarao of the National Institutes of Health (NIH) wrote last year. They called for clinical trials of live-attenuated pandemic vaccine candidates in which, to eliminate the risk of reassortment, participants would be kept in inpatient isolation. "The risk for reassortment must be carefully considered by public health authorities before a decision is made to introduce a live, attenuated vaccine in a threatened pandemic," they stated (see Bibliography: Luke 2006).
Some researchers have urged attention not to new vaccines, but to new methods of administering vaccines. Intradermal vaccination appears to provoke acceptable levels of immunity while using only 20% to 30% of the standard intramuscular dose—but the injection technique is more challenging and may not be feasible for mass vaccination programs that might use less-trained volunteers (see Bibliography: Haaheim 2007).
In another novel suggestion, academics from the University of Hong Kong recommended recently that health authorities consider giving lower-than-planned doses of vaccine during a pandemic, arguing that vaccinating more people with a reduced dose could create a mass effect large enough to slow down spread of the disease (see Bibliography: Riley 2007). That approach too has drawbacks, Christophe Fraser of Imperial College London said in a commentary: "We must . . . consider whether anyone is ready for the potential consequences of deploying a suboptimal vaccine in an uncertain attempt to maximize our herd protection, with a possible reduction in the extent of protection of individuals" (see Bibliography: Fraser 2007).
The promise of cell-culture production
The simplest but in some ways most challenging proposals for addressing the slow development of pandemic vaccines are ones that directly address the shortfall in flu antigen by radically changing production techniques.
Cell culture is a known technology that is used for vaccines such as inactivated polio vaccine, but in the United States it has never been applied to flu. Moving flu vaccine production from eggs to cell culture would simplify manufacturing in several key areas. It would free manufacturers from the necessity of procuring enough eggs up to a year in advance. By dispensing with eggs, it would eliminate the need for putting a pandemic virus through reverse genetics, shaving 4 to 6 weeks off vaccine production. And because the vaccine virus is grown in giant industrial fermenters, it could offer a vast increase in production capacity—but only if manufacturers or governments make significant capital investments (see Bibliography: GlaxoSmithKline 2005, Novartis 2006) or manufacturers quickly convert the 2.5 million liters of cell-culture capacity (see Bibliography: FDA 2007: Committee meeting transcript) in use around the world for other pharmaceutical products. Either method of creating additional capacity would require the approval of regulatory bodies such as the Food and Drug Administration (FDA) before production could begin, unless governments enacted some form of emergency release.
But additional investment at least is beginning: The Department of Health and Human Services (HHS) awarded $97 million to one manufacturer in 2005 and just over $1 billion to five manufacturers in 2006 (see Bibliography: HHS 2006), and manufacturers Novartis and GlaxoSmithKline have both begun building cell-culture plants in the United States. The first cell-culture vaccine for seasonal flu, made by Novartis, was approved by European Union authorities in June (see Bibliography: Novartis 2007: Novartis gains European approval).
A refinement of the cell-culture strategy involves isolating the flu virus's hemagglutinin gene and using recombinant technology to express the hemagglutinin in insect cells grown in bioreactors. The main commercial proponent of this process, Protein Sciences Corp., claims it can halve the standard production timeline while delivering higher yields (see Bibliography: Lauerman 2007). The baculovirus-expressed recombinant product has been successfully tested for safety and immunogenicity (see Bibliography: Treanor, Schiff 2006; Treanor, Schiff 2007), and the company has said it plans to submit a trivalent, seasonal-flu version of the vaccine to the FDA for licensure before the end of 2007 (see Bibliography: Protein Sciences Corp. 2007). Submission of a recombinant pandemic vaccine would follow approval of the seasonal vaccine, chief operating officer Manon Cox said at an FDA hearing earlier this year (see Bibliography: FDA 2007: Committee meeting transcript).
The Holy Grail
The Holy Grail of flu vaccine—and the object so far of the greatest wistfulness—is a universal vaccine. "The optimal long-term solution to pandemic vaccination is the development of a new influenza vaccine against an antigen that is present in all influenza subtypes and does not change," Ben Schwartz and Bruce Gellin of HHS's National Vaccine Program Office wrote in 2005 (see Bibliography: Schwartz 2005). So far, however, vaccines based on conserved regions of the virus such as the M2 protein have shown only the ability to reduce disease, not to prevent infection, and have been tested largely in animals, though one clinical trial in humans began last summer (see Bibliography: Acambis PLC 2007).
Although money for pandemic influenza vaccine research has begun to flow and results have picked up speed, there is widespread frustration that it all took so long.
"If we are serious about a pandemic, we should assume it is going to be imminent and we should be prepared as if it is imminent—not 10, 15 years down the road, but imminent," said David Fedson, MD, a retired vaccine industry executive who has published analyses of pandemic vaccine planning (see Bibliography: Fedson 2007: Author interview).
A chorus of calls to action
Calls have come from across the political spectrum for a more aggressive, better-funded, tightly organized research effort. Former Senate Majority Leader William H. Frist (R-Tenn.) called in August 2005 for a "Manhattan Project for the 21st century" (see Bibliography: Frist 2005). In the same month, Michael T. Osterholm, PhD, MPH, director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of CIDRAP News, recommended the creation of "an international project to develop the ability to produce a vaccine for the entire global population within several months of the start of a pandemic [that would be] a top priority of the Group of Seven industrialized nations plus Russia (the G-8)" (see Bibliography: Osterholm 2005).
Further, the nonprofit, nonpartisan advocacy group Trust for America's Health recommended in October 2006 that governments create a "multinational pandemic vaccine research and development master program" (see Bibliography: Trust for America's Health 2006), and the Infectious Diseases Society of America (IDSA) echoed that call in January 2007, recommending an appropriation of $2.8 billion in such a project's first year (see Bibliography: IDSA 2007).
"An effort on the scale of the Apollo space project is required," the IDSA said.
The Manhattan Project and the nuclear bombs that resulted from it are a sensitive subject to raise in a health crisis that demands international cooperation—particularly a health crisis centered in Asia, where the bombs were used.
But implicit in the invocation of that all-out effort is a hunger for the power, funding, freedom from bureaucracy, and single-minded focus that its leaders enjoyed. The Manhattan Project was founded at emergency speed: The lag time between Albert Einstein's famous letter advising President Franklin Roosevelt that nuclear fission might permit the creation of "extremely powerful bombs" and the first meeting of a newly formed federal Advisory Committee on Uranium was a mere 10 days. The project’s chief, Brigadier General Leslie Groves, was handpicked for his reputation for ruthless efficiency. Even after the United States entered World War II in December 1941, the project boasted the ability to cherry-pick any staff and claim any funding it needed; eventually it employed 130,000 people and received $2 billion in 1940s dollars (about $23 billion today).
Most notably for parallels to pandemic policy, the Manhattan Project simultaneously pursued multiple research paths into nuclear fission and weapons development, dropping entire avenues of inquiry and increasing other labs' funding and staff as results emerged. And from the time of Einstein's letter in 1939 to the dropping of two atomic bombs on Japan in 1945, less than 6 years elapsed (see Bibliography: Schwartz 1998; Gosling 1999).
"I feel as a scientist that we could make progress more rapidly if we sat down in advance and came up with a big-picture strategy and then funded it," said Dr. Gregory Poland, director of the Mayo Clinic's Vaccine Research Group in Rochester, Minn. "We have neither a process for rapidly developing new vaccines nor a track record" (see Bibliography: Poland 2007).
The National Institute of Allergy and Infectious Diseases (NIAID), the primary conduit of federal flu research funds to scientists, believes it does have a robust research agenda. Dr. Carole Heilman, director of the division of microbiology and infectious diseases, points to the flu-research recommendations issued by a blue-ribbon NIAID panel this year as evidence that the agency is guiding extramural researchers to critical questions about flu (see Bibliography: Heilman 2007, NIAID 2007). But with funding limited until recently, much of the research being conducted came into being because of private-sector interests rather than an overarching plan, said longtime flu researcher Dr. Arnold Monto of the University of Michigan (see Bibliography: Monto 2007).
Redefining the problem
Those calling for a Manhattan Project–like effort say that what is needed is much broader than what NIAID or all of NIH could deliver. It requires active coordination among all the federal health agencies along with cooperation from congressional funders, plus parallel efforts in other countries. "Pandemic vaccine development has been viewed primarily as a vaccine problem that should be addressed with better science," Fedson said, "but fundamentally it is a global public health problem that requires better management" (see Bibliography: Fedson and Dunnill 2007: From scarcity to abundance).
And, they say, it is urgent that such an effort be established soon, because there is no way of predicting accurately when a pandemic might arrive. If it arrives soon rather than later, the lack of vaccine in most of the world will create a divide between haves and have-nots that could corrupt international relations long after the pandemic ends.
The long standoff with the Indonesian government over sharing of H5N1 isolates has provided a foretaste of the disruption such resentment could cause. The health ministry of Indonesia—the country that has experienced the most human cases and deaths from H5N1 flu—stopped sending isolates to World Health Organization (WHO) collaborating laboratories in late 2006. Those laboratories both analyze the isolates to track the evolution of seasonal and novel flu strains and use them to develop pandemic vaccine candidates; Indonesia's decision to stop contributing was apparently triggered by the realization that it could never afford to purchase vaccines made from isolates it provided.
By challenging the WHO, Indonesia deprived the international community of a key source of information on emerging flu viruses. It also emboldened other developing countries to join its protest, leading to a week-long negotiation at the annual World Health Assembly (WHA), a WHA resolution promising reconsideration of the virus-sharing system, and WHO commitments to invest in vaccine manufacturing in the developing world. The concessions did not completely repair relations, however: The question of control over viruses remains open and will be discussed again at a WHO meeting in Geneva that opens Nov 5 (see Bibliography: McKenna 2007: System for global; McKenna 2007: Virus ownership).
It is possible that failing to achieve a pandemic vaccine when it is needed—or even failing to confront in advance the possibility that supplies will fall short—could fracture international pandemic preparations just when cooperation will be essential.
"At this point, when a pandemic happens, vaccines are going to provide some benefit to a very limited number of people," Osterholm said. "But they are also going to create a major diversion of activity and energy when the decisions have to be made about who gets what limited vaccine exists. I worry that their negative impact will outweigh their positive impact: They will cause a crisis of leadership around the world" (see Bibliography: Osterholm 2007).
This article was originally published in CIDRAP News as a seven-part series running from October 25 through November 2, 2007.
Acambis PLC. Acambis' universal influenza vaccine enters phase 1 trial. Jul 17, 2007
BD. Author interview with George Goldman, Senior Director, Hypodermic Divison, BD Medical Surgical Systems. Jul 25, 2007
Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 2007 Feb 15;256(7):685-96 [Full text]
Belshe RB, Nichol KL, Black SB, et al. Safety, efficacy, and effectiveness of live, attenuated, cold-adapted influenza vaccine in an indicated population aged 5-49 years. Clin Infect Dis 2004 Oct 1;39(7):920-7 [Full text]
Bosch Technologies. Author interview with Eric Isberg, Jack Lysfjord, and Tony Miller. Aug 3, 2007
Bresson JL, Perrone C, Launay O, et al. Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial. Lancet 2006 May 20;367(9523):1657-64 [Abstract]
CDC. Isolation of avian influenza A(H5N1) viruses from humans—Hong Kong. May-December 1997. MMWR 1997 Dec 19;46(50):1204-7 [Full text]
CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2005 Jul 29;54(RR08):1-40 [Full text]
CDC. State-specific influenza vaccination coverage among adults aged >/= 18 years—United States, 2003-04 and 2005-06 influenza seasons. MMWR 2007 Sep 21;56(37):953-9 [Full text]
Crosby AW. America's forgotten pandemic: the influenza of 1918. Cambridge [England]; New York, Cambridge University Press, 1989
ECDC (European Centre for Disease Prevention and Control). 'Pre-pandemic' vaccines might offer protection but uncertainties remain. Sep 20, 2007 [Press release]
ECDC. Expert advisory groups on human H5N1 vaccines: scientific questions. Technical report. Aug 2007 [Full text]
EMEA (European Medicines Agency). Guideline on adjuvants in vaccines for human use. Jan 20, 2005 [Full text]
Fauci AS. Seasonal and pandemic influenza preparedness: science and countermeasures. J Infect Dis 2006 Nov 1;194(suppl 2):S73-6 [Full text]
FDA. Guidance for industry: Clinical data needed to support the licensure of pandemic influenza vaccines. May 31, 2007 [Full text]
FDA. Vaccines and Related Biological Products Advisory Committee meeting transcript. Feb 27, 2007
Fedson DS. Author interview with David Fedson. Jun 19, 2007
Fedson DS. Pandemic influenza and the global vaccine supply. Clin Infect Dis 2003 Jun 15;36(12):1552-61 [Full text]
Fedson DS, Dunnill P. From scarcity to abundance: pandemic vaccines and other agents for "have not" countries. (Commentary) J Public Health Policy 2007;28(3):322-40 [Abstract]
Fedson DS, Dunnill P. New approaches to confronting an imminent influenza pandemic. (Commentary) Perm J 2007 summer;11(3):63-9 [Full text]
Ferguson NM, Cummings DA, Fraser C, et al. Strategies for mitigating an influenza pandemic. (Letter) Nature 2006 Jul 27;442(7101):448-52 (published online Apr 26) [Abstract]
Fraser C. Influenza pandemic vaccines: spread them thin? PLoS Med 2007 Jun;4(6):e228 [Full text]
Frist W. The Manhattan project for the 21st century. Presented at Nantucket Atheneum, Nantucket, MA, Aug 3, 2005 [Full text]
GAO (Government Accountability Office, formerly General Accounting Office). Flu vaccine: recent supply shortages underscore ongoing challenges. Testimony by Janet Heinrich before House Subcommittee on Health, Subcommittee on Oversight and Investigations, and Committee on Energy and Commerce. GAO-05-177T. Nov 18, 2004 [Full text]
GAO. Flu vaccine: steps are needed to better prepare for possible future shortages. Testimony by Janet Heinrich before US Senate Special Committee on Aging. GAO-01-786T. May 30, 2001 [Full text]
GAO. Flu vaccine: supply problems heighten need to ensure access for high-risk people. Report to Congressional Requestors. GAO-01-624. May 15, 2001 [Full text]
Germann TC, Kadau K, Longini IR, et al. Mitigation strategies for pandemic influenza in the United States. Proc Natl Acad Sci 2006 Apr 11;103(15):5935-40 [Abstract]
Goodman J. Considerations in the pre- and early pandemic use of influenza vaccine. Presented at FDA Center for Biologics Evaluation and Research Vaccines and Related Biological Products Advisory Committee Meeting, Gaithersburg, MD, Feb 27, 2007
Goodman J. How fast can a new vaccine for an emerging respiratory virus be developed and available for use? Presented at the International Conference on Emerging Infectious Diseases, Atlanta, GA, Mar 22, 2006
Gosling FG. The Manhattan Project: making the atomic bomb. Oak Ridge, TN: US Department of Energy History Division, Jan 1999 [Full text]
Govorkova EA, Webby RJ, Humberd J, et al. Immunization with reverse-genetics–produced H5N1 influenza vaccine protects ferrets against homologous and heterologous challenge. J Infect Dis 2006 Jul 15;194(2):159-67 [Full text]
Grady D. With few suppliers of flu shots, shortage was long in making. New York Times. Oct 17, 2004 [Full text]
GSK (GlaxoSmithKline). Backgrounder: Egg-based vs. cell-based influenza vaccine production. 2005
GSK. GlaxoSmithKline awarded $63 million HHS contract for pandemic vaccine research and development. Jan 17, 2007 [Press release]
Haaheim L. Vaccines for an influenza pandemic: scientific and political challenges. Influenza Other Respir Virus 2007;1(2):55-60 [Abstract]
Hehme N. GSK's pandemic vaccine development: from 1st to to 2nd generation candidate vaccines. Presented at the 3rd WHO Meeting on Evaluation of Pandemic Influenza Prototype Vaccines in Clinical Trials, Geneva, Feb 15-16, 2007 [Full text]
Heilman C. Author interviews with Carole Heilman. Sep 13 and Sep 24, 2007
HHS (Department of Health and Human Services). HHS awards contracts totaling more than $1 billion to develop cell-based influenza vaccine. May 4, 2006 [Full text]
HHS. HHS awards two contracts to expand domestic vaccine manufacturing capacity for a potential influenza pandemic. Jun 14, 2007 [Full text]
Hoffenbach A. Update of Sanofi Pasteur EU pandemic vaccine clinical development. Presented at the 3rd WHO Meeting on Evaluation of Pandemic Influenza Prototype Vaccines in Clinical Trials, Geneva, Feb 14, 2007 [Full text]
IDSA (Infectious Diseases Society of America). Pandemic and seasonal influenza principles for US action. Released Jan 25, 2007 [Full text]
IOM (Institute of Medicine). New vaccine development. 1985;1
IOM. Vaccines for the 21st century. Released Mar 1999 [Full text]
Iomai. Iomai awarded government contract, totaling $128 million, to develop dose-sparing patch for use in an influenza pandemic. Jan 17, 2007 [Press release]
Keitel W. A phase I-II, randomized, controlled, dose-ranging study of the safety, reactogenicity, and immunogenicity of intramuscular inactivated influenza A/H5N1 vaccine given alone or with aluminum hydroxide to healthy adults. Presented at the Options for the Control of Influenza VI meeting, Toronto, Jun 2007
Kotalik J. Preparing for an influenza pandemic: ethical issues. Bioethics 2005 Aug;19(4):422-31 [Abstract]
Kreijtz JH, Bodewes R, van Amerongen G, et al. Primary influenza A virus infection induces cross-protective immunity against a lethal infection with a heterosubtypic virus strain in mice. Vaccine 2007 Jan 8;25(4):612-20 [Abstract]
Kresse H. Author interview with Hedwig Kresse. Aug 2, 2007
Lauerman J. Glaxo, Novartis, hurt by drug setbacks, may lose flu-shot race. Bloomberg News. Aug 23, 2007
Leroux-Roels K, Borkowski A, Vanwolleghem T, et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007 Aug 18;370(9587):580-9 [Abstract]
Lin J, Zhang J, Dong X, et al. Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial. Lancet 2006 Sep 16;368(9540):991-7 [Abstract]
Lipatov AS, Webby RJ, Govorkova EA, et al. Efficacy of H5 influenza vaccines produced by reverse genetics in a lethal mouse model. J Infect Dis 2005 Apr 15;191(8):1216-20 [Full text]
Longini IM, Nizam A, Xu S, et al. Containing pandemic influenza at the source. Science 2005 (published online Aug 3) [Abstract]
Lowen AC, Mubareka S, Tumpey TM, et al. The guinea pig as a transmission model for human influenza viruses. Proc Natl Acad Sci 2006 June 27;103(26):9988-92 [Full text]
Luke CJ, Subbarao K. Vaccines for pandemic influenza. Emerg Infect Dis 2006 Jan;12(1):66-72 [Full text]
McKenna M. System for global pandemic vaccine development challenged. Minneapolis, MN: CIDRAP News, Feb 6, 2007 [Full text]
McKenna M. Virus ownership claims could disrupt flu vaccine system. Minneapolis, MN: CIDRAP News. Jun 19, 2007 [Full text]
Monto A. Author interview with Arnold Monto. Aug 2, 2007
NIAID (National Institute of Allergy and Infectious Diseases). Report of the Blue Ribbon Panel on Influenza Research. Bethesda, Md., Sep 11-12, 2006. Posted Jun 2007 [Full text]
Nicholson KG, Colegate AE, Podda A, et al. Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza. Lancet 2001 Jun 16;357(9272):1937-43 [Abstract]
NIH (National Institutes of Health). Flu 2001-2008 estimated budget numbers spreadsheet, compiled for the author by NIH press office. 2007
Novartis. Flu Cell Culture Technology: The Next Frontier. 2006
Novartis. Novartis gains European approval for its innovative flu vaccine Optaflu. Jun 13, 2007, news release
Novartis. Novartis receives US government contract to further develop a novel antigen technology that could extend vaccine supplies in a pandemic outbreak. Jan 17, 2007, news release [Full text]
OIE (World Organization for Animal Health). Update on avian influenza in animals (type h5), 15 Sep 2007 [Link updated regularly]
Osterholm MT. Author interviews with Michael Osterholm. May 3 and Aug 2, 2007
Palkonyay L. Personal communication from Laszlo Palkonyay, MD, medical officer, WHO Initiative for Vaccine Research. Oct 25, 2007
Petrovsky N. New-age vaccine adjuvants: friend or foe? BioPharm Int Aug 2, 2007 [Full text]
Poland GA. Author interview with Gregory Poland. Aug 1, 2007
Poland GA. Vaccines against avian influenza—a race against time. (Editorial) N Engl J Med 2006 Mar 30;354(13):1411-3 [Full text]
Protein Sciences Corp. Influenza vaccines under development. 2007
Riley S, Wu JT, Leung GM. Optimizing the dose of pre-pandemic influenza vaccines to reduce the infection attack rate. PLoS Med 2007 Jun;4(6):e218 [Full text]
Rosenwald MS. FluMist gets a needed boost: refrigerated version cleared. Washington Post. Jan 9, 2007 [Full Text]
Royal Society. Pandemic influenza: science to policy. Nov 2006 [Full text]
Sanofi Pasteur. Sanofi Pasteur announces completion of construction of new U.S. influenza vaccine manufacturing facility. Jun 20, 2007, news release [Full text]
Santoli J. Influenza vaccine distribution data and use of data during the 2006-07 season. Presented at the National Influenza Vaccine Summit, Atlanta, Apr 2007 [Presentation]
Schwartz SI. Atomic audit : the costs and consequences of U.S. nuclear weapons since 1940. Washington, DC: Brookings Institution Press, 1998
Smith GJD, Fan XH, Wang J, et al. Emergence and predominance of an H5N1 influenza variant in China. Proc Natl Acad Sci 2006 Nov 7;103(45):16936-41 [Full text]
Stephenson I, Bugarini R, Nicholson KG, et al. Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/duck/Singapore/97 (H5N3) vaccine: a potential priming strategy. J Infect Dis 2005 Apr 15;191(8):1210-5 [Full text]
Stephenson I, Gust I, Kieny MP, et al. Development and evaluation of influenza pandemic vaccines. Lancet Infect Dis 2006 Feb;6(2):71-2
Stephenson I, Gust I, Pervikov Y, et al. Development of vaccines against influenza H5. Lancet Infect Dis 2006 Aug;6(8):458-60
Stephenson I, Nicholson KG, Wood JM, et al. Confronting the avian influenza threat: vaccine development for a potential pandemic. Lancet Infect Dis 2004 Aug;4(8):499-509 [Abstract]
Strikas R. Pandemic influenza vaccine supply issues. Presented at the National Vaccine Advisory Committee Pandemic Influenza Working Group Meeting, Washington, DC, Apr 20, 2005
Subbarao K, Joseph T. Scientific barriers to developing vaccines against avian influenza viruses. Nat Rev Immunol 2007 April;7(4):267-78 [Full text]
Thomas A, Guldager N, Hermansen K. Pandemic flu preparedness: a manufacturing perspective. BioPharm Int 2007 Aug (supp) (published online Aug 2) [Full text]
Treanor JJ, Campbell JD, Zangwill KM, et al. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 2006 Mar 30;354(13):1343-51 [Full text]
Treanor JJ (for Goji NA, Nolan C, Hill H, et al). Immune responses of healthy subjects to a single dose of intramuscular inactivated influenza A/Vietnam/1203/2004 (H5N1) vaccine after priming with an antigenic variant. Presented at 3rd WHO Meeting on Evaluation of Pandemic Influenza Prototype Vaccines in Clinical Trials, Geneva, Feb 15-16, 2007 [Full text]
Treanor JJ, Schiff GM, Couch RB, et al. Dose-related safety and immunogenicity of a trivalent baculovirus-expressed influenza-virus hemagglutinin vaccine in elderly adults. J Infect Dis 2006 May 1;193(9):1223-8 [Full text]
Treanor JJ, Schiff GM, Hayden FG, et al. Safety and immunogenicity of a baculovirus-expressed hemagglutinin influenza vaccine: a randomized controlled trial. JAMA 2007 Apr 11;297(14):1577-82 [Abstract]
Trust for America's Health. Flu spending update: pandemic planning and resource allocation. 2007
Trust for America's Health/Infectious Diseases Society of America. Pandemic influenza: the state of the science. Oct 2006 [Full text]
Vajo Z, Kosa L, Visontay I, et al. Inactivated whole virus influenza A (H5N1) vaccine. (Letter) Emerg Infect Dis 2007 May;13(5) (published online Mar 29) [Full text]
WHO. WHO consultation on priority public health interventions before and during an influenza pandemic. Apr 27, 2004
WHO. Global Advisory Committee on Vaccine Safety, 6-7 June 2006. Meeting report released Jun 14, 2006 [Full text]
WHO. Global pandemic influenza action plan to increase vaccine supply. Released Oct 23, 2006 [Full text]
WHO. Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO, 10 Sep 2007
WHO. Projected supply of pandemic influenza vaccine sharply increases. Oct 23, 2007 [Press release]
Wood JM. Author interview with John Wood. Jun 18, 2007
Wood JM. International standards for H5N1 antibodies. Presented at the 3rd WHO meeting on evaluation of pandemic influenza prototype vaccines in clinical trials, Geneva, Feb 15-16, 2007 [Full text]
Wood JM. Reference viruses for seasonal and pandemic influenza vaccine preparation. Influenza Other Respir Virus 2007 Jan;1(1):5-9 [Abstract]
Working Group for Pandemic Influenza Preparedness. Letter to Congress. Jun 5, 2007 [Full text]
Working Group for Pandemic Influenza Preparedness. Letter to Congress. Nov 10, 2005 [Full text]
Zangwill K, Campbell J, Noah D, et al. Evaluation of a third dose of subvirion H5N1 influenza vaccine (rgA/Vietnam/1203/04 x PR8) in healthy adults. Presented at Options for the Control of Influenza VI, Toronto, Jun 17-23, 2007