Editor's note: This is the second in a seven-part series investigating the prospects for development of vaccines to head off the threat of an influenza pandemic posed by the H5N1 avian influenza virus. The series puts promising advances in vaccine technology in perspective by illuminating the formidable barriers to producing large amounts of an effective and widely usable vaccine in a short time frame. Part 1 described how flu research has been a relatively low priority until very recently, which has left many important scientific questions unanswered.
Oct 26, 2007 (CIDRAP News) 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 approvalall 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 vaccinewhich newer technologies such as cell culture could shorten to some degreebut 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 of three 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 yearsomething 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 thus rise 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 countrywhether that means Indonesia or Sweden or Spainyou get nothing" (see Bibliography: Fedson 2007: Author interview).
The nine countriesFrance, Germany, Italy, The Netherlands, Switzerland, the United Kingdom, the United States, Canada, and Australiatrade 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 risebut 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 shots69.3%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 manufacturerswitness the $133 million given to two manufacturers this past summer to retrofit existing plants and the $1 billion awarded for cell-culture researchmuch 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 incompletebecause it does nothing to expand capacity for critical downstream tasks such as bottling and administering completed vaccine.
The "fill-finish" sectorwhich puts bulk manufactured vaccine into vials or syringesis 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 anxietyon their own behalf and for the pharmaceutical manufacturers who feed product to themthat 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 and headquarters 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."
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'?