THE PANDEMIC VACCINE PUZZLE

[Guest guest]

Osterholm must not be aware of Poland's plans.

http://www.cidrap.umn.edu/cidrap/content/influenza/panflu/news/oct2607panvax2.ht\

ml

THE PANDEMIC VACCINE PUZZLE

Part 2: Vaccine production capacity falls far short n McKenna Contributing

Writer

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) ¡V 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 weeks 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¡Xall 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: 2007).

But the more difficult obstacle is not the time needed to produce vaccine¡Xwhich

newer technologies such as cell culture could shorten to some degree¡Xbut 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 year¡Xsomething 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

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¡Xwhether that means Indonesia or

Sweden or Spain¡Xyou get nothing " (see Bibliography: Fedson 2007: Author

interview).

The nine countries¡XFrance, Germany, Italy, The Netherlands, Switzerland, the

United Kingdom, the United States, Canada, and Australia¡Xtrade 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 ƒn40% 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¡Xbut 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¡X69.3%¡Xwas 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 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)¡Vfunded 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: 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¡Xwitness the $133 million given to two manufacturers this past

summer to retrofit existing plants and the $1 billion awarded for cell-culture

research¡Xmuch 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¡Xbecause it does nothing to expand

capacity for critical downstream tasks such as bottling and administering

completed vaccine.

The " fill-finish " sector¡Xwhich puts bulk manufactured vaccine into vials or

syringes¡Xis not being asked to prepare for any excess capacity, said Jack

Lysfjord, vice-president for pharmaceutical consulting in the Valicare division

of 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 Goldman, senior

director for hypodermics at BD Medical Surgical Systems in lin 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¡Xon their own behalf and for the pharmaceutical

manufacturers who feed product to them¡Xthat 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. "

Recent Activity

4

New Members

Visit Your Group

Healthy Eating

Find

that are focused

on healthy eating.

Moderator Central

get help and provide

feedback on Groups.

Dog Groups

on

discuss everything

related to dogs.

.