Wednesday, July 22, 2009

U.S. to Hog Swine Flu Vaccines?

Will U.S. follow World Health Organizations' Recommendations on Vaccine Formulation with "adjuvants," or will it hog up all the "good stuff" for itself and create a world wide shortage?

A ProMED-mail post

ProMED-mail is a program of the
International Society for Infectious Diseases

In this update:
[1] Strategy
[2] Production problems

[1] Strategy
Date: Tue 21 Jul 2009
Source: Nature, online 460, 446 (2009), 21 Jul 2009 [edited]

Imminent decisions on a strategy for H1N1 pandemic flu vaccination in
the United States could leave other countries short of vital doses if
it elects not to follow World Health Organization (WHO) advice on
vaccine formulation. The United States is the biggest buyer among a
group of rich countries whose combined orders for vaccine against the
H1N1 2009 virus could potentially tie up most of the world's pandemic
vaccine production capacity for 6 months or longer, so depriving
other countries of vaccine.

To counter this prospect, the WHO recommended on 13 Jul 2009 that
countries use shots that contain adjuvants, chemicals that boost the
immune system's response to a vaccine. This allows smaller amounts of
antigen -- the molecule that stimulates the immune response -- be
used in each dose, boosting the overall amount of vaccine available
from existing production capacity and allowing orders to be filled
more quickly.

The United States' global responsibility to consider dose-sparing
strategies is briefly alluded to in the minutes of a mid-June 2009 US
National Bio defense Science Board meeting, released on 17 Jul 2009:
"Federal decision-making will affect not only the 300 million
Americans who depend on the government to support the public health
system but also people all around the world."

The United States has certainly kept open the option of using
adjuvants. It has already allocated almost USD 2 billion for antigen
and adjuvant to provide every American with up to 2 doses of vaccine.
That sum includes orders of USD 483 million for Novartis's MF59
adjuvant, and USD 215 million for GlaxoSmithKline's AS03 adjuvant.

But although Canada and many European countries are set to use
adjuvanted pandemic flu vaccines, the United States may do so only as
a last resort. "All things being equal, an unadjuvanted vaccine is
often just fine in terms of giving protection against influenza
virus," Anne Schuchat, director of the National Center for
Immunization and Respiratory Diseases at the Centers for Disease
Control and Prevention in Atlanta, Georgia, told a media briefing on
17 Jul 2009.

"Adjuvant use would be contingent upon showing that it was needed or
clearly beneficial," added Jesse Goodman, acting chief scientist and
deputy commissioner of the Food and Drug Administration (FDA). "But
we want them on the table in case there are issues where they might
be needed to protect people in this country." If there is significant
genetic drift in the virus, for example, adjuvanted vaccines are
better able to handle such strain variations. And early attempts at
pandemic vaccine manufacture are so far producing 2 to 4 times less
antigen than seasonal flu strains, raising the threat that the
world's production capacity is actually much less than was hoped.

If each shot of pandemic flu vaccine contains 15 micrograms of
antigen -- the dose used in seasonal flu -- and no adjuvant, annual
global capacity stands at about 876 million doses, according to the
WHO. But as virtually no one is immune to the virus, most experts say
that each person will need 2 doses, immediately halving that
capacity. Moreover, higher doses of antigen may be needed to get an
adequate response, further reducing capacity. Using adjuvants would
boost annual capacity to more than 2 billion doses in some WHO

Europe is well placed to quickly authorize adjuvanted pandemic
vaccines. Since 2003, the European Medicines Agency (EMEA) has had a
fast-track approval system in which manufacturers can prepare
"mock-up dossiers," vaccine registration applications that use
non-pandemic viral strains but for which pandemic strains can
subsequently be substituted. GlaxoSmithKline and Novartis already
have mock-up dossiers in place for the H5N1 avian flu virus and plan
to file H1N1 substitutions by the end of July 2009.

Although the EMEA requires the companies to provide new clinical
testing and data as they roll out their products, the product itself
can be approved in 5 days if the agency is satisfied that the
extrapolation to the new strain is valid, says Martin Harvey-
Allchurch, a spokesman for the EMEA. In contrast, the United States
has never licensed an adjuvanted flu vaccine and has no fast-track
system in place, although the FDA can give emergency authorization
for new vaccines. The regulators are also mindful of political and
public concerns about mass vaccination of the population, given that
a vaccination programme in 1976 against a new strain of swine flu
caused neurological side effects in about one in 100 000 people and
killed 25. Modern flu vaccines, however, have a very good safety

The WHO's Global Advisory Committee on Vaccine Safety says "no
significant safety concern or barriers" exist to using adjuvanted
pandemic H1N1 vaccines. But regulatory agencies may have to approve
pandemic vaccines -- both adjuvanted and non-adjuvanted -- without
all the data they would normally require, warns Marie-Paule Kieny,
the WHO's vaccine research director. Some preliminary clinical and
safety data may be available by September 2009, when flu cases could
surge in the Northern Hemisphere, but complete data for adults are
unlikely to be available until the end of December 2009, and not
until February 2010 for children. Regulators would accompany pandemic
vaccine rollouts with parallel clinical trials, and, as in any
mass-vaccination campaign, extensive surveillance would monitor for
any adverse side effects.

[Byline: Declan Butler]

Communicated by:
ProMED-mail Rapporteur Mary Marshall

[2] Production problems
Date: Tue 21 Jul 2009
Source: CFRB Newstalk 1010, The Canadian Press report [edited]

It may take substantially longer to make the full amounts of swine
flu vaccine countries have contracted to buy because efforts to
improve the yield of the vaccine seed strains aren't bearing fruit,
experts say. Three of the laboratories involved in the work are
sounding increasingly pessimistic that the yield problem can be fixed
in the short term. Vaccine manufacturers have reported they are
getting between 50 per cent and 75 per cent less vaccine with the new
H1N1 virus as they do when they make seasonal flu vaccine. "It's not
looking very bright at the moment," John Wood, principal scientist at
Britain's National Institute for Biological Standards and Control,
said in an interview Tuesday [21 Jul 2009]. "In effect, it means if
we continue like this, manufacturers will have to keep on producing
(pandemic) vaccine for longer to make the number of doses needed."

The flu laboratories at the U.S. Centers for Disease Control have
made 3 new seed strains and are in the process of completing the
paperwork needed to ship them to the manufacturers. The head of the
CDC's influenza division said while the new vaccine candidate viruses
are growing well in the hands of her scientists, there's no guarantee
they will produce a better yield when manufacturers start to work
with them. Dr. Nancy Cox said the issue isn't simply about growth,
but also about how well the vaccine viruses hold up during the
various steps of the manufacturing process. "I think it is possible
we won't have a better yielding virus," she admitted from Atlanta.
"(But) I think that it's still too early to say how this will impact
the amount of vaccine that's available."

Each flu virus has its own characteristics, and vaccine makers are
accustomed to working with new strains, fine-tuning processes to try
to coax maximum yield from a virus. A spokesperson for vaccine giant
Sanofi Pasteur said the company feels it hasn't yet exhausted efforts
to improve the yield of the seed strain for the pandemic vaccine.
Still, Len Lavenda suggested Sanofi doesn't expect those efforts to
fully correct the problem. "Although we think it's too soon to
project what the final yield will be, we anticipate it will remain
lower than seasonal vaccine yield," Lavenda said from Sanofi's
headquarters in Swiftwater, Pa. "Certainly if the yield doesn't
increase, it means it will take longer to produce the vaccine. (But)
I think at this point in time we remain hopeful that we'll be able to
increase the yield and think it's premature to throw in the towel, so
to speak."

The various companies making pandemic vaccine have been working with
a seed strain produced at New York Medical College in Valhalla, N.Y.
Its laboratory pioneered the process of engineering vaccine viruses
to maximize growth decades ago, and scientists there have produced
many of the vaccine seed strains used since. Its 1st swine flu seed
strain was overwhelmingly viewed as the best yielder by vaccine
manufacturers. But even at that, manufacturers said they got about
half of the yield generated with seasonal flu production. Doris
Bucher, who heads the lab, says her team is trying other options, but
they haven't seen anything promising yet. And she's heard
manufacturers' efforts aren't paying off either. "Usually, they tweak
it, and it grows better. But it hasn't responded to tweaking. ...
That's the feedback I'm getting."

Seed strains are hybrid viruses that have the surface genes of the
virus the vaccine is meant to protect against merged with the
internal genes of an old flu virus that is known to grow well in
eggs. Typically those hybrids -- called reassortants -- are made up
of 6 genes from the high-growth virus with 2 genes from the target
virus, which in this case is the new H1N1.

Seed strains can be made by 2 different processes. One, called the
classical method, involves co-infecting growth medium with the 2
types of viruses and letting them swap genes on their own. The other
involves a patented process called reverse genetics that essentially
allows scientists to piece together the desired constellation of
genes. Bucher's 1st seed strain was made using the classical method,
which means any vaccine made from it wouldn't require manufacturers
to pay royalties for the seed strain. But the new CDC-produced seed
strains were made using reverse genetics. If manufacturers switch to
use one of them, royalties for every dose of vaccine sold will be due
to the U.S. vaccine company MedImmune, which holds the patent. Bucher
said her original seed strain was made with 3 genes from the swine
flu virus and 5 from the high-growth virus. Her team is now trying to
see if a 6 and 2 constellation would work better. But she and others
admitted the yield problem may be due to something inherent in the
swine flu viruses.

"It possibly is," admitted Wood, whose lab also generated seed
strains in the 1st round of production. "This is unusual, having all
the labs who usually do this work and there still being a less than
satisfactory outcome. Usually, we get at least one virus which is
good, average to good. And this time, none of them are."

[Byline: Helen Branswell]

Communicated by:
ProMED-mail Rapporteur Mary Marshall

[The logistics of production and delivery of an effective influenza
pandemic (H1N1) 2009 virus vaccine are complex and will take time to
resolve. As suggested by previous correspondents, dose sparing
measures (such as intradermal vaccination) may have to be brought
into play in the short term at least to conserve materials. - Mod.CP]

[see also:
Influenza pandemic (H1N1) 2009 (10): vaccine 20090720.2577
Influenza pandemic (H1N1) 2009 (09): UK, pig stockman 20090718.2560
Influenza pandemic (H1N1) 2009 (08): pandemic origins 20090718.2559
Influenza pandemic (H1N1) 2009 (07): Argentina, swine, alert 20090718.2557
Influenza pandemic (H1N1) 2009 (06): case reporting 20090717.2553
Influenza pandemic (H1N1) 2009 (05): vaccine 20090716.2540
Influenza pandemic (H1N1) 2009 (04): pandemic origins 20090715.2527
Influenza pandemic (H1N1) 2009 (03): vaccine 20090713.2505
Influenza pandemic (H1N1) 2009 (02): obesity risk factor 20090711.2482
Influenza pandemic (H1N1) 2009 - Viet Nam: patient data 20090708.2450
Influenza A (H1N1) - worldwide (86): official nomenclature 20090706.2430]

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