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Enough Pandemic Vaccine for the Whole World?

by: SusanC

Tue Feb 13, 2007 at 21:24:23 PM EST


( - promoted by SusanC)

Is it possible to have a pandemic vaccine for the whole world
SusanC :: Enough Pandemic Vaccine for the Whole World?
within the first six months of a pandemic caused by H5N1?
UPDATE  I believe the biggest obstacle to a pandemic vaccine was the mistake made very early on, to tie this to the seasonal vaccine.  That mistake in thinking has brought us to the present state of paralysis.

Let's look at the numbers based on current seasonal flu vaccine production techniques and capacity: (I'm keeping all antigen calculations as ug for ease of discussion)
  • world population: 6.6 billion
  • 86% of the world's population live in countries with no vaccine producing capacity
  • 9 countries produce >95% of all doses
  • global influenza vaccine distribution: 300 million trivalent (= 15ug x 3 x 300 million = 13.5 billion ug)
  • HPAI H5N1 is lethal to chickens, cannot be grown by usual egg-based methods, requires an additional reverse genetics (RG) engineered process
  • RG engineered H5N1 has poor yield in egg-culture, only 1/3 of normal antigen harvested from each egg, therefore annual yield is reduced to 13.5/3 = 4.5 billion ug antigen
  • inactivated subunit vaccine poorly immunogenic
  • non-adjuvanted vaccine needs 90ug x 2 doses (=180ug per person, or 1188 billion ug antigen for 6.6 billion people)
  • if we aim at vaccinated just under 50% of world population ie 3 billion, the requirement is 540 billion ug
  • with addition of alum as adjuvant, the antigen dose can be reduced to 10ug (whole virus, China), 5ug (whole virus, Japan), or 3.75ug (subunit or whole virus, GSK)
  • equivalent to 60/30/22.5 billion ug respectively for world population ie lowest is still at 5x annual capacity
  • using MF59 or other oil-based adjuvants, there may be a further but slight reduction

Some regulatory issues:
  • current standards are based on providing immune protection for individuals against infection during seasonal flu, not for production of herd immunity to stop pandemic
  • in the US, pandemic vaccine license is based on existing seasonal flu vaccine license
  • manufacturer also has to have at least 1 FDA approved vaccine, adding at least 2 years for a new company to successfully license a pandemic vaccine
  • current requirements incentivize towards producing enough doses and efficacy for seasonal flu; they carry no incentive for innovation towards producing massive doses of a low efficacy vaccine
  • there are regulatory barriers to sharing of technology (although BARDA seeks to reduce that)
  • FDA has no specific mandate in facilitating technology sharing and resolving intellectual property (IP) issues
  • liability protection is being offered

So do we have a chance?  Of producing enough vaccines for the world?
There are 2 candidate vaccines worth looking at.
OPTION #1
The first one is the live attenuated vaccine by MedImmune, (the seasonal flu version being FluMist), described in this study in PLOS, Live, Attenuated Influenza A H5N1 Candidate Vaccines Provide Broad Cross-Protection in Mice and Ferrets.  The paper is free, and I am only going to quote part of its editorial comment here:
The researchers developed vaccines using three artificially constructed, weakened forms of the H5N1 influenza virus....from H5N1 viruses isolated from human cases during three different years: 2004, 2003, and 1997. They grew larger quantities of the resulting viruses in hen's eggs, and tested the vaccines in chickens, ferrets, and mice.
In tests of safety, the study found that, unlike the natural viruses from which they were derived, the vaccine strains did not cause death when injected into the bloodstream of chickens, and did not even cause infection when given through the birds' breathing passages. Similarly, while the natural viruses were lethal in mice at various doses, the vaccine strains did not cause death even at the highest dose. In ferrets, infection with the vaccine strains was limited to the upper respiratory tract, while the natural viruses spread to the lungs and other organs.
In tests of protection, all mice that had received any of the three vaccines survived following infection with any of the natural viruses (so-called viral challenge), while unvaccinated mice died following viral challenge. This occurred even though standard blood tests could not detect a strong immune responses following a single dose of vaccine. Challenge virus was detected in the lungs of the immunized mice, but at lower levels than in the unvaccinated mice. Mice given two doses of a vaccine showed stronger immunity on blood tests, and almost complete protection from respiratory infection following challenge. In addition, mice and ferrets that had received two doses of vaccine were protected against challenge with H5N1 strains from more recent outbreaks in Asia that differed substantially from the strains that were used for the vaccine.
This study shows that it is possible to create a live, attenuated vaccine based on a single H5N1 virus that can provide protection (in mice and ferrets, at least) against different H5N1 viruses that emerge years later.
Tests of one of the vaccines in human volunteers in carefully conducted clinical trials are currently under way.

Advantages:
  1. According to the manufacturer, their egg-based production technique for this vaccine is 180x more efficient than for inactivated vaccines.
  2. only one dose is required
  3. needle-free delivery - can be self-administered under supervision, so you can vaccinate large numbers in one sitting.
  4. purification standards are lower than injected vaccines, so it is possible to consider using animal vaccine production facilities
  5. global avian LAIV production in 2006 50 billion doses

UPDATE An important point was brought to by attention by David Fedson, that even though the global avian vaccine production capacity is huge, apparently LAIV cannot be produced in the same type of eggs as those used for inactivated vaccines.  LAIV requires specific pathogen-free (SPF) eggs, the supply of which is not large and is difficult to expand.  Still, his estimate is probably several billion doses can be produced in a matter of months.

Hurdles:

  1. huge regulatory hurdles, national and international
  2. needs global leadership to facilitate sharing of technology and capacity (MedImmune has technology, others have the capacity)
  3. distribution, equity, funding, etc
  4. political will - need co-operation of WHO, FDA, EMEA, and other bodies as well as government and commercial input

OPTION #2

Efficacy of a trivalent recombinant influenza vaccine - Manon Cox

This vaccine is based on the haemagglutinin (HA) protein only, without any other components of the virus.  The process is shown in the following slide (click to enlarge)

Protein Sciences is a small company based in Connecticut.  The seasonal flu version of this vaccine FluBlok, is at the final stages of being licensed, which should happen some time this year.  The H5 vaccine was tested by J Treanor and published in Vaccine 2001 Safety and immunogenicity of a recombinant hemagglutinin vaccine for H5 influenza in humans
Abstract
Recent outbreaks of avian influenza in humans have demonstrated the need for vaccines for influenza viruses with pandemic potential. Recombinant hemagglutinins are an attractive option for such vaccines because they do not require handling potentially highly pathogenic influenza viruses for vaccine production. In order to evaluate the immunogenicity, optimum dosing and timing of administration of a recombinant baculovirus-expressed H5 HA (rH5) in humans, 147 healthy adults were assigned randomly to receive intramuscular rH5 as two doses of 25, 45 or 90 ug each, one dose of 90 ug followed by a dose of 10 ug, or two doses of placebo, at intervals between doses of 21, 28 or 42 days. All doses of rH5 were well tolerated. The rH5 vaccine was modestly immunogenic at high dose. Neutralizing antibody responses to a titer of 1:80 or greater were seen in 23% (14/60) of individuals after a single dose of 90 ug, and in 52% (15/29) after two doses of 90 ug. Varying intervals between doses from 21 to 42 days had no significant effect on antibody responses to vaccination. These results suggest that baculovirus-expressed H5 HA can induce functional antibody in individuals who have not had prior exposure to H5 viruses, but that further studies to improve the immunogenicity of the vaccine are needed.

Advantages:
  1. This vaccine had already been given to 200 healthcare workers in Hong Kong after their 1997 outbreak, with good antigenic titers
  2. short production time - 6 weeks from gene to product
  3. use pure protein instead of H5 virus, no biosecurity risk
  4. cell-culture based, no need for eggs
  5. company's own 10,000L bioreactor can make 1million doses of 135ug rHA vaccine in 5 days.
  6. global capacity is huge.  According to Fedson and Dunnill (unpublished observations) a conservative estimate using 25% of global bioreactor capacity can produce an adjuvanted 3.75ug rHA vaccine for 3.4 billion people in 3 months, greatly exceeding any capacity to vaccinate.

Hurdles
  1. Regulatory - Protein Sciences needs to fulfill FDA requirements of having 1 licensed product first, and having a seasonal flu vaccine using the same technology licensed.  Both will be satisfied by licensing FluBlok in 2007.
  2. This still added a major chunk to time required, and the company's projection is for development of pandemic vaccine in 2009.
  3. It's a small company, does not have the muscle to lobby or negotiate with regulators, probably needs to be target of acquisition.

As these 2 examples show, the technology already exists to produce enough vaccine for the whole world, even though final trials still need to be done.  The technical hurdles are not insurmountable, but the regulatory hurdles are huge. What is needed is political will and leadership, from the WHO, FDA, EMEA and other agencies as well as governments. 
Will it happen?  Can the world, for once, put aside differences and work towards a global solution to a global problem?  I hope so.  I'm not optimistic at this point, but I do hope so.

UPDATE  There will be no pandemic vaccine (that will alter the outcome of a pandemic) until we switch off the autopilot called 'boosting seasonal vaccine uptake' and switch on our BRAINS!
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I don't know all the science involved
But I am sure that hurdle number 3 would mean being acquired by Big Pharma, who at this time, seem to have no interest in developing enough vaccine for the entire world's population without receiving a huge, H U G E paycheck! I see someone like Merck, Pfizer, or another, "acquiring" this company, then putting the recipe on a shelf somewhere...

Right now the problem is not the paycheck
per se, if only someone will actually do it.  At the moment, everybody is standing around waiting for something to happen, for someone to take the lead. 

And when I say standing around, I mean it literally, in the vaccine conference I went to.  All these different companies, lobbyists, researchers, officials, just a lot of standing around talking. 

I had this question about how do we change the regulatory process and principles so as to facilitate a pandemic vaccine rather than a seasonal vaccine.  I asked various HHS and FDA officials, and didn't get anywhere, until one guy who shall remain nameless, after I repeated my question in different ways, gave me this response "You're asking me a policy question over which I have no power."

I also got a close-up look at buck passing:

FDA: "Tell me what you want me to make and I'll make it."
HHS: "We already have so much to do, we're only doing the best we can.  We know it's not enough, but there's only so much I can do."



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
thanks SusanC, and a handful of comments
- 50 billion in one year (for #1) means 6.6 billion in 48 days, and similar figures for #2.  And then doses have to reach recipients.  So NPI still needed, folks!  (And prioritisation starts to make more immediate sense.)
- Why pandemic only?  Can't they start with interpandemic (perhaps for the Southern hemisphere, their "next winter" will come sooner)?
- Both are USA companies - talk about responsibility, worry or stewardship! ;-)  Seriously, it may not need a global aproach, just a USA aproach - or I'm wrong.
- I wonder what China etc are doing, as they probably have facilities to vaccinate their zillion chicken (I suspect).
- They are said to be safe, but are they specifically safe for children?
- What could be our next step (in this area of the multipronged aproach) as fluwikians (or, more generally and more powerfully, as individuals reading this)?

Thanks, SusanC.

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.


definitely NPI would still be needed
And you are right about US companies.  The lead has to come both from the US and the WHO, IMHO.

Interpandemic vaccine - if you are talking about the seasonal one, that's a different story.  I believe the biggest obstacle to a pandemic vaccine was the mistake made very early on, to tie this to the seasonal vaccine.  That mistake in thinking has brought us to the present state of paralysis.

Unfortunately, when an idea has taken hold or has prior attention, it's much harder to change afterwards.  Plus you have all the vested interests, those who are invested in the seasonal vaccine and just want to keep making it year after year.  Manufacturers do not have as much incentive to make a one-off (in their perception) vaccine for something that might not happen. 

Now this could change if the size of the order is big enough, as in global.  OTOH, no single company can handle something of this size, they will have to be part of a consortium.  The regulatory, financial, IP issues involved are huge but not insurmountable.  The WHO and the US need to bring in expertise from not just the science sector, but finance, legal, regulatory, security, venture capitalists, etc.  Many of the global leaders who attend Davos would have expertise to bring this about. 

What might work is if the WHO sets up, either independently or as part of the Pandemic Task Force, a Global Pandemic Vaccine Task Force, to do a case study with a tight deadline to come up with a model with feasibility analysis, identification of stakeholders and production capacity, funding, expertise required, specific legal and regulatory challenges that need to be urgently addressed etc.

Another, less ambitious and easier, way of doing this would be for the US to unilaterally change their regulatory approach for the US pandemic vaccine market to facilitate and incentivize the evolution of the US project to a global one. 

The Indonesian government's recent high-profile refusal to share sequences underscores both the interdependencies and the conflicts between the 'have's' and 'have-not's' of this world.  This is only the foretaste of things to come as and when we edge closer to a pandemic.  I raised this point many months ago, when the debate about sharing sequences first came about.  Have we looked at it from the developing countries' POV?  Why should they give you the sequences for you to make vaccines to save your people while you abandon them to their fate?

In a globalized world where turmoil on other continents have direct repercussions in our domestic wellbeing, we ignore them to our peril. 



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Patch = ten times capacity?
Dr. Susan: Thank you for putting so much together so well. What is your take on the vaccine patch by Iomed(?) that the CEO of the company said could allow 1/10th of the dose to be used and generate the same immune reaction? Is that in the early speculative stage or closer to reality? Why should it work so well, if indeed it does?

can you give a link?
just so I know exactly which one.  thanks!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
link for Iomai patch
Dr. Susan: My apologies for being vague. The link was on CNN-money at http://
money.cnn.com/2007/02/12/news/companies/birdflu/index.htm

and the CEO of the Iomai (not Iomed) Corp. said that their experimental vaccine patch multiplied any given flu vaccine stockpile by a factor of ten, as only 1/10th of the dose was needed. He said that it has been tested on 3000 people and is ready to enter human trials. They have gotten a $128 million contract from the U>S. Health and Human Services to fund studies and test the patch so it can be submitted to the FDA.

I do not understand why the flu vaccine with a patch would be so much more immunogenic than in an injection. But if it is real, wouldn't this make a huge difference to your conclusions?


skin patch
I believe they are talking about the use of an adjuvant patch in combination with an injected vaccine Mass vaccination: solutions in the skin. Glenn et al, Curr Top Microbiol Immunol. 2006;304:247-68. PMID: 16989274

I did a search and found one study where it was used in conjunction with a flu vaccine in the elderly: Improved immune responses to influenza vaccination in the elderly using an immunostimulant patch, Frech et al, Vaccine, 2005

I don't know how well it works and what stage of trials this is at.  It's certainly something to keep in mind, but it won't be anything we can use in the near future, IMO.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
supposing that this works
we are now talking about the distribution and administration of 2 different products per person, ie injection + patch, with all the cost, production capacity etc issue.  It doesn't look like the solution for billions of people IMHO.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Harder with patches?
Dr. Susan: I defer to you in these matters, but in general, if you are talking about hundreds of millions or billions of doses, one could combine the vaccine and the patch in a single product/packet and just have people stick them on, no? I have to believe that one reason that this tiny company is getting more than GSK for bird flu from the government is that they see this as a silver bullet for mass bird flu vaccination. I remain uncertain why it should have such a multiplier effect, even with an adjuvant. But aren't there SEC laws against CEO's spreading false information about their products?

I know what you mean
but the vaccines will still need to be injected, so it can't be self-administered.

I don't think it is false information, there are a lot of studies on adjuvants as multipliers, so this one probably works.  I am only saying that

a) I don't know how far they are in clinical trials for efficacy as well as side effect, I only found one study

b) this is a new technology, so there will be a very high bar for licensing from the FDA, from my limited knowledge, hence the process is likely to take a long time.

c) the use of 2 items, vaccine plus patch is guaranteed to make it both more expensive and logistically much more complicated to manufacture and deliver.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
the 'bar' for licensing devices
is much lower than that for licensing drugs.

It is possible the patch elicits a stronger immune response than an injection of the same formulation due to the greater concentration of immune system cells, lymph nodes and such in and near the skin.

medical information provided is for discussion purposes only and should not be construed as medical advice. if you believe you have a medical problem, consult your practitioner.


[ Parent ]
First, Thanks! You guys (and gals) are 'DOING' much!
SusanC,

Thanks for such an informative post. It's a pleasure and a privilege to have this frontline info.

I have a question, (not just for SusanC),

In your option 2, advantage 3 you state/quote:
"3. use pure protein instead of H5 virus, no biosecurity risk."

Am I understanding this right, that this method provides immunity for ALL H5 viruses? (x16 N types?)

Thanx in advance.

Click here for a curious observation.


I don't know about all H5
it depends on how much the HA is different, but if you are talking about different NA, yes, that would appear to be the case.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Patches instead of needles
Dr. Susan: I went to the Iomai web site (www.iomai.com) and the avian flu patch is exactly what you said - used in addition to a shot. The patch has an adjuvant (doesn't say what it is) put over the injection site that increases immune response. They have tried this successfully on the elderly in preliminary trials. But for regular flu there is another patch that eliminates the needle and combines the vaccine with the adjuvant in a single patch. It uses "TCI" technology, whatever that is. So, at least in principle, one could imagine a patch doing it all, though that is not the work underway. A lot comes down to how much time we have.

the combined vaccine
and adjuvant is not licensed yet.  If you read the regulatory issues on the top diary, the problem is if this is a new technology, and it is, it needs to be licensed for seaseonal flu first, before they can apply for licensing for the pandemic version.  Which lenghtens the time and is IMO conceptually flawed.

I'm just using this vaccine as an example.  If you are developing a vaccine for individual use in normal times to protect against seasonal flu, then the safety barrier has to be high to make sure that the risk from the vaccine is not higher than the benefit from reducing the chance of getting flu. 

OTOH, in a mass fatality global emergency situation, the focus should be on saving as many lives as possible, including maintaining infrastructure, etc.  That being the case, we should be setting a lower safety profile and lower efficacy requirements for a pandemic flu vaccine than the seasonal one, and not a higher hurdle, which is the current situation.  If we do that, and stipulate vaccines licensed under these conditions will not be used for seasonal flu, then we will be able to actually have a pandemic vaccine faster than the current process.

Having a good safe pandemic vaccine is better than having a lower efficacy lower safety  pandemic vaccine, but having the lower efficacy lower safety one is better than not having any!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Update on LAIV, added to top diary
UPDATE An important point was brought to by attention by David Fedson, that even though the global avian vaccine production capacity is huge, apparently LAIV cannot be produced in the same type of eggs as those used for inactivated vaccines.  LAIV requires specific pathogen-free (SPF) eggs, the supply of which is not large and is difficult to expand.  Still, his estimate is probably several billion doses can be produced in a matter of months.

Comment: that probably puts the rHA vaccine in front in this context.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


and a thank you to Dr Fedson n/t




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Inactivated flu vaccine production uses SPF eggs
Inactivated human influenza vaccine, e.g. "FLUARIX" by GlaxoSmithKlein, is produced using embryonated, specific pathogen-free (SPF) chicken eggs. However, the package insert doesn't explicitly say so, while the insert for FluMist (LAIV) does.

Source: Personal phone conversation with GlaxoSmithKlein pharmacist specializing in vaccines. 05Jul06.


[ Parent ]
thanks!
which means it will be even harder to have egg-based vaccines as pandemic vaccine.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
is this being picked up by the press yet?


You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.

Just 16 vaccines needed to eliminate Type A in humans (?)
First I had my H's and N's mixed up.

There are 16 H's, and 9 N's.

With option 2..."This vaccine is based on the haemagglutinin (HA) protein only, without any other components of the virus. "

So if a H5 vaccine is effective on all H5's (N1 thru N9) and there are 16 different H's, in theory we could produce 16 different H vaccines to cover the entire spectrum of Type A influenza.

Whalaa...No more Type A pandemics.

Or am I missing something?

We should start with H5 obviously, then H1, H3, H7 etc.
This of course can't happen until high production capability is achieved, which sounds doable.

Click here for a curious observation.


H5 vs N1 vaccine
I've been reading thru the Protein Sciences web site.
I've read the abstract in their relevant patent and some other articles and reviews.

Cool stuff. It seems they take a very common insect, (larva of a moth that likes corn), and extract a certain cell type from it. This cell can replicate vast quantities of whatever protein it is subject to. Put H5 protien in it, you get lots of H5 protein. If I am reading all of this correctly, it also does NA proteins as well. If in fact that is the case, would not a N1 vaccine work on ALL H5N1 and H1N1, H3N1, etc?

references:
http://www.prnewswir...
http://www.proteinsc...
http://www.freepaten...
http://creatures.ifa...

Click here for a curious observation.


[ Parent ]
yes on N1, however
there may be some difference in antigenicity or effectiveness of antibodies against HA vs antibodies against NA.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
it also depends
on how cross-reactive the antibodies are within different clades of H5.  ie how much mutation or change can it tolerate before it is no longer effective.  We won't know that until we have tried it out.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
well, look out for clinical trials n/t




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
the vaccines...
Protein sciences cancelled vaccine included multiple strains of H5 (and no N1), which should give at least some cross-protection (attenuation of illness, prevention of death) if not full protection (prevention of illness) to descendant strains of the vaccine strains.  The result would be a broad-spectrum partial immunity to H5 viruses.

It is thought (though I do not know if it is proven) that vaccines against N1 would be effective only in attenuating illness, not preventing infection.  That is, they would have the same effect as being your own internally manufactured version of Tamiflu.  For ordinary flu strains (those for which our criteria of vaccine success is 'prevention of illness'), there has not been much deliberate targeting of the N1 moiety.  But when dealing with a high-mortality virus and redefining vaccine success as 'prevents death', targeting N1 more deliberately rather than as an 'add on' or 'afterthought' with the H5 protein, may be more attractive.

Note that it is N1-based immunity which is being postulated as one possible explanation for the age-range skew in cases thus far, with few over-40's becoming infected and a lower mortality in those of that age who do.  But remember this is postulated--a hypothesis--not *proven*, and there are other possible causes for the age distribution which have not been thoroughly ruled out at this point.

medical information provided is for discussion purposes only and should not be construed as medical advice. if you believe you have a medical problem, consult your practitioner.


[ Parent ]
WHO's one-track mind
A timely report came out today in TIME magazine A New Avian Flu Fight

"As the world health organization (WHO) representative on pandemic influenza, Dr. David Heymann has one of the most important jobs in medicine: coordinating international preparations for a possible virus outbreak that could threaten millions of lives. That job got much harder on Feb. 7, when Indonesia announced it had stopped sharing with the WHO the samples of H5N1 avian-flu virus it had isolated. Simultaneously, Jakarta announced an agreement with U.S. drug company Baxter International, which will develop a vaccine from the strains and give Indonesia technical assistance in manufacturing it."

I don't fault the Indonesians doing what they do.  After all, it is the job of their government to look after its people first. 

But the WHO's response is typical of the malaise and sclerosis in the system:

"Instead, Heymann and the WHO are working to expand vaccine production in the developing world, enlisting companies to transfer medical technology there and encouraging wider use of seasonal flu vaccines, considered a luxury in poorer countries."

Given Indonesia's seasonal flu vaccine uptake is a minuscule portion of the 253,000 doses for all of SE Asia, out of a world total of 300M doses, and with a total population of 220M people, how long do you think it's going to take for such 'encouragement of wider use of seasonal flu vaccines' to build the capacity for pandemic vaccine production, even assuming they can afford it?

As I said the other day in a different context

Typical!  Typical!  Typical!  ARGH! 



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


this is the slide that represents
the whole problem, IMHO.  Kudos to Dr Fedson.





All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
global seasonal flu vaccine distribution
from Preparing for pandemic vaccination: an international policy agenda for vaccine development. Fedson, J Public Health Policy. 2005 Apr;26(1):4-29.

also this (click to enlarge)





All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


notice that Egypt
currently uses 1 dose of seasonal flu vaccine per thousand population.  How long will it take to expand that to cover say 30% of the population?

The policy of using 'expanding seasonal flu vaccine uptake' is completely misguided and unrealistic.  It's high time that the WHO and the western nations acknowledge that, throw out those ideas and start afresh.  There is no realistic chance of giving these countries a vaccine should a pandemic start there. 

And, let's face it, wouldn't we all be better off, if we have the technology and enough capacity to comfortably manufacture and supply countries where pandemics are most likely to start as well as our own needs? 



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
enlightened self-interest, they call it - so we need a laser beam!


You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.

[ Parent ]
Indonesia?
Fourth biggest population in the world (245 Million) and where are they?

And where is the largest, China (1.3 Billion)?

ITW(Joel J)
Courage is resistance to fear, mastery of fear - not absence of fear.
- Mark Twain
 


[ Parent ]
nowhere
which shows you the extent of the problem, and why the current approach is way off the mark, IMO.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
WSJ writes about vaccines
See DemFromCT's link here: http://newfluwiki2.c...

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.

Protein Sciences to comment on this thread...
Hi All,

I sent an email to Protein Sciences with a link to this thread. Dr. Manon Cox, Chief Operating Officer at Protein Sciences, responded to that email and she says she read through the thread and will try to respond to some topics this weekend.

From Protein Sciences web site:

Drs. Manon M. J. Cox, MBA
Chief Operating Officer

Manon Cox joined the company in 1998 as Director, Business Development. She has a strong background in biopharmaceutical development, stemming from experience in research and management at Gist-Brocades, a world leader in microbial fermentation. Prior to joining Protein Sciences, she was Manager, New Business Development, Biopharmaceuticals for Gist-Brocades. Manon holds a Drs degree in Molecular Biology, Genetics and Biochemistry from the University of Nijmegen, The Netherlands and a MBA with distinction from the University of Nijenrode (The Netherlands) and the University of Rochester, NY (USA).

I'm sure she will be more than welcomed and any input from her will be greatly appreciated.

Click here for a curious observation.


JWB - that's *dialog* indeed! thanks! :-)


You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.

[ Parent ]
thank you JWB
looking forward to hearing from Dr Cox



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
No Certainty, But At Least Some Real Hope? But who gets what?
I was told just recently that things were actually looking up on this front.  I was surprised after so many false starts announced through investment-bait press releases.

Thanks Susan for boiling this down and explaining it so clearly.  Not easy with this stuff. 

NPI still needed because even if these play out well, there will still be to little for all and unless things change, not much until the pandemic actually starts.

Both issues also raise the question (now in a bit more tangible and realistic terms) of who should get what and when should they get it?

Might be worth revisiting some of the previous discussions.

Minnesota Center for Health Care Ethics
Allocating Pandemic Influenza Vaccines in Minnesota:
Recommendations of the Pandemic Influenza Ethics Work Group

Critical Infrastructure Group - Pandemic Vaccine Prioritization  June 2005

CDC Requesting Public Comment on Vaccine Prioritization - 
Bluetide's Diary

It also places Indonesia's recent 'witholding' in an interesting perspective - because the rationing will be not only within a national community, but between nations in the global community.

World Bank:

  Developing countries from Asia to the Middle East demanded on Tuesday that they receive their "fair" share of limited bird flu vaccines and anti-virals if a deadly pandemic strain emerges. Hard-hit China and Thailand promised to provide more virus samples from birds and humans -- deemed vital for developing vaccines and diagnostic tests for the deadly disease. The debate highlighting the gap between rich and poor countries was held in the Executive Board of the World Health Organization in Geneva, which warned of a "serious" threat that the H5N1 bird flu virus may mutate into a pandemic influenza strain. [Reuters/Factiva]


ITW(Joel J)
Courage is resistance to fear, mastery of fear - not absence of fear.
- Mark Twain
 


Meanwhile
The world only woke up to this problem because of Indonesia's announcement that they will stop sharing samples
Dr. Triono Soendoro, the head of Indonesia's National Institute for Health Research and Development, said the move was designed to ensure the country's 220 million people received access to a vaccine in the event of a human pandemic.

"We made the deal so we don't have to purchase the vaccines at market price," he said in an interview on Wednesday with The Associated Press.

A few notable quotes from Helen Branswell's article:
Move by Indonesia may force solution to vaccine sharing inequities

"We are sending our virus (samples) to the rich countries to produce antivirals and vaccines. And when the pandemic occurs, they survive and we die," Suwit Wibulpolprasert, Thailand.

----

"If we are asking the developing world to do its work for us, what are we giving in return?" asks Dr. Ross Upshur, director of the University of Toronto's Joint Centre for Bioethics and a key contributor to a World Health Organization-led effort to find ways to address the ethical problems posed by pandemic influenza planning.

----

"It has the capacity to undermine the capacity of the world to produce pandemic vaccines if they proceed in a conventional, business as usual way," says Dr. David Fedson, a retired academic and flu vaccine industry expert.

"We should have seen this coming, folks," he says of Indonesia's decision.


This is from The Lancet editorial
Global solidarity needed in preparing for pandemic influenza

In November, 2004, a WHO consultation reached the depressing conclusion that most developing countries would have no access to vaccine during the first wave of a pandemic and possibly throughout its duration.

----

The fairest way forward would be for WHO to seek an international agreement that would ensure that developing countries have equal access to a pandemic vaccine, at an affordable price. Such a move would demonstrate global solidarity in preparing for the next pandemic.

Even though Indonesia has now reversed its decision, and Heymann will be meeting with the Indonesians and "selected countries in the Asia- Pacific region to identify ways to provide fair access to vaccines and production capacity" I don't see how they can bring about the goal of "access to quality pandemic vaccines at affordable prices" unless the guiding principles behind the development of pandemic vaccines are changed completely.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
IN the news
WHO experts: World has greatly increased abilty to produce bird flu vaccine

Revere has an excellent blog about this at effect measure the vaccine good news story

Hmmm. I suppose if you didn't think you could make a vaccine at all and now you discover, gee, maybe we can make one, you'd be happy. But the distance between what we have now and what we would need should a pandemic occur in the next two, three or even five years, seems very large indeed.

----

So we don't know if it will work (evidence suggests it might), but we do know we won't have enough of it for years to come. At least not enough for you.

And my own response there (excuse the shameless self-promotion, all for a good cause!)

'ON the verge', is that the same as 'nearly dead'? Or 'almost pregnant'? Or maybe both?

There will be no "rapid switch from seasonal vaccine production to pandemic strain vaccine production" if by pandemic vaccine we mean not just a vaccine with the pandemic strain but something that will actually make a difference to the outcome of a pandemic.

Cos however we work the arithmetic, you will not get the numbers needed by boosting seasonal flu uptake, which has been the pipe-dream of governments who want to appear to be doing something, as well as the WHO. Current seasonal flu vaccine distribution for ALL of SE Asia is in the order of 250,000. If you give all of that to Indonesia and no other country, that's enough to vaccinate 1 in 1000 Indonesians. Hmmm, you think that might be enough to build herd immunity? Let's say that happens at 1 in 3 having immunity, we are talking about > 300 times (not percent) increase. Anyone want to place a bet on how many pandemics from now would Indonesia be able to achieve that?

But, of course, officials can get manic-euphoric at "greatly increased" ability to make a pandemic vaccine if they ignore the existence of Indonesians and others in that category, and just focus on making "enough for domestic use". But wait, didn't somebody say back in vaccine 101 class that you needed a seed strain to make a vaccine? Oh yeah, we forgot, the Indonesians were going to lay down their lives and give us their samples so we can save our kids.

Of course. Like they owe us what?

I think my good friend David Fedson sums it up best "We should have seen this coming, folks."

There will be no pandemic vaccine (that will alter the outcome of a pandemic) until we switch off the autopilot called 'boosting seasonal vaccine uptake' and switch on our BRAINS!

The saddest part of that is, they talk about every latest technological breakthrough with awe and excitement, when the technology already exists (see top diary) to make billions of vaccines in a space of weeks. Granted, we still need to do a whole load of trials, but the biggest barrier to having pandemic vaccines for the whole world is not technology, but the regulatory sclerosis and ostrich-like mindsets of officials at the FDA, EMEA and the WHO.

Maybe the Indonesians are really doing us a favor. By showing up the nakedness of you-know-who, maybe they can actually embarrass our officials enough for something to happen?

Or have I joined the manic-euphorics?





All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


what does it cost ?
> Still, his [Fedson] estimate is probably several billion
  > doses [of LAIV H5N1-vaccine]
  > can be produced in a matter of months.

----------------------

  > using 25% of global bioreactor capacity can produce an adjuvanted
  > 3.75ug rHA vaccine for 3.4 billion people in 3 months,

---------------------------

sounds good.

What does it cost ?

ask experts for their subjective
panflu death expectation values
and report the replies


Additional input for the discussion
Protein Sciences' technology is not new. Recombinant DNA technology has been around for a long time and if it wasn't for the fact that influenza vaccines are cheap a recombinant protein approach would have been embraced many years ago!

A hemagglutinin only vaccine provides a near term solution for pandemic preparedness. Personally, I think that a pandemic can only be prevented or mitigated in a pro-active manner, i.e. by offering vaccine before a pandemic threat truely emerges. This is why at Protein Sciences, we are planning to pursue licensure of a multivalent (containing HA protein from different sub-types) pre-pandemic vaccine.

Obviously, while we are already quite certain that a rHA vaccine is safe and effective, we are in the process of generating the necessary data to convince the regulatory authories. We expect to file a Biologics License Application later this year and hope to have a trivalent regular influenza vaccine available for sale in the US in time for the 2008-2009 season.

We are scaling the manufacturing process up to the 20,000L scale from our own 500L scale and once this process is completed we should be well prepared to establish technology transfer packages that would allow the production of recombinant hemagglutinin in production facilities around the world.

We are currently not performing any further clinical studies with potential pandemic vaccine candidates because we do not have the resources to support this and the US government has to date elected to only support large pharmaceutical companies with their development programs.

I agree with the comments made that one of the biggest mistakes was to focus on existing technology, this basically paralyzed the "step-change" thinking that would be required to develop a glabal approach for pandemic preparedness.

Finally, I do think that WHO has recognized the potential and the need for new technologies but since they are dependent on other parties for funding they have not been able to act independently.



thank you Dr Cox
for your input. 

We are currently not performing any further clinical studies with potential pandemic vaccine candidates because we do not have the resources to support this and the US government has to date elected to only support large pharmaceutical companies with their development programs.

I'm surprised and somewhat dismayed at this revelation.  Can you share with us whether this is stated government policy and/or what is the rationale behind their approach, from what you know, of course?  Or where one might find such information?

What other alternative sources of funding might a company in your situation consider, generally speaking?

If you are expecting to file a BLA this year and having the trivalent seasonal flu vaccine on the market in 2008-09, assuming you get the funding for further trials on the pandemic vaccine candidates, what would be your best guess when all clinical trials can be completed to fulfill current requirements for licensing, and when might the product be actually ready for market?

If, hypothetically, there was no requirement to have a seasonal flu vaccine licensed first, and no requirement for a new company to have at least one product licensed before they can file an application for a pandemic vaccine, in the case of a rHA vaccine, how much time would you estimate might have been saved in the whole process?

Thank you again for your willingness to engage in this discussion.  Whether the world manages to have a pandemic vaccine in time is an issue of enormous public interest, far beyond commercial concerns, so this discussion is absolutely necessary, IMO!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
I had a couple of email exchanges with Dr Cox
One interesting revelation, which actually was not surprising to me, was that somehow HHS grants 'prohibit' funding of novel technologies.

The reason why this is not surprising is because it is consistent with the whole set of principles, that you have to get a seasonal vaccine licensed first, etc.

OTOH, if you think of what the world needs, and the fact that after so many years and so much money has been thrown into the inactivated vaccine for pandemic use with such poor results, why are they still holding onto such dogma?

What we need IS novel technology.  We DO NOT have a pandemic vaccine capable of making a difference to the outcome of a pandemic, and WILL NOT have one in the foreseeable future.

I'm sorry if I sound frustrated, cos I am.  We are talking about a global catastrophe on the scale of several hundred or a thousand tsunami's maybe. 

It's a novel problem.  We need novel solutions.

Hello?  Is anyone home?



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Questions?
1)What about private funding?

2)Isn't there something about the current regulations being revised in light of very probable panflu event?

3)What is required to conduct clinical trials?

4)How about clinical trials conducted with... oh...I dunno...say 6 billion people? ;-)

5)Are their any loopholes to exploit? It sounds drastic but so does slowing suffocating to death.

6)Can Protein Science's vaccine be taken orally?

7)If so, how about marketing it as a supplement? (I'd buy some!)

Click here for a curious observation.


[ Parent ]
I will attempt the ones that I know
2)Isn't there something about the current regulations being revised in light of very probable panflu event?

I think that is the point I'm trying to make here, that one can't consider a pandemic vaccine in the same light as seasonal vaccine, cos they serve very different purposes.

4)How about clinical trials conducted with... oh...I dunno...say 6 billion people? ;-)

Er, I don't think so...

5)Are their any loopholes to exploit? It sounds drastic but so does slowing suffocating to death.

Can you find some?  LOL  Just kidding.  I wouldn't know.  Sorry.

I'll let Manon Cox reply to the rest, if she wants.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
we could have vaccine
> We DO NOT have a pandemic vaccine capable of making a difference
  > to the outcome of a pandemic, and WILL NOT have one in the foreseeable future

that's not what WHO says. That's not what vaccine producers say.
Seems to depend on what we are willing to pay for it.

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
no, it's not just money
they can't get enough doses out within the first 6 months to even first responders.  However much you pay, that's the current reality.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
...in the foreseeable future
so, say for season 2008/9.
With $1e8=1%of GDP I think USA could get a vaccine for that
season 4 months after possible panflu-start,
which has a probability>50%
to cut the expected US-victims by more than half.

quoting you from above

  > Still, his [Fedson] estimate is probably several billion
  > doses [of LAIV H5N1-vaccine]
  > can be produced in a matter of months.
----------------------

  > using 25% of global bioreactor capacity can produce an adjuvanted
  > 3.75ug rHA vaccine for 3.4 billion people in 3 months,

---------------------------

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
where did you get that 4 months
figure?

With $1e8=1%of GDP I think USA could get a vaccine for that
season 4 months after possible panflu-start,




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
4 months

got that from the "primer"(Enhlish?)-strategy.
"partial vaccine" produced now, the exact strain can be added
later for reduced production time.

See e.g. the Austrian vaccination plan,
they have a contract in place with Baxter, production
in Cech.
I can search for it...

Other European countries are planning for similar strategies.

AFAIR Glaxo is offering this mid this year or such

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
OK, please post them
if you find them.  Thanks!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
babelfish...
http://www.oe24.at/z...

Vienna, 20 October 2006
76 to 95 per cent effective,
successfully tested on humans - and comes from Austria.
The 1. vaccine against bird flu is there.
Success with the cell agricultural engineering for the fast production of vaccines, developed by Baxter (formerly Immuno) in Austria: A H5N1-
vaccine thought for humans was tested for the first time in the past weeks
It was well compatible, laboratory tests referred to a high protection rate against different H5N1-strains from 76 to 95 per cent after two inoculation in the distance of three weeks. That publication on Friday scientist of the enterprise with the press conference in Vienna.
...
Baxter might have the means after work for many years in addition in the hand. Responsible the specialist Univ. Doz working on the development of such Vakzine. Dr. Noel bar-save: "influenza-vakzine are manufactured today on the basis of bebrueteter huehnereier. That is the technology of our grandfathers. If it comes to a H5N1-Pandemie, perhaps there could be no more chickens. No chickens, no eggs, no vaccine." Still with Immuno of was therefore bar-saved and to its coworkers - formerly for a possible AIDS vaccine - a technology developed, with which the antigens for Vakzine in infected cell cultures (Verozellen) are produced. Bar-saved: "we are completely independent of eggs. We are also substantially faster. If we get the isolated virus trunk from the WHO (World Health Organization) in the case a influenza-pandemic made available, we can supply the vaccine within twelve weeks." Production on eggs would take at least eight weeks longer. In the case of such a crisis however as immediate an availability of a Vakzine as possible would be crucial. Exactly such a vaccine - on the basis in the past years also on humans "over-jumped" H5N1- of the virus from Viet Nam (A/Vietnam/1203/2004) - bar-saved and its team developed. In it produced and then killed whole viruses are contained in the cell culture. Already the bioassays referred to a high protection rate (up to 100 per cent) against this and other H5N1-Virus-Variants. In the past weeks first testing took place at humans in Vienna (AKH) and in Singapore. In the framework it concerned to the phase I/II test first testing the compatibility and the Immunogenicity (causing a defence reaction). Excellent Immunogenitaet Dr. Hartmut Ehrlich, Vizepraesident for research and development with Baxter, showed up over the results of the first clinical study in testpersons with the H5N1-Vakzine highly contently: "we immunisiert 270 healthy adults at the age between 18 and 45 years with two doses vaccine in an interval of 21 days. Three weeks after first and the second inoculation took place the blood acceptance. First of all an excellent compatibility "the side effects showed up such as tiredness, short fever reaction, swelling in the parting place was comparable with that one" of the normal "influenza-impfstoffes. The pro gangs received for each to inoculation 3.75, 7.5, 15 or 30 micro gram (millionth gram) the H5N1-Antigene (killed viruses). Partly also the Adjuvans aluminium hydroxide than amplifiers, well-known from vaccine production for decades, was used. The second and just as important result according to the Ehrlichs: "we observed an excellent Immunogenitaet. The dosage of 7,5 micro gram caused (after the two inoculation, Anm.) a protecting anti-body answer of 76 per cent against the H5N1-Virus from Viet Nam, used in the vaccine." The Adjuvans had obviously no additional effect. But also approximately with the Viet Nam virus more far away the Vakzine obviously works related H5N1-Viren. The expert: "against the H5N1-Virus Hongkong/156/1997 a protection rate of 95 per cent and against the Indonesia trunk (A/Indonesia/05/2005) showed up one of 72 per cent." These correspond or exceed the results, which can with the conventional and annually again formulated influenza-vakzinen be normally attained. Now a large genuine effectiveness study put on with approximately 500 pro gangs is already planned. "bureaucratic Kinkerlitzchen" certainly, these successes does not help anything, if Austria cannot decide to book for a possible influenza-pandemie the then as soon as possible newly produced vaccine in advance. The contract - in such a way it meant at the edge of the press conference - hanging now with Minister of Finance Karl-Heinz Grasser, which refuses the signature. The Austrian Pandemie plan plans the protection of all Austrians for the case of the case by a Vakzine on cell culture basis. only bureaucratic problems
The inoculation for the case of a influenza-pandemie costs about 8 Euro

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
thanks!
in simple English:

Baxter have just completed Phase I human trials of an alum-adjuvanted inactivated H5N1 whole virus vaccine grown in cell culture, with 7.5 ug/dose x 2 doses giving good immunogenicity.  Which means in terms of antigen-sparing it is not as good as the 3.8ug of GSK subunit vaccine or the 5 ug of the Chinese whole virus one.  And this is just Phase I trials. 

Also, cell culture for inactivated virus vaccine is still very much at the development stage, in terms of production capacity etc.  The various companies that I've heard presentations from generally cite 3-5 years to being market-ready, so it's possible that may apply to Baxter as well. 



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
100 million doses
the contract was signed in Nov.2006, the factory in
Cech Republic is already producing prepandemic vaccine,
for Ireland and UK, who ordered 2 million doses.

They want to reach 100 million doses per year.
They give no exact timeframe for this, but I think
they wanted to reach it by the end of this year.

http://www.dradio.de...

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
can you do babelfish for that?
Cos I want to be sure that the info is consistent.  thanks!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Bohumil-factory
02.11.2006 A new vaccine is to protect H5N1 against the virus. (picture: AP) A Sechstel of the world-wide flu vaccine of Kristin Raabe medicine produces new ways to the vaccine plant in Tschechien. New manufacturing processes offer chances for new classes of flu vaccines. The first European fabric culture production plant took up the enterprise to Tschechien and already produced a vaccine against the exciter of the bird flu H5N1. Flu vaccine is a rare property already now should it to a world-wide flu epidemic disease, a Pandemie, comes, could not the disaster with the existing production capacities not into the grasp be gotten. Because the rich only for two per cent of the population of world. Besides the production process in bebrueteten huehnereiern takes at least three months. The company Baxter developed now a new procedure for the production of flu vaccines. The first European fabric culture production plant has the enterprise taken up to Tschechien and produced there already a vaccine against the exciter of the bird flu H5N1. Noel bar-saved is the director/conductor of the vaccine development with Baxter: "there are different trunks of H5N1. It could be that these trunks would have different growth characteristics. Up to now we did not see that, but in the future it could be like that, so these numbers, says we, is not 100 per cent reliably for the pandemischen vaccine, but we saw up to now that with a certain dose, and we say the dose are to 7.5 micro gram, could we about 100 million doses per year manufacture." 100 million doses, hands for 50 million humans. Thus Baxter with only one plant a Sechstel of the quantity of flu vaccine, produced for the moment world-wide, produces. Basis of this manufacturing process are cell cultures, which originally originate from the kidneys from apes. In these cells now the inoculation virus increases. The production of vaccines in cell culture production plants makes possible besides new classes of vaccines, which could not be produced with the conventional procedures. "we work with the virus, which circulates in nature. Other groups, which made up to now clinical examinations, work with reassortanten viruses that is called, the vaccine trunk are converted, that critical protein for the Immunogenitaet genetically changed, in order it pathogen less to make. And in order to create this characteristic that the virus in eggs can grow well, genes of other Influenzaviren of H1 N1 are to it-mixed. That is called in the vaccine trunk gives it only one protein, which belongs authentically to the H5N1-Viren. And this Ressortant must be manufactured, because the virus of type of game cannot be used, by the egg manufacturers, simply because do not have the one safety level, whom we can reach with the fabric culture plants." In the fabric culture plants the Biosicherheitstufe 3 prevails. The plants, which work with huehnereiern, do not create that. In order to go surely that is innocuous the virus of type of game used by the company Baxter it is treated before, it with formaldehyde and illuminated with UV light. The fact that a virus of type of game is possibly better suitable to cause a good immune answer shows clinical studies with 270 patients. They received two doses of the vaccine with the whole H5N1-Wildtypvirus and had thereby no more side effects than with conventional flu vaccines. Hartmut Ehrlich is with Baxter vice-president for research and development. "there we confirmed, what we in the animals to have seen, and that is an excellent immune answer, on the one hand approximately into the Vakzine contained H5N1-Stamm. That is the trunk isolated in Viet Nam 2004. Thus against that the excellent immune answer is to be determined, in addition, and that is evenly the special here, approximately in quotation mark strange H5N1-Staemme, for example against the 1997 in Hong Kong isolated trunk or also against the trunk isolated in Indonesia, which actually belongs to another group of H5N1-Staemmen and was particularly interesting therefore. And also against this is it shown in the neutralization test, which we use a CROSS neutralization. That is called the anti-bodies, which are formed by the seed nuclei, those neutralizes all these trunks, which I called straight evenly." So a Kreuzimmunisierung against different Subtypen of H5N1 showed up to now no vaccine established at humans. That is possibly because of the fact that the researchers of Baxter with the variant of type of game of H5N1 work. They needed also a clearly lower dose than usual in conventional vaccines, in order to obtain a sufficient immune answer. The immune reaction did not improve surprisingly, if the researchers an inoculation amplifier, as added aluminium hydroxide. In the opposite: The immune answer failed even more badly. They do not have a founded explanation for this phenomenon. "the substantial is however that it is called a good and pleasing message for us, which the optimal formulation evenly no Alumiumhydroxid contains and is in the final result even that we can manufacture thus the final form of the vaccine without the immune amplifier." In the meantime the plant in Tschechien already produces the first loads of the bird flu vaccine for humans. Ireland and Great Britain have two million doses ordered, in order to be prepared for the Pandemie.

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
thanks.
same interpretation as before, except that the addition of alum as adjuvant actually created a lower immune response, and they don't know why.  Yes, they say they are making it.  And yes, they say the UK and Ireland are ordering it.  Doesn't take away the fact that this is an experimental product at Phase 1 trials.

They say they can make 100 million doses per year by cell culture, again we don't know how many years it takes for the technology to be ready for license.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
cheap
in the 2nd article it seems that they already have this capacity
of 100 million doses per year.
8Euro per dose. Baxter has the know-how.
And they only invested some million $ (<10,I think) into that
factory in Bohumil.
Glaxo also has the know-how.
Why doesn't USA buy or build such factories too ?
Is it all just a poker about the contracts, about the licenses,
about the price per dose ?
Calculate how much your panflu-health is worth to your government
and then compare it with the cost of your prepping.
Compare it with the cost of a severe pandemic as estimated by worldbank.

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
because vaccines are commercial ventures
very few countries have publicly owned vaccine making capacity.  Which is ok, cos businesses do some things better than government.  OTOH, government can certainly affect how businesses make decisions on what they will invest on, by changing their research funding and regulatory priorities, IMO.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
so yeah, 6 months
into a pandemic, a few lucky souls might get a vaccine shot.

But that's not going to be you.  I don't think.

Now the Indonesians have shown a way to hold everyone to ransom.  So come a pandemic, you will find WHO or whoever spending time negotiating with the country where the outbreak is happening, for the virus sequence. 

If you only have barely enough capacity to make vaccines for your first responders, are you going to give up that first lot of capacity to the country that give you the sequence?  But if you don't promise, they won't give it to you.  Chances are, even if you promise, they won't trust you enough, so you're going to have to make the first doses on their soil, just to make sure.

Which means that your first responders probably won't get the first shots for another, say 3 months, minimum?

And that's not counting all the time and energy and angst spent on arguing about it!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
available
how could any country succeed to keep a pandemic strain secret ?
Just send a helicopter to pick some sample from a sick person
(illegally).
Hey, that would be nice, if they could keep sick people
inside their borders for many weeks anyway.

In Germany or Austria we are told that there will be
vaccine for each person after 6 months, maybe 3.

UK negotiates with Glaxo for prepandemic vaccine, costs
about $20-50 per dose.
Other companies to follow soon.
This is less likely to be efficient than the pandemic vaccine,
but you could have it soon, probably (IMO) before panflu starts.

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
want to start a war? ;-) n/t




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
no war, only discussion
ahh, come on. Don't be so sensitive.
Let's figure it out, it's important.

IMO vaccine is still much cheaper than prepping
and offers better chances for success

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
in the end
it is the power tool in the toolbox.

[ Parent ]
well yes, I agree
and I'm not being sensitive.  Did have a smiley face there ;-)

But, since we need to depend on a pandemic vaccine for ultimate success, that makes it that much more important to scrutinize what is being done, whether the math being presented to us makes sense.

It doesn't look to me like even the richest countries will have a pandemic vaccine for enough of the population to produce herd immunity (say 30% minimum) for at least 9-12 months.  And the numbers will be far worse if you have to 'share' with countries that gave you the virus sequence.  With the current inactivated egg-based technology and current regulatory protocol.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
thanks, Dr. Cox
As a CT resident, I want to let the community know I have no conflict of interest and have no connection with Protein Science and have never had a connection.

We are scaling the manufacturing process up to the 20,000L scale from our own 500L scale and once this process is completed we should be well prepared to establish technology transfer packages that would allow the production of recombinant hemagglutinin in production facilities around the world.

That part is wonderful, the funding lack is not so wonderful. New thinking is needed all around. This is a flat world, and we've all got 6.6 billion people to consider.

Thanks again for reading and posting. The more our readers understand the issues, the better prepared we will be to bring this to our representatives in the various government levels and layers.


[ Parent ]
just a question of money

we could produce (pre) pandemic vaccine with some chances
to give protection.
We could already have it.Current prepandemic vaccine costs
$20 per dose with an estimated 20% chance to work,I guesstimate,
$6e9  for all US-citizens.

Mortality bonds suggest a probability of 2% per year for a pandemic worse than 1918,
let's just say 10% for 2 million US-panflu-deaths in the next 5 years ,
200000 US-deaths expectation value, $150000 per expected saved US-life for
actual prepandemic vaccine.
Also reduces morbidity.
This is improving rapidly...
And the Mortality-bond estimates are being questioned here...

I found this about the protein science vaccine:

http://www.proteinsc...


ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
it's not 'just' a question of money
It IS a question of money, and of priorities, and of governing principles, and of risk perception (from the government), etc.

Whether institutional straitjackets win over pragmatic concerns for the wellbeing and stability of the world, that is the question.

Government, when left to its own devises, often have a tendency to use rules instead of brains.  That's the difference between public and private enterprise, I'm sorry to say.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Private investment in Protein Sciences?
Dr. Manon--

Email me, I know some venture capital folk who may be able to help you if the government won't.

medical information provided is for discussion purposes only and should not be construed as medical advice. if you believe you have a medical problem, consult your practitioner.


[ Parent ]
pandemic vaccine made to order
There is an additional problem.  At the moment, government is just passively accepting whatever industry makes, pretty much like when you go to the grocery store, you can only buy whatever they decide to put on the shelf.  But, again, a pandemic is a unique PH challenge not like any other.  If you want to have vaccines for all your citizens (let's not talk about the rest of the world yet), you are talking about a very big order.

If you are a big spender, you can get the market to make the product to your specification, instead of just picking and choosing among what they present to you.

For example, if we say, we want x million doses within 3 months of y degree of efficacy and with z level of safety standard, and put this out and let manufacturers compete, then they can come up with solutions.  Some might discover after all they can cut antigen dose all the way down from the current ridiculous 90ug (for monovalent!) somehow; others might decide to abandon that and find a different technology that you can just make lots more antigen faster, and so on.

That is not what is happening.  Manufacturers are making what they want to make.  And cos they are given this mixed message on seasonal vaccines, all they want to do is to play safe, and make vaccines of good enough efficacy for seasonal use, never mind that there won't be enough in a pandemic for HCW to go to work!  It's not their problem/

We currently have at least 3 different subclades that do not have cross-immunogenicity, at least with the inactivated vaccines.  Clade 1 from vietnam, clade 2 subclade 1 from Indonesia, clade 2 subclade 3 from Anhui China.  Tashiro from the WHO said that the WHO is not likely to recommend a monovalent vaccine.  So a trivalent one, we are talking about 3 times the antigen requirement.  270ug/dose?  How much can we make?



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


4 clades
WHO sees 4 subclades : Vietnam,Indo,Qinghai,Anhui
I do see 10-20 more subclades in China, at least as different
as Indo and Qinghai.
There is some crossimmunity, see the reports last year with the Vietnam/1203

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
yes 4
I meant 1 of clade 1 and 3 of clade 2.  Can't count.

But as you say there is some cross immunity, but not much though.  At least between clade 1 and 2.  Within subclade 2, there may be a bit more.  There's not a lot of data, so we'll have to see.

So we know it is very likely that a monovalent vaccine won't be a good idea.  How many you would need in a vaccine will need to be decided further down the road.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
chances
are not so bad, that prepandemic vaccine will be protective.
2 different strains probably less likely than twice
one strain, and a boosting shot maybe recommended/necessary.

Switzerland, Singapore, Denmark?  got it for their whole population
already. USA some million doses, 20million planned in total

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
are they licensed?
delivered?  Have the governments decided they are going to use it?

Seriously, I do want to know.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Switzerland
http://www.swissinfo...

  December 5, 2006 - 6:16 PM
Swiss spell out pandemic vaccination plan

"Zeltner highlighted the stockpiling of two million doses of the antiviral drug Tamiflu and the recent SFr180 million ($150 million) order for pre-pandemic and pandemic vaccines. On Tuesday the House of Representatives approved a SFr75 million credit towards buying vaccines.

"Eight million doses of the pre-pandemic vaccine manufactured by Anglo-American firm GlaxoSmithKline are due to be delivered to the army's pharmacy division early next year."

Ordered, not delivered yet.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
scheduled for mid. Jan.
maybe there were delays, I don't know. But they should have it available
now.

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
GSK vaccine
http://www.gsk.com/C...

GlaxoSmithKline files its new pre-pandemic influenza vaccine in Europe

Issued - Monday 29 January 2007, London, UK & Rixensart, Belgium

"GlaxoSmithKline (GSK plc) today announced that its new generation H5N1 split antigen pre-pandemic influenza vaccine has been accepted for review by the Committee for Medicinal Products for Human Use (CHMP) in Europe."

Accepted for review only, not licensed, not ready for market.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
3.8ug per dose
+ proprietary adjuvant x 2 doses over 21 days. 



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
to have enough for 1/3 of the world
we will need 3.8 ug x 2 x 2 billion = 15.2 billion ug antigen PLUS adjuvant.

From the top diary, remember that total world capacity is only 4.5 billion ug antigen in 1 year.

So we need about 3.4 years to make enough for 1/3 of the population of the world.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
or 10 years for everyone n/t




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
or 5 times that money
..for 2 years. They can build new factories , given enough money.

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
gs when are you going to get
that money cannot buy everything ;-)

like if there are not enough of the right kind of eggs, for example.

Businesses have to balance their books.  They sell x no of doses of vaccines, they get so much money.  They figure out how they want to invest that money, based on what they think is best for their company.  Or what the shareholders want.  Not what is good for the country.  That is the  current reality.

If throwing money at a problem always solves it, there will be no miserable rich people on this planet!  LOL



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
license
I think, this is a new, improved version.
Governments can and do stockpile without license.

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
Hey! They are making a viable vaccine and selling it over-the-counter in that country! $1000 a dose is nothing. Why can't I get it here damn it?! Regulations?! So I will fly there with my family and f
My above point is....
.......is instead of fighting regulations, just build and dispense the vaccine in a country conducive for doing so. All of the Bio-Pharma facilities I have ever worked on were either in Ireland or Puerto Rico. I believe this was done for tax advantage purposes. Surely there is a country somewhere that has minimal red tape.

Build it and they shall come.

If I have to fly to Tasmania or wherever and pay $1000 per dose for my family, I will. There are 2,700,000 millionaires in the U.S. alone. If you get just 10,000 customers, that's 10 million dollars gross sales. How many batch runs for a small `pilot plant' to make 10,000 doses? Hell, I'll help design the plant for free. It's what I do.

It won't save the world in and of itself, but it gets the ball rolling and jumpstarts competition from paper to product.

Click here for a curious observation.


[ Parent ]
using the annual world capacity
of 4.5 billion ug antigen, if we use inactivated vaccines that generally require 2 doses, at 1 ug/dose, we will have enough antigen capacity for 2.25 billion people, approximately 1/3 of the world population, within 1 year.

At 2 ug/dose, we will be able to vaccinate 1 out of 6 people in the world in 12 months.

This compares to the Baxter vaccine quoted above at 7.5 ug/dose, or the GSK one at 3.8ug, or Sanofi (which is what the US government is spending their millions on) at 90ug/ dose.

On top of that, this is not a linear problem.  The benefits to society of an amount of vaccine available at 3 months are far higher than if the same amount were available only at 9 months, because by then far more people will have been infected, society would have been disrupted and weakened from the outbreaks.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


local stockpiling of vaccines
how is it in USA, when some states or communities want to buy
their own (non-licensed) vaccine to protect their citizens,
can the federal government forbid it ?

Are there already such communities or companies or organizations in USA
with their own panflu-vaccine stockpiles ?

ask experts for their subjective
panflu death expectation values
and report the replies


no, it's illegal to use
unlicensed vaccines.  In the US, the FDA is in charge of regulating and licensing vaccines, within the Center for Biologics Evaluation and Research (CBER) http://www.fda.gov/c...

Other countries have similar agencies.  That's why you can't just go buy a vaccine just cos you want to.

Under current regulation, pandemic and prepandemic vaccines, are not intended for private stockpile.  Some large multinational companies have been trying to get their own stockpile, but both European and US laws forbid that.  There are complaints from companies who say that they need the vaccines to protect their staff, but I can understand how with such scarcity and when the side effects are unknown, such vaccines really need to be tightly regulated.  Until they are deemed to be safe and effective, and until there are sufficient quantities, their use has to be very carefully balanced between national security or public health needs vs side effects.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
HHS control

and the pentagon and the HHS are not bound to FDA ?
The governments may violate their own laws ?

The vaccines are not taken now, they are stockpiled for the event of
a pandemic, the decision about side effects etc. is made then.

Stockpiling your own vaccine relieves HHS from doing
it for you, they spare the money for your proportion of the
HHS-stockpile, so they should welcome it.
Increased demand leads to new factories being built,
more vaccine being produced although with short-term
increasing prices.

Now, why do the feds oppose private stockpiling of
vaccines and antivirals but encourage stockpiling of food ?

Apparantly they want the vaccines and antivirals to make
pressure on citizens to behave government-conform.
e.g. : "When you are sick or suspicious and refuse to relocate,
then you get no tamiflu."
"When you violate some law, you won't get vaccine"
"When you join the wrong party, you won't get vaccine"
etc.

vaccine, antivirals is power in a pandemic.
Forbidding individuals or communities or companies
to take care for their own stockpile is just like
forbidding them to build hospitals or such - in principle.


ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
no, they are stockpiling only
The decision to use the vaccines has not been made.  Apart from the normal licensing mechanisms, there are emergency use mechanisms.  In the US, it is the EUA

The EUA is an authorization by the Food and Drug Administration (FDA) for the use of medical products, i.e., an unapproved product or for the unapproved use of an approved product, when an emergency or a potential emergency exists.

Similar mechanisms exist in other countries.




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
vaccines are different from antivirals
Because they are biological (as opposed to chemical) in nature, vaccine use has far wider implications than the use of antivirals or drugs in general.  In addition to the issue of safety to the recipient, which governments do have a certain degree of responsibility to oversee, there are additional potential effects on non-recipients and society as a whole.  For example, we have seen how the use of poor quality vaccines in poultry may encourage the adaptation of avian viruses, thereby creating more or at least new problems. 

Another example would be inadequate attenuation of vaccine virus may cause a pathogenic strain to be administered to vaccine recipients inadvertently.  Hence control and supervision for biological products such as vaccines, blood products, or transplant organs are much more stringent than chemical drugs.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
response from WHO
UPDATE

I emailed David Heymann at the WHO with the link to this discussion, and have received this reply (emphasis mine):

Dear Susan,

Your point about changing the regulatory environment is important, and we have discussed this among ourselves here at WHO.  We are working on several strategies to help make vaccines more available should there be a pandemic, and will add this to the list for future examination with our partners.

We will try to keep our website updated so that you and others are informed of our progress.

DLH (Dr David L. Heymann)

My sincere thanks to Dr Heymann for his response, and hope we can continue to have an open and constructive dialogue on this and other issues relevant to pandemic preparedness and mitigation.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


What about this:
http://penumbra-of-p...
Briefly in English:
With a geneticly recombined adenovirus vector it is possible to develop an influenza vaccine that can be produced in large amounts quickly and without need for living animal tissues like chicken eggs or embryos. The money needed for develping such a vaccine is under one million euros yearly.

(More in Finnish)

Life is a narrow bridge. Most important is to have no fear. Have no fear at all.


I guess they mean
one million euros per year for a population of Finland, which is about five million people.

Life is a narrow bridge. Most important is to have no fear. Have no fear at all.

[ Parent ]
adenovirus vaccine
I don't know which one that is but I am guessing this is the same as this http://www.scienceda... which uses an adenovirus containing the HA protein.  This is a live virus vaccine, with a genetically engineered adenovirus, which, would make it a 'medicinal product containing or consisting of genetically modified organisms' with very stringent requirements for licensing. 

So stringent, in fact, that as of February 06, no Marketing authorisation for GMO-medicinal products for human  use  has been issued yet.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
in Europe, I mean n/t




All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Yes, that sounds like the kind I'm talking about.
What do you think about it's implications? Could it work? What risks? What advantages? The article in Finnish sounded very promising indeed.

Life is a narrow bridge. Most important is to have no fear. Have no fear at all.

[ Parent ]
they always sound promising
hard to tell.  You (not you, but generally) need to read the original research and/or get some vaccine expert to comment.  There are a lot of promising products that never reach market, and vaccines are no different. 

I would suggest only pay attention to the frontrunners, which would include most of the ones already mentioned (some in passing only) on this diary.  Certainly Sanofi and GSK seems to be having a lot of success convincing countries to buy, but if they can't solve the problem of production capacity, which is the main point of this diary, then they will be replaced by other technology, IMHO.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
$10billion
are needed according to WHO to exceed the capacities:

http://www.outsourci...

but they want to be it invested over 10 years ?!?
Do they think, we have such much time ?

ask experts for their subjective
panflu death expectation values
and report the replies


No, they didn't 'think'
we have that much time. ;-)

They have no choice.  If you are talking about expanding current seasonal flu vaccine capacity, that is an impossibly slow process.  And you can only expand it by so much.

To quote Bruce Gellin of the HHS, to make enough pandemic vaccines for all Americans, we wouldn't be able to do it unless every family in America become chicken farmers, that's how many eggs we are talking about.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Eggs? Why eggs?
Isn't there a better way to make vaccines other than inside eggs?  That just seems to be to be so...last century!  What about new technologies?  Don't we have anything that's a little better than CHICKEN EGGS?

[ Parent ]
well, that's the big question
or at least one of them, that this whole diary was about.  Using current egg-based technology, we won't have enough vaccines in time to make a difference to the outcome of a pandemic.  End of story.

Other technologies are available, but we need changes in the licensing requirements to encourage, nurture, and fast track them. 

It ain't gonna happen unless somebody makes it happen!!



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
not possible
when they say something is not possible or not available
they usually mean, they want more money for it

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
What's the probability of 3 women having a baby in 3 months?
More resources don't always speed things up.

You want perspective. I want perspective. Let's talk. We don't have to agree on every thing. If we do, one of us is redundant.

[ Parent ]
biological constraints
(see anon.yyz's response) are not always amenable to dollars alone.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
no babies,please
ahh, come on, vaccine facilities are not like babies.
We can build as many as we want - as long as someone pays for it.
This should only take 1-3 years, if we push it, I assume.

Just Bush,Senate spend $50billion and there will be enough
prepandemic and 4-month-delay-pandemic vaccine for the
entire US-population of today's quality.
That's what I guesstimate.

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
price
but it can be done without chicken eggs and there are
chickens outside USA.
10 million doses of prepandemic vaccine cost $20 per dose
and can be delivered in less than a year.
how much cost 300million doses , to be delivered
end of the year, end of next year ?
I think it can be done, it's just only a price-poker.

They don't consider the threat big/likely enough to invest
$6billion into prepandemic vaccine or pandemic vaccine.

There should be competition among the countries to
get the limited resources of H5N1 vaccine and this should
drive the price up, but we don't observe this.

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
Why not get a $20.00 one time tax on each and every single person living in the US to raise the money?
Compared to thousands of dollars for preps, $20 bucks is nothing.

[ Parent ]
can someone do the maths on this?


You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.

[ Parent ]
USA population is: drumroll...
298,444,215 peeps!

Multiply this by $20.00 and you get... (drumroll again)

5.9688843 billion U.S. dollars!!!!  Badabing!  Is this enough for a vax to be created? 

Any takers? 


[ Parent ]
Kelly Phan, ;-)
http://www.pledgeban...

I don't know how massive or foolish or media attention getter this could get.  ;-)

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.


[ Parent ]
$20
why not just let and encourage them buy their own vax for $20 ?

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
Because I don't think it's available at this time yet.
However, if everyone chips in a $20.00 tax, there will be sufficient money to at least start the show and get something rolling in terms of a vax, IF the money doesn't get reallocated for something stupid like a hundred thousand dollar toilet seat.  Somebody up above is going to have to be the gate keeper and not knuckle down to the lobbyists who prowl consistently for the pork. 

[ Parent ]
overview
Switzerland 8M doses from Glaxo per $20 in Oct.2006
USA 3.7M doses from Sanofi per $32 in Nov.2006
USA 0.8M doses from Novartis per $50 in Nov.2006
USA 0.8M doses from Glaxo per $50 in Nov.2006
Austria 7Mdoses from Baxter (contract for pandemic)
UK 2M doses from Baxter
Ireland 2M doses from Baxter
Singapore 4M doses from Glaxo
Denmark from Glaxo
Indonesia from Baxter (IDN-strain)
Australia from CSL (IDN-strain)

(let's keep track of the vaccine contracts !
more important IMO than keeping track of the victims and cases)

http://money.cnn.com...

FDA experts to vote on first bird flu vaccine
FDA panel willscrutinize Sanofi's bird flu vaccine, while Glaxo develops competing vaccine in Europe.
By Aaron Smith, CNNMoney.com staff writer
February 23 2007: 9:59 AM EST

NEW YORK (CNNMoney.com) -- Worried about bird flu? If Sanofi has its way, America could soon be getting its first FDA-approved vaccine.
Advisors to the Food and Drug Administration will meet Tuesday to vote on the safety and effectiveness of Sanofi-Aventis' (down $0.09 to $43.69, Charts) experimental vaccine for bird flu, also known as H5N1. When the FDA decides at a later date whether to approve the French drugmaker's vaccine, it will take this vote into consideration as expert advice.
...
Webster...estimates a 50 percent chance of a bird flu pandemic.

GlaxoSmithKline is working on its own experimental bird flu vaccine, which was submitted to European regulators on Jan. 29. In October, the Swiss government signed a contract to buy 8 million doses of this vaccine. [about $20 per dose]

The U.S. government has poured hundreds of millions of dollars worth of contracts into companies that are working on developing vaccines and faster ways of creating them.
...
Sanofi and other drugmakers are developing quicker ways to produce vaccines in DNA cultures. Seasonal flu vaccines, as well as bird flu vaccines, could be produced through this more advanced method. Leacock of ABN AMRO said that Novartis (the recipient of a $55 million HHS bird flu grant in January) is probably the closest in terms of cellular-based production in Europe, and the company is building a plant in North Carolina.
But for right now, the vaccine market for bird flu is being supported by government contracts.
"This is a project that we've been working [on] very closely with the government, and quite frankly we see the U.S. government as the only customer," said Lavenda of Sanofi.
In November of 2006, Health & Human Services awarded Sanofi with nearly $120 million to manufacture 3.7 million doses for its strategic national stockpile. (At that time, the HHS also awarded Novartis and GlaxoSmithKline with $40 million each to produce 800,000 doses.) This is in addition to the $100 million contract awarded by HHS to Sanofi in 2005 to develop a bird flu vaccine. As part of the production ramp-up, Lavenda of Sanofi said his company is planning to start a new plant in Swiftwater, Penn.
Meanwhile, Glaxo is investing $2 billion to expand its flu vaccine manufacturing capability, including the acquisitions in 2005 of the biotechs ID Biomedical and Corixa Corp., as well as the purchase from Wyeth (down $0.19 to $50.07, Charts) of a manufacturing plant in Marietta, Penn.
To help develop a bird flu vaccine, Glaxo has also received hundreds of millions of dollars in U.S. government contracts. This includes a $63 million contract from HHS awarded on Jan. 17 to develop a pandemic flu vaccine with an adjuvant that would boost its potency, and a $40 million contract in November, 2006 to supply vaccines for the strategic national stockpile. In May of 2006, HHS awarded Glaxo a $274 million contract to develop a cell culture-based method of manufacturing vaccine that would speed up the slower egg-based process.
With all this government-fueled production going on, Gbola Amusa, analyst for Sanford C. Bernstein, said that the vaccine industry runs the risk of becoming flooded with product.
"Right now it's an urgent need, but you're going to see an excess in capacity in five years," said Amusa.
But if a pandemic strikes, the vaccine maker with the most to gain could be the one with the closest strain, said Leacock of ABN AMRO
"What matters is not who's most advanced now, because we don't know the precise makeup of the virus," said Leacock of ABN AMRO. "What matters is who's got the right vaccine at the right time."
The analysts interviewed for this story do not own shares of company stocks mentioned here, though ABN AMRO has provided corporate advice to Glaxo.
Drugs and fear: a new bird flu flurry
Drugmakers get $1 billion for bird flu

ask experts for their subjective
panflu death expectation values
and report the replies


converting money into lifes
for USA

goal is 75M courses of antivirals, most Tamiflu, by 2008 or 2009,
30M actually, I guesstimate.

they want capacity of 300doses of vaccine in 5 years, see the latest grant.

They will have spent about $10 billion in total for pandemic preparedness
by 2009 I guesstimate.

That's about $35 per citizen.

Usually they spend much more to protect lifes, e.g. equipment
to protect lifes of their employees. Let's say about
$100000 spent to protect one life.

That gives an expectation value of 100000 panflu-lifes for USA.

So, if we were offered the opportunity to get completely
rid of the pandemic threat, they were willing to accept
a price of 100000 immediate deaths (e.g. soldiers)to achieve this.
3 years of GDP per person.

So, to communicate the magnitude of the threat ....
compare it with 100000 immediate US-deaths chosen at random.

Not so bad, that would only be a chance of 1:3000 per US-citizen.

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
March 7 Financial Times article on Glaxo adjuvant vaccines
I thought that this might be a better place than the news to note that the Financial Times (www.ft.com) had a long article on how Glaxo (or GSK) decided to focus on adjuvants to increase immune response for vaccines directed at HIV, malaria and avian flu. This is a culmination of nearly 20 years of work. To quote one GSK scientist:"My gut feeling as a scientist is that new adjuvants allow for important breakthroughs and make a number of vaccines [possible] that were previously difficult or impossible." The article says that the new adjuvants provide broader protection, even against strains of flu that are not precisely in the original vaccine. Earlier threads have expressed (well-founded) fears about adjuvant side-effects and other safety issues, so this area is both hopeful and one to watch very closely. Dr. Susan is, I imagine, well on top of these developments and will let us know if anything really new is happening.
PS: It is hard to get to the story on-line. You have to go to "Industries" in the upper left column and then "Drugs and Healthcare" and then choose the story and then subscribe free for 15 days, giving personal information.

I'm working on it ;-)
Dr. Susan is, I imagine, well on top of these developments and will let us know if anything really new is happening.

It's a lot harder than one might think to get data that will tell us more than what the press releases from vaccine companies are telling us, that adjuvants are the way to go.  I have reservations, simply because there is no widespread use of such chemicals in vaccines for healthy young populations, and official guidelines on how to regulate them are full of uncertainties.  The following gives you some idea of the difficulties:

Regulatory considerations on new adjuvants and delivery systems. Sesardic D Vaccine. 2006 Apr 12;24 Suppl 2:S2-86-7.

ABSTRACT:

New and improved vaccines and delivery systems are increasingly being developed for prevention, treatment and diagnosis of human diseases. Prior to their use in humans, all new biological products must undergo pre-clinical evaluation. These pre-clinical studies are important not only to establish the biological properties of the material and to evaluate its possible risk to the public, but also to plan protocols for subsequent clinical trials from which safety and efficacy can be evaluated. For vaccines, evaluation in pre-clinical studies is particularly important as information gained may also contribute to identifying the optimum composition and formulation process and provide an opportunity to develop suitable indicator tests for quality control. Data from pre-clinical and laboratory evaluation studies, which continue during clinical studies, is used to support an application for marketing authorisation. Addition of a new adjuvant and exploration of new delivery systems for vaccines presents challenges to both manufacturers and regulatory authorities. Because no adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine, pre-clinical and appropriate toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/vaccine combination. Current regulatory requirements for the pharmaceutical and pre-clinical safety assessment of vaccines are insufficient and initiatives are in place to develop more specific guidelines for evaluation of adjuvants in vaccines.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
put it in another way
If you don't know the possible side effects of a product, how are you supposed to regulate it?  If you can't regulate it properly, how do you propose to let these vaccine/adjuvant combinations be marketed?  If they are not marketed, how are you ever going to get large enough data sets to really determine the side effects beyond immediate reactions? 

Let's say an adjuvanted vaccine is licensed only for pandemic use, the manufacturers being required to give post-licensure safety data for evaluation.  But if we are talking about vaccinating millions of people as quickly as possible in a short timeframe, even such 'provisional' licensing commits us to giving these vaccines to millions of young people.  Are we comfortable with that?

If the choice is between having adjuvanted vaccines and no vaccines, it might be easier to make the case for adjuvants given the implications of a pandemic.  But if we have other vaccine options without the use of adjuvants, and if the adjuvanted vaccine is a subunit vaccine produced by egg-based technology, then there may be a lot of hurt and not much gain by going the adjuvant route.  And that's not even mentioning the issue of cost and availability of the adjuvant itself.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Adjuvant pro and con
The article mentioned that a malaria vaccine using one of the GSK adjuvants might enter into Phase 3 trials very soon. I understand that phase 3 trials involve relatively large numbers of subjects and might give us some of the baseline data that is now lacking. Malaria kills about 1 million people per year, mainly under-fives in Africa, so if the vaccine worked, some "side effects" might be acceptable in that case. In a pandemic, the danger is that something with severe and unknown "side effects" would be hurriedly approved without a sensible balancing of costs and benefits to health.

Blocking Access to Bird Flu Virus
cross posted from the news thread, by bgw in MT

http://www.newfluwik...

This is a long article that contains more details about the subject than I've seen before.

http://health.theled...

JEFF NESMITH
c. 2007 Cox News Service
Distributed by The New York Times Syndicate

The Indonesian Ministry of Health told the World Health Organization late last year that it would no longer provide samples of the H5N1 virus until it receives assurance that it will have access to pandemic vaccines.


.....

Without the samples, flu experts are unable to track changes that are building up in the genes of H5N1, the influenza virus health experts fear could evolve into a human strain and cause a pandemic.

.....

The entire world manufacturing capacity for influenza vaccine is sufficient to immunize only 500 million people, and perhaps only half that if more than one dose is required.Most vaccine for H5N1 has been sold to developed countries before it is produced - or even completes clinical trials - to be stockpiled in case of a pandemic.

Indonesian Health Minister Siti Fadilah Supari has been quoted in press accounts as saying her government wants to "create a balance between developed and developing countries in facing catastrophe."

......
 
 





All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


David Heymann meeting with the Indonesians
"WHO official David Heymann, who has worked since December to resolve the crisis, is to meet in Jakarta on March 27 and 28 with Indonesian officials, representatives of CDC and others to get the virus samples moving again.

"All I can tell you is at the moment they (the Indonesians) are not providing virus, and the meeting in Jakarta will look at the twin issues of virus sharing and vaccine production," said WHO spokesman Gregory Hartl(cq)."

...

The best remark IMHO comes from New Scientist:

"Good for Indonesia. There, it's been said," declared the British magazine New Scientist in an editorial. "In a fair world, Indonesia would send its virus to the best labs and share in any vaccine made from it. In our world, Indonesia sends off its virus, companies make vaccine from it and sell it to countries that can pay. Indonesia is not one of them, and neither are the other countries suffering badly from H5N1."

None of us on this planet will have (or should have, IMHO) a pandemic vaccine unless we also take care of those who are first affected.  And this is not just some soppy liberal egalitarianism on my part, but also a very pragmatic view that there is no way this was not going to happen heading into a pandemic.  It would be disastrous if we get this (refusal to share samples) on the eve of a breaking pandemic.  Better to bang heads together now, and sort it out.

Just my 2C

I also understand that one option being discussed is for WHO to organize stockpiles of prepandemic vaccine, donated by various countries, for wherever a pandemic might start, .

I think that is the best next step..



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Increasing vaccine supply by a factor of 4....MF59
http://www.webwire.c...

Novartis Flu Vaccine Gets Positive Opinion From European Union

snip

An adjuvant is a substance added to a vaccine to enhance the body's immune response to the vaccine's active constituent, called the antigen. Research supporting the use of the MF59 adjuvant includes:

Clinical trial data presented at the Second International Conference on Influenza Vaccines for the World (IVW 2006) confirming that the addition of the MF59 adjuvant can augment antibody response and increase protection of subjects against circulating influenza strains not included in the vaccines

Clinical research published in The Lancet in 2001 demonstrating that an MF59-adjuvanted vaccine, based on the non-pathogenic H5N3 virus strain, induced antibodies against H5N1 influenza virus at lower antigen levels

A study published in the Journal of Infectious Diseases in 2005 showing that an MF59-adjuvanted vaccine induced broadly cross-reactive antibodies capable of neutralizing H5N1 viruses isolated from a number of Southeast Asian countries between 1997 and 2004

Clinical trial data, supported by the US National Institutes of Health (NIH), of an MF59-adjuvanted vaccine against an H9N2 avian influenza virus that were published in 2006 in the online edition of Clinical Infectious Diseases; in this study, an MF59-adjuvanted vaccine induced antibody levels believed to offer protection using one quarter of the dose level used against a seasonal flu strain

Additionally, Novartis has developed a new vaccine manufacturing process that uses cell cultures rather than chicken eggs for antigen production. The new technology may reduce production time to meet demands of influenza outbreaks and to combat evolving strains of the virus, including avian influenza strains that are difficult to grow in eggs. The cell culture-based vaccine OptafluĀ® was submitted for EU regulatory approval in July 2006 and is currently in clinical studies in the US.

Comment: I expect "MF59" to be in the news more often in the future. Amazing stuff.

Click here for a curious observation.


[ Parent ]
any idea on timing?
If anyone (you?) hear anything more about universal vaccines (there is a thread about that but not much info or new stuff) could you post it?  Or the cell culture method?  A friend who is trying to prepare for a few people (who I am trying to help) has run into someone who told him "don't worry, there's a universal vaccine soon and there won't be a flu pandemic since everyone will be vaccinated", or words to that effect.

I've not read as carefully as I should've/could've since I don't plan on getting any vaccines or depending on them to "save" me.  But I want to get educated.  My understanding (no doubt partial/faulty) is that even cell culture vaccines will take too long to trial and manufacture for much percentage of the world's population.  And I would like to know more about the universal vaccine.


[ Parent ]
universal vaccine
is the M2 protein one, which is still very much in the theoretical stage, not even showing any results on animals studies yet, I don't think. 

The problem with cell culture for human use, is that basically you are genetically manueurving viral RNA and DNA in various cells, so there are dangers of inadvertent introduction of genetic material into humans.  There are also potential tumorogenic issues to be solved, for regulatory purposes.  All this is true for all cell culture except for the protein vaccine, because in that one you are using the virus vector to make the protein only, ie what you eventually inject into humans is just the protein antigen and not any genetically active material.  That's why cell culture vaccines still need a number of years, except for the rHA one.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
thank you, Susan! Now I have another ?
Thank you, Susan!  I was hoping you might answer...  just a couple of more, now:

1.  Isn't the univseral vaccine (should it work) using just the protein?  And if so, would this then be safer than the RNA and/or DNA ones?

2.  What is the rHA one that you mention?  Is that the protein one (or another kind), and would it then NOT take years to make it safe?

3.  IF this universal vaccine were to prove both safe and effective, would it take years to produce, or is the "years" part just for fine tuning and testing it?

Thank you very much and keep in mind I am a laymans' layman!  ;-)


[ Parent ]
the M2 vaccine
is still under development.  I'm not exactly sure but I believe it hasn't even been successful in animal studies yet, so it's very much a concept on the drawing board right now, whereas the H5 vaccine using the HA protein has been used already for vaccination of HCW in Hong Kong after the 1997 outbreak, but it is not yet licensed to be used for the general public as a pandemic vaccine. 

In that series of 200 vaccinations, they had very good antibody response.  Now this was based on the 1997 H5N1 virus, which is different from all the current clades.  What's even more interesting is that a recent study by Treanor found that those same HCW ie those who had prior vaccination with the 97 H5, when given a booster H5 vaccine from the Vietnam 03 virus (90ug subunit inactivated ie same as the Sanofi one), had a much enhanced antibody response against the Vietnam virus compared to those not previously primed.  This means that the HA vaccinations the 97 virus had some cross immunity with the Vietnam clade.

As for when this might be ready, here is the current status as I understand it.  The seasonal flu version of the HA vaccine, called FluBlok, is at the final stages before BLA filing, which is the technical term for getting final approval for market, which should happen at the end of this year.  Getting the seasonal vaccine licensed is necessary before the actual development of the pandemic vaccine beause of FDA requirements that the pandemic vaccine has to be based on an existing licensed seasonal flu vaccine.

After that, further clinical trials on the pandemic H5 vaccine based on current clades can commence.  Put it in a different way, the technology for the rHA H5 vaccine is pretty much ready, but they have to do Phase 2 and 3 clinical trials (I believe, I may not be exactly accurate on this) go through the FDA process, after FluBlok is licensed.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Baxter vaccine
some reports about the Baxter vaccine today, I couldn't find it at FW,
so I copy it here:

--------------------------------------------------------------------------------

http://www.medicalne...

some excerts:

The global healthcare company plans to start Phase III trials in the next few months, with results expected by the end of the year.
Phase III trials will test the vaccine on healthy European volunteers. This phase will evaluate the safety of the whole-virus candidate vaccine and assess its protective power in large groups before and during a potential pandemic.
The Baxter candidate vaccine showed a strong immune response without the help of adjuvants or additional agents used to boost responses.

The Phase III trial will also test the vaccine without adjuvant, and will be administered by intra-muscular injection.

7.5 micrograms of antigen, the seroprotection rate at day 42 was 76.2 per cent.

Baxter developed its candidate vaccine from a strain of H5N1 known as A/Vietnam/1203/2004 using a cell-based as opposed to an egg-based technology.

This speeds up vaccine production, allowing it to be available much earlier, within 12 weeks, Baxter says.
Side-effects were similar to those reported for licensed, seasonal, egg-based flu vaccines and mostly comprised reactions at the injection site, headaches and fatigue.

and some more excerts from
http://www.newspress...

study of 270 patients from Europe and Asia.
In the next two months, Baxter will begin enrolling more than 600 patients in the final clinical trial
_________________
 

ask experts for their subjective
panflu death expectation values
and report the replies


[ Parent ]
thank you
as I wrote in another post, the Baxter vaccine is a whole virus vaccine based on the wild-type virus, ie one that has not been modified by reverse genetic engineering to remove the characteristic cleavage site that causes it to be high-path, so maybe that's the reason why it is so effective.  http://www.newfluwik... 

OTOH, this also means that the vaccine has to be made in BSL3 labs, which severely limits the ability to produce massive quantities, in addition to the usual issues with cell-culture vaccines.



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
more thanks
SusanC, thank you very much for your continued explanations.  As I mentioned on PFI, I'm trying to play catchup about vaccinations, with my brain limping along behind me.

[ Parent ]
One more question...
You mentioned:

"...in addition to the usual issues with cell-culture vaccines."

If you would be so kind as to provide a link or a simple explanation (just so my limping brain gets a small clue), thanks.


[ Parent ]
here is a good summary
of regulatory requirements for new cell lines for vaccine development.  From this most excellent review issue of the Bridge Engineering and Vaccine Production for an Influenza Pandemic 





All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
vaccine for the whole world - a needed (technical and regulatory) "revolution"
Hellen Branswell writes about the political and supply struggle here: http://newfluwiki2.c...  (have a look at the full article: Branswell writes gold)

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.

revere comments
So for vaccines there are really two problems. One is determining how many people you would have to give the vaccine to in order to attain an effective level of herd immunity. That depends on the effective R0, which depends on the vaccine's effectiveness but also on a whole lot of other things that will vary from population to population. The other is determining how much vaccine you would need to get to that level, whatever the level is. That will depend on what level of antibody is needed to protect most people. Maybe it will take less than we think and we can stretch the vaccine supply by diluting it. On the other hand, maybe our current guesses, based on data from H1N1 and H3N2 vaccines, doesn't work for H5N1 and we would need more.

The difference between our current productive vaccine capacity and what would be needed to protect most of the world's population is pretty large. On the other hand, how big that gap is will vary from place to place and depend on a lot of things we don't know at the moment.

Meanwhile too little is being done to ramp up vaccine production and make sure the product is accessible to those who need it. That's one thing we can be certain about.



Be kind, for everyone you meet is engaged in a great struggle.--Philo of Alexandria

Melanie, thanks - link is here for reference and details
http://scienceblogs....

You arm yourself to the teeth just in case.  You don't leave the gun near the baby's hand.

[ Parent ]
this was posted on the HHS blog in response to Leavitt
Mr Secretary,

Thank you for sharing your experiences and insights. I agree with you that countries should support the Global Influenza Surveillance Network and work towards full compliance with the International Health Regulations. At the same time, I would suggest that we also need to see this from the developing countries' points of view. Until the Indonesians started holding the world to ransom, there was no political will to ensure that these countries have access to a pandemic vaccine. Essentially, we were just going to take their patient samples (yes, folks, that's what they are! Ultimately, the virus samples came from real people!), and make vaccines to save our children and leave theirs to die!

As my good friend Dr David Fedson said, "We should have seen this coming, folks!"

We know that with existing egg-based technology, there is no way we can build enough capacity to make a pandemic vaccine enough to cover developing countries as well as our own needs for the foreseeable future. We know that we need to develop new cell-culture based vaccines to overcome the problem. We know that we need to do that quickly.

The US government is commendably willing to invest in development of such new technologies. However, the system, as always, is only as strong as the weakest link(s).

Please correct me if I'm wrong, but it is my understanding that current regulatory requirements are such that the serologic end-points required for licensing for a pandemic vaccine is similar to that for seasonal vaccine, which IMHO creates an unnecessarily high hurdle since the goal of seasonal flu vaccination (protection of the vaccinee) is substantially different from that in a pandemic (development of herd immunity to stop the spread of the virus).

Secondly, it is also my understanding that companies can only submit a BLA licensing application for a pandemic vaccine if they already have a seasonal vaccine licensed using the same technology. Since all existing licensed seasonal vaccines are egg-based, this in essence means that to develop a pandemic vaccine using new technology, a company needs to develop not one, but 2 products, consecutively, and have them both successfully go all the way through the licensing process. I am guessing, and please tell me whether I am correct on this, that this adds between 5-8 years to the process.

Is that really necessary? I understand the importance of ensuring that we do not make a pandemic vaccine that does more harm than good. I know that many in the profession still have not gotten over their nightmares from the 1976 swine flu vaccine complications. But this is 30 years later, and we are facing a virus which is much more virulent, widespread, and persistent than the one that attacked handfuls of soldiers in one army camp in 1976. Isn't it time that we get out from under the shadow of the past and look at the problem with new eyes?

Furthermore, again please correct me if I am wrong, it is also my understanding that the US government has a policy of not funding the research of 'novel' vaccine technologies and/or companies that do not already have a licensed product approved by the FDA. Which in essence tilts the playing field heavily in favor of existing big conglomerates against some small but innovative companies. At the very least, this has the potential of excluding from contention some perfectly good products simply by reason of their 'accident of birth'?

Mr Secretary, the world desperately needs to have the ability to make enough pandemic vaccines fast enough to make a difference to the outcome should we have a pandemic.
The Indonesians may be misguided and irresponsible in threatening to not share virus samples. But they are also doing us a favor by awakening us to the need to abandon our fixation to 'tried and true' ways of doing things and start afresh!

At the end of the day, what is the use of having a virus sample if we cannot make the vaccines that will make a difference to the number of people who will die in the next pandemic?

Susan Chu MD
Editor, Flu Wiki

ps these issues are explored in more depth in this diary Enough Pandemic Vaccine for the Whole World?
Posted June 15th, 2007 at 10:09 pm



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


link to HHS blog
http://blog.pandemic...



All 'safety concerns' are hypothetical.  If not, they'd be called side effects...


[ Parent ]
Osterhaus recommends prepandemic vaccine
http://www.flutracke...

ask experts for their subjective
panflu death expectation values
and report the replies


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