FluTrackers Interviews David S. Fedson, M.D. - Meeting the Challenge of Influenza Pandemic Preparedness in Developing Countries

[sharon sanders]

Recently I interviewed David Fedson, M.D., an expert in pandemic preparedness and vaccine issues, regarding his latest paper: "Meeting the challenge of influenza pandemic preparedness in developing countries". (link <http://www.cdc.gov/eid/content/15/3/pdfs/08-0857.pdf> )

He earned his medical degree from Yale University in 1965. Later he obtained a fellowship studying smallpox in India, and interned at the Osler Medical Service at The Johns Hopkins Hospital. He was a Clinical Associate in the Laboratory of Clinical Investigation at the National Institutes of Health and was a Chief Medical Resident at the University of Chicago. He has held faculty appointments at the University of Chicago and also the University of Virgina, where he was the Harry T. Peters, Jr. Professor of Medicine and Head of the Division of General Medicine.

In 1995, Dr. Fedson joined the Medical Department of Aventis Pasteur MSD. There he concentrated his work on the epidemiology and cost-effectiveness of influenza and pneumococcal vaccination. In 1999, he received the Research Achievement Award in Adult Immunization in the United States, bestowed by the Centers for Disease Control and Prevention and the National Coalition on Adult Immunization. He participated in the establishment of the Influenza Vaccine Supply (IVS) International Task Force in 2001 which considers vaccine topics for the next influenza pandemic. He retired in November 2002 and has continued to work on influenza and pneumococcal vaccination issues. He organized the Macroepidemiology of Influenza Vaccination (MIV) Study Group. Dr. Fedson has published over 160 scientific articles and papers on issues concerning adult immunization.


SS -- Dr. Fedson, thank you for giving this interview. In your paper you urge the leaders of developing countries, scientists, and international organizations to begin the research into inexpensive generic agents to mitigate an influenza pandemic, what response have you received?



DSF — I’ve received no response. Since I work alone and am not affiliated with an institution or organization, I’ve not expected to be contacted directly, However, the idea for conducting research on inexpensive generic agents is one that I have been “peddling” to international organizations, health agencies and influenza investigators for almost five years. I’ve received very few expressions of interest. For example, on four separate occasions I‘ve asked WHO to hold a technical consultation to review the scientific merits of the generics approach and, if it seems reasonable, to set forth a research agenda. On each occasion, WHO has turned me down. The Gates Foundation has not been interested. I even met with a senior advisor to the Indonesian Health Minister to introduce him to these ideas, but I don’t think our conversation led to anything. However, I have been encouraged by the response of a well-positioned Chinese investigator. When we discussed these ideas last fall, he said he would take them back to Beijing and get to work. He understands better than I that with 1.3 billion people to look after and few prospects for adequate supplies of pandemic vaccines and antivirals, his country will need one or more effective alternatives. Since several of the generic agents I’ve discussed are produced in China, Chinese health officials have a strong incentive to take the generics approach seriously. And China has many experienced investigators who are capable of doing the research.



SS --You have suggested the possibility of using statins, peroxisome proliferator-activated receptor (PPAR)a and PPARg agonists (fibrates and glitazones, respectively), chloroquine, resveratrol, catechins, and curcumin for treating pandemic influenza. Why do you think research is lacking in determining the effectiveness of these agents to mitigate a pandemic?



DSF — From what we know of the molecular biology of these agents, they are among the most promising candidates for testing in research laboratories. However, they are not by any means the only ones. What characterizes them is that, with one exception, they are generically produced in developing countries and consequently they are inexpensive and could be made widely available. Of course, because they are generic agents, no pharmaceutical company is interested in sponsoring such research.



Influenza virologists are not studying these agents because they are experts on the virus and seek to develop either vaccines or antiviral agents. The generic agents I talk about affect the host response, and this is something that, with the exception of the immune response, influenza virologist know little about.



Not long ago, I asked a group of distinguished influenza scientists if any of them had heard of heme oxygenase-1 or high molecular group box 1 protein. None of them had. Yet anyone who studies the molecular biology of sepsis or acute lung injury will be familiar with these terms, and will know that they must be included in any serious discussion of the host response to infection.



Donald Rumsfeld once said, “There are known knowns, ... (the) ... things we know that we know. There are known unknowns, ... (the) things that we know we don't know. But there are also unknown unknowns, ... (the) ... things we don't know we don't know.”



For influenza scientists and the host response, there are lots of unknown unknowns.That’s why I say in my article that pandemic preparedness is too important to leave to the influenza scientists alone. We must enlist the support of scientists in other fields – sepsis, critical care, cardiovascular and pulmonary diseases, metabolic disorders, mitochondrial function. They must tell influenza scientists what they know is known and unknown about the host response to infection.



GM -- What is the possible role for quinine (antimalarial) and derivatives for treatment of influenza infections during pandemics, addressing the issue of possible treatment failures that caused health authorities to refrain for using these compounds - theoretically useful even in chikungunya epidemics, for example - so far. Further, can ribarivin and protease inhibitors (ie: Rebetol and Kaletra) be seen as synergistic therapeuticals in addition to neuraminidase inhibitors?



DSF – I have no opinion on the potential for using quinine for pandemic treatment. Chloroquine, or better hydroxychloroquine, should be considered because for at least some influenza viruses, these agents prevent the acidification of the endosome and this means that influenza virus genetic material can’t be released into the cytoplasm of an infected cell. If hydroxychloroquine were shown to be of benefit, it would be very, very inexpensive.



Regarding additional agents such as ribavirin and protease inhibitors, several influential influenza virologists have recently called for treating individual patients with more than one antiviral agent. Their recommendation is an obvious response to the development of resistance to oseltamivir (Tamiflu) in almost all isolates of seasonal H1N1 influenza viruses, and a recognition that the same thing might occur with a pandemic virus. But we should stop for a moment and ask: would adequate supplies of ribavirin and protease inhibitors be available at affordable prices if and when a pandemic virus appears? The answer to that question is most certainly they wouldn’t be. I point out in my article that global supplies of oseltamivir, the most widely stockpiled antiviral agent, will be sufficient to treat about 1% of the people who live in countries that don’t produce vaccines. If this is true for oseltamivir, it’s my guess that supplies of ribarivin and protease inhibitors will probably be much more limited. While a recommendation for combination antiviral treatment is sensible from a purely scientific point of view, it has virtually no chance of ever being implemented in populations. Recommendations on how to confront a pandemic in populations must be relentlessly practical; if they are anything less, they shouldn’t be taken seriously.


SS -- In your paper you say, "In Indonesia, physicians have reported that everyone infected with the clade 2 influenza virus A (H5N1) who did not receive antiviral treatment has died". In your opinion do we have time for the lengthy process to quantify and approve such a protocol as you suggest for treatment of pandemic (potentially H5N1) influenza? Would it be possible to establish a treatment protocol for humans after initial tests/findings on mice?



DSF — If we had started doing the animal research several years ago, by now we would have identified one or more treatment regimens that might be promising (or perhaps shown that none of them would work). We could still do the research in mice, ferrets and nonhuman primates and get many of the answers we need within six to twelve months. The cost would not be very high, but it would require some serious organization and the collaborative efforts of many scientists, along the lines of the international collaboration that quickly led to the identification of the SARS coronavirus. As I point out in my article, this WHO initiative for SARS was spectacularly successful. I don’t understand why WHO hasn’t seen the need to do something similar for pandemic preparedness. The stakes are immeasurably higher.



Testing promising treatments in ferrets and at least some nonhuman primates should be the goal; basing decisions on which regimens to test in man on mouse data alone could be misleading. But no matter how much animal research precedes human testing, the protocols for clinical trials must be in place before the next pandemic virus emerges. Ideally they should be drawn up by an international group of scientists and clinical investigators, but this would require an organization like WHO or the NIH to bring them together. If this doesn’t happen (which is likely), individual institutions will undertake trials on their own. Recently I spoke with investigators at my local university hospital, and they said they would seek approval from their hospital ethics committee for a clinical trial protocol that could be implemented when they admit their first pandemic patient. It will be unfortunate in the extreme if we have to rely solely on the ad hoc efforts of a few individual investigators to provide us with critical information on how to manage a global pandemic.



I should add that clinical investigators in the US, the UK and Australia are already conducting randomized controlled trials of statins in the treatment of sepsis, and at least one study on statin treatment of ICU patients with pneumonia will soon to be completed in South Korea. These trials should provide important information to guide clinical trials of pandemic treatments.



SS -- If an influenza pandemic strikes before a treatment protocol is established via traditional methodology, do you have a suggested course of treatment?



DSF — I have a good sense of which agents I personally might wish to test first, but this would be like placing a bet on a favorite horse. Our approach should be more rational.



In my article I outline a five-point agenda for research on generic agents that should be undertaken before the emergence of a new pandemic virus. The first two steps describe the laboratory research that must be conducted in mice, ferrets and non-human primates. I emphasize that this research must seek to identify promising regimens at can be used to manage a pandemic. Explaining precisely how these agents work is of secondary importance. We should keep in mind that Jenner didn’t understand the germ theory of disease when he vaccinated against smallpox. Knowing so little, he nonetheless achieved so much.



SS - In today's depressed economic climate, in your opinion, what or which, global entities could fund the parallel studies/research as suggested in your paper?



DSF — The amounts of money that we would need to first test promising treatment regimens in mice would not be very large. I’ve been told by one investigator who works with mice that studies in 5000 mice would cost no more than $250,000, not counting the costs for personnel. Keep in mind that Ian Clark and his colleagues in Australia used fewer than 100 mice to show that gemfibrozil, a fibrate, reduced mortality H2N2-infected mice by more than 50%. With 5000 mice, we could undertake 50 similar trials. Tests in 300 ferrets could probably be done for $500,000. Compared with what is now being spent by governments to rescue their banks, these amounts are less than trivial. But someone will have to come up with the money, and it will have to be either a national government, the US being far and away the most likely, or institutions like the Gates Foundation or the Wellcome Trust. But they will have to get interested first. Thus far, they have focused their support on developing vaccines and antiviral agents. Unfortunately, I don’t think they understand the arithmetic of the limited supplies of vaccines and antivirals , and the potential for much larger and much more affordable supplies of generic agents.



SS - What can the average citizen do to promote a "bottom-up" approach based on inexpensive generic agents for preparation of an influenza pandemic?



DSF —The average citizen can follow Flu Trackers closely, write to his or her Congressman or Congresswoman and Senator, and contact the local newspaper and media. We need to get more political support for this idea if we are to move it along. This means that a lot more people are going to have to start making a lot more noise.




by Sharon Sanders


Contributors:

Sally Furniss
Giuseppe Michieli


for FluTrackers.com

[gsgs]

could (cell-based) production be scaled up in a pandemic ?



what about Super-Relenza ?

[sharon sanders]

The vaccine production facilities can not provide enough vaccine for the 6.7 billion people on earth.

Who gets what vaccine is produced? And when?

There also will not be enough Relenza.

[sharon sanders]

hat tip Senior Moderator Fla Medic -


February 21, 2009

Fedson On Meeting The Challenge Of A Pandemic



# 2816


Dr. David Fedson's views have appeared in this space on more than one occasion over the past 3 years. The first time I wrote about him was during the summer of 2006.

At the time, Dr. Fedson was proposing that research be conducted on the potential usefulness of statins - cholesterol reducing drugs - in the treatment of pandemic influenza. He'd just released a paper entitled Pandemic influenza: a potential role for statins in treatment and prophylaxis.

He pointed out that the world's capacity to produce vaccines and antivirals was insufficient to adequately combat a severe influenza pandemic, and that developing countries in particular are unlikely to see these interventions.

What the world would need is a cheap, easy to produce, and abundant pharmacological intervention if it was to stave off the worst effects of a pandemic.

Dr. Fedson proposed statins might do the trick. They, after all, are known to have anti-inflammatory and immunomodulatory effects. This was all just theory, of course.

He was simply calling for more research.

In April of 2007 we saw a new study that indicated that statins, indeed, lowered the mortality rate of people with pneumonia.

Statin drugs lower respiratory death risk: study

Tue Apr 10, 2007 12:40pm EDT
By Maggie Fox, Health and Science Editor
WASHINGTON (Reuters) - People who use statin drugs are less likely to die of influenza and chronic bronchitis, according to a study that shows yet another unexpected benefit of the cholesterol-lowering medications.

Their study of more than 76,000 people showed that those who had taken statins for at least 90 days had a much lower risk of dying from chronic obstructive pulmonary disease or COPD, the technical name for emphysema and chronic bronchitis.

Patients on statins also had a lower risk of dying from influenza or pneumonia, the researchers reported on Monday.

Dr Fedson and Peter Dunnill, DSc,FREng then collaborated on a commentary, published in the Permanente Journal, Summer 2007 edition, on how we might confront an imminent pandemic.

The commentary was called New Approaches to Confronting an Imminent Influenza Pandemic, and in it the authors presented options including two possible routes to producing vaccine in quantity, and the use of statins to mitigate the effects of a cytokine storm.



In January of 2008, Australian researchers announced encouraging results from studies conducted on mice given gemfibrozil, a fibrate, which is another class of cholesterol lowering drug.

Tests home in on new hope against bird flu


Julia Hinde | January 19, 2008
Now a group of Australian researchers has published data that might point the way to an alternative - and potentially cheaper - way to fight the next major outbreak.

Led by Ian Clark of the Australian National University (ANU), the researchers used gemfibrozil, a drug already approved for human use as a cholesterol-lowering medication, to treat mice infected with a potent influenza virus.

The team reports a doubling in survival rates for infected mice when they were given a course of gemfibrozil, starting four days after they became infected.

And only last October, we learned of another study showing that pneumonia patients benefited greatly from being on statins.

Statins may cut pneumonia death, blood clot risks
27 Oct 2008 20:00:13 GMT
Source: Reuters
By Will Dunham
WASHINGTON, Oct 27 (Reuters) - Cholesterol-fighting drugs known as statins reduced the risk of dying from pneumonia or developing dangerous blood clots in the legs, adding to a growing list of benefits from the popular drugs, two research groups said on Monday.

Statins, the world's top-selling drugs, cut heart attack and stroke risk, and research has suggested other benefits including possibly protecting against Alzheimer's disease.

Some studies have linked statin use with decreased risk of severe sepsis -- infection of the bloodstream -- or death associated with infections, but there had been conflicting findings on pneumonia, according to Dr. Reimar Thomsen of Aarhus University and Aalborg Hospital in Denmark.

While certainly not definitive, the research studies undertaken since Dr. Fedson made his proposal three years ago are encouraging.


The latest (March 09) issue of the CDC's journal of Emerging Infectious Diseases has a perspective by Dr. Fedson, once again urging that researchers consider statins as a possible therapeutic agent during a pandemic.

I've reproduced the abstract here (reparagraphed for readability), but by all means follow the link and read it in its entirety.

Meeting the Challenge of Influenza Pandemic Preparedness in Developing Countries

David S. Fedson
Author affiliation: Retired
Fedson DS. Meeting the challenge of influenza pandemic preparedness in developing countries. Emerg Infect Dis [serial on the Internet]. 2009 Mar [date cited]. Available from http://www.cdc.gov/EID/content/15/3/365.htm
DOI: 10.3201/eid1503.080857
Abstract
Developing countries face unique difficulties preparing for an influenza pandemic. Our current top-down approach will not provide these countries with adequate supplies of vaccines and antiviral agents.

Consequently, they will have to use a bottom-up approach based on inexpensive generic agents that either modify the host response to influenza virus or act as antiviral agents. Several of these agents have shown promise, and many are currently produced in developing countries.

Investigators must primarily identify agents for managing infection in populations and not simply seek explanations for how they work. They must determine in which countries these agents are produced and define patterns of distribution and costs.

Because prepandemic research cannot establish whether these agents will be effective in a pandemic, randomized controlled trials must begin immediately after a new pandemic virus has emerged. Without this research, industrialized and developing countries could face an unprecedented health crisis.

[gsgs]

> The vaccine production facilities can not provide enough
> vaccine for the 6.7 billion people on earth.

that's what Fedson (and all the other experts...) told us in 2004ff
and why we needed
cell based production, which could be scaled up.
Now we have cell based production, still people complain
about production limitation ?!

> Who gets what vaccine is produced? And when?

they made the "tiers..." . After 4 months, they say

> There also will not be enough Relenza.

we could produce it, just a matter of cost. (how much was the bailout ?)
But I meant Super-Relenza, CS-8958, Daiichi Sankyo
http://www.flutrackers.com/forum/showthread.php?t=92115

[tropical]

Originally Posted by gsgs

> The vaccine production facilities can not provide enough
> vaccine for the 6.7 billion people on earth.

that's what Fedson (and all the other experts...) told us in 2004ff
and why we needed
cell based production, which could be scaled up.
Now we have cell based production, still people complain
about production limitation ?!

> Who gets what vaccine is produced? And when?

they made the "tiers..." . After 4 months, they say

> There also will not be enough Relenza.

we could produce it, just a matter of cost. (how much was the bailout ?)
But I meant Super-Relenza, CS-8958, Daiichi Sankyo
http://www.flutrackers.com/forum/showthread.php?t=92115

Looking at the recent WHO posture to not suggest anything precisely on depoting prepandemic vaccines to the member states, the chances to "make a change" are small ...

[sharon sanders]

from April 11, 2007, hat tip revere, who is also a member of FT


The statin story continues to hold up

Category: Bird flu

Posted on: April 11, 2007 6:52 AM, by revere


The newswires are carrying a story that the journal, Chest, is about to publish a retrospective study of influenza mortality and statin use. As happens more and more frequently, press reports are appearing prior to the actual article, so I haven't read it yet. This is very irritating. The whole press embargo system is irritating, in fact, and should be deep-sixed (Full discolosure: I frequently get advance copies of embargoed articles and I honor the dates. But I don't think journals should do it. It serves no useful purpose.).


The embargo issue aside, here is what the press is saying:

People who use statin drugs are less likely to die of influenza and chronic bronchitis, according to a study that shows yet another unexpected benefit of the cholesterol-lowering medications.

Their study of more than 76,000 people showed that those who had taken statins for at least 90 days had a much lower risk of dying from chronic obstructive pulmonary disease or COPD, the technical name for emphysema and chronic bronchitis.


Patients on statins also had a lower risk of dying from influenza or pneumonia, the researchers reported Monday.
[snip]


The new study supports a theory proposed last year that statin drugs might help patients with H5N1 avian influenza, which some studies suggest kills by causing an immune system overreaction called a cytokine storm.


Floyd Frost of the Lovelace Respiratory Research Institute in Albuquerque, New Mexico, and colleagues analyzed their institute's database of medical records from several health maintenance organizations.


They looked at incidence of influenza and pneumonia and of COPD [chronic obstructive pulmonary disease], and then cross-checked to see which patients were also taking statins.
"This study found a dramatically reduced risk of death from COPD among statin users and a significantly reduced risk of death from influenza/pneumonia," the researchers wrote in their report, published in the journal Chest.


"These findings suggest that moderate-dose statin use reduces the risk of influenza/pneumonia death and strongly suggest that statins reduce the risk of COPD death." (CNN)

We've posted on this before (see here and here). Some statins have now gone off patent and are available in generic form. They are among the highest volume drugs and supplies are plentiful, so if they are truly protective of the most virulent outcomes of H5N1 infection this is good news.


It isn't at all clear how statins work to protect against cytokine storm (if in fact they do). David Fedson, who has done more than anyone else to alert the flu community to the potential of this class of drugs in a pandemic, has reviewed the literature (abstract here). We know some virulent strains of H5N1 can interfere with cytokine signalling in the immune system (parts of the nonstructural protein 1 [NS1] inhibit the action of interferons and tumor necrosis factor in the test tube) and there is a marked elaboration of proinflammatory cytokines in patients with H5N1 infection. But the cytokine signalling system is complicated and it can make a big difference if you inhibit one of the interferons early in an infection or later on. The advantage of statins is that they are taken continuously for other purposes (cholesterol lowering) and are relatively non-toxic. This means that whatever their effects on cytokines the timing can be easily duplicated.prophylactically.


Not a silver bullet. But like everything else connected with this nasty virus, we'll take whatever we can get.

[ironorehopper]

I would like to express both Sharon Sanders and Dr Fedson my congratulation for the words expressed in interview.

I think it is of general interest to pursue every way to reduce morbidity and mortality from a pandemic or another biological emergency with therapeuticals and common-sense measures affordable to all people in the world.

Sometimes, great ideas have seen unexpected fortune but initially they have encountered strong opposition if not ostracism from people who have power...

Thank you again. IOH (GM)

[sharon sanders]

Originally Posted by ironorehopper

I would like to express both Sharon Sanders and Dr Fedson my congratulation for the words expressed in interview.

I think it is of general interest to pursue every way to reduce morbidity and mortality from a pandemic or another biological emergency with therapeuticals and common-sense measures affordable to all people in the world.

Sometimes, great ideas have seen unexpected fortune but initially they have encountered strong opposition if not ostracism from people who have power...

Thank you again. IOH (GM)

Thank you for assisting with the interview Giuseppe.

We need help.

We are on our own.

Apparently there will not be any effective and safe vaccine for years for the majority of the world's populations.

If tamilflu is still working against the pandemic influenza strain, there will be only enough for approximately 3% of the world's citizens.

Relenza is in relatively short supply. Antibody treatment? Also years away. Masks? The supply of these too will be exhausted for most of the world's humans.

So what do we do about this?

We take charge of our personal lives. We find a way. We take care of ourselves.

We help our friends, families, communities - hand-in-hand - we reach to those who lack the means to help themselves.

[Sally Furniss]

Not long ago, I asked a group of distinguished influenza scientists if any of them had heard of heme oxygenase-1 or high molecular group box 1 protein. None of them had. Yet anyone who studies the molecular biology of sepsis or acute lung injury will be familiar with these terms, and will know that they must be included in any serious discussion of the host response to infection.

Critical Care and Shock
http://www.flutrackers.com/forum/showthread.php?t=98277&highlight=hmgb1

Systemic Release of High Mobility Group Box 1 Protein during Severe Murine Influenza.
http://www.flutrackers.com/forum/sho...d.php?p=168809


Can this be applied to other parts of the body?
http://www.flutrackers.com/forum/showthread.php?t=26534
.... In a mouse model of cerebral malaria, free heme molecules can induce inflammation and permeabilization of the blood brain barrier, leading to death. The enzyme heme oxygenase-1 or its product carbon monoxide can decrease free heme levels, offering a new therapeutic approach to this deadly complication....

[sharon sanders]

bump this.

[gsgs]

he could make his own research company
he could post to the forums (occasionally)
he could make his webpage (someone help !)


he could give panflu probanility estimates

[pamwv41]

In response to the post on this page by Florida on statins, I'm wondering if one of the reasons the elderly are not being as affected by H1N1 is because so many of them are on statin drugs. That may be a another reason in addition to the amount of immunity they have been afforded by antibody levels from the 1957 flu.

[LMonty]

pam I think thats a brilliant piece of insight.

[sharon sanders]

I agree.

[St Michael]

Keep up the good work, Sharon!

For anyone looking at Dr. Fedson's research, just remember that it can be dangerous to take statins at the same time as fibrates:

Gemfibrozil, when used together with the statin family of cholesterol-reducing medications, for example, lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), rosuvastatin (Crestor), and atorvastatin (Lipitor) increases the risk of a condition called rhabdomyolysis (muscle injury) which when severe can lead to kidney damage and seven death. Rhabdomyolysis may occur as early as three weeks or several months after starting combination therapy. The benefit of combining gemfibrozil with statins does not outweigh the risk of rhabdomyolysis.

Here's the research article on Gemfibrozil Treatment of Severe Mouse Influenza:


Increased Survival after Gemfibrozil Treatment of Severe Mouse Influenza

...

We have shown that gemfibrozil, when administered i.p. on days 4 to 10 after exposure to virus, after the onset of illness, significantly increased survival in mice with severe influenza.
...

Although gemfibrozil is as yet untried in human influenza, it could have two major advantages. First, it is already approved for daily human use, albeit by a different route, to lower plasma lipids and cholesterol (18, 23). Second, from our data, enhanced survival did not depend on giving gemfibrozil before the onset of illness, since treatment begun 4 days after exposure to virus, when mice were already sick and had lost weight, was effective. This implies that gemfibrozil has the potential to be a treatment rather than a preventative in human disease, allowing limited stocks of the drug to be focused where required in a pandemic. The idea that severe systemic inflammatory disease arises through overproduction of proinflammatory cytokines in influenza (6, 8) now also has general acceptance. This made it attractive to test the effects of gemfibrozil on influenza, a disease acknowledged to operate through these cytokines. No fibrate appears to have been previously tested against an infectious disease.

Using anti-inflammatory agents against influenza is a recent suggestion, with Fedson proposing statins as a prophylaxis and treatment for an influenza pandemic (11, 12). While the concept has been gaining favor (20), no direct data are as yet available. Since the aim of this study was to find an agent useful in animals already sick from influenza, our initial trials included simvastatin at the human daily maintenance dose for lowering blood lipids. Unlike gemfibrozil, simvastatin had a negligible effect on sick animals under these conditions. Nevertheless, the use of statins in influenza, including as prophylactic agents, warrants closer examination, since the epidemiological data that support the protective effects of statins arose from sepsis patients who were already taking these drugs at the time they became ill (1).

We also found that gemfibrozil gave some protection, in survival terms, against the severe systemic inflammatory illness that results from administering LPS (Fig. 3). This suggests that it could also protect against other similar inflammatory conditions as well as influenza. In addition, activity against LPS implies that at least a major effect of gemfibrozil against influenza is to inhibit inflammatory cytokines, not the virus. Nevertheless, the mechanisms by which gemfibrozil exerts the effects we have observed are yet to be elucidated. Our next priorities are to examine whether inflammatory cytokine production is inhibited and to determine if gemfibrozil has any direct antiviral action.

Although the published mouse 50% lethal dose of gemfibrozil is 3,162 mg/kg for a single orally administered dose, and 300 mg/kg/day of gemfibrozil, given for 3 or 12 months, is well tolerated in rats (15), we are wary of extrapolating this to pathogen-infected mice without further study. Also, it is yet to be ascertained how outcomes of oral and i.p. dosages compare. As noted elsewhere (3), gemfibrozil reduces the production of inflammatory cytokines, molecules that are involved in the host response against pathogens as well as disease pathophysiology (6). The literature on the effects of anti-TNF agents in rheumatoid arthritis provides an example of this useful and harmful duality of inflammatory cytokines (22). This possibility in influenza will be examined in several ways, including further parallel studies using gemfibrozil against influenza and LPS toxicity. The LPS model is useful because it involves no cytokine-susceptible infectious agent and causes pathology only through excessive cytokine production.

In summary, if these results translate to human infections, gemfibrozil may prove to be a readily testable and useful treatment for influenza, both in high-risk individuals with the currently circulating influenza virus strain and in any pandemic resulting from an antigenic shift in a subtype, including the current avian H5N1 influenza virus.

[sharon sanders]

hat tip Senior Moderator Fla Medic -

Tuesday, May 19, 2009

Swine Flu Vaccine Production Delayed



# 3220



Anyone who didn’t see this one coming hasn’t been paying attention.

Swine Flu Vaccine Will Take Months, Health Officials Say

By THE ASSOCIATED PRESS Published: May 19, 2009
Filed at 7:06 a.m. ET
GENEVA (AP) -- Drug manufacturers won't be able to start making a swine flu vaccine until mid-July at the earliest, months later than previous predictions, the World Health Organization said Tuesday.

The disclosure that making a swine flu vaccine is proving more difficult than experts first thought came as U.N. Secretary-General Ban Ki-moon and WHO chief Dr. Margaret Chan met Tuesday with representatives from up to 30 pharmaceutical companies to discuss the subject.

Health officials from around the world are attending WHO's annual meeting in Geneva this week to discuss the outbreak that has infected 9,830 people in over 40 countries, killing 79 of them.

According to vaccine experts convened by WHO last week, swine flu virus is not growing very fast in laboratories, making it difficult for scientists to get the key ingredient they need for a vaccine, the ''seed stock'' from the virus.

The flu experts said vaccine manufacturers will not be ready to produce a swine flu vaccine until mid-July at the earliest, the agency reported Tuesday on its Web site. Previously, WHO officials had estimated that production could start in late May.
(Continue . . . .)

The hope was that (and you need to insert a small miracle here) somehow vast quantities of H1N1 vaccine could be produced, and distributed in time for this fall’s flu season.

On May 9th, in A Vaccine Reality Check , I rattled off just a few obstacles that I felt could interfere with that timetable.

• The virus could mutate over the summer or fall, possibly rendering any vaccine being manufactured now less protective (or even useless).

• The virus may not grow well in eggs (that happens sometimes), reducing the amount of antigen that can be produced.

• They could discover problems during the animal and human testing phase, which can’t even begin until late July.

• The much vaunted global manufacturing capacity may not be as high as some have projected.

• People may need more than the standard 15 mcg flu shot to provoke an immune response, or need two shots, which would cut down on the number of doses that could be produced.

• The logistics of delivering a (prioritized) vaccine to hundreds of millions of people (possibly in two shots a month apart) over a short period of time are tremendous.

• And of course, there could be diplomatic wrangling over the sharing of vaccines with developing countries, or over the export of vaccine from the manufacturer’s country until their needs have been met.

Apparently #2 on my hit parade has already proven to be a problem; The virus isn’t growing well in the lab.

In this case, the seed stock for a candidate vaccine isn’t growing well, which could prove problematic for mass production later on as well.

All of these other problems are still in play, by the way.

And if you follow the link to read the AP article, the estimates of our being able to produce 5 billion doses of vaccine are – to put it kindly – generous.

The promise of a vaccine, I’m sure, mollifies a lot of fears.

But the logistics of producing, and delivering a vaccine are enormous, and should not be underestimated.

Better, I think, that we lower expectations on having a vaccine (and if we get lucky, hey, we can celebrate), than to make promises today that will likely crumble in the fall.

The CDC, to their credit, has steadfastly refused to speculate on when, or how much, swine flu vaccine will be available.

A course that is looking more prudent every day.

[gsgs]

> The CDC, to their credit, has steadfastly refused to speculate on when,
> or how much, swine flu vaccine will be available.
> A course that is looking more prudent every day.

so we have to rely on the estimates of other organizations.
ECDC,RKI,vaccine producers, etc.