The unforgiving arithmetic of pandemic

©L'Osservatore Romano
15 July 2009

Dr David Fedson on aiding developing countries in the treatment of pandemic diseases

"The world situation, as the news in recent months amply demonstrates, continues to present
serious problems and the "scandal' of glaring inequalities which have endured despite past
efforts". These were the words of Pope Benedict XVI during the General Audience Catechesis
outlining the fundamental messages of his recently released Encyclical Letter, Caritas in Veritate
(see p. 11).

When viewing the current world situation from a Catholic perspective, the pursuit of social
justice within all sectors is essential, as the Holy Father clearly expresses in his social Encyclical.
This constitutes the task of securing both the physical and spiritual well-being of every human
being.

For this to happen the support of the governmental, medical and philanthropic communities of
first world nations is urgently needed. Thus a broader vision concerning the challenges facing the
world's less developed areas is crucial. This view was also expressed at the recent G8 Summit.

In the spirit of this same kind of solidarity, Brian J. Kopp, DPM, spoke with David Fedson, MD,
on 3 July about the current H1N1 swine flu pandemic and the prospects for equitable treatment
alternatives in developing countries. Indeed, a testament to the importance of this particular issue
was President Obama's participation from Italy via telephone link in the Influenza Preparedness
Summit held at the National Institutes of Health on 9 July.

Dr. Fedson is a retired American physician living in France. He has long worked on the
epidemiology of influenza and influenza vaccination, first as a Professor of Medicine at the
University of Virginia and later as Director of Medical Affairs for Aventis Pasteur MSD. He has
served on several American and World Health Organization (WHO) committees on influenza
immunization, and was instrumental in establishing the Influenza Vaccine Supply (IVS)
International Task Force and the Macroepidemiology of Influenza Vaccination (MIV) Study
Group. He clearly knows the influenza vaccine industry from the inside. He also knows that the
arithmetic for a pandemic is simple: you can only treat the victims of a pandemic if effective
vaccines and medications are widely available. For 90% of the world's population, this won't be
the case.

With the current swine H1N1 pandemic influenza virus, as with the H5N1 avian flu and 1918
pandemic viruses, deaths have been prominent among the 15- to 45-year old adults. These deaths
have been associated with a severe immune reaction, often called a "cytokine storm." For more
than five years, Fedson has been calling for urgent and sharply focused research to determine
whether drugs that reduce inflammation or modify the host response the way that the body
responds to infection or injury could be used to manage the pandemic. Focusing on inexpensive
generic drugs that are readily available, even in developing countries, could address the inequity
already being seen, and could save millions of lives in the current and in future pandemics.
Roche announced on 2 July that they would now sell their Tamiflu to third world nations at a
reduced price. Is Tamiflu still a reliable treatment option?

Tamiflu resistant swine flu viruses have already been isolated in Denmark, Japan, and Hong
Kong, and the virus that was isolated in Hong Kong came from a woman who had not taken
Tamiflu. Knowing that seasonal H1N1 viruses are now almost completely resistant to Tamiflu,
we should expect Tamiflu-resistant swine flu viruses to appear sooner or later. It's just a matter
of time, and we're seeing it already. Yet if we're fortunate and this doesn't happen, we will still
have problems. Current government stockpiles of Tamiflu in "have not' countries (countries that
don't produce influenza vaccines) would be sufficient to treat only 1% of the people who live in
these countries. Roche has said publicly that its capacity for producing courses of Tamiflu
treatment is 400 million doses per year. That's it; they can't go beyond that.

Has vaccine production capacity improved in the last few years?

No, the situation has not changed a great deal. I keep going back to the arithmetic. Two years
ago it was estimated that within 9 months of the emergence of the pandemic virus, all of the
world's influenza vaccine companies could produce enough doses of a new pandemic vaccine to
vaccinate with two doses approximately 750 million people. More recently, a report sponsored
by the WHO estimated that 6 months after the emergence of a new pandemic virus, the
companies could produce 860 million doses of vaccine. These numbers are similar to the number
of people living in the nine countries that produce almost all of the world's seasonal influenza
vaccines.

If you're talking only about the US and want to vaccinate everyone, you will need 300 million
doses. If you need two doses per person, you'll need 600 million doses and you're not going to
get 600 million doses right away unless you have an antigen sparing formulation. This requires
adding an adjuvant, a chemical that boosts the immune response and allows companies to
decrease the amount of virus in each dose. However, US regulatory authorities are concerned
about the safety of adjuvanted vaccines. As long as the virus doesn't get more virulent and the
case fatality rate among non vaccinated individuals remains very low, the social and political
impact of the pandemic will be tolerable; although a huge number of infections will occur,
99.5% of those infected will survive. The choice between an adjuvanted or non adjuvanted
vaccine will determine whether companies produce more or fewer doses of vaccine. Erring on
the side of caution will mean that developing countries will have even less chance of obtaining
supplies of pandemic vaccines.

Are there any plans to provide vaccines to developing countries?

Currently, there is no logistical plan for distributing supplies of pandemic vaccines to the "have
not' countries that will not be able to produce them. These countries are home to approximately
88% of the world's population.

Whether the political leaders of the nine countries that produce almost all of the world's
influenza vaccines will take an active role in the allocation of H1N1 vaccines supplies is an
important question, at least in my view. Given the desire of political leaders never to make
decisions unless they are absolutely unavoidable, they may view the H1N1 pandemic as being no
more severe in its consequences for individuals than a seasonal H1N1 outbreak. Therefore, they
may decide they don't need to take an active role in deciding where doses of vaccine will be
distributed, at least after they have satisfied their domestic needs. Yet we must keep in mind that
whatever WHO, companies and governments do for a mild H1N1 pandemic will establish the
precedents for managing vaccine production, licensing and distribution for a more severe H5N1
pandemic. For me, this is the most fascinating aspect of what we are currently seeing. It is also
the most unpredictable and consequently the most worrisome.

If there will be inadequate supplies of vaccines and Tamiflu, what other options are being
pursued?

Since 2004 I have tried to persuade government agencies and foundations in the US and Europe
as well as the WHO to convene one or more workshops that would bring together 25-30
scientists who work with animal models of influenza, sepsis and multi-organ failure. They would
be asked to review the scientific rationale for using agents that modify the host response. The
agents they should consider most strongly are those that are now produced as inexpensive
generics and that are widely available in developing countries. Statins, fibrates and glitazones
are, in my view, prime candidates. No one has been interested in this proposal.

The generic agents I talk about affect the host response, and this is something that, with the
exception of the immune response, influenza virologists know little about. We must enlist the
support of scientists in other fields sepsis, critical care, cardiovascular and pulmonary diseases,
metabolic disorders and mitochondrial function. They must tell influenza scientists what they
know about the host response to infection, and how it might be useful to them in their research.

I'm worried that the H1N1 virus could get worse, that it could develop the virulence of the 1918
pandemic virus, or possibly combine with an H5N1 avian flu virus to give us a monster virus.
Each of these developments is possible. Now if they're possible, we could spend perhaps 10 to
20 million dollars and get 90% of the answers we need to determine whether these generic agents
could save lives. Is it worth organizing the research in such a way that we could quickly get the
answers needed to manage a global pandemic? That's the big question. Why don't we do it?

Where, then, would efforts ideally be focused in the fight against this pandemic?

The focus of all of our efforts right now must be on ways to manage the pandemic throughout the
world in ways that will save lives in this and any future pandemic. This will require a focus on
the host response.

Several studies have suggested that prescriptions for statins are associated with a 50% reduction
in pneumonia hospitalizations and deaths. If statins prove to be effective against pneumonia, they
might be similarly effective against pandemic influenza. Experimental studies in mice show that
gemfibrozil and pioglitazone dramatically reduce influenza-related mortality. A 2005 study of
resveratrol showed a 54% decrease in mortality in a mouse model of influenza.
The practical implications of these findings for an influenza pandemic are enormous. For
example, in 2008, 29 billion doses of statins were produced worldwide, 16 billion of them as
generics. If only 5% of this output had been set aside, it would have been sufficient to provide
five days of treatment for 160 million people. Since treatment would probably be necessary only
for those patients at risk of serious complications, multi-organ failure and death, supplies
sufficient to over 2-10% of an infected population would probably be sufficient (perhaps H5N1
excepted). Gemfibrozil and pioglitazone are also produced as generics, and many of the
companies that produce them are located in developing countries. As generics, these agents
would be far less expensive than vaccines and antiviral agents; according to 2008 prices, five
days of treatment would cost less than $1.00. Thus, stockpiles would be affordable and
distribution channels could be set up in advance of a pandemic.

We don't know how any of these drugs are handled in people who are already sick. That's key.
However, we have a wonderful research opportunity right now to develop multi-center trials of
single dose treatment in patients with severe H1N1 influenza. We could measure drug levels and
cytokine changes following treatment at different times during the course of illness. It would not
be difficult to recruit several hundred people for studies like this, but no one is organized to do
them. We can't afford not to do this work.

The message that needs to go out to the world is that health officials everywhere have a
responsibility to find ways to manage a pandemic in all countries. This means that they don't
have to explain the molecular biology of everything that's going on. Instead, they must find
agents that can be used to save lives. We have enough evidence from experimental work and
enough suggestions from clinical observations to suggest that we could do this by modifying the
host response using inexpensive generic agents that are already being produced in developing
countries. Making effective therapies widely available is the key to a global response to a
pandemic, whether it is caused by the current swine H1N1 virus, an H5N1 virus or something in
between.

Sadly, the arithmetic for pandemic vaccines and antivirals is unforgiving. WHO is focused on
vaccines and antivirals that will only be available to people who can afford them, and that's ten
percent of the world's population. Consequently, it doesn't matter that arguments for their use are
scientifically well grounded; in practical terms they are pointless, in the same way that it is
pointless to tell a starving man he should eat if there's no food in the kitchen. For pandemic
vaccines and antiviral agents, the kitchen is empty. We should stop talking about things that
people in developing countries will never have, and start talking about things they've already got.