The Unforgiving Arithmetic Of Pandemic

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.