SGE Morning Seminar
New Approaches to Confronting an Influenza Pandemic
Monday, December 4, 2006
Review of Presentation by Dr. David Fedson
Reviewed by Philip Webre, an economist at the Congressional Budget Office (CBO). The views expressed in this review are those of the author and should not be interpreted as those of the CBO.
The title of Dr. David Fedson’s presentation to the SGE was “New Approaches to Confronting an Imminent Pandemic.” Dr. Fedson’s introductory idea was that pandemic influenza occurred regularly during the 20th century and science has given us no reason to believe this pattern has changed. The latest influenza variant (H5N1) has proved lethal to both birds and mammals. The mortality rates for the few persons who have been infected have varied from 33 percent to more than 60 percent and, in recent years, it has been rising, not falling. Sustained transmission from human to human, however, has not yet occurred. Once it does, a global pandemic seems certain.
Dr. Fedson argues that the fact that the influenza virus mutates so easily implies that policy makers cannot afford to assume that the virus will never jump from birds to humans, just because it hasn’t done so to date. In the 1980s, a different avian flu (H7N7) jumped directly from migratory waterfowl into harbor seals along the North Atlantic coast and killed 20 percent of them in a few months. The 1918 influenza pandemic killed between 2 and 5 percent of the global population, according to Dr. Fedson. A pandemic with a similar mortality rate today could kill between 175 million and 350 million people.
His strategy for developing vaccines for the next pandemic is based on four assumptions:
1. Assume the pandemic is imminent. If policy makers assume that they have 5 to 7 years to develop new technology and the pandemic hits before then, the consequences would be disastrous. On the other hand, if policy makers devise contingency plans to deal with a pandemic that comes within the next 1-3 years and the pandemic doesn’t occur, little will have been lost.
2. Vaccine development must be based on a global estimate of vaccine demand and existing production capacity.
3. The vaccine strategy must be optimal for populations, not necessarily for individuals.
4. Vaccines are only one component of a complete pandemic strategy.
Vaccine Production and Consumption
Vaccine production for annual seasonal flu is very concentrated: nine countries produce 95 percent of the seasonal vaccines used each year. Consumers in countries without any domestic production account for one third of demand for seasonal vaccine and demand is growing especially rapidly in these countries. In 2005, almost 330 million doses of influenza vaccine were distributed throughout the world. The companies that produced these vaccines will be called on to produce pandemic vaccines for a global population that now exceeds 6.5 billion people.
In the event of the appearance of a deadly pandemic virus, Dr. Fedson assumes that there would be great political pressure on the governments of vaccine-producing countries to nationalize domestic production and prohibit exports until domestic needs had been satisfied. The United States could be seriously affected as much of our current supply of seasonal flu vaccine is imported. Furthermore, the production of the seasonal flu currently does not allow for surge capacity to meet a greatly increased pandemic demand. Consequently there are likely to be vaccine shortages, especially in countries without a domestic vaccine industry. Inevitably, this will lead to a global political as well as public health crisis.
For the United States, the unforgiving arithmetic of pandemic vaccine supply is as follows. Assume that each person would require two shots, as shown in recent clinical trials. This means that the United States would require 600 million doses. Because to date the vaccines against the H5N1 require a much higher level of active ingredient, even using the best available science, our current domestic production capacity could produce enough doses of pandemic vaccine in six months to vaccinate only 5 million people. The global situation is even more bleak. Thus, the challenge is to find a way to stretch our current domestic capacity to produce enough doses to vaccinate everyone in the country and people in other countries as well.
According to Dr. Fedson, influenza scientists and vaccine companies must make two advances regardless of the details of the strategy ultimately chosen to combat the pandemic flu. First, they must make better use of antigen sparing chemicals called adjuvants. Vaccines that use adjuvants offer the same level of immunity but use much lower levels of active ingredients; 20-fold reductions have been achieved in the past. Currently, only a fraction of the seasonal flu vaccines distributed worldwide (and none of those in the United States) uses these chemicals. Furthermore, the H5N1 vaccines being stockpiled are not being designed to make use of those chemicals. Second, the process of using reverse genetics to change a wild-type H5N1 virus into one that will be suitable for vaccine production has proven very disappointing; vaccine production levels have been much lower than what would normally be expected. Unless the efficiency of producing this reverse genetics-engineered H5N1 virus rises, the unforgiving arithmetic of pandemic vaccine need described above will be much worse.
Optimizing Herd Immunity
Part of Dr. Fedson’s argument was that because of the unforgiving arithmetic, the vaccine strategy would have to change from giving each person a vaccine that will induce optimal personal protection to one that uses a vaccine that maximizes protection for the general population. Experiments with H5N1 vaccines have shown that reductions in the amount of their active ingredients do not result in proportional decreases in immunity. For example, a 12-fold reduction in the active ingredients resulted in only a 6-fold drop in protection. Consequently, Dr. Fedson calculated, by reducing the amount of active ingredient in each dose, twice as many people could be protected.
Any plan to adopt this strategy would require a national dialog about the role of medicine in a public health emergency, Dr. Fedson noted. Like triage, this strategy would require an economic allocation of medical assets very different from the entitlement mentality that currently dominates the practice of medicine in the United States.
New Approaches
Dr. Fedson presented three new approaches for dealing with what might be an imminent pandemic of avian influenza.
1. Develop a live-attenuated virus vaccine to increase the efficiency of current production systems.
2. Develop a recombinant DNA-based vaccine that could be produced in existing pharmaceutical bioreactors.
3. Develop better treatment of the sick persons based on combating the molecular changes induced in the body by the virus instead of using treatments directed at the virus itself.
Live-attenuated virus vaccine. There are two polio vaccines: the Salk vaccine contains inactivated (killed) polioviruses, whereas the Sabin vaccine contains live-attenuated polioviruses. (An attenuated vaccine contains a weakened virus, one that is capable of stimulating immunity and protects against natural disease but does not cause disease itself.) Flu vaccine is similar, although, except for one manufacturer, all companies producing the flu vaccines used in the United States produce inactivated virus vaccines.
But by using a live-attenuated virus, each unit of productive capacity (currently usually eggs) can produce more doses of vaccine. This is because the viruses in the inactivated vaccine do not reproduce in the human body, so the amount of active ingredient in the vaccine itself is all that the recipient gets. With a live-attenuated virus vaccine, the level of active ingredient in the vaccine is only the starting point. The virus is able to reproduce itself in the body without actually causing disease (it is attenuated), thereby increasing the immune response to vaccination. Thus, the active material can be stretched to cover more doses. According to Dr. Fedson, the number of doses of live-attenuated pandemic vaccine that could be produced is approximately 100-180 times greater than the number of doses of killed virus vaccine. This remarkable increase in productivity would go a long way to counteract the otherwise unforgiving arithmetic of pandemic vaccine supply.
Live-attenuated influenza vaccines are already licensed for seasonal flu in the United States. Dr. Fedson proposes that the Federal government lead the way by persuading the owners of the technology for this vaccine to share their know how and intellectual property so that FDA-approved live-attenuated pandemic vaccines could be developed and produced in the existing production facilities owned by competitors who would otherwise produce inactivated vaccines. His belief in strong federal technological and administrative leadership in developing innovative solutions to confronting an imminent pandemic was a theme to which he returned frequently.
Using existing human vaccine facilities and converting veterinary avian flu facilities to the production of live-attenuated vaccine could allow the production of several billion doses of pandemic vaccine in a few months. Given the realities of converting facilities and administrative and other friction, the actual number of doses that could be produced is uncertain, Nonetheless, Dr. Fedson argued that his back of the envelope calculation gives a sense what might be achieved with creative federal leadership.
Recombinant Technology. Currently, many medicines and products are produced using recombinant DNA technology. The Biotechnology Industry Association, for instance, lists over 100 approved biologic drugs made using this technology. Many consumer and industrial products such as enzymes in cleaning detergent are also manufactured using recombinant technology. For these consumer, industrial, and pharmaceutical products, the DNA of an organism is typically altered by inserting genes that code for a desired protein. The recipient organisms range from viruses to single-celled creatures to plants and animals. The DNA functions as the software that tells cells what kind of protein to make. The challenge that biotechnology companies face every day is to produce large quantities of highly specific and highly purified proteins and to do so at low cost. Some proteins are very hard to make, which partially explains why some of them are priced at $1000 per dose.
One biotechnology company has successfully completed clinical tests for a seasonal influenza vaccine using recombinant DNA technology. This development is relevant to the challenge of an imminent pandemic. Because a wide range of products is currently being manufactured using recombinant technologies, the global capacity to produce them is very large. According to Dr. Fedson, the existing global stock of pharmaceutical bioreactors is about 2 million liters, of which approximately 60 percent is located in the United States. Dr. Fedson argues that if a fraction of this capacity could be harnessed to produce a recombinant pandemic vaccine and if conservative estimates of manufacturing production efficiency are used, enough doses of vaccine could be produced in one or two months to vaccinate several billion people.
As with the live-attenuated pandemic vaccine, Dr. Fedson proposed a top down command and control federal effort to develop these vaccines and get the capacity lined up and ready to go into action should the need arise.
Treating the Person with the Disease. According to Dr. Fedson, at present, persons who are infected with the H5N1 virus are typically treated with antiviral drugs and yet 60 percent or more of them still die. Many of these patients die in a manner similar to those who died in the 1918 pandemic: the lining of their lungs becomes inflamed and they drown in their own fluids. This condition is now called hypercytokinemia or “cytokine storm”, and it has been clearly documented in patients infected with H5N1 influenza viruses.
Modern medicine has inexpensive generic drugs that fight inflammation which are widely used by medical professionals. Surprisingly, these drugs that millions of people take to lower their cholesterol levels – the statins – also have remarkable anti-inflammatory effects. If found effective for treating influenza, these drugs, Dr. Fedson argued, wouldn’t cure the disease; instead they would “keep the lid on” the cytokine storm and prevent the infection from becoming fatal. To date, no experimental or clinical studies have been undertaken to determine whether statins or other anti-inflammatory drugs would be effective in treating H5N1 patients. Controlling the severe biochemical and molecular abnormalities of a disease while it runs its course is a strategy physicians use to manage many diseases. Dr. Fedson could not explain why influenza scientists have shown little interest in testing this approach, especially given the poor response of so many H5N1 patients to antivirals.
Conclusions
According to Dr. Fedson, the situation we face should a pandemic flu virus emerge within the next few years is not hopeless. We currently have the scientific understanding and technological resources that, if properly mobilized, would allow billions of people to get vaccinated or receive some form of treatment. The big hurdles, he argues, are political and social. A national dialog on how to mobilize these resources would be different in each country. For the United States, Dr. Fedson advocates a strong command and control approach such as the Apollo mission to the moon where a strong administrator would set the scientific and technological agenda and persuade others in government, academia and industry with requisite physical and intellectual assets to commit to an emergency plan. Only the United States, he argues, has proved itself capable of mounting such an effort.