The clock is ticking
The impact of yearly outbreaks of influenza on the health and economic well being of people living in developed countries is well understood. Also understood is the important role of influenza vaccination in reducing the burden of the disease. As a result, vaccine use is increasing in many of these countries. Remarkably, vaccine use is also increasing in developing countries, few of which have any information on the health or economic impact of the disease on their populations. Because the use of influenza vaccine is increasing worldwide, the sudden appearance of a new influenza virus that threatens to cause a global pandemic will present a major problem for vaccine supply. Dr David Fedson explained to Phacilitate why we are woefully unprepared for the next influenza pandemic and outlined major issues regarding the science and politics of pandemic vaccine supply that must be faced now.
Dr Fedson has more than 25 years’ experience in academic research and public policy in the field of adult immunization. He has published more than 125 articles and chapters on influenza and pneumococcal vaccination and has served on the Advisory Committee on Immunization Practices and the National Vaccine Advisory Committee in the United States. He retired recently from his position as Director of Medical Affairs for Aventis Pasteur MSD in Lyon, France.
Phacilitate: Just how damaging can outbreaks of influenza be?
Fedson: Outbreaks of influenza occur almost every year and their severity varies considerably. Yearly outbreaks differ from pandemic influenza, and it’s important to understand the difference between the two. The influenza virus changes from year to year as a result of a series of small genetic mutations. This process is commonly referred to as antigenic drift. Occasionally, however, there is a major genetic shift in the influenza virus and this leads to a global outbreak of influenza known as a pandemic. The new pandemic virus spreads rapidly because few people, except perhaps the elderly, have had any past experience with this virus. The most severe pandemic in modern memory occurred in 1918 - 1920, and caused an estimated 40 million or more deaths worldwide. Other pandemics occurred in 1957 (Asian influenza A/H2N2) and in 1968 (Hong Kong influenza A/H3N2). In 1977 we didn’t have a severe pandemic because the virus that re-emerged was a milder influenza A/H1N1 variant.
The health and economic impact of influenza varies substantially from year to year. It is important to understand, however, that interpandemic influenza (disease that occurs each year between the arrival of new pandemics) has a cumulative morbidity and mortality that is far greater than what occurs in the first year or two of a new pandemic period. Thus, we need to pay attention to influenza prevention every year, not just when a new pandemic threatens.
Phacilitate: Who is most at risk?
Fedson: In interpandemic periods, the people who are at greatest risk are very young children - especially those less than two years in age - and older people over 60-65 years of age. Underlying medical conditions such as heart and lung disease or diabetes confer an even greater risk of serious complications or death. Consequently, in most countries where the influenza vaccine is used national recommendations target elderly people over the age of 60 or 65 years and younger people with high-risk medical conditions. No country currently has a recommendation for vaccinating children, although for 20 years during the 1970s and 1980s the Japanese vaccinated schoolchildren and later demonstrated that this programme had had a major impact on excess mortality among the elderly. In 2000, the Canadian province of Ontario decided to offer and pay for vaccination of everyone over six months in age. This innovative programme dramatically increased the level of influenza vaccine use, especially among people younger than 65 years in age who had high-risk medical conditions.
When a new pandemic virus appears, people of all ages are suddenly at risk. Within the first year or two of the pandemic period, there is substantial morbidity and mortality in people younger than 65 years. Because the clinical effectiveness and cost-effectiveness of influenza vaccination in interpandemic years are well established for people of all ages, recommendations for pandemic vaccination in many countries will probably not be limited to elderly, high-risk individuals that are the usual target population during the interpandemic period. Instead, vaccination may be recommended for people of all ages.
Phacilitate: Are influenza pandemics in any way predictable?
Fedson: We have no clear understanding of what determines when a new pandemic virus will appear; all we can confidently say is that its appearance is inevitable. As the former chairman of the National Vaccine Advisory Committee in the United States put it 7 years ago, "the pandemic clock is ticking; we just don’t know what time it is."
Phacilitate: How important is surveillance?
Fedson: For more than 50 years, the World Health Organisation has coordinated an international programme for influenza virus surveillance. This system allows WHO national influenza laboratories to identify new viruses as they appear, often in China or other countries in the Far East. The viruses are characterized at a molecular level and WHO experts then choose the strains that should be included in next season’s influenza vaccine. Although the WHO surveillance system is not perfect, it is difficult to imagine what kind of investments would be needed for it to become even more precise.
Compared with virological surveillance, the epidemiological surveillance of the health and economic consequences of influenza is not well developed. In several developed countries, population-based surveillance systems are able to generate estimates of the excess mortality associated with influenza each year. Such epidemiological surveillance does not exist in many other developed countries and is virtually never found in developing countries. Today, there is a much greater need to improve surveillance of the burden of influenza disease than there is to improve the international surveillance of influenza viruses. If we are to do anything to improve the prevention and control of influenza with vaccines and antiviral agents, we must develop a much better understanding of its health and economic impact. If we fail to do this, we will not recognize influenza as a problem and will not consider prevention and control efforts to be worthwhile.
Phacilitate: How prepared are we for a pandemic?
Fedson: Our preparations for the next pandemic are woefully inadequate. We will probably recognize a pandemic threat fairly quickly because we will see emerging in some part of the world an outbreak of influenza-like disease that affects a broad range of the population. The virus will be isolated and characterized as a new pandemic strain within a few weeks. What happens next is an open question. It will take many months to produce a new pandemic vaccine, so in the early months antiviral agents will be the only feasible measure for disease control. However, huge stockpiles of these agents will have to be established well in advance of the pandemic. As of today, no country has made concrete plans to stockpile antiviral agents. Simply put, we are not prepared to meet the threat of the next pandemic.
There is a wide range of issues related to effective pandemic preparedness planning. Some of them are scientific and others relate to questions of culture, social values and the international political dimensions of influenza prevention and control. At the scientific level, vaccine companies will be capable of producing vaccines only if they are given vaccine seed strains that can be quickly put into production. The seed strains are usually prepared in laboratories that are part of the WHO network of Collaborating Centres. Vaccine companies are entirely dependent on these laboratories to provide them with the seeds strains necessary for vaccine production.
The production capacity of all the world’s vaccine companies is determined by the current size of the world market for influenza vaccine. For example, in 2000, vaccine companies distributed almost 250 million doses of influenza vaccine throughout the world. Approximately 85% of these doses were produced in the production facilities of nine companies located in nine developed countries (USA, Canada, Australia and six countries in Western Europe). These nine companies dominate the global production of influenza vaccines, but they do not have unlimited capacity to suddenly increase their production. They do, however, have the capacity to increase somewhat the number of doses in a pandemic situation. This is because the vaccine used in interpandemic years is trivalent; it contains the three strains (A/H3N2, A/H1N1 and B) considered most likely to cause disease. A pandemic vaccine will undoubtedly contain only the pandemic strain of virus; in other words, it will be a monovalent vaccine. Theoretically, for every one dose of trivalent vaccine produced for interpandemic use, three doses of pandemic vaccine could be produced – a ‘3-for-1’ scenario. Thus, it should be possible to increase global vaccine production from 250 million to 750 million doses. Unfortunately, things are unlikely to be that simple. We will not know ahead of time what the growth characteristics of the pandemic seed strain will be under production conditions. In addition, most susceptible individuals will never have experienced past infection with the pandemic strain of virus, so they are likely to require two doses of vaccine; one to prime their immune system and the second to boost their antibody response to a protective level. This will make vaccine delivery very complicated.
We can probably greatly increase the number of doses of vaccine that will be available by using adjuvants to enhance its immunogenicity. This will allow the vaccine companies to use much lower amounts of antigen for each dose of vaccine they produce. Current information indicates that an alum-adjuvanted vaccine might increase by four- to six-fold the number of doses that could be produced. This could be of immense importance in meeting what is likely to be intense global demand for pandemic vaccine. We might also be able to produce vaccines more rapidly and more precisely using the modern molecular techniques of reverse genetics to prepare pandemic vaccine seed strains. The main obstacles to doing so are the intellectual property rights that are attached to the techniques of reverse genetics. Whether seed strains prepared using reverse genetics could be made available quickly in a pandemic situation is something no one yet knows.
In thinking about policy issues for pandemic vaccination, it is important to recognize at the outset that we have no idea of what the global demand for pandemic vaccine will be. Let’s say, for example, that the ‘3-for-1’ scenario will apply, and that all vaccine companies working together will be able to 750 million doses worldwide. If the world wants only 750 million doses, we won’t have a problem, but this is not a safe assumption. As pointed out earlier, 85% of the vaccine currently produced comes from only nine countries. Given current understanding of the health and economic benefits of influenza vaccination, we must anticipate that health officials in these nine countries will choose to vaccinate not just their elderly populations but people of all ages. Consequently, political pressure will be exerted within the nine vaccine-producing countries to guarantee that sufficient supplies of vaccine to protect their domestic populations will be available. This will severely limit the amounts of vaccine that can be exported to other countries. Thus, ensuring the global supply of pandemic vaccine must be viewed as a highly political issue and policy makers will face several difficult questions. For example, how will it be decided which countries get the ‘spill over’ once the domestic demands of vaccine-producing countries have been satisfied? How will the needs of the rest of the world be met. In 2000, 34% of the doses of influenza vaccine distributed worldwide were used in countries outside North America, Western Europe and Australia and New Zealand. Much of this vaccine was imported from one or more of the nine vaccine-producing countries. For example, all 26 million doses supplied to Latin America were imported from vaccine-producing countries outside Latin America. From where will these and many other countries (e.g., Spain, Sweden) obtain their supplies of pandemic vaccine? No one knows.
Distributing pandemic vaccines in an equitable fashion will be a daunting problem. There is currently no internationalprocess for doing this that is politically and morally acceptable. We will definitely need one.
Phacilitate: Is anyone taking the initiative to try to resolve this internationally?
Fedson: Most developed countries have pandemic preparedness plans that vary in their levels of detail and comprehensiveness. Most plans attempt to define target groups for pandemic vaccination, but no plan states where the vaccine will come from. All plans need to address this question.
Last November, the European Commission convened a meeting in Brussels to address questions of influenza pandemic preparedness at a European level. It was made very clear to those present that there was no overall plan for how the 15 Member States of the European Union will obtain supplies of pandemic vaccine. The issue of what to do about the non-vaccine producing countries within the European Union was brought to a high level of political awareness. Currently there is no other international effort that is looking at issue of equitable levels of vaccine distribution to non-producing countries. The European Commission is aware of how this issue could affect its current Member States. In two or three years, 10 new countries with 75 million people will be added to the 380 million people already living within the European Union, compounding an already difficult situation. When Turkey, Bulgaria and Romania join, almost 600 million people will be members of an expanded European Union. None of these new countries currently has any significant capacity to produce influenza vaccines.
The European Union must also consider what will happen to the rest of the world if all of the pandemic vaccine produced in European countries is used only within Europe. If this troublesome, but unavoidable, issue is not faced, the political fallout will be extraordinary.
Phacilitate: What about the relative roles of vaccines and antiviral drugs?
Fedson: No one who understands the issues of how to control a pandemic, particularly in the early stage, says we have anything available for use except antiviral agents. Antivirals will be helpful in reducing the duration of illness and there is early evidence to suggest that they may reduce complications in severe cases. But antivirals are expensive, and like vaccines the global production capacity for antivirals is defined by the size of the market. Currently, the market for antivirals is not large. Even though we've had one class of antiviral agents - the ion channel inhibitors - available for 30 years, pharmaceutical companies have not invested in building production capacity or promoted their widespread use in populations. When the next pandemic threat appears, several billion people will want to use antivirals but there won’t be any available. The best way to deal with this issue would be to stockpile the antiviral agents well in advance of the pandemic. If stockpiled in bulk, they could be packaged in syrup, capsules or perhaps even blister packs and then distributed through pharmacies or grocery stores without a doctor’s prescription. All of this is possible, but who will pay for the stockpiles and how big should they be? Nobody has answers to these questions. But it should be clear to everyone that it makes no commercial sense for companies to expand their production capacities for antiviral agents beyond the level that current market conditions indicate will be used.
It is ironic that Europe, with its Common Agricultural Policy (recently extended), has built ‘butter mountains’ that no one needs, yet it has no plan to stockpile an important pharmaceutical product that could save the lives of tens of thousands of its citizens. European countries, and indeed all countries of the world, need to recognize that public efforts will be necessary if stockpiles of antiviral agents are to be established. Without public commitments, no stockpiles will be created and only trivial amounts of antiviral agents will be available to help control the pandemic.
Phacilitate: So how do we move toward the production of quantities of vaccines and antiviral agents that are more in tune with future needs?
Fedson: The bottom line is this: if a country wants to do something to control influenza during the interpandemic period and when faced with a pandemic, it must develop plans for how many doses of vaccine and antiviral agents it wishes to use. Vaccine companies know how to plan for the production of paediatric vaccines because demographers can tell them what the birth cohort is going to be 5 or 10 years from now. The size of the birth cohort multiplied by 3 or 4 (a primary series and a booster dose) gives them the size of the overall market for their product. Each company then has only to build the production capacity to supply whatever share of the market it wishes to capture. For influenza vaccine, however, the size of future markets is simply not known. Vaccination recommendations in different countries vary; target populations include the elderly but some countries also include younger adults at risk, pregnant women and eventually they may include children. Vaccination coverage also varies, even between countries where the target groups for vaccination are essentially the same. Vaccine distribution levels in these countries vary by more than 200%. This variation often reflects the presence or absence of public reimbursement for vaccination, as well as the general interest of health authorities and the public at large in doing anything at all about preventing influenza.
The only way to begin sensible planning for expanding the capacity of companies to produce influenza vaccines is to provide the companies with a better idea of what the future market demand for their vaccines will be. If, for example, companies know with greater certainty that 5 years from now the world will want three times as much influenza vaccine, they will begin today to make concrete plans for expanding their production capacities. This could be done by asking the health ministries of all countries to define explicitly the number of doses they expect to use each year for the next five years. They should also specify the number of doses of pandemic vaccine they will require in the event a pandemic threat appears during this period. These demand forecasts would be updated each year, and the cumulative rolling forecasts for all countries communicated to all companies producing influenza vaccines. In this way the companies would have better information about the future market demand for interpandemic and pandemic vaccines. Whether government health ministries, which are always politically vulnerable, would be willing to do this is unknown. However, it would be worthwhile setting up such a system just to find out. The World Health Organization is probably the only institution in a position to coordinate it.
Phacilitate: Science, politics and the global supply of pandemic vaccine...
Fedson: Many important scientific questions need to be answered if we are to guarantee an adequate supply of influenza vaccine for the next pandemic. But answering the scientific questions alone will not be sufficient. The political dimensions of pandemic vaccine supply present even greater problems. Vaccine companies know how to produce influenza vaccines and they could expand production capacity given adequate information on how much vaccine will be needed in future years. They cannot, however, determine future demand on their own. This responsibility rests squarely on the shoulders of health officials in each country of the world. Only by developing explicit projections of the future worldwide demand for influenza vaccines will individual countries and the world community be able to avoid the political crisis that will accompany the emergence of the next pandemic threat. Producing an adequate supply of pandemic vaccine and ensuring its equitable distribution to all countries that wish to use it represents one of the most compelling challenges facing global public health. It is also a challenge that can be successfully met if there is the political will to do so.
