The epidemiology of influenza vaccination: implications for global vaccine supply for an influenza pandemic

The epidemiology of influenza vaccination: implications for global vaccine supply for an influenza pandemic

International Congress Series 1219 (2001) 723 – 731 The epidemiology of inf luenza vaccination: implications for global vaccine supply for an inf lue...

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International Congress Series 1219 (2001) 723 – 731

The epidemiology of inf luenza vaccination: implications for global vaccine supply for an inf luenza pandemic David S. Fedson* Aventis Pasteur MSD, 8, rue Jonas Salk, 69367 Lyon Cedex 07, France

Keywords: Influenza; Vaccination; Pandemic

The societal benefits of influenza vaccination are firmly established [1]. Among elderly persons, vaccination reduces both hospitalization for influenza-associated respiratory conditions and all-cause mortality. Among healthy working adults, schoolchildren and pre-schoolchildren, vaccination prevents influenza-related respiratory illness and work and school absence. In pre-schoolchildren it also reduces the occurrence of otitis media. For people of all ages, influenza vaccination is highly cost-effective. Nonetheless, the full benefits of influenza vaccination have not been achieved. If this is to occur, one requirement will be a better understanding of the epidemiology of influenza vaccination. Other reports in this volume address issues related to influenza vaccination by individual practitioners or within regions of individual countries. This article focuses on the comparative use of influenza vaccine in different countries. Three earlier publications document vaccine use for the period 1980 to 1997 [2– 4]. Information on vaccination in 1998 has also been presented [5]. Understanding the changing patterns of vaccine use in interpandemic years has been useful. It is likely to be even more helpful in planning for vaccine use in the event of an influenza pandemic.

1. Inf luenza vaccine use in individual countries, 1999 –2000 Fig. 1 shows the use of influenza vaccine in Western Europe, the United States, Canada and Australia during the period July 1, 1999 to June 30, 2000. Although all of these *

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Fig. 1. Influenza vaccine use in Western Europe, the United States, Canada and Australia in 1999 – 2000. Vaccine use is shown as the estimated number of doses distributed per 1000 total population. Vaccine data were provided by Aventis Pasteur MSD and by Marika Iwane, Centers for Disease Control and Prevention, Atlanta, GA. For Canada, data for 1998 are shown because 1999 data were not available. Elderly persons were those  65 years in age except for Belgium, Germany and Iceland (  60), France (  70) and the United Kingdom (  75). In Denmark and Sweden, publicly supported programs for influenza vaccination were conducted in Copenhagen and Stockholm.

countries had age-based recommendations for older adults, those without some form of public reimbursement tended to use less vaccine. For calendar year 1999, substantial vaccine use was also reported for several other countries: in South America — Argentina, Uruguay, Brazil, Chile and Mexico; in Central and Eastern Europe — Russia, Poland, Latvia, Slovakia, the Czech Republic and Estonia; in the Middle East — Tunisia and Lebanon; in East Asia — the Republic of Korea, Japan, Taiwan and Hong Kong; and in South Africa. In all other countries for which data are available, little if any influenza vaccine was used. It is important to recognize that influenza vaccine is produced in only a few countries [6]. In the United States, three companies produce influenza vaccine and in Canada there is one producer. In Western Europe, Italy has three producers, Germany has two and Austria, Belgium, France, the United Kingdom, the Netherlands and Switzerland have one each. There are no vaccine producers in Ireland, Spain or Scandinavia. In Central and Eastern European, Russia is the main producer, and apparently there are small production facilities in Romania (2), Slovakia and the former Republic of Yugoslavia. In East Asia, there are at least six producers in Japan (1999) and one each in the Republic of Korea and Australia. Not only are there few influenza vaccine producers, the production capacities of many producers are limited. To illustrate this, if it is assumed that each country with one or more vaccine producers obtained all of the doses it used in 1999 – 2000 from domestic

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Table 1 Influenza vaccination outside Western Europe, North America and Australia, 1999 Region

Estimated number of doses distributed (000s)a

Source of vaccine supply (%) Within region

Central Europe, Eastern Europe and Russiab East Asia Latin America Middle East and Africa Total

Western Europe, North America or Australia

12,581

59.1

40.9

22,258 19,115 4495 58,449

38.7 1.1 – 28.2

61.3 98.9 100.0 71.8

a

Vaccine distribution data were provided by Aventis Pasteur. Includes Israel. No data were available on vaccine use in Belarus, Bulgaria, Moldova and the countries of Southeast Europe. b

producers, only 10 countries could be considered self-sufficient: the United States, Belgium, France, Italy, the Netherlands, Switzerland, Australia, Russia, Japan and the Republic of Korea. For this reason, there is substantial international trade in influenza vaccines. Table 1 shows for 1999 the source of supply of the influenza vaccine used in countries outside Western Europe, North America and Australia. In Central and Eastern Europe and in Russia, almost all of the doses produced were used in Russia. Countries outside Russia had to import their vaccine. In East Asia, vaccine companies in Japan and Korea supplied their own domestic needs, yet almost two-thirds of the 22 million doses used in the region had to be imported. In Latin America, the Middle-East and Africa, virtually all of the vaccine used was imported.

2. Two lessons for vaccine supply for an influenza pandemic In recent years, many countries have developed national plans for managing a future influenza pandemic [7]. The World Health Organization (WHO) has issued an important set of guidelines for national and regional pandemic preparedness planning [6]. Included in these guidelines are a set of points to consider regarding vaccine production and distribution. Unfortunately, there is little historical experience to tell us how the WHO guidelines for pandemic vaccine supply might be implemented. Experience in the United States in 1976, however, gives some indication of what to expect. In that year, the isolation of a Swine influenza virus from a military recruit who died of influenza eventually led to the national program to produce and administer a Swine influenza vaccine to a large proportion of the U.S. population [8]. Many problems arose as the program unfolded, including concerns among the vaccine producers about legal liability. The occurrence of Guillain Barre´ syndrome in vaccine recipients six weeks after the vaccination program began led to its abrupt cessation. Although only 45 million doses had been given, this decision was considered reasonable because by then there was no indication a pandemic would occur.

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The 1976 Swine influenza experience provided at least two important lessons for the future supply of vaccine for a pandemic; one hopeful, the other disturbing. First, because American vaccine companies had been able to produce approximately 25 million doses of a trivalent, full-strength (45 mg HA antigen) vaccine in 1975, they were able to produce approximately 150 million doses of a monovalent, half-strength (7.5 mg HA) Swine influenza vaccine [8]. Second, because 150 million doses were insufficient to provide one dose for every person in the United States, the vaccine producers were not allowed to export Swine influenza vaccine to other countries.

3. Increasing influenza vaccine use in interpandemic years and its importance for vaccine supply in a pandemic All health officials concerned with influenza pandemic preparedness planning acknowledge the importance of increasing the levels of vaccine use in interpandemic years before a pandemic actually arrives. Increasing the levels of interpandemic vaccine use leads vaccine companies to expand their production capacities. Furthermore, by increasing vaccine coverage, healthcare systems gain valuable experience in dealing with practical issues of vaccine delivery. For a pandemic, it is almost certain that a monovalent vaccine will be produced. If a dose of 15 mg HA is sufficient, the supply of a pandemic vaccine could be three times the number of doses of trivalent vaccine used in the most recent interpandemic year, a ‘‘3-for-1’’ scenario. If a half-strength pandemic vaccine is sufficient, the supply could increase sixfold, a ‘‘6-for-1’’ scenario. The epidemiology of influenza vaccine use in 1999 provides useful insight into why increasing the level of interpandemic vaccine use will be important for the future supply of a pandemic vaccine. Under the optimistic ‘‘6-for-1’’ scenario, any country that continues to use  167 doses of trivalent vaccine per 1000 population will theoretically have one dose Table 2 Vaccine supply for an influenza pandemic Countries

Population, 1999 (millions)

Estimated number of doses of vaccine distributed, 1999 (millions)a

Additional doses of trivalent – equivalent vaccine needed (millions)b

United States, Canada, Australia Western Europe Argentina, Brazil, Chile, Mexico and Uruguay Central Europe, Eastern Europe and Russiac Japan, Republic of Korea Total 29 other countries

323 386 328 298 176 1511 3148

82.0 56.4 18.7 12.8 6.4 176.3 7.5

(28.2) 8.1 34.6 40.0 13.1 67.6 ?

a Vaccine distribution data were provided by Aventis Pasteur MSD and Aventis Pasteur. The estimates refer to the number of doses distributed by all vaccine producers. b Additional doses of trivalent vaccine needed to reach a level of 167 doses per 1000 population. Achieving this level will ensure that one dose of monovalent pandemic vaccine (7.5 mg HA) is available for each person. c Includes Israel, but excludes Belarus, Bulgaria, Moldova and the countries of Southeast Europe.

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of pandemic vaccine for each of its citizens (1000  6 = 167). Fig. 1 and Table 2 show that in 1999– 2000, only eight countries met or exceeded this cut off level (  160 doses). Western Europe as a whole fell short by 8.1 million doses. In Latin America, the five countries that used influenza vaccine (very little vaccine was used in the other Latin American countries) fell short of the cut off by 35 million doses. Central Europe, Eastern Europe and Russia fell short by 40 millions doses, and Japan and the Republic of Korea also failed to reach the cut off level. Under the ‘‘6-for-1’’ scenario, only the United States would have had the ability to export a pandemic vaccine. If this vaccine were sent only to the countries shown in Table 2, they would still have needed to increase their collective use of trivalent influenza vaccine by 67.6 million doses (27%) to reach the cut off level of 167 doses per 1000 population. Under the less optimistic ‘‘3-for-1’’ scenario, they would have had to increase their level of trivalent vaccine use by 326.8 million doses (185%). The countries shown in Table 2 accounted for almost all of the influenza vaccine used in 1999, yet they contained only one-fourth of the world’s population. Very little vaccine was used in the rest of the world.

4. Distributing the global supply of pandemic influenza vaccine: the limitations of the market The WHO Influenza Pandemic Preparedness Plan identifies several issues that will affect the production and distribution of a pandemic vaccine [6]. Scientific and technical issues include the possibility of preparing a number of potential pandemic virus ‘‘vaccine seeds’’. In the event of a pandemic, the appropriate seed will be provided to all vaccine producers. New testing reagents, new production procedures (especially cell culture) and centralized registration will be critically important if production times are to be reduced and vaccine supplies increased. In addition to vaccine production, the WHO guidelines suggest that countries should plan for emergencies when negotiating vaccine procurement contracts, stating, ‘‘each vaccine manufacturer should discuss (italics added) with the country(ies) where. . . vaccine is usually produced or distributed,. . . what can be the expected rate of production. . . It may be desirable to build flexibility into procurement procedures to allow for different vaccination strategies . . .Each government and vaccine supplier will need to consider how much vaccine they will guarantee to purchase or sell in an emergency situation. The cost per dose may be different if vaccine is being purchased by governments. . . (or) at the user’s expense. Without a ‘‘clearing house’’, . . .cost considerations rather than public health may drive vaccine distribution (and). . .non-industrialized countries. . .may be completely overlooked . . .A central clearing house, operated and funded by a number of co-operating countries, might allow for vaccine purchases to be ‘‘pooled’’ and distributed more equitably. . . (and could ensure that some). . .vaccine is purchased as a humanitarian donation for. . . (those). . . in non-industrialized countries. . . who play essential long-term roles in society’’ [6]. The WHO guidelines identify many of the key issues for global supply of a pandemic influenza vaccine. However, in outlining what should be done, the guidelines do not say how it could be accomplished. Instead, the guidelines implicitly rely on the continued

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use of market mechanisms. Currently, individual countries either negotiate with one or more vaccine producers to provide a one-year supply of vaccine or, more commonly, several vaccine companies either bid for public contracts or sell their vaccines privately to distributors, pharmacies and individual physicians. This market mechanism allows vaccine producers to prudently expand their production capacity to meet next year’s market forecast. However, because this mechanism functions on a year-to-year basis, it provides companies with little guidance for making decisions on long-term investments that would increase production capacity. Given the current situation, one can easily imagine that when a pandemic threat appears, scores of governmental health agencies will simultaneously attempt to negotiate vaccine supply contracts with a limited number of producers, in effect leaving decisions on who will or will not be vaccinated in the hands of company executives. Alternatively, the U.S. experience in 1976 might be repeated, and the governments of the few countries which have their own influenza vaccine producers could in one way or another ‘‘nationalize’’ their companies in order to guarantee an adequate domestic supply of vaccine. Such a long-term arrangement has already been negotiated with the one vaccine producer in Canada (G. Ball, personal communication). Once domestic needs have been met, any excess production could be exported to other countries. If this happens, country presidents and prime ministers will have the power to decide who will or will not be vaccinated.

5. The rationale for developing a global approach for pandemic vaccine supply The solutions to several of mankind’s most important problems can be achieved only by efforts that are transnational in nature [9 – 11]. Whenever a solution is achieved, it is called a global public ‘‘good’’ [12,13]. Public goods are essential resources or services that, by their very nature, cannot be provided solely by the ‘‘invisible hand’’ of the market and require some form of governmental intervention [13]. Within nations, effective policing, a sound currency and widespread literacy are recognized as public goods, and their provision is ensured through a variety of laws and regulations. At the international level, different approaches must be taken to ensure global public goods. For example, the global consequences of environmental change have been addressed through legally binding international agreements and institutions, including the Vienna Convention for the Protection of the Ozone Layer, the Montreal Ozone Protocol and the London Amendments enacted in the 1980s, and more recently by the Framework Convention on Climate Change [14]. For global public health there may be no greater challenge than developing effective approaches to meet the threat of emerging and re-emergent infectious diseases. WHO can and should be expected to play a leading role in meeting this challenge. For decades, WHO has administered a set of international health regulations which apply to plague, yellow fever and cholera [9]. Although WHO established a unit for emerging infections in the mid-1990s, its activities have been largely concerned with strengthening the international public health infrastructure in order to improve research, training, and surveillance activities needed to deal with threats posed by emerging infectious diseases [9]. Public health institutions in individual countries have been encouraged to improve their capacities

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and to coordinate their activities with those of other countries and WHO. None of these efforts has relied on international health law. WHO began to use a new approach to confronting a global threat to public health when in 1999 the World Health Assembly authorized multilateral negotiations for a Framework Convention on Tobacco Control (FCTC) [14]. Scientific evidence for the devastating health and economic consequences of tobacco use was well known. What was new was a recognition that the global nature of the tobacco industry and the international trade in tobacco products required a public health response that transcended that of individual national governments. Under the FCTC, a Technical Working Group was charged with developing protocols to cover issues such as tobacco pricing, taxation, advertising, sponsorship, package design and labelling, smuggling, agriculture, information sharing and the Internet. The first meeting of the FCTC’s Intergovernmental Negotiating Body was held in October 2000. This group will negotiate and draft the proposed FCTC and related protocols which will be presented to the World Health Assembly for adoption in May 2003. In authorizing the FCTC, the World Health Assembly has firmly committed WHO to using international health law to address a problem of enormous importance for global public health.

6. A proposal to implement the WHO Influenza Pandemic Preparedness Plan and ensure vaccine supply The fundamental weakness of WHO’s Influenza Pandemic Preparedness Plan regarding vaccine production is self-evident; it offers no solution to the problem of maximizing the global supply of a pandemic vaccine and ensuring its equitable distribution. It is highly unlikely that market mechanisms can be counted on to effectively deal with this problem because they force company executives or national political leaders to make decisions on who will and will not be vaccinated. It also seems self-evident that the only way health authorities and vaccine producers will be able to optimise the production and distribution of a pandemic vaccine will be to work out the necessary conditions well before a pandemic threat appears. Failure to do so could have serious political as well as health and economic consequences worldwide [9,15,16]. Because the issues of pandemic vaccine supply will require negotiations between health officials representing a large number of countries and company officials representing a small number of vaccine producers, they are likely to succeed only if the negotiations are legally binding and conducted on a global basis. One possible mechanism to accomplish this would be a Framework Convention for Pandemic Influenza Vaccine Supply. If authorized by a resolution of the World Health Assembly, a Framework Convention would establish Technical Working Groups (TWGs) that would meet a least once a year. The TWGs would include representatives of the health ministries of all national governments that wish to participate in the process. These health officials would be invited to present five-year forecasts of the annual number of doses of trivalent influenza vaccine they will commit to purchase and how the vaccine will be paid for. The TWGs would also include representatives of each company that produces influenza vaccine as well as representatives of regulatory authorities, interna-

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tional agencies and nongovernmental organizations. Through a process that is consistent with the international competition policies and trade regulations and yet also recognizes the primacy of global public health, the vaccine producers would determine the extent to which they will be able to meet the vaccine supply needs that health officials have forecasted and how the needs of public and private markets can be accommodated. If additional production capacity is required, the negotiators might need to explore tax credits or other financial incentives to ensure that companies are able to make the necessary capital investments. The TWGs would also need to anticipate and propose solutions to regulatory problems, especially if new production techniques such as cell culture are involved. The rolling five-year forecasts of trivalent vaccine supply would serve as the basis for determining, according to several plausible scenarios, how vaccine companies would produce, finance and distribute a pandemic vaccine. Once the TWGs have prepared their protocols, an Intergovernmental Negotiating Body should draft and negotiate a Framework Convention for Pandemic Influenza Vaccine Supply. It could serve as a forerunner to the recently proposed Framework Convention on Global Infectious Disease Prevention and Control [17].

7. Conclusion The health benefits of annual influenza vaccination are evident [1] and may be greater than currently understood [18,19]. The importance of annual influenza vaccination in interpandemic years has been acknowledged in a recent WHO statement [20]. Moreover, the urgent need for an effective mechanism for pandemic vaccine supply has been emphasized by the H5N1 experience in Hong Kong [21]. A Framework Convention for Pandemic Influenza Vaccine Supply would provide a legally binding mechanism for optimizing the production and distribution of a pandemic vaccine. It would accelerate the already increasing use of trivalent influenza vaccine in developed and developing countries. It could also provide useful experience for forecasting the needs for other vaccines for children and adults [22] and for anticipating global mechanisms that could be used to introduce vaccines against HIV, tuberculosis and malaria, a goal that leaders of the G8 countries are committed to achieving [23]. Unlike the Framework Convention on Tobacco Control, which pits the needs of global public health against the interests of international tobacco companies, a Framework Convention for Pandemic Influenza Vaccine Supply would benefit both individual countries and vaccine producers. Ensuring that such a process is actually established, however, will require the active support of health officials, physicians and scientists throughout the world.

Acknowledgements The author thanks Isabelle Berthaut, Vincent Demenil, Salah Eddine Mahyaoui and Karim Kashi for information on influenza vaccine distribution; Paula Soper for

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information on the World Health Organization’s Tobacco Free Initiative; and David P. Fidler for comments on the manuscript.

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