Will Vaccines Be Available for the Next Influenza Pandemic?

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Science  24 Dec 2004:
Vol. 306, Issue 5705, pp. 2195-2196
DOI: 10.1126/science.1108165

Twenty per cent of the world's population falls ill. One in every hundred of those ill is hospitalized (if enough beds are available). Seven million deaths occur in a few months and 28 million are hospitalized. This is how the next influenza pandemic [HN1] might look, according to optimistic estimates (1, 2) (see the figure, below). Estimates from other models are far more frightening, but even this best-case scenario is cause for considerable concern.

The events leading to influenza pandemics are recurring biological phenomena and cannot be prevented. Influenza pandemics are caused by sudden emergence of a new influenza subtype in humans. New subtypes most probably derive from the vast animal influenza reservoir, where 15 different influenza A subtypes freely circulate, mainly in aquatic migratory birds. Only two subtypes (H3 and H1) are presently circulating in humans. If a subtype extends its host range to include humans, it will ignite the next pandemic. A pandemic virus will cause moving waves of outbreaks in humans lasting 1 to 2 months in a given region and complete its global spread in less than 8 to 12 months. During this time, it will cause a global health emergency. It would probably, as a strong competitor, replace the currently circulating subtypes. Finally, the pandemic virus will settle down to cause much milder seasonal epidemics, until the next pandemic virus takes over. Three to four influenza pandemics have occurred each century, and there is no reason to believe this century will be spared. [HN2]

With the unprecedented outbreak of avian influenza [HN3] in Asia (caused by H5N1), the world has come closer than ever to the first pandemic since 1968. The currently very widely circulating avian H5N1 strain has already caused disease in at least 44 persons and killed 32 of them. It is not easily transmissible between humans. However, it is feared that this would quickly change if, for example, it picks up a few genes from a human influenza virus during a coinfection; this change would ignite a new influenza pandemic.

Projections of numbers of deaths during the next influenza pandemic for selected countries based on statistics from the 1918–1919 pandemic (4).

All existing data suggest that vaccines would be the best line of defense against the high morbidity and mortality invariably associated with influenza pandemics. [HN4] However, vaccines have never been used to any large degree during a pandemic, including the last two, in 1957 and 1968, when vaccination against seasonal influenza was fully established. There are several reasons, all associated with sudden emergence of the pandemic virus and the small window for interventions (6 to 10 months) before the virus had completed global spread.

Delayed recognition may have arisen from inadequate surveillance systems and/or from an increase in human transmissibility so gradual it escaped early detection. Preparing a prototype seed virus for vaccine manufacturing took much too long. Preclinical and clinical vaccine testing was difficult and an optimal formulation (content of vaccine virus, number of doses, etc.) could not be established. Vaccine production capacity was extremely limited, and strategies for antigen sparing (using less vaccine virus per dose to achieve equivalent vaccine efficacy) remained unexplored. Finally, the regulatory pathways were not fixed by licensing agencies, which created uncertainty about requirements for testing and manufacturing of a safe and effective pandemic vaccine.

Most of the technical obstacles that precluded availability of a vaccine at the start of a pandemic have now been overcome. Human disease surveillance systems [HN5], although far from perfect, have become more sensitive, and case reporting is now more reliable. Laboratories in the WHO Global Influenza Surveillance Network can rapidly assess emerging field strains and provide prototype strains for vaccine production. Although new avenues for rapid influenza vaccine production during pandemics are being pursued (e.g., cell culture vaccines and recombinant antigen production), they are not yet available. A major breakthrough has been development of laboratory methods to design pandemic vaccine prototype strains rapidly and with predictable characteristics, such as the absence of avian pathogenicity. [HN6] This allows vaccine manufacturing in eggs and compliance with biosafety requirements for production plants. Furthermore, annual influenza vaccine production capacity, although still insufficient to meet an explosive global demand, has doubled during the last 10 years alone, reaching almost 0.9 billion doses of a monovalent vaccine.

Finally, major national and international licensing agencies have published safety and efficacy requirements for pandemic vaccine registration, thus providing a predictable regulatory environment in which companies can plan vaccine testing and development. Such registration, which can be done with any influenza subtype of pandemic potential, is the condition that every manufacturer must fulfill to receive market authorization for making a pandemic vaccine, regardless of when the next pandemic occurs and which strain causes it.

Currently, manufacturers would need an estimated 6 to 8 months to advance a pandemic influenza vaccine to obtain registration and begin commercial production (excluding ∼2 months for vaccine prototype development). If this development process only begins once the pandemic virus has started to spread, the virus will probably cover the world before large-scale manufacturing can be initiated.

Unfortunately, that would be the current reality. No “template” influenza pandemic vaccine has been licensed by any company. The formulation of an efficient H5N1 pandemic vaccine has not been established by clinical trials, nor are antigen-sparing formulations known. Should a pandemic virus emerge at the end of 2004, most manufacturers would need to start the groundwork of pandemic vaccine testing and registration: upgrading production facilities to fulfill biosafety requirements; preparation of master and production seed; and initiation of laboratory, animal, and clinical trials. Pandemic vaccine production would not begin before mid-2005, and significant amounts would not be available until several months later.

Slow progress of influenza pandemic vaccine development is no longer caused by insurmountable technical hurdles. The hurdles are political and economic in nature. Uncertainty over a viable market prevents companies from investing in pandemic vaccine development, and many governments see no reason to step in, as availability of pandemic vaccines is not considered a public health good. This is surprising in view of the expected benefits of influenza vaccination during a pandemic. If only 10% of the world population were vaccinated, the death toll, hospitalizations, and disease would likely be cut at about the same rate.

For the first time in history, the virus subtype of a possibly looming pandemic is known, and a vaccine against it could be stored for immediate use at the start of efficient human-to-human transmission. WHO is therefore recommending creation of national and international stockpiles of H5N1 vaccine, for emergency use in affected areas and as a defense strategy for slowing international spread. This might allow more time to increase vaccine supplies, especially if it acts as an incentive to vaccine companies.

Of the nearly 10 companies that represent about 90% of the global production capacity, five have begun or finished with seed development for H2, H5, H7, or H9 influenza A subtypes. Only three have taken the next steps and are preparing small batches of an H5N1 pandemic vaccine for clinical testing, scheduled for early 2005. One other company has completed trials with an H2 virus and will request licensing shortly. Many of the remaining companies have plans to consider seed development, after mid- to end-2005, and clinical testing, pending external funding.

A recent WHO meeting [HN7] (3) has outlined several avenues to overcome the key hurdle, the lack of market forces, and to save time in pandemic vaccine development. It is hoped that governments will create incentives. The National Institutes of Health support clinical trials with H5N1 influenza vaccines for companies with seasonal influenza vaccines licensed in the United States. In addition, government purchase of 2 million doses of an H5N1 vaccine certainly facilitated the manufacturers' decision to invest in vaccine seed development. [HN8] The Japanese Ministry of Health will spend US$ 1.2 million in 2005 to assist with pandemic vaccine development by the country's four influenza vaccine manufacturers and is considering additional support in 2006. The French government is negotiating a national stockpile of an H5N1 vaccine with a domestic company that is already investing in pandemic vaccine development.

International coordination to facilitate simultaneous clinical trials for vaccine licensing and studies on antigen-sparing strategies is also essential. Coordination will include rapid exchange of preclinical and clinical study results to avoid duplication. Regulatory coordination would facilitate defining expectations for immunogenicity studies and clinical trials and support standardization.

Influenza vaccine manufacturers should develop contingency plans to expedite the rapid switch from epidemic to pandemic vaccine production, considering the need for reallocation of intracompany vaccine production, filling, packaging, and distribution resources. Furthermore, governmental agencies of countries that plan vaccine use during pandemics need to address the liability issues that will arise during mass immunization campaigns.

If these measures were implemented, the time between the start of a pandemic and the start of commercial-scale production could be reduced by at least 6 to 8 months. Each day of manufacturing gained could represent at least 5 million additional doses, if global influenza vaccine manufacturing is operating at its full potential.

Global distribution of influenza vaccine by WHO region.

Data compiled by the Influenza Vaccine Supply International Task Force of the International Federation of Pharmaceutical Manufacturers Associations; it covers >95% of the total annual worldwide distribution. [Source (5)]

In the long term, manufacturing capacity can only be increased sustainably through augmented use of vaccines for seasonal epidemics of influenza. Capacity to manufacture a pandemic vaccine is dependent on existing production capacity, which is driven by the annual demand for vaccines for seasonal influenza. [HN9]

Almost all manufacturing capacity for influenza vaccines is concentrated in the industrialized world (∼65% in Europe alone), and almost all seasonal influenza vaccine is used there (see the figure, above). Affluent countries also have the means to support domestic manufacturers, if they consider pandemic vaccines a public good. Furthermore, the attention these countries attach to pandemic vaccine development will also influence how much, if any, influenza vaccine will be left for nonproducing countries, as governments have historically nationalized production of vital medicines only until domestic demand was satisfied.

Will vaccines be available for the next influenza pandemic? Yes, but there is no doubt that current production capacity is insufficient to meet, within a few months, world need for vaccine during an influenza pandemic. The better we prepare now, the more vaccine will eventually be available hopefully also for nonproducing countries. The window of opportunity for coordinated and rapid action is still open. It can only be hoped that the national and international public health communities will live up to the expectations of the population at risk for the next influenza pandemic: everybody.

HyperNotes Related Resources on the World Wide Web

General Hypernotes

Dictionaries and Glossaries

The On-line Medical Dictionary is provided by CancerWeb.

The InteliHealth Web site makes available the Merriam-Webster Medical Dictionary.

A vaccine glossary is provided by the Sabin Vaccine Institute.

Web Collections, References, and Resource Lists

The Google Directory includes links to influenza Internet resources.

The Yahoo Directory provides links to Internet resources on influenza and avian influenza. Yahoo News provides links to news coverage of bird flu outbreaks.

D. Sander's All the Virology on the WWW is a resource for virology information on the Internet.

An Internet resource collection on influenza is provided by M. Vadivale.

Online Texts and Lecture Notes

J. Kimball maintains Kimball's Biology Pages, an online biology textbook and glossary. Presentations on viruses, influenza, and vaccines are included.

Influenza is an introduction to the virus and the disease presented by the National Foundation for Infectious Diseases.

Epidemic: The World of Infectious Diseases is a presentation of the American Museum of Natural History.

Influenza Virus is a student project prepared for a course on the development of vaccines to infectious diseases taught by A. De Groot and P. Knopf of Brown University.

Influenza is a presentation of the Swiss Federal Office of Public Health.

Focus on the Flu is a resource page from the National Institute of Allergy and Infectious Disease (NIAID).

The influenza resource page from the U.S. Centers for Disease Control and Prevention (CDC) includes a section on avian influenza.

The Department of Communicable Disease Surveillance and Response (CSR) of the World Health Organization (WHO) provides resources pages on influenza and avian influenza.

The UK Health Protection Agency offers resource pages on influenza and avian influenza.

General Reports and Articles

The Threat of Pandemic Influenza: Are We Ready? is a 2004 workshop summary available from the National Academies Press. Slides and other presentations from the workshop are made available by the Institute of Medicine of the National Academies.

The 25 May 2004 issue of the Proceedings of the National Academy of Sciences had an article by Y. Guan et al. titled “H5N1 influenza: A protean pandemic threat.”

The September 2003 issue of Avian Diseases was a special issue on avian influenza.

The December 2003 issue of the CDC's Emerging Infectious Diseases had an article by K. F. Gensheimer, M. I. Meltzer, A. S. Postema, and R. A. Strikas titled “Influenza pandemic preparedness.” The September-October 1999 issue had an article by M. I. Meltzer, N. J. Cox, and K. Fukuda titled “The economic impact of pandemic influenza in the United States: Implications for setting priorities for interventions” (1).

The 28 November 2003 issue of Science had a review by R. J. Webby and R. G. Webster titled “Are we ready for pandemic influenza?”

The 14 May 2004 issue of Science had an Enhanced Policy Forum by N. M. Ferguson et al. titled “Public health risk from the avian H5N1 influenza epidemic.”

The 7 September 2001 issue of Science had an Enhanced Perspective by G. Laver and E. Garman titled “The origin and control of pandemic influenza” and an Enhanced Perspective by R. G. Webster titled “A molecular whodunit.”

Numbered Hypernotes

1. Influenza pandemics. NIAID's Focus on the Flu includes a section on pandemic influenza titled “Are we ready? Preparing for a pandemic.” Pandemic Influenza is a resource page provided by the National Vaccine Program Office, U.S. Department of Health and Human Services (HHS); the draft of the Pandemic Influenza Response and Preparedness Plan is included. WHO CSR provides a resource page on pandemic preparedness; the 1999 guidelines titled “Influenza pandemic preparedness plan: The role of WHO” and the April 2004 report titled “WHO consultation on priority public health interventions before and during an influenza pandemic” are available. The Public Health Agency of Canada presents the Canadian pandemic influenza plan. The National Institute of General Medical Sciences issued a 15 November 2004 news release and research brief titled “Computer models to simulate hypothetical outbreak of avian flu.” The 29 December 2001 issue of Philosophical Transactions: Biological Sciences was a special issue on the origin and control of pandemic influenza. A video titled “Pandemic influenza—A global threat” is available from the European Scientific Working Group on Influenza (ESWI).

2. Past pandemics. Kimball's Biology Pages include a section on the 1957 and 1968 influenza pandemics. The National Vaccine Program Office offers a summary of pandemics and pandemic scares in the 20th century. Influenza 1918 is a presentation of PBS Online's The American Experience. R. Siegel, Department of Microbiology and Immunology, Stanford University, makes available a student presentation by M. Billings about the influenza pandemic of 1918. Historical background information about pandemics is included in WHO's Influenza pandemic preparedness plan. The Spanish Influenza of 1918 is a resource page provided by S. Guðnadóttir. The 19 March 2004 issue of Science had an Enhanced Perspective by E. C. Holmes titled “1918 and all that.”

3. Avian influenza. Dangers of “Bird Flu” is a presentation of the University of Wisconsin's Why Files. The Animal Production and Health Division of the Food and Agriculture Organization of the United Nations (FAO) offers an Animal Health Special Report on Avian Influenza. The April 2004 issue of the Bulletin of the World Health Organization had an article by S. Lazzari and K. Stöhr titled “Avian influenza and influenza pandemics.” The New York Times had a 30 September 2004 article by K. Bradsher and L. K. Altman titled “Experts confront hurdles in containing bird flu.” MSNBC makes available a 13 December 2004 Newsweek International article by M. Hastings and F. Guterl titled “Bird-flu challenge.” The 15 October 2004 issue of Science had a collection of News Focus articles on avian influenza including an article by M. Enserink titled “Girding for disaster: Looking the pandemic in the eye.” The CDC's avian influenza resource page makes available a 7 December 2004 update titled “Avian influenza infection in humans.” The University of Minnesota's Center for Infectious Disease Research & Policy (CIPRAP) provides an overview of avian flu titled “Avian influenza (bird flu): Implications for human disease” and news coverage. WHO CSR's avian influenza resource page provides situation updates on avian influenza and reports of human cases.

4. Vaccines against pandemic influenza. Understanding Vaccines is an introduction (PDF format) from NIAID. An introduction to vaccine science is provided by the Sabin Vaccine Institute. The WHO influenza preparedness plan has a section on influenza vaccines. Presentations from a November 2003 workshop on human pandemic influenza vaccine are made available by the European Commission's Pharmaceuticals Unit. The 29 December 2001 issue of Philosophical Transactions: Biological Sciences had an article by J. M. Wood titled “Developing vaccines against pandemic influenza.” The 17 June 2004 issue of Eurosurveillance Weekly had an article by J. M. Wood and J. S Robertson titled “Development of a vaccine for humans against highly pathogenic avian influenza virus.”

5. Surveillance systems. Information about the WHO Global Influenza Surveillance Network is provided by WHO CSR. The September 2003 issue of Avian Diseases had an article by K. Stöhr titled “The WHO global influenza program and its animal influenza network.” The European Influenza Surveillance Scheme (EISS) Web site provides an introduction to EISS, as well as news, publications, and links on pandemic planning. The CDC provides information about influenza reports and surveillance methods in the United States.

6. Breakthroughs in vaccine development. NIAID's Focus on the Flu offers a presentation titled “Reverse genetics: Building flu vaccines piece by piece” as well as an illustrated introduction to reassortment vs. reverse genetics. The Agricultural Research Service offers a presentation on using reverse genetics titled “Reverse process may be key to developing swine flu vaccine.” The Scientist makes available a 9 April 2003 article by T. M. Powledge titled “Quick custom flu vaccines” and a 29 January 2004 article by R. Walgate titled “H5N1 vaccine strain in a week: Using reverse genetics, WHO thinks a prototype bird flu strain likely to be ready in a week.” WHO CSR provides a 20 January 2004 update titled “Development of a vaccine effective against avian influenza H5N1 infection in humans.” The St. Jude Children's Research Hospital offers an 2 April 2003 press release titled “Special reversed genetics used for vaccine against H5N1.” Scientific American makes available a 23 February 2004 article by K. Hopkin titled “Egg beaters: Flu vaccine makers look beyond the chicken egg.” The September 2003 issue of Avian Diseases had an article by G. Neumann, M. Hatta, and Y. Kawaoka titled “Reverse genetics for the control of avian influenza.”

7. Recent WHO meeting on influenza pandemic vaccine development. “Vaccines for pandemic influenza” is the summary report (PDF format) (3) of the November 2004 meeting on influenza pandemic vaccines with participants from WHO, influenza vaccine manufacturers, national licensing agencies, and governmental agencies. CIDRAP makes available a news article about the meeting.

8. U.S. support for H5N1 vaccine development. NIAID's Division of Microbiology and Infectious Diseases makes available the presentations (PDF format) from the September 2003 meeting titled “Development of a clinical trial plan for pandemic influenza vaccines”; a meeting summary is provided. NIAID issued a 27 May 2004 press release titled “NIAID announces contracts to develop vaccine against H5N1 avian influenza.” Press releases about these agreements were issued by Chiron and Aventis. CIDRAP offers a 17 November 2004 news article by R. Roos titled “Clinical trials of human H5N1 flu vaccine to start soon.” The U.S. Department of Health and Human Services issued a 21 September 2004 news release titled “HHS orders avian flu vaccine doses as preventive measure.”

9. Vaccine production. WHO CSR provides a list of influenza vaccine manufacturers. An Influenza Vaccine Production Fact Sheet is provided by the Center for Biosecurity, University of Pittsburgh Medical Center. The 15 June 2003 issue of Clinical Infectious Diseases had an article by D. S. Fedson titled “Pandemic influenza and global vaccine supply.” The European Commission's November 2003 workshop on human pandemic influenza vaccine included a presentation by F. Senatore titled “Vaccine industry's capacity to respond.” Aventis provides an introduction to pandemic influenza preparedness. The Sabin Vaccine Institute issued a 28 October 2004 press release (PDF format) titled “Global health experts strategize vaccine plan for pandemic influenza outbreaks.”

10. Klaus Stöhr and Marja Esveld are in the World Health Organization Influenza Programme.

References and Notes

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