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Institute of Medicine (US) Forum on Microbial Threats; Knobler SL, Mack A, Mahmoud A, et al., editors. The Threat of Pandemic Influenza: Are We Ready? Workshop Summary. Washington (DC): National Academies Press (US); 2005.

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The Threat of Pandemic Influenza: Are We Ready? Workshop Summary.

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3Toward Preparedness: Opportunities and Obstacles

OVERVIEW

The odds of detecting, controlling, and perhaps preventing the spread of an influenza virus with pandemic potential have improved dramatically since 1918, and they continue to increase with expanding knowledge of influenza viruses and the threat they present to human and animal health. Today, international programs permit the characterization of thousands of viral isolates each year and support worldwide surveillance and communications networks. These efforts are informed by research on viral molecular biology and evolution, and bolstered by simultaneous preparations against the threat of bioterrorism.

Yet major challenges to pandemic preparedness remain to be overcome. The world's growing—and increasingly urbanized—population and the speed and volume of international travel create abundant opportunities for widespread viral transmission. Some countries will respond to a pandemic with abundant resources and expertise, but many others remain essentially defenseless. Even populations wealthy enough to obtain vaccine are unlikely to get enough to prevent significant morbidity and mortality from pandemic influenza unless more rapid vaccine production methods or novel prophylactic vaccines can be introduced before the next pandemic strikes. The circumstances surrounding 2 consecutive years of interpandemic flu vaccine shortages in the United States clearly illustrate this vulnerability. The 2003–2004 shortage, discussed by Glen Nowak in Chapter 6, resulted from increased demand for vaccine during an early and intense flu season, while the 2004–2005 shortage resulted from contamination that rendered half of the U.S. vaccine supply—the product of a single manufacturer, Chiron, Inc.—unusable.

This chapter discusses challenges to pandemic preparedness at international, national, and state levels. It begins with the executive summary of a technical consultation convened by the World Health Organization (WHO) in March 2004 in response to the threat posed by H5N1 avian influenza, and in particular to the evidence that this virus had been transmitted to humans in Vietnam and Thailand, with deadly results. More than 100 experts from 33 countries discussed a broad range of measures that could be introduced by WHO and national authorities to forestall emerging pandemics, slow their spread, and reduce their potential toll of morbidity, mortality, and social disruption. The executive summary presents the recommendations and conclusions of four working groups (surveillance, public health interventions, antivirals, and vaccines) regarding key issues in pandemic preparedness.

In the United States, the Department of Health and Human Services released a draft Pandemic Preparedness and Response Plan for a 60-day period of public comment on August 26, 2004. This chapter includes an executive summary and a synopsis of this plan, which describes coordination and decision making at the national level; provides an overview of key issues; and outlines steps that should be taken at the national, state, and local levels before and during a pandemic. It is followed by two contributions that further discuss pandemic planning from the perspective of state and local public health officials, who will be largely responsible for implementing pandemic prevention and control actions in the United States. The first essay discusses pandemic planning as a collaborative process that involves officials at all levels of government and that is guided by federal priorities. The second essay highlights the importance of strengthening influenza surveillance at the state and local levels, both as a means to early detection of an emerging pandemic and to inform the public health response to interpandemic influenza.

The chapter continues with a consideration of pharmaceutical defenses against pandemic influenza. Vaccines significantly reduce morbidity and mortality during annual (interpandemic) flu seasons, but as this chapter demonstrates, considerable obstacles currently hinder the production of a vaccine against a pandemic strain of influenza. The critical role of vaccine manufacturers in addressing a pandemic is described, accompanied by a review of methods and logistics for the development and production of a pandemic vaccine.

Demand for vaccine during a pandemic will likely far exceed supply. These considerations are subsequently explored first in a discussion of the challenges to equitable and effective vaccine distribution, and then in a description of the potential use of antiviral drugs to fill unmet need for vaccine, particularly during the initial phase of a pandemic. David Fedson advises that efforts toward pandemic vaccine development should initially focus on producing the largest possible supply of pandemic vaccine as quickly as possible. Europeans will most likely pursue this goal by developing a low-dose adjuvant pandemic vaccine, which differs from the strategy that will be undertaken by the National Institute of Allergy and Infectious Diseases in the United States. He also describes the potential advantages of engineering viral seed strains with reverse genetics and urges a quick resolution to the ongoing dispute regarding ownership of intellectual property for this technology.

Given these obstacles to the timely production of pandemic vaccine, it is also imperative to develop near-term strategies to address a pandemic threat without recourse to vaccination. Dr. Fedson recounts recent findings suggesting that prophylaxis with statins or other commonly available therapeutic agents, which have recently been found to reduce serum concentrations of several inflammatory mediators, might mitigate the clinical course of human influenza. He suggests next steps in pursuing this idea, but it is not without risk or controversy. For example, a recent case study describes a patient undergoing therapy with two statins (cerivastatin and bezafibrate) who developed acute renal failure due to rhabdomyolysis only after being administered an influenza vaccine; similar cases had occurred in several patients receiving this combined therapy who had contracted influenza (Plotkin et al., 2000). Researchers have also reported that the in-vitro treatment of macrophages with another statin (lovastatin) did not decrease tumor necrotic factor (TNF) production, as would be expected to occur with lovastatin-induced immunosuppression, but instead resulted in increased production of TNF (Monick et al., 2003). The apparent contradiction between this observation and the reports cited by Dr. Fedson may be explained by tolerance induced in vivo subsequent to lovastatin-induced TNF production, or perhaps by differences between the long-term and acute effects of lovastatin.

A second, more widely accepted strategy for coping with pandemic influenza in absence of vaccine is described in the subsequent review by Frederick Hayden, which focuses on the potential role of currently available antiviral drugs in such a pandemic response. However, as this review makes clear, a variety of supply and distribution problems must be solved before this promising strategy could be implemented.

Although the American health care system is overwhelmingly privatized, little attention has yet been paid to private medicine's potential role in preparing for pandemic influenza. This chapter concludes with a description of the status of pandemic planning within the private health care system, and suggestions for ways that private health care organizations could contribute to pandemic preparedness at all levels of government.

WHO CONSULTATION ON PRIORITY PUBLIC HEALTH INTERVENTIONS BEFORE AND DURING INFLUENZA PANDEMIC EXECUTIVE SUMMARY

World Health Organization1

Reprinted with permission from the World Health Organization, Copyright World Health Organization, 2004, All Rights Reserved

Background

In January 2004, health authorities in Viet Nam and Thailand reported their first human cases of infection with avian influenza, caused by an H5N1 strain. The cases in humans are directly linked to outbreaks of highly pathogenic H5N1 avian influenza in poultry initially reported in the Republic of Korea in mid-December 2003 and subsequently confirmed in an additional seven Asian countries (Viet Nam, Japan, Thailand, Cambodia, China, Laos, and Indonesia). As at end-March 2004, no countries other than Viet Nam and Thailand had reported human cases. The number of human cases has remained small to date, but treatment has been largely ineffective and case fatality rates have been high. Moreover, the situation has several disturbing features, including the historically unprecedented scale of the outbreak in poultry.

Of foremost concern is the risk that conditions present in parts of Asia could give rise to an influenza pandemic. Pandemics, which recur at unpredictable intervals, invariably cause high morbidity and mortality and great social disruption and economic losses. Conservative estimates based on mathematical modelling suggest that the next pandemic could cause from 2 million to 7.4 million deaths.

Conditions favourable to the start of a pandemic are now much better understood than in the previous century, which witnessed three pandemics. Influenza research was greatly stimulated in 1997, when the world's first known cases of human infection with the H5N1 strain of avian influenza virus were documented in Hong Kong Special Administrative Region of China. Investigations launched by that outbreak, including studies in molecular biology and epidemiology, helped elucidate the mechanisms by which pandemic viruses could emerge and further clarified the conditions that favour such an event. These studies also demonstrated, for the first time, that the H5N1 strain can infect humans directly without prior adaptation in a mammalian host. On that occasion, the culling within three days of Hong Kong's poultry population, estimated at 1.5 million birds, is thought to have possibly averted a pandemic.

Some experts believe that this improved understanding, when combined with efficient surveillance and immediate and aggressive action, might make it possible to detect events with pandemic potential and delay—or even prevent—their escalation and global spread. Research has identified three essential prerequisites for the start of a pandemic. First, a novel influenza subtype must be transmitted to humans. Second, the new virus must be able to replicate in humans and cause disease. Third, the new virus must be efficiently transmitted from one human to another; efficient human-to-human transmission is expressed as sustained chains of transmission causing community-wide outbreaks. Since 1997, the first two prerequisites have been met on four occasions: Hong Kong in 1997 (H5N1), Hong Kong in 2003 (H5N1), the Netherlands in 2003 (H7N7), and Viet Nam and Thailand in 2004 (H5N1). Of these outbreaks, those caused by H5N1 are of particular concern because of their association with severe illness and a high case fatality. Of even greater concern is the uniqueness of the present H5N1 situation in Asia. Never before has an avian influenza virus with a documented ability to infect humans caused such widespread outbreaks in birds in so many countries. This unprecedented situation has significantly increased the risk for the emergence of an influenza pandemic.

A pandemic virus capable of efficient human-to-human transmission could arise via two mechanisms: virus reassortment (the swapping of genetic material between viruses) when humans or pigs are co-infected with H5N1 and a human influenza virus, and adaptive mutation during human infection. The risk that either event will occur remains so long as H5N1 is present in an animal reservoir, thus allowing continuing opportunities for human exposure and infection. The level of risk is determined most directly by the prevalence of the virus in poultry and the frequency of its transmission to humans. The risk also depends on the co-circulation of human and avian influenza viruses and the inherent propensity of these viruses to reassort. Most experts agree that control of the present outbreaks in poultry will take several months or even years; some believe that the virus may have already established endemicity in domestic poultry. The recent detection of highly pathogenic avian influenza in wild birds adds another layer of complexity to control.

The world may therefore remain on the verge of a pandemic for some time to come. At the same time, the unpredictability of influenza viruses and the speed with which transmissibility can improve mean that the time for preparedness planning is right now. Such a task takes on added urgency because of the prospects opened by recent research: good planning and preparedness might mitigate the enormous consequences of a pandemic, and this opportunity must not be missed.

The Consultation

In response to these concerns, WHO convened a technical consultation on preparedness for an influenza pandemic from 16 to 18 March 2004. The consultation, attended by more than 100 experts from 33 countries, considered a wide range of measures that could be introduced, by WHO and national authorities, both before and during a pandemic. Three main objectives were identified: to forestall potential pandemics as they emerge, to slow national and international spread, and to reduce the usually high levels of morbidity, mortality, and social disruption. Participants agreed that the effectiveness of specific interventions would change over time in line with distinct phases, defined by epidemiological criteria, during the progression from an incipient pandemic situation to the declaration of a pandemic. Interventions were therefore discussed in terms of their objectives and likely impact at different phases as well as their feasibility in different resource settings. Epidemiological triggers for shifting objectives and adapting the recommended mix of measures were also identified. The consultation fully recognized that the best opportunity for mitigating the consequences of a pandemic would occur early on, and that planning and preparedness, at both national and global levels, would be needed to take full advantage of this opportunity.

Many key characteristics of a new pandemic virus—its pathogenicity, attack rate in different age groups, susceptibility to antivirals, and response to other treatments—would guide the selection of control measures, but could not be known with certainty in advance. In addition, many characteristics of normal human influenza, such as the role of asymptomatic transmission and the effectiveness of non-medical control measures, are poorly understood. During the chaos of a pandemic, health authorities would almost certainly need to make decisions, often with major social and economic consequences, in an atmosphere of considerable scientific uncertainty. To reduce some of this uncertainty, participants based their recommendations on relevant lessons from the recent SARS outbreak, knowledge about the epidemiology of previous influenza pandemics, and clinical data from outbreaks of H5N1 infection in Hong Kong in 1997 and Viet Nam and Thailand in 2004. Modelling of various scenarios for the emergence of a pandemic strain provided an especially useful planning tool.

Against this background, three main questions were addressed: what reporting and monitoring systems are needed to detect the start of a pandemic at the earliest possible stage and track its evolution, which interventions will be both feasible and effective at different phases and in different resource settings, and what policy options might best cope with the inevitable shortage of vaccines and antivirals. These questions were considered by four working groups focused on surveillance, public health interventions, antivirals, and vaccines. A more complete account of the deliberations and conclusions of each working group is provided in the main body of this report.

Some discussion centered on the question of whether—with better scientific knowledge, better control tools, and the international solidarity shown during the SARS response—something might be done to prevent the present situation from evolving towards a pandemic. In this regard, good surveillance in all countries experiencing outbreaks of highly pathogenic avian influenza in poultry was considered to be a fundamental prerequisite. Guarding against the start of a pandemic would also depend on rapid detection, prompt laboratory confirmation, and accurate reporting of human cases, and the transparent sharing of all relevant information with WHO.

Participants readily agreed that vaccines—the first line of defence for reducing morbidity and mortality—would not be available at the start of a pandemic and would remain in short supply throughout the first wave of international spread. For this reason, efforts to prevent or delay initial spread would have paramount importance. All countries would need to prioritize vaccine distribution and consider difficult ethical and practical questions of eligibility. Developing countries would face the most acute shortages, as manufacturing capacity is concentrated in Europe and North America, and countries can be expected to reserve scarce supplies for their own populations. In the absence of vaccines, antivirals would initially assume greater importance as a prophylactic and treatment tool for reducing morbidity and mortality. In practice, however, this potential role could be undermined by several problems, including high costs, uncertain efficacy, propensity to develop resistance, and extremely limited supplies, further constrained by the absence of any surge capacity for production.

With the first line of defence not a viable option at the start of a pandemic, participants looked at interventions that could forestall or delay national and international spread pending antiviral availability, the augmentation of vaccine supplies, and the implementation of mass vaccination strategies. This strategy of “buying time” was linked to assumptions, partially based on modelling, that the first chains of human-to-human transmission might not reach the efficiency needed to initiate and sustain pandemic spread. In such a scenario, the first evidence of limited human-to-human transmission, most likely expressed as clusters of cases, would be the epidemiological trigger for intense international efforts aimed at interrupting further transmission or at least delaying further national and international spread. For this reason, surveillance systems in countries with outbreaks in animals caused by H5N1 or other influenza viruses of known human pathogenicity should be oriented towards early detection, reporting, and investigation of clusters of human cases, followed by aggressive containment measures, including tracing and management of contacts, targeted prophylactic use of antivirals, and travel-related measures. Participants recommended consideration of whether an international stockpile of antivirals should be established for use exclusively during this critical window of opportunity.

Should early containment fail, the consultation concluded that, once a certain level of efficient transmission was reached, no interventions could halt further spread, and priorities would need to shift to the reduction of morbidity and mortality. It was also recognized that a reassortment event could result in a virus fully equipped for efficient human-to-human transmission, thus immediately curtailing opportunities to “buy time” through measures aimed at preventing geographical spread. Should early surveillance fail, the detection of transmission would likely take place only after efficient transmission was established, again curtailing opportunities to intervene. However, in these cases as well, advance planning had much to offer. As the consequences of a pandemic became apparent, public health authorities would face great public and political pressure to maintain or introduce often drastic, costly, and disruptive protective measures (travel restrictions, screening measures at borders, contacting tracing, isolation and quarantine) which, though useful at earlier stages, might have little or no impact once efficient transmission was established. By including provisions for stopping or adjusting measures in line with clear epidemiological criteria, preparedness plans would help public health authorities withstand this pressure and thus conserve resources for the next objectives: constraining transmission, preventing severe disease, and reducing case fatality.

When objectives shift, clear and frank public information and good communications systems would be essential in helping lower expectations and discouraging the continuation of personal protective measures no longer considered effective. Participants agreed that, once a pandemic begins, its overall management would move outside the public health sector and take on great political and economic significance. Good public information might also protect governments from accusations that extraordinary measures introduced at earlier phases—causing great economic costs and social disruption—failed and were therefore inappropriate. In addition, populations would need to be prepared for the even greater social disruption, linked to high morbidity and mortality that could be expected as the pandemic progressed.

Conclusions

Some General Conclusions

During the deliberations of the working groups and discussions in plenary session, the picture that emerged was one of a world inadequately prepared to respond to an influenza pandemic. Response capacity was considered insufficient at levels ranging from vaccine manufacturing to the sensitivity of surveillance systems, the number of hospital beds, the affordability of diagnostic tests, and the supply of respirators and face masks. A recurring theme was the need to engage government departments beyond the health sector. At the same time, the urgency of the present situation was fully appreciated, and participants made a number of suggestions for improving capacity now. For example, better use of vaccines and antivirals during the inter-pandemic period would improve manufacturing capacity while also helping to reduce the estimated 250,000 to 500,000 deaths caused by seasonal influenza epidemics each year. The burden of influenza in developing countries, including its contribution to overall morbidity and mortality and economic impact, was virtually unknown in most cases. Studies of this burden would give national authorities a better foundation for making influenza a priority and bargaining for a share of resources. Establishment of vaccine manufacturing capacity in developing countries could be expected to improve access while reducing costs.

Moreover, most participants agreed that, under the pressures of an eminent or unfolding pandemic, innovative solutions to some problems would be found. For example, manufacturing capacity for vaccines might be augmented by decreasing the antigen quantity per dose or using adjuvants. Research on antivirals could determine whether reduced drug dose or shortened treatment course might still have a prophylactic or therapeutic effect, and whether administration later in the course of infection might influence transmission dynamics by reducing virus shedding.

As in all public health emergencies caused by an infectious agent, international mechanisms for alert and response can go only a certain way towards mitigating the consequences of an influenza pandemic. In the final analysis, each national health system will bear the burden of protecting populations and managing the emergency. The consultation concluded that international solidarity would have the greatest role to play at the start of human-to-human transmission, when an all-out effort would have the best chance of halting or at least delaying further national and international spread. Should that effort fail, inequities in capacity and the distribution of resources mean that the consequences of a pandemic would almost certainly be most severe in the developing world. Participants stressed the importance of addressing these inequalities now—before a pandemic makes the ethical implications of failing to do so both blatantly apparent and irrevocable.

Conclusions from the Working Groups

Working Group One: Surveillance for pandemic preparedness

  1. One of the most important functions of surveillance is to ensure the detection of unusual clusters of cases and of the occurrence of human-to-human transmission at the earliest possible stage, when public health interventions have the greatest chance to prevent or delay further national and international spread. Once a pandemic is fully under way, no interventions are likely to halt further international spread during the first wave of infection.
  2. Influenza pandemics are, by their very nature, matters of global concern. Prompt and transparent reporting of early cases and results from the investigation of clusters related to novel influenza viruses is essential for the protection of international public health.
  3. The use of limited supplies of vaccines and antivirals will depend on the national situation and should consider the protection of essential community functions and the treatment of groups at highest risk of severe disease. Data from a national risk assessment and internationally coordinated epidemiological investigations will assist in the development of policies for vaccine and antiviral utilization. Data to inform policy decisions need to be produced as quickly and cost-effectively as possible.
  4. As the origins of pandemic influenza viruses have historically involved animal species, surveillance activities surrounding the emergence of a potentially pandemic virus require intersectoral collaboration with veterinarians as well as with clinicians, virologists, epidemiologists, and public health professionals.
  5. Given resource constraints in many countries, strengthening existing systems to include a capacity to detect and investigate clusters of acute febrile respiratory disease may be the best value for money.
  6. The objectives, methods, and attributes of an influenza surveillance system will vary according to different phases in the pre-pandemic and pandemic periods.
  7. To assist in preparedness planning, the group set out recommended objectives for influenza surveillance and identified the corresponding methods and activities appropriate at different inter-pandemic, pre-pandemic, and pandemic phases. These recommendations appear as a table in the working group's report.

Working Group Two: Public health interventions

  1. An influenza pandemic is a public health emergency that rapidly takes on significant political, social, and economic dimensions. A broad range of government departments apart from public health should be engaged in pandemic preparedness planning and will need to be involved in decisions regarding interventions having potentially broad impact outside the health sector.
  2. Emergency decisions will need to be made in an atmosphere of scientific uncertainty. Health authorities may need to change recommended measures as data about the causative agent become available and the epidemiological situation evolves, and as interventions either succeed in containing transmission or lose their effectiveness. The basis for all interventions should be carefully explained to the public and professionals, as well as the fact that changes can be expected.
  3. Non-medical interventions will be the principal control measures pending the availability of adequate supplies of an effective vaccine. Many will have their greatest potential impact in pre-pandemic phases while others will have a role after a pandemic has begun. In some resource-poor settings, non-medical interventions will be the only control measures available throughout the course of a pandemic.
  4. Non-medical interventions considered by the consultation include public risk communication, isolation of cases, tracing and appropriate management of contacts, measures to “increase social distance” (such as cancellation of mass gatherings and closure of schools), limiting the spread of infection by domestic and international travel, and the targeted use of antiviral drugs. Certain measures are recommended for consideration based on a public health perspective, although it is recognized that other factors (such as availability of health resources, political, economic and social considerations) and a country's special circumstances will legitimately influence national decisions regarding prioritization and implementation of the various options.
  5. In general, providing information to domestic and international travellers (risks to avoid, symptoms to look for, when to seek care) is a better use of health resources than formal screening. Entry screening of travellers at international borders will incur considerable expense with a disproportionately small impact on international spread, although exit screening should be considered in some situations.
  6. Emerging virus strains with pandemic potential require urgent and aggressive investigation to provide a stronger scientific basis for control recommendations and the strategic use of resources. Confirmation of early episodes of human-to-human transmission is especially important. Biological specimens as well as epidemiological and clinical data must be obtained and shared with extreme urgency, under the leadership of WHO. Advance planning is needed to take advantage of this narrow window of opportunity to contain or slow transmission, which will close quickly once a pandemic begins.
  7. Health authorities may need to introduce extraordinary measures under emergency conditions. This is likely to require improvement of public health capacities and modernization of public health laws at national and international levels. The necessary legal authority for implementation of these measures must be in place before a pandemic begins. Respect for public health ethics and fundamental human rights is critical.
  8. To assist in preparedness planning, the group assessed more than 30 public health interventions in terms of their feasibility and likely effectiveness at each of four phases in the progression from a pre-pandemic situation to the declaration of a pandemic. Recommended measures, at national and international level, appear as tables in the working group's report.

Working Group Three: Antivirals—their use and availability

  1. Antivirals are expected to be effective against human illness caused by avian influenza and human pandemic strains. Pending the availability of vaccines, they will be the only influenza-specific medical intervention for use in a pandemic.
  2. Inadequate supplies are a major constraint. Supplies are presently extremely limited and manufacturing capacity could not be augmented during the course of a pandemic. At current capacity, several years would be needed to increase supplies appreciably.
  3. Most countries will have no access to antivirals throughout the course of a pandemic and will need to rely on public health measures and supportive care until vaccines become available.
  4. Conditions of access will be best in countries that have manufacturing capacity, regularly purchase antivirals for seasonal use, or have stockpiled drugs in advance.
  5. Stockpiling of drugs in advance is currently the only way to ensure sufficient supplies at the start of a pandemic. Governments with adequate resources should consider pursuing this option as a precautionary measure.
  6. Establishment of an international stockpile of antivirals should be considered for use for specific objectives in the pre-pandemic period, when opportunities for averting a pandemic or delaying its further spread are likely to be greatest. An international stockpile could not be used to meet the needs of individual countries once a pandemic is fully under way.
  7. Increased use of antivirals during the inter-pandemic years, based on better understanding of the medical and economic burden of annual influenza epidemics, is one strategy for augmenting production capacity.
  8. Price is the second major constraint. Current costs for widespread use of even the shortest duration of treatment place these drugs outside health budgets in the vast majority of countries.
  9. Additional obstacles to wide-scale use include side effects of certain agents (especially amantadine), the risk of drug resistance, and limited safety data in key sub-populations.
  10. Early treatment is a more efficient use of resources than prophylaxis, which requires a prohibitively large stockpile.
  11. Where available, the neuraminidase inhibitors are the preferred drugs for treatment. If the M2 inhibitors must be used for treatment, this should be done with a full awareness of their side effects and propensity to develop resistance.
  12. Scarce supplies of an emergency intervention create ethical dilemmas of priority access both within and among countries. Ethical dilemmas regarding fair access and rationing of finite supplies will be difficult to resolve but must be addressed.

Working Group Four: Better vaccines—better access

  1. Vaccines are the single most important intervention for preventing influenza associated morbidity and mortality during both seasonal epidemics and pandemics.
  2. No country will have adequate supplies of vaccine at the start of a pandemic. At least 4 to 6 months will be needed to produce the first doses of vaccine following isolation of a new pandemic virus. The subsequent augmentation of supplies will be progressive. Stockpiling in advance is not an option.
  3. Global manufacturing capacity, which is driven by vaccine demand during the inter-pandemic years, is finite and inadequate. More than 90 percent of current production capacity is concentrated in countries in Europe and North America accounting for less than 10 percent of the world's population.
  4. Equitable access will not be possible so long as global manufacturing capacity remains inadequate. Countries without manufacturing capacity will face the most acute vaccine shortages, as countries with manufacturing capacity can be expected to reserve scarce supplies for their own populations.
  5. The production of a vaccine for a pandemic virus is a unique process that requires emergency procedures for its development, licensing, production, and delivery.
  6. Important constraints to rapid and large-scale production of a pandemic vaccine include intellectual property rights, biosafety requirements for production facilities, and coordination and funding of clinical trials. A global effort to address these constraints is an efficient approach.
  7. Country-specific issues to be addressed by national authorities include procedures for licensing and testing and liability issues surrounding mass use of a new vaccine with an unknown safety profile.
  8. Short-term solutions for augmenting supplies include the development of vaccines using a lower antigen content, use of adjuvants to improve immunogenicity, and outsourcing of certain production steps. Another strategy involves advance preparation of pilot lots of vaccine against virus subtypes with pandemic potential. To pursue this strategy, manufacturers may need financial or other incentives to support investments in a product that might never be used.
  9. Public funding should give priority to research on cross-subtype vaccines conferring long-lasting protection. Development of vaccines protective against several candidate pandemic viruses is a particularly effective long-term solution, as it opens possibilities for stockpiling. If the vaccine confers long-lasting immunity, preventive vaccination for a future pandemic will be possible as a major step forward.
  10. Increased vaccine use during the inter-pandemic years will increase production capacity, but depends upon the burden of influenza within individual countries compared with other health priorities. Regional production strategies and purchasing schemes should be explored as a strategy for increasing vaccine use during the inter-pandemic years.
  11. All countries should decide in advance on priority groups for vaccination when supplies are limited and develop strategies for expanding coverage when supplies increase.
  12. Vaccine manufacturers in developing countries should participate in the influenza vaccine supply task force of the International Federation of Pharmaceutical Manufacturers.

PANDEMIC INFLUENZA PREPAREDNESS AND RESPONSE PLAN

Department of Health and Human Services2

**August 2004 Draft Version for Public Comment**

Reprinted with permission from Department of Health and Human Services

Available online: http://www.hhs.gov/nvpo/pandemicplan/

Executive Summary

An influenza pandemic has a greater potential to cause rapid increases in death and illness than virtually any other natural health threat. Planning and preparedness before the next pandemic strikes—the interpandemic period—is critical for an effective response. This Draft Pandemic Influenza Preparedness and Response Plan describes a coordinated strategy to prepare for and respond to an influenza pandemic. It also provides guidance to state and local health departments and the health care system to enhance planning and preparedness at the levels where the primary response activities in the United States will be implemented.

Influenza causes seasonal epidemics of disease resulting in an average of 36,000 deaths each year. A pandemic—or global epidemic—occurs when there is a major change in the influenza virus so that most or all of the world's population has never been exposed previously and is thus vulnerable to the virus. Three pandemics occurred during the twentieth century, the most severe of which, in 1918, caused over 500,000 U.S. deaths and more than 20 million deaths worldwide. Recent outbreaks of human disease caused by avian influenza strains in Asia and Europe highlight the potential of new strains to be introduced into the population. Recent studies suggest that avian strains are becoming more capable of causing severe disease in humans and that these strains have become endemic in some wild birds. If these strains reassort with human influenza viruses such that they can be effectively transmitted between people, a pandemic can occur.

Characteristics of an influenza pandemic that must be considered in preparedness and response planning include: (1) simultaneous impacts in communities across the United States, limiting the ability of any jurisdiction to provide support and assistance to other areas; (2) an overwhelming burden of ill persons requiring hospitalization or outpatient medical care; (3) likely shortages and delays in the availability of vaccines and antiviral drugs; (4) disruption of national and community infrastructures including transportation, commerce, utilities and public safety; and (5) global spread of infection with outbreaks throughout the world.

The Department of Health and Human Services (HHS) continues to make progress in preparing to effectively respond to an influenza pandemic. This has been done through programs specific for influenza and those focused more generally on increasing preparedness for bioterrorism and other emerging infectious disease health threats. Substantial resources have been allocated to assure and expand influenza vaccine production capacity; increase influenza vaccination use; stockpile influenza antiviral drugs in the Strategic National Stockpile (SNS); enhance U.S. and global disease detection and surveillance infrastructures; expand influenza-related research; support public health planning and laboratory; and improve health care system readiness at the community level.

Additional preparation is also ongoing in several critical areas. Vaccination is the primary strategy to reduce the impact of a pandemic but the time required currently to develop a vaccine and the limited U.S. influenza vaccine production capacity represent barriers to optimal prevention. Enhancing existing U.S. and global influenza surveillance networks can lead to earlier detection of a pandemic virus or one with pandemic potential. Virus identification and the generation of seed viruses for vaccine production is a critical first step for influenza vaccine development.

In addition to expanding the number of global surveillance sites and extending existing sentinel surveillance sites to perform surveillance throughout the year, there has been a concomitant enhancement of laboratory capacity to identify and subtype influenza strains. Vaccine research and development can be accelerated during the inter-pandemic period by preparing and testing candidate vaccines for influenza strains that have pandemic potential, conducting research that will guide optimal vaccine formulation and schedule, and assessing techniques that can enhance manufacturing yields using current and prospective production methods. Plans are in place to increase U.S. influenza vaccine manufacturing capacity through a partnership with industry to assure that vaccine can be produced at any time throughout the year. This includes increasing the demand for annual influenza vaccine by the Centers for Medicaid and Medicare Services (CMS) and the Centers for Disease Control and Prevention (CDC), which will have the dual benefits of improving annual influenza prevention and control by strengthening the vaccine delivery system, and expanding manufacturing capacity to meet this increased demand—and also promoting the diversification of existing vaccine production with technology that is amenable to rapid expansion to meet vaccine needs in a pandemic. Enhanced planning by the public and private health care sectors to assure the ability to distribute vaccine, targeting available supply to priority groups, and monitoring vaccine effectiveness and adverse events also are critical to meet pandemic response goals.

Early in a pandemic, especially before vaccine is available or during a period of limited supply, use of other interventions may have a significant effect. For example, antiviral drugs are effective as therapy against susceptible influenza virus strains when used early in infection and can also prevent infection (prophylaxis). In 2003, the antiviral drug oseltamivir was added to the SNS. Analysis is ongoing to define optimal antiviral use strategies, potential health impacts, and cost-effectiveness of antiviral drugs in the setting of a pandemic. Results of these analyses will contribute to decisions regarding the appropriate type and quantity of antiviral drugs to maintain in the SNS. Planning by public and private health care organizations is needed to assure effective use of available drugs, whether from a national stockpile, state stockpiles or in private sector inventories.

Implementing infection control strategies to decrease the global and community spread of infection, while not changing the overall magnitude of a pandemic, may reduce the number of people infected early in the course of the outbreak, before vaccines are available for prevention. Travel advisories and precautions, screening persons arriving from affected areas, closing schools and restricting public gatherings, and quarantine of exposed persons may be important strategies for reducing transmission. The application of these interventions will be guided by the evolving epidemiologic pattern of the pandemic.

Planning by state and local health departments and by the health care system and coordination between the two is critical to assure effective implementation of response activities and delivery of quality medical care in the context of increased demand for services. Guidance included in this plan and from other organizations, as well as technical assistance and funding are available to facilitate planning. Coordination in planning and consistency in implementation with other emergency response plans, such as those for bioterrorist threats and SARS can improve efficiency and effectiveness. In addition, other public health emergency programs such as the Health Resources and Services Administration (HRSA) Hospital Preparedness Program and the CDC Public Health Preparedness and Response Cooperative Agreements are providing states with resources to strengthen their ability to respond to bioterror attacks, infectious diseases and natural disaster. For example, initiatives and funding being provided by HRSA will help states improve coordination of health care services and emergency response capacity and facilitate preparedness for influenza, smallpox, SARS, as well as other public health emergencies. In FY 04, HHS introduced a cross-cutting critical benchmark for state pandemic influenza preparedness planning as part of the Department's awards to states to improve hospitals' response to bioterrorism and other diseases. The goal of this planning activity is to assure implementation of an effective response including the delivery of quality medical care in the context of the anticipated increased demand for services in a pandemic (www.hhs.gov/asphep/FY04benchmarks.html). Completing pandemic preparedness and response plans and testing them in tabletop and field exercises are key next steps. All totaled since September 11, 2001, HHS has invested more than $3.7 billion in strengthening the Nation's public health infrastructure.

Preparedness for an influenza pandemic is coordinated in the office of the Assistant Secretary for Health, HHS. Response activities will be coordinated by the Assistant Secretary for Public Health Emergency Preparedness, on behalf of the Secretary in close coordination with the Department of Homeland Security as stipulated in HSPD#5. Other federal agencies will play critical roles as well.

Pandemic influenza response activities are outlined by pandemic phase, a classification system developed by the World Health Organization (WHO) in 1999. Phase 0, the inter-pandemic phase, is divided into 4 levels: Phase 0, Level 0 (0.0; with no recognized human infections caused by a novel influenza strain; Phase 0, Level 1 (0.1; (“new virus alert”) with a case of human infection caused by a novel strain; Phase 0, Level 2 (0.2; with two or more human cases but no documented person-to-person transmission and unclear ability to cause outbreaks; and phase 0, Level 3 (0.3; (“pandemic alert”) with person-to-person spread in the community and an outbreak in one country lasting for more than two weeks. Progression from a new virus alert to a pandemic alert will be accompanied by response activities that include intensified U.S. and global surveillance; investigation of the virology and epidemiology of the novel influenza strain including collaboration with international partners on containment; vaccine development and clinical testing leading toward licensure of a pandemic vaccine; coordination with health departments and activation of local plans, and implementation of the communications plan which includes education of health care providers and the public.

Pandemic Phase 1 occurs with confirmation that the novel influenza virus is causing outbreaks in one country, has spread to others, and disease patterns indicate that serious morbidity and mortality are likely to occur. In Phase 2, outbreaks and epidemics occur in multiple countries with global disease spread. Response activities during these phases depend, in part, on the extent of disease internationally and in the U.S. community-level interventions and travel restrictions may decrease disease spread. Once vaccine becomes available, immunization programs will begin. At this phase, antiviral prophylaxis and therapy targeted to maximize impact, local coordination of hospital and outpatient medical care and triage, and activation of emergency response plans to preserve community services also will occur. Federal agencies and personnel will support response activities, monitor vaccine effectiveness and adverse events following vaccination and antiviral drug use, conduct surveillance to track disease burden, and disseminate information.

Widespread pandemic disease, as with annual influenza outbreaks, is likely to be seasonal. Thus, Phase 3 signals the end of the first pandemic wave and may be followed by a second seasonal wave in Phase 4. A pandemic will end, Phase 5, as population immunity to the pandemic strain becomes high due to disease or vaccination, the virus changes, and/or another influenza strain becomes predominant. Phase 3 activities include recovery, assessment and refinement of response strategies, ongoing vaccine production and vaccination and restocking supplies such as antiviral drugs. Greater vaccine availability, experience with and improved strategies for a pandemic response, and increased immunity to the pandemic strain should decrease the impact of the second pandemic wave.

Synopsis

Purposes of the Pandemic Influenza Preparedness and Response Plan

  • To define and recommend preparedness activities that should be undertaken before a pandemic that will enhance the effectiveness of a pandemic response.
  • To describe federal coordination of a pandemic response and collaboration with state and local levels including definition of roles, responsibilities, and actions.
  • To describe interventions that should be implemented as components of an effective influenza pandemic response.
  • To guide health departments and the health care system in the development of state and local pandemic influenza preparedness and response plans.
  • To provide technical information on which recommendations for preparedness and response are based.

Components of the Pandemic Influenza Preparedness and Response Plan

  • The plan includes this core section and twelve annexes.
  • The core plan describes coordination and decision making at the national level; provides an overview of key issues for preparedness and response; and outlines action steps to be taken at the national, state, and local levels before and during a pandemic.
  • Annexes 1 and 2 provide information to health departments and private sector organizations to assist them in developing state and local pandemic influenza preparedness and response plans.
  • Annexes 3–12 contain technical information about specific preparedness and response components. They include a description of influenza disease and pandemics; surveillance; vaccine development and production; vaccine use strategies; antiviral medication use strategies; strategies to decrease transmission of influenza; communications; research; observations and lessons learned from the 1976 swine influenza program; and comparisons between planning for an influenza pandemic and Severe Acute Respiratory Syndrome (SARS) outbreaks.

Pandemic Plan Development Process

  • The first national pandemic influenza plan was developed in 1978, shortly after the swine influenza cases and vaccination campaign in 1976.
  • In 1993, a U.S. Working Group on Influenza Pandemic Preparedness and Emergency Response was formed to draft an updated national plan. This group included representatives from the HHS agencies (CDC, FDA, NIH, HRSA and others) and coordinated by the National Vaccine Program Office (NVPO).
  • Comments and input on specific issues included in the plan has been obtained from a wide range of groups in the public and private sectors; and from other pandemic influenza preparedness plans (see weblinks) or planning guides (such as the Association of State and Territorial Health Officials [ASTHO]).
  • Recent developments that have influenced the influenza pandemic planning process include experience gained through planning for bioterrorist events and other health emergencies such as the international response to SARS and the national responses to anthrax cases and the implementation of a the US smallpox vaccination program.
  • Ongoing enhancements in public health and communications infrastructure and development of new technologies, for example in vaccine development and production, are likely to influence portions of the plan. Therefore, it is envisioned that the Plan will be an evergreen document, which will be modified as new developments warrant. Supporting materials (such as educational materials, fact sheets, question and answer documents, etc.) will be added to the Plan or modified as needed.

Goals of a Pandemic Response

  • Limit morbidity and mortality of influenza and its complications during a pandemic.
  • Decrease social disruption and economic loss.

Key Pandemic Preparedness and Response Principles

  • Detect novel influenza strains through clinical and virologic surveillance of human and animal influenza disease.
    • Global surveillance networks identify circulating influenza strains informing recommendations for annual influenza vaccines in the U.S. and around the world.
    • Surveillance also has identified novel strains that have caused outbreaks among domestic animals and persons in several countries.
    • Given the speed with which infection may spread globally via international travel, effective international surveillance to identify persons who have influenza illness coupled with laboratory testing to determine the infecting strain is a critical early warning system for potential pandemics.
    • Effective U.S. surveillance systems also are fundamental in the detection of influenza disease and the causative strains, and to monitor the burden of morbidity and mortality.
  • Rapidly develop, evaluate, and license vaccines against the pandemic strain and produce them in sufficient quantity to protect the population.
    • The production timeline of the annual influenza vaccine. The time from identification of a new influenza strain to production, licensure, and distribution- is approximately six to eight months. In contrast to the protracted timelines in the development, licensure and use of other vaccines, the accelerated timeline for the annual influenza vaccine reflects active collaboration and coordination of the World Health Organization, HHS agencies and influenza vaccine manufacturers.
    • Use of new molecular techniques to develop high-yield vaccine reference strains (the “seed” viruses that will be prepared by public sector labs and provided to vaccine manufacturers) and production of monovalent vaccine containing only the pandemic strain could shorten the timeline to initial availability of a pandemic vaccine.
    • Currently, three manufacturers produce influenza vaccine that is licensed for the U.S. market, two with all or part of the production process located in the United States. The amount of pandemic influenza vaccine produced depends on the physical capacity of the manufacturing facilities, the growth characteristics of the pandemic virus in embryonated chicken eggs used for vaccine production, and the amount of influenza virus protein that is included in each dose to achieve optimal protection. The number of available doses also is limited by manufacturing capacity for filling and labeling vials or syringes. In 2004, HHS worked with industry to assure year-round supply of eggs for vaccine production. In addition HHS is supporting the expansion of production capacity and diversification of influenza manufacturing technology, particularly the development of influenza vaccines made in cell culture.
  • Implement a vaccination program that rapidly administers vaccine to priority groups and monitors vaccine effectiveness and safety.
    • In contrast to the childhood immunization program, the distribution and administration of influenza vaccine during the annual seasonal epidemic occurs largely through the private sector.
    • In a pandemic, vaccine supply levels will change over time.
      1. When a pandemic first strikes vaccine will likely not be ready for distribution. Because of this, antiviral drug therapy and preventive use in those not infected (prophylaxis), quality medical care, and interventions to decrease exposure and/or transmission of infection will be important approaches to decrease the disease burden and potentially the spread of the pandemic until vaccine becomes available.
      2. Vaccine will require six to eight months to produce. Once the first lots of vaccine are available, there is likely to be much greater demand than supply. Vaccine will need to be first be targeted to priority groups that will be defined on the basis of several factors. These may include the risk of occupational infections/transmission (e.g., health care workers); the responsibilities of certain occupations in providing essential public health safety services; impact of the circulating pandemic virus on various age groups; and heightened risks for persons with specific conditions. Although the priority groups for annual influenza vaccination will provide some guidance for vaccine priority-setting for a pandemic, the risk profile for a pandemic strain and the priorities for vaccination may differ substantially and therefore will need to be guided by the epidemiologic pattern of the pandemic as it unfolds.
      3. Later in the pandemic, vaccine supply will approximate demand, and vaccination of the full at-risk population can occur.
    • Given the time required for vaccine development and vaccine production capacity, shortages may exist throughout the first pandemic wave.
    • In recent years when influenza vaccine was delayed or in short supply for annual influenza epidemics, many persons were vaccinated who were not in recommended priority groups, vaccine distribution was inequitable, and a gray market developed in response to increased demand, with high prices being paid for some vaccine doses. During a pandemic, increased demand for vaccine could exacerbate these problems.
    • Several options exist for purchase and distribution of influenza vaccine during a pandemic. The Federal government could purchase all available pandemic influenza vaccine with pro rata distribution to state and local health departments; there could be a mixed system of Federal and private sector purchase; or the current, primarily private system could be utilized. It should be noted that the Federal government already finances a substantial portion of influenza vaccine, including that purchased for eligible children under the Vaccines for Children (VFC) program and reimbursement for doses administered to persons 65 years old or older under the Medicare Modernization Act. In a mixed system with public and private vaccine supply, the proportion in each sector may change as target groups and available vaccine supply change during the course of a pandemic response. The range of options is currently being considered by HHS.
  • Determine the susceptibility of the pandemic strain to existing influenza antiviral drugs and target use of available supplies; avoid inappropriate use to limit the development of antiviral resistance and ensure that this limited resource is used effectively.
    • The objective of antiviral prophylaxis is to prevent influenza illness. Prophylaxis would need to continue throughout the period of exposure in a community. The objective of treatment is to decrease the consequences of infection. For optimal impact, treatment needs to be started as soon as possible and within 48 hours of the onset of illness.
    • Two classes of drugs are used to prevent and treat influenza infections.
      • Adamantines (amantadine and rimantadine) are effective as prophylaxis and have been shown to decrease the duration of illness when used for treatment of susceptible viruses. However, resistance often develops during therapy. The adamantines are available from proprietary and generic manufacturers.
      • Neuraminidase inhibitors (NI; oseltamivir and zanamivir) also are effective for prophylaxis and treatment of susceptible strains. New data suggests that NI treatment can decrease complications such as pneumonia and bronchitis, and decrease hospitalizations. The development of antiviral resistance, to date, has been uncommon. The NIs are produced by European manufacturers. The U.S. supply of NIs is limited as demand for these drugs during annual influenza outbreaks is low. Zanamivir supply is limited in the United States.
    • The available supply of influenza antiviral medications is limited and production cannot be rapidly expanded: there are few manufacturers and these drugs have a long production process. In 2003, oseltamivir was added to the SNS. Analysis is ongoing to define optimal antiviral use strategies, potential health impacts, and cost-effectiveness of antiviral drugs in the setting of a pandemic. Results of these analyses will contribute to decisions regarding the appropriate antiviral drugs to maintain in the SNS. Planning by public and private health care organizations is needed to assure effective use of available drugs, whether from a national stockpile, state stockpiles or the private sector.
    • Developing guidelines and educating physicians, nurses, and other health care workers before and during the pandemic will be important to promote effective use of these agents in the private sector.
  • Implement measures to decrease the spread of disease internationally and within the United States guided by the epidemiology of the pandemic.
    • Infection control in hospitals and long-term care facilities prevents the spread of infection among high-risk populations and health care workers.
    • Because influenza strains that cause annual outbreaks are effectively transmitted between people and can be transmitted by people who are infected but appear well, efforts to prevent their introduction into the United States or decrease transmission in the community have limited effectiveness.
    • If a novel influenza strain that is not as efficiently spread between people causes outbreaks in other countries or the United States, measures such as screening travelers from affected areas, limiting public gatherings, closing schools, and/or quarantine of exposed persons could slow the spread of disease. Decisions regarding use of these measures will need to be based on their effectiveness and the epidemiology of the pandemic.
  • Assist state and local governments and the health care system with preparedness planning in order to provide optimal medical care and maintain essential community services.
    • An influenza pandemic will place a substantial burden on inpatient and outpatient health care services. Because of the increased risk of exposure to pandemic virus in health care settings, illness and absenteeism among health care workers in the context of increased demand will further strain the ability to provide quality care.
    • In addition to a limited number of hospital beds and staff shortages, equipment and supplies may be in short supply. The disruptions in the health care system that result from a pandemic may also have an impact on blood donation and supply.
    • Planning by local health departments and the health care system is important to address potential shortages. Strategies to increase hospital bed availability include deferring elective procedures, more stringent triage for admission, and earlier discharge with follow-up by home health care personnel. Local coordination can help direct patients to hospitals with available beds and distribute resources to sites where they are needed.
    • Health care facilities may need to be established in nontraditional sites to help address temporary surge needs. Specific challenges in these settings such as infection control must be addressed.
    • Not all ill persons will require hospital care but many may need other support services. These include home health care, delivery of prescription drugs, and meals. Local planning is needed to address the delivery of these and essential community functions such as police, fire, and utility service.
  • Communicate effectively with the public, health care providers, community leaders, and the media.
    • Informing health care providers and the public about influenza disease and the course of the pandemic, the ability to treat mild illness at home, the availability of vaccine, and priority groups for earlier vaccination will be important to ensure appropriate use of medical resources and avoid possible panic or overwhelming of vaccine delivery sites. Effective communication with community leaders and the media also is important to maintain public awareness, avoid social disruption, and provide information on evolving pandemic response activities.

Coordination of a Pandemic Response

An influenza pandemic will represent a national health emergency requiring coordination of response activities. As outlined in Homeland Security Presidential Directive 5 (http://www.fema.gov/pdf/reg-ii/hspd_5.pdf), the Department of Homeland Security (DHS) has primary responsibility for coordinating domestic incident management and will coordinate all nonmedical support and response actions across all federal departments and agencies. HHS will coordinate the overall public health and medical emergency response efforts across all federal departments and agencies. Authorities exist under the Public Health Service Act for the HHS Secretary to declare a public health emergency and to coordinate response functions. In addition, the President can declare an emergency activating the Federal Response Plan, in accordance with the Stafford Act, under which HHS has lead authority for Emergency Support Function #8 (ESF8)

  • HHS response activities will be coordinated in the Office of the Assistant Secretary for Public Health Emergency Preparedness in collaboration with the Office of the Assistant Secretary for Public Health and Science and will be directed through the Secretary's Command Center. The Command Center will maintain communication with HHS agency emergency operations centers and with other Departments.
  • HHS agencies will coordinate activities in their areas of expertise. Chartered advisory committees will provide recommendations and advice. Expert reviews and guidance also may be obtained from committees established by the National Academy of Sciences, Institute of Medicine or in other forms.

Preparedness Activities

  • During the inter-pandemic period many activities can be pursued to assure that the government is as prepared as possible for a pandemic. These include:
    • Expand manufacturing capacity for influenza vaccine, develop surge capacity for a pandemic vaccine production, and assess potential approaches to optimize vaccine dose, and diversify manufacturing.
    • Strengthen global surveillance—human and veterinary—leading to earlier detection of novel influenza strains that infect humans, cause severe disease and are capable of person-to-person transmission such that they have a high probability of international spread and assess the susceptibility of the pandemic virus to antiviral drugs. Enhanced surveillance infrastructure also will strengthen detection of other respiratory pathogens—as occurred with SARS. In addition to coordination between HHS and USDA, building and strengthening a global veterinary surveillance network will complement the existing clinical laboratory network organized by WHO.
    • Strengthen U.S. surveillance by expanding to year-round surveillance for influenza disease and the viral strains that cause it. Develop hospital-based surveillance for severe respiratory illness (e.g., influenza and other infectious agents) and identify methods to rapidly expand the current sentinel physician surveillance system during an influenza pandemic or other health emergency.
    • Conduct research to better understand the pathogenic and transmission potential of novel influenza viruses in order to improve predictions about the strains that could trigger an outbreak that could lead to a pandemic.
    • To shorten the timeline to vaccine availability in a pandemic, develop collections (libraries) of novel influenza strains that may cause a pandemic; prepare reagents to diagnose infection and evaluate candidate vaccines; and develop high-growth reference strains that can be used for vaccine production.
    • For selected novel influenza strains, develop investigational vaccine lots and perform clinical studies to evaluate immunogenicity, safety, and whether one or two doses are needed for protection. In the determination of the optimal vaccine dose, studies should also be performed to assess whether adding an adjuvant—a substance to enhance the immune response to vaccination—or alternative vaccine administration approaches will lead to improved protection and/or the ability to protect more people with the available amount of vaccine virus and effectively expand the vaccine supply.
    • Conduct research to develop new influenza vaccines that are highly efficacious, are easier to administer, or that are directed against a constant portion of the influenza virus and thus side-stepping the need to develop a new vaccine every year to match the predominant viral strains that are most likely to cause disease. With this approach it may be possible to create an influenza vaccine stockpile in the future.
    • Continue efforts to expand annual influenza vaccine use and provide appropriate incentives to strengthen the vaccine delivery system, increase vaccine use and acceptance by the public, and to manufacturers to increase overall capacity.
    • Improve capacity to monitor influenza vaccine effectiveness and to track vaccine distribution and coverage.
    • Periodically assess the appropriateness of the types and quantities of antiviral drugs included in the SNS.
    • Promote planning and provide guidance to groups that will have the lead role in a pandemic response such as state and local health departments, the public and private health care organizations, and emergency response groups; and review, test and revise the plans, as needed.
    • Evaluate the potential impacts of interventions to decrease transmission of infection such as travel advisories, school closings, limiting public gatherings, and quarantine and isolation.
    • Develop materials for various audiences that will inform and educate them about influenza and pandemic influenza.

CONSIDERATIONS FOR PANDEMIC INFLUENZA PLANNING: A STATE PERSPECTIVE

Kathleen F. Gensheimer, MD, MPH

Maine Department of Health and Human Services

Need for a National Plan

Planning for pandemic influenza is a critical process that needs to take place at the local, state, and national levels. Planning at any of these government levels is interdependent on the process taking place at any of these levels, and cannot be viewed as an isolated or independent process. State and local planning is especially dependent on decisions, guidance, and priorities established by the federal government. Not only do state and local government agencies lack the specific expertise in pandemic influenza that could best guide the planning process, but independent and potentially disparate decisions made at the state and local levels will ultimately result in public confusion and mistrust. For example, if one state established a response to issues posed by a pandemic that differed dramatically from a neighboring state, such as totally dissimilar priority groups for influenza vaccine, chaos would ensue. Therefore, the national plan needs to address many of the decision-making aspects unique to pandemic influenza in order to avoid such confusion, versus leaving “100 flowers to bloom” at the state and local levels. Furthermore, given the influenza clock whereby we truly do not “know what time it is,” it is critical to have the national plan completed, approved, and distributed as soon as possible, allowing states to be better informed as they move forward with their own planning process.

Public Health Preparedness: A Never-Ending Process

Public health preparedness for an act of bioterrorism has only begun to raise the importance of pandemic influenza planning. It is critical to emphasize the “dual use” concept and to avoid a categorical “stovepipe” approach that has been so characteristic of federally funded projects in the past. An integrated planning approach is not only more efficient and effective, but can allow lessons learned from previous crises—whether they are of a natural, environmental, or infectious disease etiology—to be incorporated into revising what should be a dynamic and continuous process.

Lack of Human Resources

Planning requires professional human resources to adequately initiate and complete the process. Qualified and experienced public health professionals represent a limited resource. This core group is becoming increasingly burned out responding around the clock to one perceived crisis after the next, whether it is smallpox, SARS, monkeypox, or West Nile virus. Thus the planning process needs to be efficient to conserve these limited human resources. However, such limitations also argue in favor of the dual use concept and of finalizing and distributing a national plan, enabling states to have access to a rich resource afforded by a carefully written and fully documented national plan.

Public Health Powers

Public health authorities may need to revert to nontraditional means of disease control in the event of a pandemic. Although public health holds broad powers, such authority has not been tested within the United States in the twenty-first century. SARS introduced the concept of quarantine into everyday vocabulary in the spring of 2003. Although the public may not question the legality of such broad public health powers, the societal acceptance of such authority may be questioned. Even though the Toronto experience suggested that the Canadians were compliant with quarantine, and that future public health measures may be informed by the Toronto experience, serious doubt remains that the rural Mainer is going to passively sit home in a state of quarantine when an imminent plague is present. Northern New England Yankees have demonstrated a fierce independence when confronted with various crises in the past, and tout “Live Free or Die” on their license plates.

Risk Communication

Clearly a risk communication nightmare will be on our hands if discussions regarding specific controversial aspects of the pandemic plan are not communicated to the public prior to the crisis. Such discussions need to address controversial public health control measures, such as imposition of quarantine, as well as decisions regarding priority groups targeted to receive limited amounts of vaccines or antivirals. Preferably, the general public will be a player in the decision-making and planning process, thus enhancing the public's acceptance of such deliberations as a workable public health tool. By addressing the public's concerns now, in the prepandemic planning stages, the ultimate outcome will be a more realistic approach to dealing effectively with the crisis at hand and to soliciting the cooperation of the public in accepting protective courses of action. In addition, public health needs to advocate for research into the effectiveness of nonmedical interventions, such as masks and banning of mass gatherings, creating a sound scientific base that can lend further support to such recommendations.

Sustainability of Preparedness Funding

In recent years, local and state public health agencies have received substantial funding resources for bioterrorism/catastrophic planning. Such funding has been critical in addressing the languishing infrastructure that has characterized public health in this country for too long. Considerable strides have been made, including engaging most states in pandemic influenza planning. Such funding support needs to be sustained into the future to reap the benefits of recent efforts, recognizing that the payoff is enhanced capacity to monitor, respond, investigate, and ultimately, prevent the next public health crisis. Reducing funding support at this point will only repeat the age-old truism in public health, which sadly has been to eliminate the program before the disease is eliminated. In this instance, it would be a disaster to reduce funding support for planning efforts prior to the inescapable fact that there will be another pandemic. Investing in public health is an investment in securing the public's health and well-being.

Narrowing the Gap Between Public Health and the Health Care/Hospital Community

The age-old gap between funding support for public health, which targets control and prevention, and the traditional health care community, which emphasizes diagnosis and treatment, could potentially be narrowed if the two components work together to address the core need to promote influenza vaccination of health care workers. By promoting health care worker acceptance of influenza vaccine, we would also protect the patients those health care workers serve, representing a boost for this cost-effective prevention strategy. Furthermore, improving on the current 34 percent acceptance rate of influenza vaccine among health care workers will also boost demand for the vaccine during the interpandemic years, which will result in an increased number of doses of influenza vaccine produced by manufacturers annually. Enhanced demand and production will ultimately represent a key component to pandemic influenza preparedness.

Integrated, Coordinated Surveillance Systems Monitoring the Impact of the Population Affected

Influenza-like illness (ILI) is a hallmark of not only influenza, but of other viral syndromes and other potential bioterrorist events. For this reason, ILI should be at the top of the list of syndromes that receive priority for surveillance purposes. Such surveillance systems need to be expanded from seasonal to year round. As evidenced from this past influenza season, during an influenza outbreak the media and the public demand accurate, timely, and local surveillance data to respond to the questions that will be posed to public health authorities: Who is affected? When is the peak of the outbreak and over what time period do we expect to see disease reports? Where is influenza activity currently most active? Not only are such questions posed during the interpandemic years, but accurate responses to such inquiries will be critical during a pandemic.

Uniform criteria for influenza surveillance need to be strengthened across the nation to encompass not only outpatient visits as ascertained through the current sentinel physician surveillance system, but to expand to a surveillance system that can encompass significant morbidity such as patients hospitalized with pneumonia or other ILI complications. Strategies to obtain prompt and timely reporting of pneumonia and influenza deaths need to be extended beyond the current 122-city death reporting system to address surveillance gaps in those states not represented in this system. Finally, as was demonstrated in 1999 with the arrival of West Nile virus in the Western Hemisphere, surveillance for emerging and remerging infectious diseases needs to involve our wildlife and veterinarian partners. The current H5N1 scenario in southeast Asia is one more example of where animal and human health surveillance data need to be exchanged on a regular and ongoing basis if we are to effectively monitor for pandemic influenza and other zoonoses.

Don't Repeat Swine Flu

The response to disease crises from yesterday should assist us in planning for the crises of tomorrow. We need to take seriously lessons learned from recent events such as SARS and smallpox vaccine initiatives and to incorporate those lessons in our pandemic planning efforts. We need to be proactive in our planning, not reactive; establish priorities for scarce resources; and invest in a wide range of activities that will enhance our collective response. We can't just “turn on the faucet” when the next crisis hits, but utilize limited resources strategically, allowing an effective collective response.

Invest in the Future

The influenza virus obeys or recognizes no rules. Ultimately, we need a collective change in mindset regarding influenza—in that it is not an entity that we just “have to tolerate” every winter, but rather a serious vaccine-preventable disease that results in 38,000 deaths annually in the United States. A recent call from a Maine nursing home nursing supervisor sums up the current mentality regarding influenza. She called to report an outbreak of influenza-like illness in a 60-bed nursing home. The supervisor realized she was obligated by law to report such outbreaks and provided the off-handed comment that 12 residents had died of ILI complications within the past several days. However, she was quick to note the deceased were all elderly and “would have died anyway.” Why is it that the public and medical communities have chosen to ignore what could be a preventable disease entity?

Conclusion

In summary, the challenges are many, but the issues are real. We cannot afford to lose the momentum afforded by public interest in influenza as generated during the 2003–04 season, to squander the financial resources currently dedicated to bioterrorism/catastrophic public health planning, or to turn our backs on a significant vaccine-preventable disease. Instead, we need to collaboratively accept the challenges posed by the virus that follows no rules, and to embark on a coordinated planning effort at the national, state, and local levels.

PREPARING FOR PANDEMIC INFLUENZA: THE NEED FOR ENHANCED SURVEILLANCE

Kathleen F. Gensheimer,3 Keiji Fukuda,4 Lynette Brammer,3 Nancy Cox,4 Peter A. Patriarca,3 Raymond A. Strikes3

Reprinted from Vaccine, vol. 20, Gensheimer et al., Preparing for pandemic influenza: The need for enhanced surveillance, pp. 63–65, Copyright 2002, with permission from Elsevier

Abstract

In the United States, planning for the next influenza pandemic is occurring in parallel at the national, state and local levels. Certain issues, such as conducting surveillance and purchasing pandemic vaccine, require coordination at the national level. However, most prevention and control actions will be implemented at the state and local levels, which vary widely in terms of population demographics, culture (e.g., rural versus urban) and available resources. In 1995, a survey by the Council of State and Territorial Epidemiologists (CSTE) found that only 29 (59%) states perceived a need to develop a specific influenza pandemic plan for their jurisdiction. Since then, the process of developing slate and local plans has gained considerable momentum. Integration of these efforts with the national planning process has been facilitated by: (1) the mutual involvement of state and federal staff in both processes; (2) the sharing of draft documents; (3) the ongoing occurrence of local and national coordinating meetings; (4) the provision of financial resources by the federal government. So far, approximately 12 states either have drafted or begun drafting a state and local influenza pandemic plan. One of the benefits of the collaborative planning process has been the development of new working relationships and partnerships among several agencies at the state, local and national levels. Such efforts will improve our collective ability to rapidly investigate and control other emerging or re-emerging public health threats in the twenty-first century, be it a bioterrorist event, pandemic influenza, or any other catastrophic health event.

Introduction

In the United States, public health services, including surveillance, are provided most directly by municipal, county and state health departments, or a combination of all three. The scope and extent of these services depend upon the resources and interests of each particular state. However, all states recognize the importance of sharing their surveillance data. This is accomplished through the close working relationship established between the states and the national centers for disease control and prevention.

Although a surveillance system for influenza has historically been in place in the United States, the system is in jeopardy due to the misperception that influenza is not an important public health problem and the continued erosion of resources supporting the public health infrastructure at the state and local levels over the years. Critical health department services, including disease and virologic surveillance activities, have been dismantled in many states. As a result, a piecemeal type of surveillance for influenza exists within the United States with 50 states each having their own surveillance system, some being extensive, and others practically non-existent.

National Influenza Pandemic Preparedness

In 1993, the National Working Group on influenza pandemic preparedness and emergency response (GrIPPE), began to develop an updated, comprehensive blueprint for an action influenza pandemic plan for the United States. The GrIPPE identified influenza surveillance as a key component of the pandemic plan. This national group includes experts from the public and private sectors, including. those listed as contributors to this paper because of their support for influenza surveillance at the state and local levels. The group has also recognized that to effectively address the threat of an influenza pandemic, measures to reduce the impact of influenza must be in place and operational at the state and local levels now, during the pre-pandemic period. Because more influenza-related illness and death occur in the aggregate during regularly recurring influenza epidemics than during the pandemics themselves, the GrIPPE has attempted to link its plan to other relevant public health initiatives such as those related to emerging infections and adult immunization.

Process

In 1994, the Council of State and Territorial Epidemiologists (CSTE) was formally asked by the GrIPPE to participate in the national pandemic influenza planning process. The CSTE is a professional association of 400 epidemiologists in the United States and territories working together to detect, prevent and control conditions of public health significance through actively promoting disease surveillance activities. As part of this effort, the CSTE conducted a survey of state epidemiologists in 1995 to assess influenza surveillance systems currently in place. All 50 states and the DC responded to the survey.

All 51 respondents reported at least one source of influenza surveillance information, and 39 (77%) identified sentinel physicians as the primary source of disease reports. However, in 1995, the sentinel physicians were not a definable entity as they are now. Forty-eight (94%) states had the capacity, either through some private or public health laboratory, to identify influenza viruses isolated in tissue culture. Of 47 laboratories that indicated to what degree they could characterize influenza viruses, 37 (79%) could subtype the viruses, while 10 (21%) could identify viruses only as influenza A or B. Another 1995 survey by the Association of State and Public Health Laboratory Directors (ASTHPHL) of its membership was more specific in defining influenza virologic resources available at each state's public health laboratory, with 10 (20%) states indicating no state public health laboratory capacity to isolate viruses and 13 (25%) state public laboratories reporting no ability to subtype influenza isolates.

In the CSTE survey, 34 (67%) states responded that their laboratory surveillance system would be adequate to detect a new pandemic virus, with 29 (57 percent) states indicating that their disease surveillance system would be adequate. Among the reasons given for the difficulty in detecting a new pandemic strain: 20 (83%) respondents indicated inadequate financial resources; 19 (79%) reported inadequate personnel; and 10 (42%) responded that influenza was not considered a high priority.

However, if targeted resources were made available, 44 (86%) respondents indicated that they would increase laboratory surveillance for influenza, and 39 (76%) indicated they would increase disease surveillance activities. The estimates provided for surveillance activities were modest ranging from US$ 2000-100,000 (mean of US$ 37,602) for laboratory surveillance and US$ 2000-100,000 (mean US$ 40,914) for disease surveillance.

In summary, the 1995 CSTE survey found that many states lacked surveillance activities dedicated to influenza, but that many states would expand virologic and disease-based surveillance systems if nominal resources were made available.

Pandemic Planning at State and Local Levels

Several efforts have been undertaken at the national level to respond to states needs and to promote enhanced preparedness for pandemic influenza. A “Pandemic Influenza Planning Guide for State and Local Health” officials was developed as a result of these efforts.

The surveillance component of the planning guide calls for enhancements in virologic and disease-based surveillance, and improvements in surveillance information systems. The planning guide makes the following recommendations during the pre-pandemic period:

  • Virologic surveillance capability must be improved by ensuring that at least one laboratory in each state and/or major metropolitan area has the capacity of to isolate and subtype influenza viruses.
  • Disease-based surveillance capacity must also be improved by defining the existing sentinel physician network, with the aim of establishing a population based system of approximately one sentinel physician per 250,000 population.
  • Contingency plans for enhancing state and local virologic and disease-based surveillance systems in the event of a novel virus or pandemic alert must be developed.
  • Electronic and telecommunications capability with neighboring jurisdictions and with CDC needs to be enhanced

One component of the existing influenza surveillance system is weekly reports to CDC's national notifiable disease system from each state epidemiologist designating the level of influenza activity during the preceding week. Levels of estimated activity were reported as widespread, regional, sporadic, or non-existent. The validity of these estimates has long been questioned, since they may primarily reflect local interest or availability of resources. The means of collecting the information does not appear to be consistent across geographic regions. As a result, it is difficult to determine the extent of influenza-related morbidity on a regional or national level on the basis of reports from state epidemiologists.

Many states lack the financial resources to conduct influenza virologic surveillance. State public health laboratories are under attack by state legislatures and many are being dismantled or privatized, which has led to the loss of core public health activities. State public health laboratories need consistent financial support to culture and characterize isolates on a timely basis. However, one concern is that specimen submissions will diminish as health maintenance organizations implement cost-cutting measures. In addition, submissions of specimens for virus isolation are expected to decrease as rapid antigen test kits are improved and become more widely available. Having fewer isolates available for characterization is a potential public health problem.

The demands of pandemic planning have prompted CDC and CSTE to begin to change influenza surveillance. Disease and laboratory-based surveillance are being reinforced as a result of these pandemic planning efforts and other databases are explored as potential sources of additional qualitative or quantitative data. Efforts are under way to:

  • upgrade the sentinel physician network by enlisting and retraining more participants;
  • use uniform definitions and outcomes, integrating influenza reporting with other state-based systems;
  • standardize reporting procedures by adopting uniform methods of data transmission;
  • develop a semi-automated data management system to provide rapid feedback.

One benefit of such efforts may be to increase the public's, medical providers' and public health practitioners' understanding of influenza as a potentially preventable disease.

Conclusion

National efforts to prepare for the next influenza pandemic require the support and interaction from partners at the state, local and federal levels. A solid influenza surveillance system in place at the state and local levels will assist in proactively planning for the regularly recurring epidemics as well as for the inevitable pandemic. We will need initiatives such as the national pandemic planning effort to direct financial resources dedicated to influenza surveillance activities. I too would like to commend Dr. Alan Kendal for his comments yesterday urging that we share our limited resources with the developing countries around the world throughout the pandemic planning process and into the pandemic itself. I would also like to congratulate the organizers of this conference for bringing together the world community to discuss surveillance, so that we may all benefit from the lessons learned in recent.

PREPAREDNESS OPPORTUNITIES AND OBSTACLES

Philip H. Hosbach

Aventis Pasteur

Pandemic Planning: Vaccine Development and Production Issues

Aventis Pasteur is one of the world's leading vaccine manufacturers. Today, the company accounts for approximately 40 percent of the world's influenza vaccine supply. It manufactures influenza vaccine in the France and the United States, and has the only U.S. manufacturing site for inactivated influenza vaccine. In the 2003–2004 season, Aventis Pasteur shipped more than 43 million influenza doses in the United States. This year we intend to ship between 48 and 50 million doses.

In addition to its vaccines to protect against influenza and a host of other diseases, including meningitis, pertussis, tetanus, and polio, the company has entered into agreements with the National Institute of Allergy and Infectious Diseases (NIAID) to conduct research and development on an inactivated SARS vaccine and an avian influenza vaccine.

Experts believe that an influenza pandemic originating from natural origins will inevitably occur (Patriarca and Cox, 1997) and will likely cause substantial illness, death, social disruption, and widespread panic. In the United States alone, the next pandemic could cause an estimated 89,000 to 207,000 deaths, 314,000 to 734,000 hospitalizations, 18 to 42 million outpatient visits, and 20 to 47 million additional illnesses (Meltzer et al., 1999).

Among the necessary preparations for any catastrophic infectious disease event, such as pandemic influenza, planning appropriately for the supply and delivery of vaccines is essential. The expertise of vaccine manufacturers, particularly those with a track record of influenza vaccine production and distribution, should be utilized at the earliest stage of planning and vaccine development. Manufacturers have access to vaccine production information regarding the timeframes needed to implement specific policy changes. They are also in direct contact with health care providers and are in a strong position to understand how policies will be accepted (or not accepted) and applied (or not)—particularly in the private sector. Also critical is their unequaled experience and resources in the efficient distribution of large amounts of vaccine to numerous distribution and provider locations in short periods of time. Manufacturers' knowledge and experience with the complex processes, logistics, and all the associated moving parts make industry an essential partner in pandemic planning and policy formulation.

Possibly the most practical and cost-effective strategy for ensuring pandemic readiness involves maximizing immunization rates during interpandemic years in order to build demand and supply. The company believes that the work of the influenza immunization enterprise to increase the availability and use of influenza vaccine over the past 10 years has provided a solid foundation for a pandemic immunization program.

Aventis Pasteur's preparations for an influenza pandemic are well underway. The company has entered into an agreement with NIAID to produce influenza vaccine based on a potential pandemic strain. Previously, the company responded to an NIAID challenge grant to develop a variety of potential pandemic strains to see if they could be produced in egg or cell cultures.

We have started production of two pilot H5N1 lots of 8,000 doses. Also, the company plans to continue to expand its operations and will complete a new formulation and filling plant, which is expected to be online in 2006 or 2007.

In addition, Aventis Pasteur entered into a strategic agreement with Crucell N.V. that gives it an exclusive license to research, develop, manufacture, and market cell-based influenza vaccines based on Crucell's proprietary PER.C6™ cell line technology.

While the industry continues to explore newer methods for producing influenza vaccines, manufacturers must recognize that egg-based production is the only proven and rigorously tested large-scale production method and it will remain so for the near- to mid-term future. Companies must work off this assumption and ensure flock protection and egg reserves. Also, manufacturers should consider the use of alternative methods to enhance the supply and performance of the vaccine, including the consideration of appropriate adjuvants and delivery devices.

As the government and industry work together toward pandemic preparedness, manufacturers have requested that the government issue Requests for Proposals (RFP) that realistically reflect pandemic requirements and that there is clear and effective coordination throughout the U.S. government of various RFPs. Furthermore, the U.S. government must supply the proper liability protection for full industry participation in pandemic influenza planning and preparedness. This is a key lesson we learned from past experiences and it is crucial to avoiding potentially life-threatening delays.

Manufacturing of Influenza Vaccine

The production of influenza vaccine is based on a multitiered process with extensive quality assurance and quality control. A number of internal and external factors affect production, including guidance and requirements from government agencies, how quickly vaccine strains grow, manufacturing capacity, forecasts, and the timing of orders. Therefore, it is essential to have realistic vaccine production timelines.

To prepare for a pandemic, production capacity and capabilities will need to be significantly increased. This is feasible, but supply and demand factors must be considered. When it comes to influenza vaccine, these two elements are inextricably connected.

On the “supply” side are three principal elements. First is the length of time required to produce vaccine. Then there is the need for a system to get those doses to immunization providers as quickly as we can make the vaccine. This is something we do regularly with influenza as we are producing an essentially new vaccine every year. Third, we need manufacturing capacity—including physical facilities, validated equipment and processes, and trained personnel—dedicated to producing this one vaccine in a short period of time.

Three main variables govern the amount of traditional trivalent influenza vaccine that Aventis Pasteur can produce in any season. The first is the timing of the selection of the three strains of the virus. Manufacturers receive word of the strains to be used as soon as the World Health Organization has the information from its worldwide monitoring operation. If the announcement of the third strain runs late—that is, past mid-March—and that third strain proves difficult to grow, it makes for a more challenging production schedule. If any of the strains produces lower yields than expected, there can be delays in getting vaccine to market. During the time period of January through May, industry is consumed with the virus-growing process. We do not actually begin to fill even the first vials with finished vaccine until early summer. Subsequently, each and every lot needs to be tested separately by the FDA before release to health care providers.

When looking at the manufacturing process, the single most important element is capacity. The doses of trivalent vaccine that the company currently produces translate to up to 150 million doses of monovalent vaccine for pandemic use. For an influenza pandemic, it is estimated that as many as 600 million pandemic doses need to be produced, which means that capacity to routinely produce between 150 and 200 million trivalent doses is required annually. Clearly, we must work to increase immunization rates (demand) and bring the nation closer to the immunization goal of 185 million Americans, who the CDC considers at “high risk” for complications associated with influenza. Manufacturers will invest (supply) to meet rising demand, expanding capacity to meet our nation's pandemic needs.

In addition to the need for significantly expanded capacity, the other challenges facing the industry as it prepares for pandemic influenza include the limited advance notice between production waves and the requirement for additional materials (e.g., syringes, vials) to expand industry surge capacity. At the same time, the FDA's Center for Biologics Evaluation and Research (CBER) will need to significantly increase its own capacity in order to test more quickly and expedite the release process. In recognition of the importance of CBER and the challenges it faces in the twenty-first century, Aventis Pasteur continues to call for additional agency funding.

Today, distribution of influenza vaccine rests primarily in the private sector, which has expertise in order processing, storage, distribution, and shipment. In the United States, 85 percent of influenza vaccine is sold, distributed, and administered in the private market. This approach is working well and should serve as the basis in preparing for a pandemic vaccine. Although the system is not perfect, we should build on the existing private–public system rather than trying to replace the system during a pandemic event.

Other planning assumptions include the need for enhanced worldwide surveillance and detection; the ability to relay information quickly to private industry; rapid strain identification and seed preparation; maximization of internal and external industry communications; and government policies regarding exports of vaccine during a pandemic. There must also be flexibility in sending influenza vaccine overseas to stem small, virulent outbreaks. We recognize that the threat from influenza does not have borders and that preventing the spread of the disease may greatly reduce mortality rates in all countries. If more influenza vaccine were manufactured in the United States, we would be in a better position to consider global needs.

Increasing Interpandemic Influenza Vaccine Demand

Increasing interpandemic influenza vaccine demand is essential for improving public health today, enabling predictable and steady vaccine supply, and preparing for pandemic influenza.

In 2003, the late season spike in influenza vaccine demand dramatically reinforced the need to develop a national consensus in the United States about how to predictably increase the annual demand for influenza vaccine immunization. Manufacturers will respond to increased demand by producing as much product as they can sell and will continue to invest to expand current capabilities.

Increased demand will drive increases in the annual vaccine supply. Government health planners have recognized the importance of influenza immunization. As part of the Healthy People 2010 program, they have set ambitious but imminently achievable goals for influenza. The year 2010 is not many influenza seasons away. The focus on influenza immunization demand is essential to achieve Healthy People 2010 goals and to effectively plan for a pandemic event. Although the Healthy People 2010 goal is to immunize 185 million Americans, currently only 75 to 85 million Americans are immunized annually and only 38 percent of health care workers receive influenza vaccination. Increased immunization rates in this group are especially critical.

As a charter member of the National Influenza Summit's private–public partnership and the global leader in influenza vaccine development and production, Aventis Pasteur has recommended a number of steps, described below, to increase influenza immunization. These principles were proposed by the company to the National Vaccine Advisory Committee in Washington, D.C., in February 2004, and reiterated at the Influenza Summit in Atlanta, Ga., in April 2004.

Best practices. Encourage practitioners, managed care organizations, insurers, health care institutions, and community-based immunizers to develop, share, and implement best practices to run seasonal surge adult/ pediatric immunization campaigns. This begins with timely prebooking and may include flexible scheduling of patients, periodic reminders from physicians, and implementation of standing orders to offer immunization to meet patient care quality objectives.

Annual national awareness and educational campaigns. Support public health authorities, the National Influenza Summit, and advocacy organizations and coalitions in managing sustained, annual public awareness/education programs. These programs should convey consistent information about high-risk groups (e.g., health care workers, first responders, and police), articulate key influenza recommendations to the public, and communicate information regarding the timing and length of the influenza immunization season. Programs should also be tailored to “at risk” target groups, including minorities.

Support the U.S. Department of Health and Human Services' agencies in meeting their annual influenza immunization goals as a unified Department, including:

  • National Vaccine Program Office: Gain consensus among public and private partners about national immunization goals, and convene annual reviews of progress toward objectives for supply and demand goals.
  • Centers for Disease Control and Prevention: Support annual widespread practitioner and public education and awareness campaigns and advocacy coalitions. Add routine publication of adult/pediatric influenza immunization rates by risk group and states to help target and measure specific improvements.
  • Centers for Medicare & Medicaid Services: Annually inform all Medicare and Medicaid providers and other parties about influenza recommendations, coverage and reimbursement, and the importance of early prebooking to implement successful seasonal campaigns. Publish adequate and timely reimbursement notices for providers and make available Medicare immunization rate information to public health to measure further improvement.
  • Food and Drug Administration: Support FDA efforts to provide up-to-date technical expertise and oversight in order to ensure vaccine safety, the timely availability of vaccine, and increased public confidence in vaccines.

Extend immunization season. Consider expanding the immunization season into December and possibly beyond.

Emphasize exemplary health care worker immunization efforts. Identify and resolve barriers to health care worker immunization by emphasizing the responsibilities to protect oneself, one's patients, and one's family. Provide workers with information designed to educate patients year round concerning influenza and immunization.

Mobilize insurers/managed care providers. Secure agreement among managed care/insurance companies about the importance of covering influenza immunization and administration; ensure that managed care system, health care professionals, relevant institutions, and all immunizers understand the need to preorder vaccine; remind at-risk patients why immunization is so important; and implement standing orders.

Establish strategic influenza vaccine reserves. Immediately establish shared risk reserves for influenza vaccine to ensure protection for unforeseen outbreaks and/or in the event of a pandemic. Influenza vaccine cannot be stockpiled from year to year, but government negotiations with the private sector of an annual strategic vaccine shared-risk reserve could offer the public and health care providers additional confidence that supply will meet ever-increasing demand.

Looking beyond influenza vaccines, stockpiles for all other routine pediatric vaccines must be in place before a pandemic due to the need for manufacturers to focus their efforts on the manufacture, formulation, and filling of 300 to 600 million monovalent doses for a pandemic. During a pandemic, which can last more than 2 years, Aventis Pasteur would need the flexibility to shift resources and facilities to the production and filling of influenza vaccine, which could postpone or delay the filling and release of the other routinely used vaccines.

A 6-month stockpile should be sufficient to enable manufacturers to make their way through the rescheduling process. In support of stockpiles, government funding has been allocated and the CDC has developed a strategic plan. Still, certain accounting rules of the Securities and Exchange Commission are severely hindering the establishment of stockpiles.

Looking ahead to the 2004–2005 influenza season and beyond, it is imperative for planning to begin as early as possible. Planning early assists all stakeholders and allows manufacturers to more precisely forecast demand. Manufacturers recommend that providers prebook vaccines every year because prebookings drive annual supply and ensure a more stable process. Prebookings for the 2004–2005 influenza season began in December 2003. The estimated capacity in the United States for this upcoming season is 90 to 100 million doses of trivalent vaccine. Production will, as always, depend on strain yields.

In summary, there are a number of key lessons and principles that the industry, government, and medical community must consider for pandemic influenza planning:

  • Demand drives supply; industry can optimize and expand influenza production if demand is stable and predictable
    • Sustainable initiatives are needed to drive demand
  • Manufacturers' expertise should be utilized at the earliest stage of the policy process
    • Companies with a track record of influenza vaccine production should be involved in policy development; pandemic plans conceived without manufacturer involvement run the risk of not being executable
  • RFP deliverables should realistically reflect pandemic requirements and include appropriate liability protection
  • The current private–public distribution system provides a strong foundation on which to build
  • Identify high-risk groups and establish priorities for phased immunization
  • Extend the immunization season
  • Send influenza vaccine overseas to stem small, virulent outbreaks
  • Develop shared-risk reserves for unanticipated demand/outbreaks on an annual basis and establish stockpiles of routinely used vaccines

PANDEMIC INFLUENZA VACCINES: OBSTACLES AND OPPORTUNITIES

David Fedson

Sergy Haut, France

This section highlights opportunities and obstacles presented by two key issues in pandemic preparedness: the development and registration of a “pandemic-like” vaccine, and the use of reverse genetics to prepare seed strains for vaccine development. These issues are introduced with an overview of global vaccine production and distribution and followed by an exploration of the idea that prophylaxis and/or treatment with certain commonly available therapeutic agents such as statins could possibly have beneficial effects on the clinical course of human influenza. If these effects could be confirmed, they could potentially mitigate the morbidity and mortality of pandemic influenza when there are limited supplies of vaccines and antiviral drugs.

Global Distribution of Influenza Vaccine, 2000–2003

According to a recent report by the Influenza Vaccine Supply (IVS) Task Force, 230 million doses of influenza vaccine were distributed worldwide in 2000, of which 162 million (70 percent) were distributed in Canada, the United States, Western Europe, Australasia, and Japan (Table 3-1). In 2003, vaccine distribution increased to 292 million doses, of which 207 million (71 percent) were distributed in the same countries. During this 4-year period, vaccine distribution increased 20 percent in Canada and the United States, 18 percent in Western Europe, 25 percent in Australasia, and 134 percent in Japan. For the rest of the world, vaccine distribution increased from 69 million doses to 85 million doses, a 23 percent increase. For these other countries, the use of influenza vaccine was largely limited to four countries in South America (Argentina, Brazil, Chile, and Uruguay), several countries in Central Europe (especially Hungary and Poland), Russia, and South Korea. When individual countries were compared according to per capita vaccine distribution levels in 2003, the leading countries (doses distributed/1,000 total population) were Canada (344), South Korea (311), the United States (286), and Japan (230) (Macroepidemiology of Influenza Vaccination Study Group, unpublished observations).

TABLE 3-1. Global Distribution of Influenza Vaccine, 2000–2003 .

TABLE 3-1

Global Distribution of Influenza Vaccine, 2000–2003 .

Nearly all of the world's influenza vaccine is produced in nine countries: Australia, Canada, France, Germany, Italy, Japan, Netherlands, United Kingdom, and United States. In 2003, these countries had only 12 percent of the world's population, yet they produced 95 percent of the world's influenza vaccine. Almost none of the doses produced in Canada, Japan, and the United States were exported to other countries. Companies located in five Western European countries produced 190 million doses, 65 percent of the world's supply. Excluding the 13.8 million doses produced in Hungary, Romania, and Russia (all of which were distributed domestically), these companies produced 99.3 percent of the 79 million doses of influenza vaccine used in countries outside Western Europe, Canada, the United States, Australasia, and Japan.

These results demonstrate that in the event of a new pandemic, most countries in the world will be critically dependent on vaccines produced in five Western European countries. Although the United States is unlikely to contribute any supplies of influenza vaccine to other countries, it can and should contribute in other ways to help prepare the global community for the next pandemic.

Pandemic Vaccine Development and Registration

Recent outbreaks of avian influenza in Asia and other parts of the world suggest it is unwise to assume that the next pandemic will delay its appearance for another 5 years. Thus the strategy for pandemic vaccine development should initially focus on what needs to be done to ensure that the largest possible supply of pandemic vaccine can be made available as quickly as possible in order to respond to the needs of populations in all countries. It should be based on the existing global capacity to produce trivalent influenza vaccines in egg-based production systems. Its goal should be to determine the lowest amount of HA antigen that can be included in an adjuvanted vaccine that will be acceptably immunogenic when given in a two-dose schedule to a population.

The low-dose adjuvanted pandemic vaccine development strategy is one that will most likely be pursued by European vaccine companies in collaboration with the European Medicines Evaluation Agency (EMEA). It differs from the strategy that will be undertaken by NIAID in the United States. Both strategies are described in detail below.

Pandemic Vaccine Development and Registration in Europe

European vaccine companies have a unique responsibility to the 25 countries that are now part of the European Union (EU) and to the many non-EU countries that will be entirely dependent on European companies for supplies of pandemic vaccine. For this reason, in September 2002, representatives of the member companies of the IVS Task Force met with staff of WHO and its Collaborating Centers and with a representative of the EMEA. The purpose of the meeting was to review steps needed to develop and register pandemic vaccines in Europe.

In the EU, the annual updating of marketing authorizations for interpandemic influenza vaccines is handled by a “fast track” variation of a decentralized registration procedure (Official Journal of the European Community, 1995; Wood and Lewandowski, 2003). Unlike registration of influenza vaccines in the United States, EU registration requires demonstration of safety and satisfactory serum anti-HA antibody responses for each company's vaccine (CPMP, 1997; Wood and Lewandowski, 2003). The process can take as long as 73 days. Registration of a pandemic vaccine will be handled differently for several reasons. The vaccine will likely not be a variation of a current vaccine, but an entirely new vaccine. The EU centralized procedure will be used, and this will be especially important if the vaccine is produced using a reverse genetics-engineered seed strain and is thus considered a biotechnology product. The pressure of time will be severe. Fortunately, in the event of a pandemic threat, an EU regulation allows national authorities to “exceptionally and temporarily consider the variation to be accepted after a complete application has been lodged and before the end of the procedure …” (Official Journal of the European Community, 2003). This regulation provides the legal basis for the European approach to developing and registering pandemic vaccines.

In September 2002, the EMEA began a process of discussion and collaboration with the Regulatory Working Group of the European Vaccine Manufacturers (EVM) to discuss basic principles for the development and the regulatory strategy for pandemic vaccines. (All European vaccine manufacturers are members of the EVM.) In April 2004, the results of this process were published by the EMEA in the form of two “Notes for Guidance” documents (CPMP, 2004a; CPMP, 2004b), which set forth requirements for demonstrating the quality, safety, and immunogenicity of a “mock-up” (i.e., candidate) pandemic vaccine that will be developed during the interpandemic period.

The core pandemic dossier will document the production process for the “mock-up” vaccine and its final formulation (CPMP, 2004a). With these data, a company can submit its dossier and receive a marketing authorization via the EMEA centralized procedure. When a pandemic threat is declared and a true pandemic vaccine is produced, only quality data related to the pandemic variation need to be submitted. Each pandemic vaccine variation will receive a fast-track assessment (within 3 days) and approval by the Committee for Proprietary Medicinal Products (CPMP) and a final European Community decision within another 24 hours (Official Journal of the European Community, 2003; CPMP, 2004b). Approval will be given with the understanding that companies will gather safety, immunogenicity, and effectiveness data on the pandemic vaccine during clinical use (CPMP, 2004b). Precise details on how this will be done have yet to be worked out.

The EMEA scientific guidance for a “mock-up” vaccine recognizes that clinical data on interpandemic vaccines cannot be extrapolated to a pandemic situation because the pandemic vaccine will be different (CPMP, 2004a). It will be monovalent, have a different antigen content, probably be adjuvanted, contain preservatives, and probably require a different vaccination schedule, especially for immunologically naive subjects. Consequently, companies have been asked to develop prototype pandemic vaccines during the interpandemic period. They must include viral antigens to which humans have had no previous exposure (e.g., H5N1). Companies will be required to conduct clinical trials for safety and to establish the dosage and schedule for their “mock-up” vaccines in order to obtain marketing authorization for their pandemic vaccines.

The EMEA has not published its own clinical development plan for a “mock-up” pandemic vaccine. However, the EVM Clinical Working Group, which represents all major European vaccine companies, has proposed a step-wise clinical development plan of its own. The plan calls for an initial set of safety and immunogenicity studies in healthy adults 18 to 40 years of age. Each study group will include at least 30 immunologically naive subjects. Three hemagglutinin antigen (HA) dosages will probably be tested, each with and without an adjuvant. Two doses will be given 3 weeks apart. The goal of the initial studies will be to determine the formulation that best balances acceptable immunogenicity with an antigen-sparing dosage level that will maximize pandemic vaccine supply. Following initial studies, larger (>300 subjects) safety and immunogenicity studies will be conduced in immunologically naive, healthy younger (18 to 59 years of age) and older (>60) adults. Two doses of the chosen formulation will be given, vaccine safety will be evaluated over 6 months, and a booster dose will be given at 6 (and perhaps also 12) months. Primary immunogenicity will be assessed on day 42, and secondary immunogenicity on day 21 and at 6 ± 12 months. According to the EMEA, immunogenicity will be judged as satisfactory only if all three CPMP criteria (seroconversion, seroprotection, and geometric mean titers (GMT)) are met (Official Journal of the European Community, 1995). These criteria are stricter than those for interpandemic vaccines and may be modified later.

The EMEA procedural guidance sets up several task force groups (CPMP, 2004b). The Joint EMEA-Industry Task Force will meet yearly and have a general advisory role. During the interpandemic period, it will monitor the availability of reference strains and reagents, the status of core dossier authorizations, and manufacturing issues. The EMEA Task Force will provide advice to regulatory authorities, work with companies before they submit their pandemic variation applications, and review safety and effectiveness data obtained during the pandemic. Because of the global implications of European vaccine production, WHO will probably be represented on the EMEA Task Force. The EMEA Evaluation Project Team will evaluate the pandemic variation applications for each product.

Over a period of 18 months, EMEA staff vaccine experts and European vaccine companies put together an integrated “roadmap” that outlines most of the steps for developing and registering a “mock-up” pandemic vaccine. Once a company obtains a marketing authorization for its core dossier, regulatory approval for a true pandemic vaccine can be quickly obtained. Australian regulatory authorities will likely follow the European approach, but it is unclear what will be done in Canada, Japan, Russia, and other vaccine-producing countries.

In spite of having a strategy for developing “mock-up” pandemic vaccines, it is uncertain whether European companies will actually follow through on the strategy. The companies may be reluctant to pay for developing vaccines that will never be marketed (unless the “mock-up” vaccine and pandemic viruses are closely matched). Expectations that the sunk costs of “mock-up” vaccine development will be quickly recovered when a pandemic arrives will be tempered by uncertainty over vaccine prices, liability issues, purchasing guarantees, and political takeover of pandemic vaccination programs. Although all companies are interested in developing “mock-up” vaccines, they know that the early costs will be modest compared with the much larger costs of full-scale clinical development later on. EC officials and vaccine companies have yet to discuss EC funding for the more expensive stages of clinical development. If the emergence of the next pandemic virus is delayed for several years, Europeans may have enough time to solve these difficult problems. However, if the pandemic virus emerges within the next year or two, Europeans, like their colleagues in the United States and elsewhere, will need to make their decision on how to formulate a pandemic vaccine based on existing clinical data. In all likelihood, they will choose a low-dose, alum-adjuvanted vaccine because it appears to be the only vaccine formulation that will meet the population needs of Europeans and those of other countries that will depend on Europe for supplies of pandemic vaccines (Fedson, 2003a,b; Wood, 2001; Hehme et al., 2002; Hehme et al., 2004).

Pandemic Vaccine Clinical Trials in the United States

In May 2004, the U.S. government awarded contracts to Aventis Pasteur and Chiron5 to produce pilot lots of monovalent H5N1 “pandemic-like” vaccines. These vaccines will be formulated at two dosage strengths: 15 µg and 45 µg of HA antigen (standard and high dose, respectively). These two dosages comply with FDA requirements for currently licensed influenza vaccines. The vaccines will be tested in the National Institutes of Health Vaccine Trial and Evaluation Units.

If a pandemic virus emerges within the next year or two, the national governments of vaccine-producing countries will probably not allow their companies to export pandemic vaccine to other countries until their own domestic needs have been met (Fedson, 2003a,b). Any doses left over will likely be exported to countries that have no vaccine-producing capacity. As a result, the United States will be forced to depend on its sole domestic producer for supplies of pandemic vaccine. Moreover, in the event of a pandemic, it will probably be necessary to administer two doses of vaccine to a largely if not entirely immunologically naive population (Fedson, 2003a,b; Wood, 2001). How will the United States be able to adequately meet its needs for pandemic vaccine?

In 2004, domestic vaccine production in the United States will be approximately 50 million doses of trivalent vaccine. Assuming a comparable 6-month production cycle, this will be equivalent to 150 million doses of standard-dose (15 µg HA) monovalent pandemic vaccine and 50 million doses of high-dose (45 µg HA) vaccine. This would be enough to vaccinate (with two doses) 75 million people with a standard-dose pandemic vaccine and only 25 million people with a high-dose vaccine, fewer people than are now being vaccinated each year with the trivalent vaccine. For the United States to be able to offer two doses of standard-dose or high-dose pandemic vaccine to each person (assume 300 million people), domestic production of trivalent vaccine would have to increase to either 200 million or 600 million doses per year. Even with greatly expanded domestic vaccine production, it is clear that the number of doses of pandemic vaccine formulated according to the NIH strategy will fall far short of meeting the needs of the American people. Furthermore, the United States will have no pandemic vaccine to offer people in other countries.

European investigators have shown that two doses of a pandemic vaccine (perhaps whole virus), formulated with a low amount of HA antigen per dose (perhaps as low as 1.875 µg HA) and combined with an alum adjuvant, could realistically offer significant clinical protection to large populations of immunologically naive individuals (Wood, 2001; Hehme et al., 2002; Hehme et al., 2004). For example, if all of the world's vaccine companies were instructed to produce a 1.875 µg HA alum-adjuvanted monovalent subunit pandemic vaccine, they could hypothetically produce (over 6 months) 7.2 billion doses of pandemic vaccine (300 million × 3 × 8). This would be enough to vaccinate 3.6 billion people, more than half the world's population. This amount of vaccine would probably exceed the combined capacities of the world's health care systems to deliver it. For the United States, with its vaccine production capacity limited to 50 million doses of trivalent vaccine, the low-dose strategy would allow the United States to produce enough vaccine to vaccinate 600 million people: 300 million Americans and 300 million people in other countries. Even more important, in the early weeks of the pandemic, this strategy would increase by 8-fold the number of doses available for use each week compared with the standard-dose strategy and by 24-fold the number of doses compared with the high-dose strategy.

The low-dose, adjuvanted pandemic vaccine strategy is central to the thinking of major influenza vaccine companies located outside the United States. The EMEA Vaccine Expert Group considers it the most promising approach for producing adequate supplies of pandemic vaccines. Experts who work with WHO regard it as essential. It figures prominently among the recommendations on priorities for pandemic preparedness recently published by WHO. How low the HA content of an “antigen-sparing” adjuvanted pandemic vaccine can be set is uncertain. This can best be determined in large multinational, publicly funded clinical trials of one or more pandemic-like vaccines produced by all companies that intend to produce true pandemic vaccines (Fedson, 2003a,b). In the United States, however, the strategy for developing an H5N1 vaccine appears to be based on determining a dosage that is optimally immunogenic and safe for an individual rather than one that is acceptably immunogenic for a population. The U.S. strategy also seems to assume that the pandemic will not emerge for 5 or more years.

During this 5-year period, the U.S. government hopes to accelerate the introduction of cell culture vaccine production and expand the supply of embryonated eggs. These efforts could increase domestic capacity to produce trivalent and pandemic vaccines. Given enough time, U.S. investigators might also settle on a low-dose, adjuvanted formulation for a pandemic vaccine. However, if the pandemic arrives within the next few years, current efforts will not lead to a greatly expanded capacity for vaccine production and will not provide information on the pandemic vaccine formulation and vaccination schedule that will meet the needs of public health.

Conclusion

The United States can learn an important lesson from the rapid progress Europeans have made in conceptualizing a process for pandemic vaccine development and registration. Likewise, Europeans can learn from Americans that public funding will play an essential role in accelerating the clinical development process. Given the common needs of nations on both sides of the Atlantic, Americans and Europeans should develop a common process for publicly funding clinical trials of low-dose, adjuvanted candidate (“mock-up”) pandemic vaccines.

Reverse Genetics, Intellectual Property, and Influenza Vaccination

Each year, the production of influenza vaccines begins when reference strains are provided to vaccine companies by WHO. Since the early 1970s, the reference strains have been prepared using the technique of genetic reassortment. With this technique, embryonated eggs are co-infected with an influenza virus considered most likely to cause epidemic disease and a high-growth strain of influenza A/PR8 virus. Following subsequent cloning, a progeny genetic reassortant virus is isolated that has two genes coding for the surface (HA and neuraminidase [NA]) antigens of the epidemic virus and six PR8 genes that are associated with high growth.

Genetic reassortants have been essential to the success of influenza vaccine production for more than 30 years, but they have disadvantages. The time needed to isolate a genetic reassortant suitable for commercial vaccine production can take many weeks. The reassortants do not always grow efficiently in egg-based production systems. Importantly, the avian H5N1 viruses associated with human disease are lethal for embryonated eggs. Largely for this reason, no commercially viable H5N1 seed strain for human vaccine production has yet been prepared using genetic reassortment.

In the past few years, reference strains suitable for producing human H5N1 influenza vaccines have been prepared in several laboratories using the techniques of reverse genetics (RG) (Fodor et al., 1999; Subbarao et al., 2003; Webby et al., 2004). With these techniques, the polybasic amino acids associated with H5N1 virulence are removed from the HA cleavage site. Plasmids containing the genes for the avian virus HA and NA antigens are then cloned and transfected into Vero cells along with plasmids containing the six PR8 genes. The progeny virus is rescued from cell culture, purified, propagated in embryonated eggs, and tested for stability and pathogenicity. The methods for preparing RG-engineered viruses are straightforward, the results are predictable, and the process can take as little as 15 to 20 days. Moreover, it can be used with avian viruses that cannot be propagated in eggs.

The techniques of reverse genetics differ from genetic reassortment in one important respect; they are associated with patents. The intellectual property (IP) rights for RG are held by at least two academic institutions (Mt. Sinai Medical Center and the University of Wisconsin) and one pharmaceutical company (MedImmune, Inc.). At least one patent holder has agreed to allow RG to be used to prepare reference strains for research purposes. However, all patent holders expect to be paid royalties if RG-engineered seed strains are used for commercial vaccine production.

If we were now facing a true pandemic threat from an H5N1 virus, most vaccine companies would be uncertain about the precise ownership of the IP rights for the RG-engineered seed strains they would be called on to use. Some companies have already undertaken their own analyses of RG patent rights, but they should not be expected to disclose their findings. DHHS has conducted a patent search of its own and formulated its policy options, but they are not publicly known. Even if they were, the patent rights would apply only to the United States; patent rights in Europe and Japan are independent of those in the United States. In the absence of knowing who owns the intellectual property for RG, it would be difficult for a vaccine company to enter into negotiations on royalty payments for pandemic vaccine production. If negotiations with only one patent holder were attempted, litigation by the others could follow. Given these uncertainties, if presented with a pandemic threat, the United States and other national governments would probably exercise government use or similar rights for RG. Royalty payments would not be negotiated between patent holders and patent users; they would be determined by courts or governments.

A strong argument can be made for resolving RG-IP ownership before the next pandemic threat appears. This would allow companies to determine whether using RG-engineered seed strains would offer advantages over genetic reassortants for interpandemic as well as pandemic vaccine production. Companies would have time to respond to regulatory requirements to upgrade their production facilities. Because European countries regard RG-engineered viruses as genetically modified organisms (GMOs), there would be time for European-based companies to resolve uncertainties over GMO issues with regulators and with the public. Royalty payments could be negotiated with the RG patent holders, avoiding litigation. However, several obstacles still stand in the way. In interpandemic years, companies have enough time to produce their vaccines using genetic reassortants, which are provided free of charge. They have no compelling commercial reasons to use RG-engineered seed strains. If they did, their vaccines could not command higher prices and consequently paying royalties would erode their profit margins. The RG patent holders could facilitate negotiations with the companies by forming a patent pool, but thus far they have shown no interest in doing so.

One way to accelerate the introduction of RG-engineered seed strains during the interpandemic period would be to conduct multinational, publicly funded clinical trials of candidate pandemic-like vaccines (Fedson, 2003a,b). This “dress rehearsal” strategy would challenge companies and their production facilities, national regulatory agencies, and European public opinion on GMO issues. All would gain the practical experience needed to prepare them for pandemic vaccine production. However, most vaccine companies won't fund expensive clinical trials of vaccines that won't be marketed. The U.S. clinical development program for H5N1 vaccine responds only to U.S., not global, needs, and only two companies will participate. Although the EMEA has developed a thoughtful process that will lead to licensure of a true pandemic vaccine, it has yet to identify public funding for the clinical trials that will make it a reality. More disturbing are recent decisions by three of the four major European vaccine companies not to produce pilot lots of a European H5N1 “mock-up” vaccine. Although these vaccines would be used only for research purposes, the companies are unwilling to participate largely because of restrictions and uncertainties related to intellectual property rights for reverse genetics.

Experts in intellectual property describe the RG-IP issue as a classic example of market failure. Unless the public sector provides a framework for negotiations for RG-IP during interpandemic years, companies will not be prepared to produce pandemic vaccines using RG-engineered seed strains. Moreover, because IP issues are governed by national patent laws, the negotiating framework must be international. The need for an international solution has been acknowledged by WHO (WHO, 2004), but WHO has authority and capability to address the technical but not the IP issues related to RG.

Because of its importance to the global supply of pandemic vaccine, efforts must be undertaken immediately to solve the intellectual property issues related to reverse genetics. An international solution is not readily apparent. The national governments of vaccine-producing countries must take an interest in solving this problem (Hollis, 2002). The intellectual property rules of the World Trade Organization and the needs of international public health must be reconciled (Novak, 2003). Political and technical support might be sought from organizations such as the Organization for Economic Cooperation and Development (OECD); nearly all countries with vaccine companies are OECD Member States. The technical assistance of the World Intellectual Property Organization (WIPO) and the WIPO Arbitration and Mediation Center could be especially important (see http://www.wipo.int/). It may be adequate to bring together the various patent holders, assuming they see the possibility of a substantial market. Whatever process is chosen, achieving a solution to the problem of intellectual property for reverse genetics represents an important criterion for judging the ability of countries to work together to achieve good governance for global public health (Fidler, 2004).

**Please see the statement immediately following this paper for MedImmune, Inc.'s comments on the above section.

Clinical and Experimental Studies of the Molecular Pathophysiology of Influenza

Recent studies suggest that the biological basis for severe disease associated with influenza virus infections is virus-induced cytokine dysregulation (Julkunen et al., 2001). Avian H5N1 influenza viruses are potent inducers of proinflammatory cytokines (TNF-alpha and interferon beta) (Cheung et al., 2002). High serum concentrations of the chemokine interferon induced protein-10 (IP-10) and the monokine induced by interferon gamma (MIG) have been reported in patients with H5N1 disease (Peiris et al., 2004). In addition to these laboratory findings, epidemiologists have long recognized that influenza is associated with an increased risk of hospitalization and death due to cardiovascular and cerebrovascular diseases (Madjid et al., 2003; Reichert et al., 2004). Observational studies have documented a reduction in hospitalizations for congestive heart failure, recurrent myocardial infarction, and stroke following influenza vaccination (Nichol et al., 2003; Majid et al., 2003). Given these findings, recent advances in cardiovascular treatment could have important implications for the prophylaxis and treatment of interpandemic and pandemic influenza.

Much attention has been given recently to the effects of high-intensity statin treatment for coronary heart disease (Sacks, 2004; Cannon et al., 2004; Topol, 2004). The protection afforded by these agents seems to be above and beyond their effects in lowering serum levels of low-density lipoprotein cholesterol. The “cholesterol-centric” explanation for the clinical benefits of statins appears to be giving way to their “pleiotropic” effects. One recent study showed that patients with nonischemic dilated cardiomyopathy who were treated with low-dose simvastatin resulted in clinical improvement that was associated with a substantial lowering of serum concentrations of several inflammatory mediators, including TNF-alpha and IL-6 (Node et al., 2003). Similar effects have been seen on levels of C-reactive protein and the results have been dose related (Sacks, 2004). Finally, experimental (Merx et al., 2004) and clinical (Almog et al., 2004) studies have shown that statins have a dramatic effect in protecting against mortality caused by bacterial sepsis. These findings suggest that prophylaxis with statins or perhaps other commonly available therapeutic agents could possibly have beneficial effects on the clinical course of human influenza. Although this is only an idea, given the need for effective interventions in an emergent pandemic, it is one worth pursuing.

Several avenues of study could be considered. First, during the next influenza season (or for past influenza seasons for which appropriate administrative databases exist), case-control studies could be undertaken to determine whether common treatments for cardiovascular and cerebrovascular diseases are associated with reductions in all influenza-related hospitalizations and deaths, not just those associated with underlying cardiovascular or cerebrovascular diseases. Second, the existing databases for large-scale prospective trials of cardiovascular therapies could be reanalyzed to determine whether treatment is associated with reductions in influenza-related events that are independent of the effects of influenza vaccination. Third, studies of influenza in experimental animals could be undertaken to determine whether any of these treatments has an effect on clinical illness and/or virus shedding. Special attention could be given to the effects of treatment on the development of secondary bacterial pneumonia (McCullers and Rehg, 2002). Finally, in vitro studies could be undertaken to determine whether treatment of cell cultures with statins and other agents before or shortly after infection with influenza viruses has any effect on their subsequent production of proinflammatory cytokines.

If the studies outlined above should prove to be positive, their benefits for the next pandemic could be overwhelmingly important because, unlike antiviral agents and vaccines, supplies of these agents will be abundant and their availability widespread.

STATEMENT FROM MEDIMMUNE, INC., REGARDING REVERSE GENETICS TECHNOLOGY

MedImmune, Inc.

Mountain View, California

There are generally regarded to be four patent portfolios associated with the reverse genetics technology. An earlier filed portfolio developed by Palese et al. (WO 91/03552) at Mt. Sinai School of Medicine is owned by MedImmune, Inc. Later filed portfolios developed by Kawaoka et al. (WO 00/60050) at University of Wisconsin and Hoffmann (WO 01/83794) at St. Jude Children's Research Hospital are exclusively licensed by MedImmune, Inc. Finally, another later filed portfolio, also developed by Palese et al. (U.S. Patent No. 6,544,785), is owned by Mt. Sinai. Thus, these four patent portfolios are currently controlled by two parties.

For its part, MedImmune, Inc., has taken steps to ensure that its patent rights do not inhibit the development and commercialization of a pandemic influenza vaccine. Specifically, MedImmune, Inc., proactively notified the World Health Organization in December 2003 that it would grant free access to its intellectual property to government organizations and companies developing pandemic influenza vaccines gratis for public health purposes. In addition, MedImmune, Inc., has given similar notification to NIH and NVPO in the United States, and the National Institute for Biological Standards and Control (NIBSC) in the United Kingdom. For corporate manufacturers considering the commercial sale of pandemic influenza vaccines produced by reverse genetics, MedImmune, Inc., has sent out letters to all such manufacturers offering licenses to its intellectual property under reasonable terms. MedImmune, Inc., has made it clear to its commercial peers that it will waive royalties on its intellectual property for any and all pandemic influenza vaccines that are offered free of charge in the interest of public health. MedImmune, Inc., expects to apply this same pandemic licensing policy to any additional intellectual property rights for reverse genetics it should control in the future.

This intellectual property landscape is relatively simple compared to the typically complex field of biotechnology, where experienced companies like the influenza vaccine manufacturers are used to securing multiple licenses for a single product. Thus, influenza vaccine manufacturers should face little difficulty in obtaining licenses to the relevant intellectual property, and may direct their resources instead toward obtaining regulatory approval for pandemic vaccines.

PERSPECTIVES ON ANTIVIRAL USE DURING PANDEMIC INFLUENZA

Frederick G. Hayden6,7,8

Reprinted, with permission, from Hayden (2001), Copyright 2001 by The Royal Society

Antiviral agents could potentially play a major role in the initial response to pandemic influenza, particularly with the likelihood that an effective vaccine is unavailable, by reducing morbidity and mortality. The M2 inhibitors are partially effective for chemoprophylaxis of pandemic influenza and evidence from studies of interpandemic influenza indicate that the neuraminidase inhibitors would be effective in prevention. In addition to the symptom benefit observed with M2 inhibitor treatment, early therapeutic use of neuraminidase inhibitors has been shown to reduce the risk of lower respiratory complications. Clinical pharmacology and adverse drug effect profiles indicate that the neuraminidase inhibitors and rimantadine are preferable to amantadine with regard to the need for individual prescribing and tolerance monitoring. Transmission of drug-resistant virus could substantially limit the effectiveness of M2 inhibitors and the possibility exists for primary M2 inhibitor resistance in a pandemic strain. The frequency of resistance emergence is lower with neuraminidase inhibitors and mathematical modelling studies indicate that the reduced transmissibility of drug-resistant virus observed with neuraminidase inhibitor-resistant variants would lead to negligible community spread of such variants. Thus, there are antiviral drugs currently available that hold considerable promise for response to pandemic influenza before a vaccine is available, although considerable work remains in realizing this potential. Markedly increasing the quantity of available antiviral agents through mechanisms such as stockpiling, educating health care providers and the public and developing effective means of rapid distribution to those in need are essential in developing an effective response, but remain currently unresolved problems.

Introduction

This article provides personal perspectives on selected issues that are relevant to the use of antiviral drugs during the next influenza pandemic. It expands on previously published comments (Hayden, 1997) that were made before the availability of the novel class of anti-influenza agents, the neuraminidase inhibitors, and focuses on three areas: antiviral agent selection, antiviral resistance and the application of mathematical models. This discussion does not consider other important public health issues such as costs and their reimbursement, the stability of raw materials or formulated drug and their potential for stockpiling and rationing or distribution of limited drug supplies. However, it is obvious that adequate supplies and rapid access to antiviral drugs are essential if they are to be useful. In this regard, increasing appropriate use and fostering both health care provider and public familiarity with the available agents during the interpandemic period are essential for their effective use during the next pandemic.

Improvements in medical care since the last pandemic, including the introduction of new antiviral drugs that are specific for influenza A and B viruses, offer potential for reducing the impact of the next one. However, the health care systems of the USA and many other countries are sometimes unable to cope with the relatively modest increases in demand that occur with interpandemic disease. Mathematical models based on assumptions derived largely from the 1957 and 1968 pandemic experiences and the recent interpandemic period have estimated that 89,000–207,000 deaths, 314,000–734,000 hospitalizations, 18–42 million out-patient visits and 20–47 million additional illnesses will occur during the next pandemic (Meltzer et al., 1999). A pandemic like that occurring in 1918 would probably increase the impact by another order of magnitude. Most of these illnesses and deaths will occur over a short period of weeks to several months in a given region and overwhelm health care services. The mass casualties, which will include health care workers and providers of the essential community services, will not only rapidly fill hospital beds and exhaust available supplies of antivirals, antibiotics and other essential medications, but could also lead to substantial disruption of societal services, industrial production and infrastructure such as transportation, food supply and communications (Schoch-Spana, 2000). The 1918 pandemic incapacitated the health care system as well as other basic functions of many cities.

Antiviral agents could potentially play a major role in the initial response to pandemic influenza, particularly with the likelihood that an effective vaccine is unavailable, and might substantially reduce morbidity, hospitalizations, other demands on the health care system and mortality. However, a number of limitations regarding antiviral use during a pandemic warrant consideration.

The major current impediment to effective use in a pandemic would be limited availability coupled with high demand during a short period. In particular, restricted availability, drug costs, the risks of adverse effects and the potential for the emergence of drug resistance are constraints on prolonged prophylactic administration during the initial wave or waves of a pandemic. Fair allocation of available resources would be extremely difficult in the context of an ongoing pandemic or even major epidemic. As summarized below, antivirals have proven efficacy in treatment and prevention, but an inadequate supply and limited surge capacity in production would result in lack of use. Markedly increasing the quantity of available antiviral agents through mechanisms such as stockpiling and developing effective means of rapid distribution to those in need are essential in developing an effective response, but remain currently unresolved problems.

Selection of Antivirals

A fundamental question is which agent or agents should be selected for potential stockpiling and widespread use in the population. Most countries currently have one M2 inhibitor (amantadine) and one or two neuraminidase inhibitors (zanamivir and oseltamivir) approved for use in influenza treatment and/or prophylaxis and in the USA four agents including rimantadine are currently available (Table 3-2). Although other neuraminidase inhibitors are in various stages of development, these four agents are the ones that require scrutiny at present with regard to their use in response to a pandemic. Efficacy, tolerability, ease of administration and the potential for clinically important drug resistance are all factors that warrant consideration in selecting among the available agents. Data regarding use in pandemic influenza are only available with the M2 inhibitors, but extensive clinical testing of the neuraminidase inhibitors in interpandemic influenza permits reasonable conclusions regarding their efficacy.

TABLE 3-2. Currently Available Antiviral Agents for Influenza .

TABLE 3-2

Currently Available Antiviral Agents for Influenza .

Efficacy for Prophylaxis

The comparative efficacies of these agents have received limited study. In general, amantadine and rimantadine have comparable antiviral and clinical activities when used in chemoprophylaxis or in the treatment of influenza A virus illness (reviewed in Hayden & Aoki, 1999). The evidence from placebo-controlled, blinded studies of amantadine and rimantadine during the 1968 H3N2 pandemic and 1977 H1N1 reappearance establish that these agents are effective for chemoprophylaxis in immunologically naive adult populations (Table 3-3), although the observed levels of protection against influenza illness varied considerably across studies and were generally lower than the 80–90% protective efficacies against illness observed in studies of interpandemic influenza. Lower protection rates are observed for laboratory documented infection (Table 3-3), an observation that, in part, reflects the occurrence of subclinical and likely immunizing infections during chemoprophylaxis. The neuraminidase inhibitors are highly effective in chemoprophylaxis against epidemic influenza in studies assessing both seasonal prophylaxis in non-immunized adults (Hayden et al., 1989; Monto el al., 1999a) or immunized nursing home residents (Peters et al., 2001) and post exposure prophylaxis in families (Hayden et al., 2000; Welliver et al., 2001). The single study comparing the prophylactic efficacy of an M2 with a neuraminidase inhibitor found that inhaled zanamivir was superior to oral rimantadine in short-term influenza prophylaxis in nursing home outbreaks, largely because of frequent rimantadine prophylaxis failures secondary to resistant virus (Gravenstein et al., 2000). Such results would predict that the neuraminidase inhibitors would also be effective for prophylaxis of pandemic influenza.

TABLE 3-3. Amantadine Prophylaxis During Pandemic Influenza .

TABLE 3-3

Amantadine Prophylaxis During Pandemic Influenza .

Efficacy for Treatment

One clinical feature of previous pandemic influenza, particularly the 1918 disease, was that convalescence was protracted, with fatigue and functional impairment lasting for weeks. Early antiviral treatment has been shown to reduce the time to functional recovery by up to several days in adults and children with acute influenza. Placebo-controlled, blinded studies during the 1968 H3N2 pandemic and 1977 H1N1 reappearance showed that amantadine and rimantadine provided therapeutic benefit in uncomplicated illness in previously healthy adults, with reductions in fever, symptom severity and the time to resuming normal activities (Knight et al., 1970; Galbraith et al., 1971; Van Voris et al., 1981). However, most controlled treatment studies of the M2 inhibitors have enrolled relatively few patients and none to date have documented reductions in complications or antibiotic use.

The antiviral and clinical benefits of early antiviral treatment have not been directly compared between an M2 and a neuraminidase inhibitor. Several large placebo-controlled, blinded studies have shown that treatment with either inhaled zanamivir or oral oseltamivir reduces illness duration, the time to resuming normal activities and the likelihood of physician-diagnosed lower respiratory complications leading to antibiotic use in adults (Monto et al., 1999b; Kaiser et al., 2000; Treanor et al., 2000). Such benefits have also been observed in zanamivir treatment studies involving patients with asthma or chronic obstructive airways disease (Murphy et al., 2000) and in oseltamivir treatment studies involving children aged 1–12 years, in whom new otitis media diagnoses were reduced by over 40% (Whitley et al., 2001). In contrast, one earlier pediatric study of rimantadine found no beneficial effects on earache or presumed otitis media risk following influenza (Hall et al., 1987). Both intranasal zanamivir and oral oseltamivir reduce otologic abnormalities in experimental human influenza (Hayden et al., 1999; Walker et al., 1997), whereas oral rimantadine does not (Doyle et al., 1998). Furthermore, preliminary analysis of the aggregated clinical trials experience with oseltamivir indicates that early treatment is also associated with reductions in hospitalizations. Until a direct comparison of the relative therapeutic effects of an M2 and a neuraminidase inhibitor is performed, the available data indicate that a neuraminidase inhibitor would be the preferred antiviral agent for treatment during pandemic influenza from the perspective of therapeutic benefit.

Ease of Administration

The selection of an antiviral agent for wide-scale use also depends heavily on its pharmacological properties, which in turn influence the complexity of its dose regimens, the route and frequency of administration, the need for therapeutic monitoring and dose adjustments and the potential for clinically important drug-drug or drug-disease interactions. Clinically important differences exist among the M2 inhibitors (reviewed in Hayden & Aoki, 1999) and the neuraminidase inhibitors (reviewed in Gubareva et al., 2000) with regard to their human pharmacology. Each of the available agents can be dosed infrequently, with once daily for prevention and once (rimantadine and amantadine) or twice daily for treatment. Dose adjustments are rarely needed for rimantadine and the neuraminidase inhibitors (Table 3-2). No age related adjustments are required for the neuraminidase inhibitors.

In contrast, amantadine depends directly on renal excretion for elimination and has a narrow therapeutic index (ca. 2:1 ratio of the one associated with frequent adverse effects to the therapeutic dose), such that amantadine dose adjustments are required for relatively modest decrements in renal function, including those usually observed with ageing. Furthermore, amantadine has several recognized drug interactions that increase the likelihood of side-effects (Table 3-2) and the need for close clinical monitoring in certain patient groups. The need for individual prescribing of amantadine based on knowledge of renal function is a significant limitation to its wide-scale use. The inhaler device used for zanamivir dosing is also an obstacle with respect to the ease of administration. The current delivery system requires a cooperative, informed patient who is able to make an adequate inspiratory effort. Elderly hospitalized patients often have problems using the delivery system effectively (Diggory et al., 2001) and the current device is not appropriate for use in young children (below 5 years of age) or those with cognitive impairment or marked frailty. While the need for device training is an important concern in treating acutely ill patients, most studies to date have shown good compliance and the inhaled route may offer certain advantages in the chemoprophylaxis of influenza.

Tolerability and Safety

Similarly, the type, frequency, severity and management of adverse drug effects and their relationships to drug dose are all considerations in agent selection (Table 3-4). The duration of drug exposure, short-term treatment versus longer periods for prophylaxis and the timing of onset with regard to initiation of dosing are, again, all considerations in this regard.

TABLE 3-4. Adverse Drug Reaction Profiles of Currently Available Anti-Influenza Agents .

TABLE 3-4

Adverse Drug Reaction Profiles of Currently Available Anti-Influenza Agents .

Amantadine has the narrowest toxic:therapeutic ratio among the available agents and is commonly associated with dose-related minor central nervous system (CNS) side-effects, that are probably related to its amphetamine like CNS stimulatory properties and, less often, severe CNS toxicities (Table 3-4). The latter occur most often in those with high plasma concentrations due to impaired renal excretion. Rimantadine has a significantly lower potential for causing CNS adverse effects, in part related to differences in its pharmacokinetics (Hayden & Aoki, 1999), although dose reductions are recommended in the elderly. For example, one recent crossover study in an elderly nursing home resident population compared prolonged amantadine chemoprophylaxis, at the currently recommended reduced dose of 100 mg day−1 further adjusted for renal function, with rimantadine chemoprophylaxis at the same dose and found ca. 10-fold higher frequencies of overall adverse events, including confusion and hallucinosis and drop-out during amantadine administration (Keyser et al., 2000).

Inhaled zanamivir treatment has been very infrequently described as causing bronchospasm, sometimes severe or associated with fatal outcome, in acute influenza sufferers with pre-existing airways disease. Influenza itself often causes severe exacerbations in such patients so that the possible causal relationship to zanamivir administration is uncertain, as is the actual frequency of such events. One large placebo-controlled study of influenza-infected patients with underlying mild-moderate asthma or, less often, chronic obstructive airways disease found no excess of serious respiratory adverse events and more rapid clinical recovery including peak expiratory flow rates in zanamivir recipients (Murphy et al., 2000). However, until further data are available, zanamivir use in patients with underlying airways disease requires close clinical monitoring. Like the M2 inhibitors, oseltamivir is associated with mild-moderate gastrointestinal (GI) upset in a minority of patients, but no other serious end-organ toxicity has been recognized to date.

In most instances, the adverse effects associated with these drugs are readily reversible after the cessation of administration. Severe CNS adverse reactions related to excess amantadine accumulation in the blood can be an exception, because such toxicity is usually due to a failure to reduce the dose in the setting of renal impairment with its attendant prolonged elimination half-life. Another concern with regard to extensive community use of antivirals during pandemic influenza is their potential for adverse effects during pregnancy. Amantadine and rimantadine are recognized teratogens in animals and, consequently, are relatively contraindicated in pregnancy. The clinical pharmacology and adverse drug effect profiles of the antivirals for influenza indicate that the neuraminidase inhibitors and rimantadine are preferable to amantadine with regard to the need for individual prescribing, tolerance monitoring and the seriousness of side-effects. When these findings are considered in the context of the available information about efficacy and antiviral resistance (discussed below), it is clear that the neuraminidase inhibitors would be the preferred agent for treatment and, in some instances, prophylaxis during pandemic influenza.

Antiviral Resistance

An important issue in pandemic influenza is the potential for the emergence and spread of drug-resistant influenza A viruses that cause the loss of the clinical effectiveness of antiviral drugs. The M2 and neuraminidase inhibitors have important differences with respect to the frequency and biological properties of resistant variants (Table 3-5). In addition to the selection of drug resistant variants during antiviral use, the possibility of primary or de novo drug resistance in a pandemic strain warrants consideration. Primary resistance to the neuraminidase inhibitors has not been described at the enzyme level and these agents are active against all of the nine neuraminidase subtypes recognized in avian influenza viruses (reviewed in Gubareva et al., 2000; Tisdale, 2000). In contrast, primary resistance to the M2 inhibitors has been described in swine influenza viruses of the H1N1 subtype in the 1930s in the absence of selective drug pressure. More recently, swine viruses in Europe and North America and isolates from several zoonotically infected humans of H1N1 and H3N2 subtypes have shown primary resistance (A. Hay, personal communication). Amantadine resistance has also been described in a small portion (<1%) of field isolates (Ziegler et al., 1999) and in those receiving the drug for the treatment of Parkinsonian symptoms (Iwahashi et al., 2001). Such observations raise the concern that amantadine-resistant isolates circulate naturally under certain conditions. In addition, the use of amantadine for influenza management in China also increases the potential that a pandemic strain might show primary resistance to amantadine and rimantadine.

TABLE 3-5. Epidemiological and Biological Features of Drug-Resistant Influenza Viruses Recovered During Clinical Use .

TABLE 3-5

Epidemiological and Biological Features of Drug-Resistant Influenza Viruses Recovered During Clinical Use .

Another generic issue regarding resistance emergence is the proposed tactic for extending the availability of limited antiviral drug supplies during pandemic influenza by reductions in either the dose level or, in the case of treatment, the duration of therapy. Theoretically, a short course therapy of 1–3 days might reduce viral loads sufficiently to provide clinical benefit. Obvious concerns related to this approach would include the potential loss of therapeutic or prophylactic efficacy, rebound in viral replication and symptoms after the cessation of administration and fostering emergence of drug resistance, in part due to continued viral replication in the setting of subinhibitory drug concentrations. The risks of these events would probably be higher in pandemic influenza than in interpandemic disease because of the lack of specific immunity to an antigenic ally novel strain and the potential for higher or more protracted levels of viral replication in affected persons. Indeed, higher drug doses might be required for exerting comparable antiviral effects and clinical benefits in pandemic as compared with interpandemic infections. Consequently, the minimally effective doses and durations of therapy need careful study in epidemic influenza before recommendations might be considered for the pandemic situation. Conducting such studies in unprimed populations such as young children or in immunocompromised hosts might provide useful insights.

Amantadine and Rimantadine

The M2 inhibitors have been associated with the rapid emergence of high-level resistant variants during therapeutic use and failures of chemoprophylaxis due to the transmission of such strains under close contact conditions, as in households and nursing homes (reviewed in Hayden, 1996). These variants are due to point mutations in the M gene and corresponding single amino acid substitutions in the target M2 protein (reviewed in Hay, 1996). They show no obvious loss of virulence or transmissibility in animal models or humans (Table 3-5) and have been shown to compete effectively with wild-type, susceptible virus for multiple-cycle transmission in the absence of selective drug pressure in an avian model (Bean et al., 1989). The frequency of observing such resistant variants has averaged ca. 30% in treated adults and children, but ranges to over 50% of immunocompromised hosts (Englund et al., 1998).

A key aspect of the clinical and public health implications of resistance emergence is the transmissibility of resistant variants. For example, one older study employing rimantadine for index case treatment and post-exposure prophylaxis in families observed negligible prophylactic efficacy due to high rates of resistance emergence and probable transmission leading to failures of drug prophylaxis (Hayden et al., 1989). A similar study with amantadine during the 1968 pandemic also found low prophylactic efficacy, although the reasons were not elucidated (Galbraith et al., 1969). In contrast, inhaled zanamivir used for both treatment and post-exposure prophylaxis in families was highly effective and not associated with resistance emergence (Hayden et al., 2000). A recent nursing home-based study comparing 2 weeks' prophylaxis with oral rimantadine or inhaled zanamivir after recognized outbreaks found over 60% higher protection in zanamivir recipients as compared with rimantadine, in part due to high frequencies of prophylaxis failures due to rimantadine-resistant viruses (Gravenstein et al., 2000). The extensive use of rimantadine for prophylaxis and treatment of non-study participants on the same wards may have contributed to the observed prophylaxis failures. Such experiences highlight the potential for the emergence of amantadine-resistant influenza A viruses and spread under close contact conditions.

Oseltamivir and Zanamivir

The neuraminidase inhibitors appear to be associated with a lower frequency of resistance emergence due to neuraminidase mutations (reviewed in McKimm-Breschkin, 2000; Tisdale, 2000) and a lower risk of transmission (Table 3-5). To date, only one instance of zanamivir resistance in an immunocompromised host has been documented (Gubareva et al., 1998) and no resistance has been found in immunocompetent persons receiving treatment (Barnett et al., 2000; Boivin et al., 2000; Hayden et al., 2000). The frequency of recovering resistant variants may be higher with oseltamivir therapy in that variants exhibiting neuraminidase resistance have been recovered from ca. 0.4% of treated adults and 4% of treated children (N. Roberts, personal communication; Treanor et al., 2000; Whitley et al., 2001). However, the oseltamivir resistant variants show reduced infectivity and virulence in animal models and the commonest variant with amino acid substitution at position 292 shows reduced transmissibility in a ferret model (Carr et al., 2001). These observations indicate that antiviral resistance due to neuraminidase resistance appears to alter the fitness of influenza viruses and suggests that resistance will be much less likely to be a threat during drug use in epidemic or pandemic influenza.

Modelling Studies

Mathematical models can be used for assessing the potential for the spread of drug-resistant influenza viruses under both epidemic and pandemic circumstances (Stilianakis et al., 1998). Such models can be used for assessing the effectiveness and potential impact of antiviral resistance transmission during different strategies of antiviral intervention, such as chemoprophylaxis alone, the treatment of ill persons alone or combined treatment and prophylaxis. For example, one such study examined the effect of these different approaches using amantadine or rimantadine in a closed population during a theoretical pandemic outbreak in which all residents were assumed to be susceptible and become infected (Stilianakis et al., 1998). The model, which is based on studies with amantadine and rimantadine, predicted that treatment alone would affect the epidemic curve minimally, whereas chemoprophylaxis alone or a combination of treatment and chemoprophylaxis both reduce the number of symptomatic cases (Table 3-6). However, the observed outcomes depended heavily on the transmissibility of drug-resistant virus relative to wild-type, susceptible virus (Table 3-6). When transmissibility of the resistant variant was comparable to the wild-type, prophylaxis failures due to resistant virus were common, particularly with the combined approach for which one-half of illnesses were due to resistant virus. A relatively modest fivefold reduction in transmissibility was associated with substantial reductions in the impact of resistant virus and improved effectiveness for both the prophylaxis alone or combined intervention approaches (Table 3-6). Another recently described model examining the effects of resistance emergence also predicts that decreases in biological fitness and associated transmissibility of drug-resistant virus, as observed with neuraminidase inhibitor-resistant variants, will lead to negligible community spread of such variants (Ferguson and Mallett, 2001).

TABLE 3-6. Effect of the Transmissibility of Drug-Resistant Virus on Outcomes in a Theoretical Closed Population Pandemic Influenza Outbreak .

TABLE 3-6

Effect of the Transmissibility of Drug-Resistant Virus on Outcomes in a Theoretical Closed Population Pandemic Influenza Outbreak .

The Economic Impact

In the absence of a mass immunization programme, the costs, excluding disruptions to commerce and society, of the next pandemic are projected to range from US$71.3 billion to US$166.5 billion for hospitalizations, outpatient care, self-treatment and lost work days and wages in the United States alone (Meltzer et al., 1999). Formal pharmacoeconomic analyses of antiviral interventions have not been reported to date for pandemic influenza, but could be helpful in selecting the appropriate strategies and target populations for antiviral use. Through use of the economic model developed by Meltzer et al. (1999) and assumptions regarding drug effectiveness derived from recent therapeutic trials with oseltamivir, preliminary assessment of the economic impact of using antivirals for treatment during an influenza pandemic are possible (Table 3-7). Extensive therapeutic use would be projected to save many days off work, out-patients visits for presumed complications and, particularly in older adults, hospitalizations (M.I. Meltzer and F.G. Hayden, unpublished observations). These preliminary analyses suggest that treatment in high-risk older adults would reduce hospitalizations, whereas treatment in non-high-risk younger adults and children would reduce out-patient visits and work/school days lost. By assigning direct and indirect dollar valuations to the health outcomes averted, it was estimated that the treatment of high-risk persons aged 65 years and older and non-high-risk persons aged 20–64 years would generate the largest and comparable savings per 1000 ill.

TABLE 3-7. Projected Economic Impact of Neuraminidase Inhibitor Treatment on Selected Outcomes During Pandemic Influenza .

TABLE 3-7

Projected Economic Impact of Neuraminidase Inhibitor Treatment on Selected Outcomes During Pandemic Influenza .

If it were possible to extend early treatment to those who would not seek medical care, considerable savings in indirect costs due to days off work/school could be achieved across all age groups. However, the actual implementation of that strategy would require the development and validation of new treatment paradigms, such as telephone triage by non-physician health care providers or self-diagnosis through symptom checklists and then rapid access to antiviral drugs for patient-initiated therapy. Such assessments need to be undertaken during the interpandemic influenza period so that they might be acceptable for use during the next pandemic. In general, the results of such economic analyses depend on the nature of the pandemic and its associated age-related morbidity and mortality rates, the projected costs of outcomes and the assumed effectiveness of the intervention. Future research will need to include estimates of the cost of delivering treatments to various age and risk groups and examine other drug treatments and strategies including prophylaxis. However, such economic models can help guide decisions about the potential benefits of antiviral treatment or prophylaxis in different populations groups.

PARTNERING WITH THE PRIVATE MEDICAL SYSTEM

Gordon W. Grundy, MD, MBA

Aetna, Inc.

Health plans and managed care organizations (MCOs) operate at the center of the private medical system. Over 200 million American citizens are privately insured by more than 1,300 health care organizations. Aetna is among the largest with more than 13 million members. By virtue of financing, facilitating, and coordinating the delivery of health services, health plans have fiduciary and contractual relationships with a variety of constituents. These include individual citizens (health plan members), employers (payers of private health insurance), physicians, hospitals, and other ancillary providers (e.g., home health care agencies, skilled nursing facilities, and urgent care centers).

In planning for pandemic influenza, the role of the private medical system as mediated through health plans and MCOs can be framed by addressing four key questions:

  1. What capabilities can private health plans bring to influenza pandemic planning?
  2. How and why should health plans and MCOs interface with the planning process?
  3. How can health plans and MCOs facilitate the delivery of medical services during an influenza pandemic?
  4. How might a public–private partnership to address pandemic influenza be achieved?

Capabilities of Private Health Plans

Health plans and MCOs can contribute a broad range of resources to the pandemic planning process. They are experienced at increasing health awareness through educational initiatives and promoting preventive care with timely reminders to insured members. In addition, health plans often provide performance feedback to the physicians and hospitals with which they have contractual relationships. These activities reach significant numbers of constituents. For example, a single large health plan such as Aetna can communicate nationwide with more than 13 million individuals, 350,000 physicians, and 3,500 hospitals. Because MCO databases contain information on members, physicians' practice locations, and hospital contacts, they are well positioned to conduct outreach in the event of a public health crisis.

Education

Most health plans have developed educational components within their wellness programs as well as in case and disease management functional areas. With some modification, these resources could be adapted to inform the public during an influenza pandemic. Health plans generally find that individual members attend to the topics that are discussed in mailings and in telephone campaigns. Given the proven capability of health plans and MCOs in outreach and education activities, public health agencies should consider them as potential partners in communicating with citizens during an influenza pandemic threat.

Immunization Campaigns

Aetna is one of many health plans that have experience in conducting preventive immunization campaigns and our ability to do so has been measured and accredited. In support of these efforts, we have established alternative sites for providing immunizations, such as retail establishments and pharmacies, and we have developed a variety of ways to get people to sites where they can be appropriately immunized. Aetna's extensive database enables us to target high-risk individuals and to build predictive modeling tools, including risk stratification. This allows us to identify those individuals within our health plan who would be at high risk for complications from influenza, whether due to age or a chronic condition.

In December 2003, for example, when the influenza season got off to an early and severe start and the potential for a vaccine shortage became apparent, Aetna conducted an outreach campaign within its southeast region to urge health plan members at high risk for flu complications due to a chronic medical condition to be immunized. Over a period of 4 days, Aetna placed more than 134,000 telephone calls to insured members and ultimately contacted more than 100,000 people—many of whom received as many as 4 calls. Information was disseminated rapidly and thoroughly, reaching about 80 percent of our at-risk regional members. This success at sending public health messages quickly and broadly is an asset, and one that we and other health care plans can contribute in addressing pandemic influenza.

Incentives for Physicians and Insured Members

Through contractual relationships with physicians, health plans and MCOs can encourage them to improve annual influenza immunization rates. Physicians can receive feedback on their vaccination rates for members, especially those at high risk for flu complications. In addition, financial incentives might be established for outstanding performance in this area. Members can also be rewarded for taking appropriate preventive health measures by enhancing their plan benefits.

Research and Demonstration Projects

An Institute of Medicine workshop in 1998 noted a potential role for MCOs in research and demonstration projects related to emerging infections. In the past, however, there has been little incentive for health plans to participate in these projects. With the looming threat of an influenza pandemic, this worthwhile concept might well be revisited and meaningful incentives considered.

The Planning Process

How then should health plans and MCOs interface effectively with the planning process for pandemic influenza? First and foremost, they need to be part of the planning process. In addition to offering the previously described capabilities, health plan representatives need to be at the table because they understand how specific medical systems in individual communities actually work. Their unique viewpoint can complement the knowledge of local public health departments.

Health plan managers are familiar with each hospital's issues, capacities, referral patterns, and nearby lower level care providers. In the course of health plan work, every effort is made to ensure that members who are hospitalized in acute care facilities are transitioned into lower levels of care as appropriate. Based on that experience, health plans may be able to assist in addressing the expected strain on hospital surge capacity resulting from pandemic influenza, particularly in intensive care units. For example, MCOs may be able to help transition or move hospitalized individuals into alternative sites of care in order to make optimal use of acute care resources.

Health plans also need clear policies, directives, and recommendations from the CDC and other governmental agencies in order to ensure our effective participation in the response to pandemic influenza. In this, as in all medical circumstances, we rely on authoritative sources in the public health field and evidence-based literature to frame and craft our policies. Although health plans recognize the considerable uncertainties inherent in predicting the pandemic course and outcome, the clearer the statements we (and the public) receive, the more support we can provide. For example, if health plans are to encourage and incentivize immunization during a pandemic, we will need to know which populations to target. Will the focus be on people with chronic conditions in order to reduce morbidity and mortality? Alternatively, will the priority be working adults and children in order to reduce the economic impact of lost productivity by ensuring the health of caregivers? Or will we have a universal immunization program to decrease the overall burden of illness? Health plans can most effectively assist in implementing the strategy when it is clearly stated and understood.

Finally, the planning process should recognize the full financial ramifications of an influenza pandemic. This goes beyond calculating the percentage increase in utilization of services and estimates of the aggregate dollar amounts that will be spent as a result. Cost estimates need to reach a more granular level, one that acknowledges that health care is delivered by individuals who get paid for their services. A considerable portion of the health services delivered in a pandemic will be provided by private practitioners who will expect reimbursement. Although certain expenses may be waived, the basic financial support system for the private medical system is carried by employers and needs to stay afloat. This issue requires further study and understanding before positing any recommendations.

Facilitating Delivery of Medical Services

In many circumstances, health plans can most effectively facilitate the delivery of medical services during an influenza pandemic by removing obstacles. More specifically, in the event of a pandemic, health plans will need to temporarily remove or waive many of the policies and procedures that have been established to manage costs but could hinder the response to a public health crisis.

This is exactly what many health plans did following the events of September 11, 2001, as well as after several recent natural disasters and the blackout that affected much of the northeastern United States during the summer of 2003. Most plans in the affected areas issued time-limited waivers of prior approval, referral, and formulary requirements, enabling their members to access care wherever they found it. Aetna even went a step further in September 2001 by bringing counseling teams to worksites in the metropolitan New York area to provide ready access to behavioral health services for plan members.

This precedent to respond quickly and productively in emergency situations will no doubt be replicated during an influenza pandemic. Whether educating their members, promoting immunization, waiving procedures, enhancing surge capacity, or ensuring access to antiviral medications, health plans will play an important role in the day-to-day management of the pandemic. The challenge and responsibility for the private medical system will be to develop a coordinated response that can be launched at the direction of public health officials.

Achieving Public–Private Partnership

To comprehensively address the threat of pandemic influenza, a public–private partnership would most effectively leverage the strengths of health plans and MCOs. Many health plans—potentially every plan—would need to be involved in such an effort. A leading organization that could establish such broad representation is the trade association known as America's Health Insurance Plans (AHIP). Composed of 1,300 health plans that insure more than 200 million citizens, AHIP is engaged in several activities that have public health dimensions. It has had a Disease Prevention and Public Health Work Group in place since 1996 and currently partners with the CDC to work on vaccine surveillance and safety assessment research. In addition, AHIP focuses on emergency preparedness related to bioterrorism and periodically issues public health updates for its member plans.

Another possible partner is the Council for Affordable Quality Health Care (CAQH). Including 22 of the largest national and regional health plans, its member organizations insure more than 100 million Americans. Although less than 5 years old, CAQH is establishing a track record of public awareness initiatives, the most notable of which is a joint effort with the CDC to promote the appropriate use of antibiotics.

The strengths of these national organizations could also be complemented by a series of partnerships with state-based health plan associations that are closer to local public health agencies and often emphasize preventive care and quality.

Should a public–private partnership in pandemic planning be pursued? The advantages are persuasive. Collaboration between public and private entities will bring different techniques and skill sets to bear on public health challenges while fostering innovation. Such partnerships seem likely to increase the chance for success in planning for and managing a future influenza pandemic.

REFERENCES

  1. Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, Friger M, Zeller L, Danon A. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation. 2004;110:880–885. [PubMed: 15289367]
  2. Barnett JM, Cadman A, Gor D, Dempsey M, Walters M, Candlin A, Tisdale M, Morley PJ, Owens IJ, Fenton RJ, Lewis AP, Claas EC, Rimmelzwaan GF, De Groot R, Osterhaus AD. Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies. Antimicrob Agents Chemother. 2000;44:78–87. [PMC free article: PMC89632] [PubMed: 10602727]
  3. Bean WJ, Thelkeld SC, Webster RG. Biologic potential of amantadine-resistant influenza A virus in an avian model. J Infect Dis. 1989;159:1050–1056. [PubMed: 2723453]
  4. Boivin G, Goyette N, Hardy I, Aoki FY, Wagner A, Trottier S. Rapid antiviral effect of inhaled zanamivir in the treatment of naturally occurring influenza in otherwise healthy adults. J Infect Dis. 2000;181:1471–1474. [PubMed: 10762579]
  5. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–1504. [PubMed: 15007110]
  6. Carr J, Herlocher L, Elias S, Harrison S, Gibson V, Clark L, Roberts N, Ives J, Monto AS. Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets. Antiviral Res. 2001;50:A85. [PubMed: 12062395]
  7. Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan Y, Peiris JS. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: A mechanism for the unusual severity of human disease? Lancet. 2002;360:1831–1837. [PubMed: 12480361]
  8. Chiron Corporation. Chiron to Produce Further Pandemic-Like Influenza Vaccines for National Institutes of Health Clinical Studies. 2004. [accessed November 10, 2004]. [Online]. Available: http://phx​.corporate-ir​.net/phoenix.zhtml?c​=105850&p​=irol-newsArticle&ID​=604514&highlight=
  9. CPMP (Committee for Proprietary Medicinal Products). Note for Guidance on Harmonization of Requirements for Influenza Vaccines. 1997. [accessed December 17, 2004]. pp. 1–2. CPMP/BWP/214/96 Circular No. 96-0666. [Online]. Available: http://www​.emea.eu.int​/pdfs/human/bwp/021496en.pdf.
  10. CPMP. Guideline on Dossier Structure and Content for Pandemic Influenza Vaccine Marketing Authorisation Applications. 2004a. [accessed December 17, 2004]. [Online]. Available: http://www​.emea.eu.int​/pdfs/human/veg/4710703en.pdf.
  11. CPMP. Guideline on Submission of Marketing Authorisation Applications for Pandemic Influenza Vaccine Through the Centralized Procedure. 2004b. [accessed December 17, 2004]. [Online]. Available: http://www​.emea.eu.int​/pdfs/human/veg/498603en.pdf.
  12. Diggory P, Fernandez C, Humphrey A, Jones V, Murphy M. Comparison of elderly people's technique in using two dry powder inhalers to deliver zanamivir: Randomised controlled trial. BMJ. 2001;322:1–4. [PMC free article: PMC26548] [PubMed: 11238150]
  13. Doyle WJ, Skoner D, Alper CM, Allen G, Moody SA, Seroky J, Hayden FG. Effect of rimantadine treatment on clinical manifestations and otologic complications in adults experimentally infected with influenza A (H1N1) virus. J Infect Dis. 1998;177:1260–1265. [PubMed: 9593010]
  14. Englund JA, Champlin RE, Wyde PR, Kantarjian H, Atmar RL, Tarrand J, Yousuf H, Regnery H, Klimov AI, Cox NJ, Whimbey E. Common emergence of amantadine and rimantadine resistant influenza A viruses in symptomatic immunocompromised adults. Clin Infect Dis. 1998;26:1418–1424. [PubMed: 9636873]
  15. Fedson DS. Pandemic influenza and the global vaccine supply. Clin Infec Dis. 2003a;36:1552–1561. [PubMed: 12802755]
  16. Fedson DS. Pandemic flu vaccine trials and reverse genetics: Foundation for effective response to next pandemic. Ensuring an adequate global supply of influenza vaccine. Infect Dis News. 2003b;4:13.
  17. Ferguson NM, Mallett S. An epidemiological model of influenza to investigate the potential transmission of drug resistant virus during community use of antiviral treatment of influenza. Antiviral Res. 2001;50:A85.
  18. Fidler DP. Germs, governance, and global health in the wake of SARS. J Clin Invest. 2004;113:799–804. [PMC free article: PMC362129] [PubMed: 15067309]
  19. Fodor E, Devenish L, Engelhardt OG, Palese P, Brownlee GG, Garcia-Sastre A. Rescue of influenza A virus from recombinant DNA. J Virol. 1999;73:9679–9682. [PMC free article: PMC113010] [PubMed: 10516084]
  20. Galbraith AW, Oxford JS, Schild GC, Watson GI. Study of L-adamantanamine hydrochloride used prophylactically during the Hong Kong influenza epidemic in the family environment. Bull WHO. 1969;41:677–682. [PMC free article: PMC2427729] [PubMed: 4908342]
  21. Galbraith AW, Oxford JS, Schild GC, Potter CW, Watson GI. Therapeutic effect of L-adamantanamine hydrochloride in naturally occurring influenza A 2-Hong Kong infection. A controlled double-blind study. Lancet. 1971;2:113–115. [PubMed: 4104457]
  22. Gravenstein S, Drinka P, Osterweil D, Schilling M, McElhaney JE, Elliott M, Hammond J, Keene O, Krause P, Flack N. A multicenter prospective double-blind randomized controlled trial comparing the relative safety and efficacy of zanamivir to rimantadine for nursing home influenza outbreak control. Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; Washington, DC: American Society for Microbiology; 2000. p. 270.
  23. Gubareva LV, Matrosovich MN, Brenner MK, Bethell R, Webster RG. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis. 1998;178:1257–1262. [PubMed: 9780244]
  24. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet. 2000;355:827–835. [PubMed: 10711940]
  25. Hall CB, Dolin R, Gala CL, Markovitz DM, Zhang YQ, Madore PH, Disney FA, Talpey WB, Green JL, Francis AB, et al. Children with influenza A infection: Treatment with rimantadine. Pediatrics. 1987;80:275–282. [PubMed: 3302925]
  26. Hay AJ. Amantadine and rimantadine-mechanisms. In: Richman DD, editor. Antiviral Drug Resistance. Chichester, United Kingdom: John Wiley & Sons Ltd; 1996. pp. 43–58.
  27. Hayden FG. Amantadine and rimantadine-clinical aspects. In: Richman DD, editor. Antiviral Drug Resistance. Chichester, United Kingdom: John Wiley & Sons Ltd; 1996. pp. 59–77.
  28. Hayden FG. Antivirals for pandemic influenza. J Infect Dis. 1997;176(Suppl I):S56–S61. [PubMed: 9240696]
  29. Hayden FG. Perspectives on antiviral use during pandemic influenza. Philos Trans R Soc Lond B Biol Sci. 2001;356(1416):1877–1884. [PMC free article: PMC1088564] [PubMed: 11779387]
  30. Hayden FG, Aoki FY. Amantadine, rimantadine, and related agents. In: Yu VL, Merigan TC, Barriere SL, editors. Antimicrobial Therapy and Vaccines. Baltimore, MD: Williams and Wilkins; 1999. pp. 1344–1365.
  31. Hayden FG, Belshe RB, Clover RD, Hay AJ, Oakes MG, Soo W. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Engl J Med. 1989;321:1696–1702. [PubMed: 2687687]
  32. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M, Kinnersley N, Mills RG, Ward P, Straus SE. Use of the oral neuraminidase inhibitor oseltamivir in experimental influenza: Randomized controlled trials for prevention and treatment. JAMA. 1999;282:1240–1246. [PubMed: 10517426]
  33. Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliot MJ, Hammond JM, Sharp SJ, Ossi MJ. Zanamivir Family Study Group. Inhaled zanamivir for prevention of influenza in families. Zanamivir Family Study Group. N Eng J Med. 2000;343(18):1282–1289. [PubMed: 11058672]
  34. Hehme N, Engelmann H, Kunzel W, Neumeier E, Sanger R. Pandemic preparedness: Lessons learnt from H2N2 and H9N2 candidate vaccines. Med Microbiol Immunol (Berl) 2002;191:203–208. [PubMed: 12458361]
  35. Hehme N, Engelmann H, Kuenzel W, Neumeier E, Saenger R. Immunogenicity of a monovalent, aluminum-adjuvanted influenza whole virus vaccine for pandemic use. Virus Res. 2004;103:163–171. [PubMed: 15163505]
  36. Hollis A. The link between publicly funded health care and compulsory licensing. CMAJ. 2002;167:765–766. [PMC free article: PMC126509] [PubMed: 12389839]
  37. Iwahashi J, Tsuji K, Ishibashi T, Kajiwara J, Imamura Y, Mori R, Hara K, Kashiwagi T, Ohtsu Y, Hamada N, Maeda H, Toyoda M, Toyoda T. Isolation of amantadine resistant influenza A viruses (H3N2) from patients following administration of amantadine in Japan. J Clin Microbiol. 2001;39:1652–1653. [PMC free article: PMC87992] [PubMed: 11283109]
  38. Julkunen I, Sareneva T, Pirohonen J, Ronni T, Melen K, Matikainen S. Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression. Cytokine Growth Factor Rev. 2001;12:171–180. [PubMed: 11325600]
  39. Kaiser L, Keene ON, Hammond J, Elliott M, Hayden FG. Impact of zanamivir on antibiotics use for respiratory events following acute influenza in adolescents and adults. Arch Intern Med. 2000;160:3234–3240. [PubMed: 11088083]
  40. Keyser LA, Karl M, Nafziger AN, Bertino JS Jr. Comparison of central nervous system adverse effects of amantadine and rimantadine used as sequential prophylaxis of influenza A in elderly nursing home patients. Arch Intern Med. 2000;160:1485–1488. [PubMed: 10826462]
  41. Knight V, Fedson D, Baldini J, Douglas RG, Couch RB. Amantadine therapy of epidemic influenza A2-Hong Kong. Infect Immun. 1970;1:200–204. [PMC free article: PMC415878] [PubMed: 16557714]
  42. Madjid M, Naghavi M, Litovsky S, Casscells SW. Influenza and cardiovascular disease. A new opportunity for prevention and the need for further studies. Circulation. 2003;108:2730–2736. [PubMed: 14610013]
  43. McCullers JA, Rehg JE. Lethal synergism between influenza virus and Streptococcus pneumoniae: Characterizations of a mouse model and the role of platelet-activating factor receptor. J Infect Dis. 2002;186:341–350. [PubMed: 12134230]
  44. McKimm-Breschkin JL. Resistance of influenza viruses to neuraminidase inhibitors—a review. Antiviral Res. 2000;47:1–17. [PubMed: 10930642]
  45. Meltzer MI, Cox NJ, Fukuda K. The economic impact of pandemic influenza in the United States: Priorities for intervention. EID. 1999;5:659–671. [PMC free article: PMC2627723] [PubMed: 10511522]
  46. Merx MW, Liehn EA, Janssens U, Lutticken R, Schrader J, Hanrath P, Weber C. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation. 2004;109:2560–2565. [PubMed: 15123521]
  47. Monick M, Powers L, Butler S, Hunninghake GW. Inhibition of Rho family GTPases results in increased TNF-alpha production after lipopolysaccharide exposure. J Immunol. 2003;171:2625–2630. [PubMed: 12928415]
  48. Monto AS, Gunn RA, Bandyk MG, King CL. Prevention of Russian influenza by amantadine. JAMA. 1979;241:1003–1007. [PubMed: 368354]
  49. Monto AS, Robinson DP, Herlocher ML, Hinson JM Jr, Elliott MJ, Crisp A. Zanamivir in the prevention of influenza among healthy adults: A randomized controlled trial. JAMA. 1999a;282:31–35. [PubMed: 10404908]
  50. Monto AS, Webster A, Keene O. Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: Pooled efficacy analysis. J Antimicrob Chemother. 1999b;44(Suppl B):23–29. [PubMed: 10877459]
  51. Murphy K, Eivindson A, Pauksens K, Stein WJ, Tellier G, Watts R, Leophonte P, Sharp SJ, Loeschel E. Efficacy and safety of inhaled zanamivir for the treatment of influenza in patients with asthma or chronic obstructive pulmonary disease. Clin Drug Invest. 2000;20:337–349.
  52. Nafta I, Turcanu AG, Braun I, Companetz W, Simionescu A, Birt E, Florea V. Administration of amantadine for the prevention of Hong Kong influenza. Bull WHO. 1970;42:423–427. [PMC free article: PMC2427540] [PubMed: 5310209]
  53. NIAID (National Institute of Allergy and Infectious Diseases). NIAID Taps Chiron to Develop Vaccine Against H9N2 Avian Influenza. Award Part of NIAID Pandemic Influenza Preparedness Program. 2004. [accessed November 10, 2004]. [Online]. Available: http://www2.niaid.nih.gov/newsroom/ releases/h9n2.htm.
  54. Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med. 2003;348:1322–1332. [PubMed: 12672859]
  55. Node K, Fujita M, Kitakaze M, Hori M, Liao JK. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation. 2003;108:839–843. [PMC free article: PMC2665260] [PubMed: 12885745]
  56. Novak K. The WTO's balancing act. J Clin Invest. 2003;112:1269–1273. [PMC free article: PMC228482] [PubMed: 14597749]
  57. Official Journal of the European Community. Article 7b, Regulation 541/95. European Union: Publications Office of the European Union; 1995.
  58. Official Journal of the European Community. European Union: Publications Office of the European Union; 2003. Article 8, Regulation 1085/2003.
  59. Oker-Blom N, Hovi T, Leinikki P, Palosuo T, Pettersson R, Suni J. Protection of man from natural infection with influenza A2 Hong Kong virus by amantadine: A controlled field trial. BMJ. 1970;3:676–678. [PMC free article: PMC1701794] [PubMed: 4919024]
  60. Patriarca PA, Cox NJ. Influenza pandemic preparedness plan for the United States. J Infect Dis. 1997;176(Suppl 1):S4–S7. [PubMed: 9240686]
  61. Peiris JS, Yu WC, Leung CW, Cheung CY, Ng WF, Nicholls JM, Ng TK, Chan KH, Lai ST, Lim WL, Yuen KY, Guan Y. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet. 2004;363:617–619. [PubMed: 14987888]
  62. Peters PH, Gravenstein S, Norwood P, De Bock V, Van Couter A, Gibbens M, van Planta T-A, Ward P. Long term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatr Soc. 2001;49(8):1025–1031. [PubMed: 11555062]
  63. Pettersson RF, Hellstrom PE, Penttinen K, Pyhala R, Tokola O, Vartio T, Visakorpi R. Evaluation of amantadine in the prophylaxis of influenza A (H1N1) virus infection: A controlled field trial among young adults and high-risk patients. J Infect Dis. 1980;142:377–383. [PubMed: 7003032]
  64. Plotkin E, Bernheim J, Ben-Chetrit S, Mor A, Korzets Z. Influenza vaccine—a possible trigger of rhabdomyolysis induced acute renal failure due to the combined use of cerivastatin and bezafibrate. Nephrol Dial Transplant. 2000;15:740–741. [PubMed: 10809833]
  65. Quarles JM, Couch RB, Cate TR, Goswick CB. Comparison of amantadine and rimantadine for prevention of type A (Russian) influenza. Antiviral Res. 1981;1:149–155. [PubMed: 7337431]
  66. Reichert TA, Simonsen L, Sharma A, Pardo SA, Fedson DS, Miller MA. Influenza and the winter increase in mortality in the United States, 1959–1999. Am J Epidemiol. 2004;160:492–502. [PubMed: 15321847]
  67. Sacks FM. High-intensity statin treatment for coronary heart disease. JAMA. 2004;291:1132–1134. [PubMed: 14996784]
  68. Schoch-Spana M. Implications of pandemic influenza for bioterrorism response. Clinical Infectious Diseases. 2000. pp. 1409–1413. [Online]. Available: http://www​.wipo.int. [PubMed: 11096011]
  69. Smorodintsev AA, Karpuhin GI, Zlydnikov DM, Malyseva AM, Svecova EG, Burov SA, Hramcova LM, Romanov JA, Taros LJ, Ivannikov JG, Novoselov SD. The prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong Kong influenza in Leningrad in 1969. Bull WHO. 1970;42:865–872. [PMC free article: PMC2427564] [PubMed: 5312248]
  70. Stilianakis NI, Perelson AS, Hayden FG. Emergence of drug resistance during an influenza epidemic: Insights from a mathematical model. J Infect Dis. 1998;177:863–873. [PubMed: 9534957]
  71. Subbarao K, Chen H, Swayne D, Mingay L, Fodor E, Brownlee G, Xu X, Lu X, Katz J, Cox N, Matsuoka Y. Evaluation of a genetically modified reassortant H5N1 influenza A virus vaccine candidate generated by plasmid-based reverse genetics. Virology. 2003;305:192–200. [PubMed: 12504552]
  72. Tisdale M. Monitoring of viral susceptibility: New challenges with the development of influenza NA inhibitors. Rev Med Virol. 2000;10:45–55. [PubMed: 10654004]
  73. Topol EJ. Intensive statin therapy—a sea change in cardiovascular prevention. N Engl J Med. 2004;350:1562–1564. [PubMed: 15007111]
  74. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, Singh S, Kinnersley N, Ward P, Mills RG. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: A randomized controlled trial. U.S. Oral Neuraminidase Study Group. JAMA. 2000;283:1016–1024. [PubMed: 10697061]
  75. Van Voris LP, Betts RF, Hayden FG, Christmas WA, Douglas RGJ. Successful treatment of naturally occurring influenza A/USSR/77 HIN1. JAMA. 1981;245:1128–1131. [PubMed: 7007668]
  76. Walker JB, Hussey EK, Treanor JJ, Montalvo A, Hayden FG. Effects of the neuraminidase inhibitor zanamivir on otologic manifestations of experimental human influenza. J Infect Dis. 1997;176:1417–1422. [PubMed: 9395349]
  77. Webby RJ, Perez DR, Coleman JS, Guan Y, Knight JH, Govorkova EA, McClain-Moss LR, Peiris JS, Rehg JE, Tuomanen EI, Webster RG. Responsiveness to a pandemic alert: Use of reverse genetics for rapid development of influenza vaccines. Lancet. 2004;363:1099–1103. [PubMed: 15064027]
  78. Welliver R, Manto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, Huson L, Ward P, Oxford JS. Effectiveness of oseltamivir in preventing influenza in household contacts. JAMA. 2001;285:748–754. [PubMed: 11176912]
  79. Whitley RJ, Hayden FG, Reisinger K, Young N, Dutkowski R, Ipe D, Mills RG, Ward P. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J. 2001;20:127–133. [PubMed: 11224828]
  80. WHO (World Health Organization). WHO Consultation on Priority Public Health Interventions Before and During an Influenza Pandemic. Apr 27, 2004. [accessed December 17, 2004]. [Online]. Available: http://www​.who.int/csr​/disease/avian_influenza​/guidelines/pandemicconsultation​/en/ [PubMed: 15114955]
  81. Wood JM. Developing vaccines against pandemic influenza. Philos Trans R Soc Lond B Biol Sci. 2001;356:1953–1960. [PMC free article: PMC1088574] [PubMed: 11779397]
  82. Wood JM, Lewandowski RA. The influenza vaccine licensing process. Vaccine. 2003;21:1786–1788. [PubMed: 12686095]
  83. Ziegler T, Hemphill ML, Ziegler ML, Perez-Oronoz G, Klimov AI, Hampson AW, Regnery HL, Cox NJ. Low incidence of rimantadine resistance in field isolates of influenza A viruses. J Infect Dis. 1999;180:935–939. [PubMed: 10479115]

Footnotes

1

Editor's note: During the production of this report, the WHO Executive Board released additional recommendations. For more information, see the following (1) Influenza Pandemic Preparedness and Response, available at: http://www​.who.int/gb​/ebwha/pdf_files/EB115/B115_44-en.pdf and (2) Strengthening Pandemic Influenza Preparedness and Response, available at: http://www​.who.int/gb​/ebwha/pdf_files/EB115/B115_R16-en.pdf.

2

Comments on this plan should be forwarded to: National Vaccine Program Office, Office of the Assistant Secretary for Health, Department of Health and Human Services, Hubert H. Humphrey Building, 200 Independence Ave, SW—Room 725H, Washington, DC 20201-0004, e-mail: vog.shhd.shposo@azneulfnicimednap.

3

Division of Disease Control, Augusta, ME, 04333.

4

Centers for Disease Control and Prevention, Atlanta, GA.

5

Editor's note: This vaccine is being manufactured at a different facility from the one making the interpandemic, seasonal influenza vaccine that was recently cited for “good manufacturing practice violations” by the FDA (Chiron Corporation, 2004; NIAID, 2004).

6

Department of Internal Medicine, PO Box 800473, University of Virginia Health Sciences Center, Charlottesville, VA 22908; ude.ainigriv@hgf.

7

Keywords: amantadine; rimantadine; oseltamivir; zanamivir; antivirals; resistance.

8

I would like to thank Dr. Fred Aoki and Dr. Martin Meltzer for their ideas and constructive comments and Diane Ramm for help with manuscript preparation.

Copyright © 2005, National Academy of Sciences.
Bookshelf ID: NBK22157