Last updated January 21, 2005

Agent
General Considerations
Historical Perspective
Pandemics of the 20th Century
The Current H5N1 Threat
Vaccine Development
Pandemic Preparedness Planning
Infection Control Considerations
References

Agent

• Family: Orthomyxoviridae
• Genus: Influenza
• Virions are 80 to 120 nm in diameter and may be filamentous.
• Eight different segments of negative-stranded RNA are present; this allows for genetic reassortments in single cells infected with more than one virus and may result in multiple strains that are different from the initial ones (see References: Voyles 2002).
• Type designation is based on the antigenic character of the M protein located in the virus envelope and the nucleoprotein within the virus particle. There are three types of influenza viruses (A, B, and C).
• The virus envelope glycoproteins have hemagglutinin (HA) and neuraminidase (NA) activity; these characteristics are used to subtype the A, B, and C viruses.
• Type: Influenza A
• Influenza A viruses are a major cause of influenza in humans.
• All past influenza pandemics have been caused by influenza A viruses
• There are 15 different HA antigens (H1 to H15) and nine different NA antigens (N1 to N9) for influenza A.
• Human disease historically has been caused by three subtypes of HA (H1, H2, and H3) and two subtypes of NA (N1 and N2).
• More recently, human disease has been recognized to be caused by additional HA subtypes, including H5, H7, and H9.
• All known subtypes of influenza A can be found in birds, and feral aquatic birds are the major reservoir for influenza A viruses. Feral birds generally do not develop severe disease from influenza.
• Several subtypes (H5 and H7) have caused severe outbreaks of disease in domestic bird populations (referred to as "highly pathogenic avian influenza").
• Influenza A has been known to also cause disease in horses, pigs, whales, and seals. More recently, the range of H5N1 influenza A has expanded to include cats, leopards, and tigers (see References: Keawcharoen 2004).

General Considerations

Antigenic Drift vs Antigenic Shift

Influenza viruses continuously undergo small genetic changes (referred to as "antigenic drift") that require development of new influenza vaccines from year to year. Influenza pandemics result when strains undergo a more dramatic genetic change caused by genetic reassortment (referred to as "antigenic shift").

Sources of Pandemic Strains

Past influenza pandemics occurring during the 20th century apparently all arose from the Eurasian avian lineage of viruses (see References: Horimoto 2001). Over the past several years, a great deal of attention has been focused on the role of avian influenza viruses as the source of the next pandemic strain (see References: Horimoto 2001). Subtypes H5, H7, and H9 have received considerable attention in this regard (see References: Capua 2004, Li 2003, Peiris 2001, Webster 1997). At the current time, H5N1 is considered to pose the greatest threat (see the section below on H5N1 in Asia). However, it is certainly possible that a different subtype will reassort to create the next pandemic strain.

Pigs have receptors for avian and human influenza viruses and are susceptible to both; therefore, pigs have been considered logical intermediary hosts for viral reassortment between avian and human influenza strains (see References: Guan 1996, Horimoto 2001, Peiris 2001, Webster 2002). However, the role of pigs in creation of pandemic strains is still not clear. It is also not clear if reassortment in another animal host is necessary or whether an avian strain could directly cause a global pandemic in humans (see References: Webster 1997).

Features of Pandemic Strains

Pandemics occur when a novel influenza strain emerges that has the following features:

• Highly pathogenic for humans
• Easily transmitted between humans
• Genetically unique (ie, lack of preexisting immunity in the human population)

Pandemic Phases

In reviewing the public health implications of a pandemic, it is useful to understand the various phases that a pandemic will go through. These are outlined in the following table.

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Historical Perspective

Earliest reports of influenza epidemics date back to the early 1500s (see References: Cunha 2004). During the ensuing centuries, several influenza pandemics were recorded (see References: Cunha 2004).

• The first recorded pandemic occurred in 1580 and spread from Europe to Asia and Africa.
• During the 17th century, localized epidemics were reported and in the 18th century and least three pandemics occurred (1729-1730, 1732-17333, and 1781-1782).
• Three influenza pandemics also occurred during the 19th century (1830-1831, 1833-1834, 1889-1890). The 1889 pandemic began in Russia and spread rapidly throughout Europe (known as the "Russian Flu"). It reached North America in December 1989 and spread to Latin America and Asia in February of 1890. Approximately 1 million people died as a result of this pandemic.

Pandemics of the 20th Century

Three pandemics occurred during the 20th century. These are outlined in the table below and then briefly summarized.

1918-1919 (Spanish Flu)

This pandemic was caused by an influenza A (H1N1) strain. Worldwide, over 200 million people were infected and an estimated 50 to 100 million died (see References: Barry 2004). Earlier estimates implied that the death toll was 20 to 40 million, but more recent evidence supports the higher figures. Adjusting for today's population, a similar pandemic would yield a modern death toll of 175 to 350 million.

• The pandemic began with a relatively mild "herald" wave in the spring of 1918. During that time, outbreaks were reported in Europe and in the United States (particularly in military training camps for new recruits headed to the war in Europe) (see References: Reid 2001, Glezen 1996).
• Many investigators believe that the strain originated in the United States (perhaps in rural Kansas) and then migrated initially to France before spreading throughout Europe (see References: Barry 2004). However, others believe that the strain may have been circulating in the Mid-Atlantic States as early as February of 1918 (see References: Simonsen 2004). Furthermore, an outbreak of severe respiratory disease occurred in an army camp in France in 1916-17 (see References: Oxford 2000). A significant clinical feature of the disease was cyanosis, which also was a predominant finding among those who acquired the pandemic strain of influenza. It is possible that this outbreak represented H1N1 infection and was an early precursor to the pandemic. At any rate, it is clear that the 1918-19 pandemic did not begin in Asia.
• A second, highly virulent wave spread rapidly around the world in the fall of 1918; it took only 2 months for the pandemic to circle the globe at that time.
• Additional waves that were not as severe occurred in 1919 and 1920.

An unusual feature of the pandemic was the age-related mortality; the pandemic strain killed a disproportionate number of healthy young adults. This led to the observation of a "W" shaped age-related mortality curve in the United States, with high rates of mortality among very young children, persons 15 to 45 years of age, and the elderly (see References: Reid 2001; Glezen 1996). Usually the curve associated with influenza mortality follows a "U" shape, with excess deaths occurring only among the very young and the elderly. One striking feature of the pandemic was its impact on pregnant women; a summary of 13 studies involving pregnant women demonstrated that case-fatality rates ranged from 23% to 71% (see References: Barry 2004).

Recent studies in mice using genetically engineered influenza strains similar to the H1N1 pandemic strain suggest that macrophage activation with high levels of cytokine production may be a key factor in lung damage caused by that strain (see References: Kobasa 2004). It is possible that an overly robust immune response inducing a "cytokine storm" may have been responsible for the high fatality rates seen in younger populations during the 1918 pandemic.

Recorded case fatality rates varied around the globe. In the US military, death rates ranged from 5% to 10% (see References: Barry 2004). Higher rates were reported in some areas.

1957-1958 (Asian Flu)

The Asian flu was caused by an H2N2 strain and originated in China. The virus was initially isolated in Singapore in February 1957 and in Hong Kong in April of that year. The pandemic spread to the Southern Hemisphere during the summer of 1957 and reached the United States in June 1957 (see References: Glezen 1996). The pandemic strain acquired three genes from the avian influenza gene pool in wild ducks by genetic reassortment and obtained five other genes from the then-circulating human strain.

About 69,800 people in the United States died and mortality was spread over three seasons. Overall, the highest mortality rates occurred among the elderly; however, during the initial season in 1957, nearly 40% of the influenza deaths occurred among persons less than 65 years of age (see References: Simonsen 2004). The high case-fatality rate in this age-group declined in subsequent years. Globally, approximately 1 million people died during this pandemic.

1968-1969 (Hong Kong Flu)

The Hong Kong flu was caused by an H3N2 strain. The strain acquired two genes from the duck reservoir by reassortment and kept six genes from the virus circulating at the time in humans.

During the pandemic, about 33,800 people died in the United States. The death rate from this pandemic may have been lower because the strain had a shift in the hemagglutinin (H) antigen only and not in the neuraminidase (N) antigen. Although antibodies to neuraminidase antigen do not prevent infection, they may modify the severity of disease (see References: Glezen 1996). Also, an H3 strain had apparently circulated in the United States around the turn of the century, so very old persons may have had some protective antibody from past exposure to an H3 strain (see References: Simonsen 2004). This could have caused a lower fatality rate in the elderly.

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The Current H5N1 Threat

Detailed information about H5N1 influenza in bird populations can be found in the document Avian Influenza (Bird Flu): Agricultural and Wildlife Considerations and in human populations in the document Avian Influenza (Bird Flu): Implications for Human Disease.

Of the avian influenza subtypes, currently the H5N1 subtype is of greatest pandemic concern for the following reasons (see References: WHO: Avian influenza fact sheet):

• The virus has spread rapidly throughout poultry flocks in Asia over the past 2 years and now appears to be enzootic in eastern Asia (see References: Kaye 2005, Li 2004).
• The subtype mutates rapidly.
• It has shown a propensity to acquire genes from viruses infecting other animal species.
• It causes severe disease in humans, with a high case-fatality rate (reportedly at about 70%, although adequate surveillance data are lacking to accurately define the rate).

Since January 2002, the predominant avian H5N1 strain in southern China has been genotype Z. Since its emergence, this strain has replaced other genotypes and has become the predominant genotype circulating in aquatic and terrestrial poultry in the region (see References: Li 2004). This strain circulating in Asia appears to be highly pathogenic for humans, and immunity in the human population is generally lacking. However, the strain has not yet been shown to be easily transmitted between humans, and sustained person-to-person transmission has not occurred. Reassortment with human strain(s) would be necessary for the current virus to acquire this attribute.

If H5N1 continues to circulate widely among poultry, the potential for emergence of a pandemic strain remains high. For example, H5N1 viruses have been found in pigs in southern China, and human H3N2 influenza viruses are endemic in pigs in that area. Thus, the conditions exist for exchange of genetic material between the different viruses in the pig host (see References: Li 2004; WHO: Avian influenza update: implications of H5N1 infections in pigs in China).

As of January 2005, human cases of H5N1 have been recognized in Vietnam and Thailand (see References: Chotpitayasunondh 2005, Hien 2004). By year-end 2004, 28 confirmed cases of H5N1 with 20 deaths had been reported from Vietnam and 17 confirmed cases with 12 deaths had been reported from Thailand. Additional cases, some fatal, are being reported in January 2005 (see References: WHO: Cumulative number of confirmed human cases of avian influenza, and see CIDRAP News for updated information).

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Vaccine Development

Development of an effective vaccine is considered the cornerstone for controlling a global influenza pandemic. In general, if a novel strain occurs without adequate warning, WHO has indicated that it will take at least 4 to 6 months to develop a vaccine (see References: WHO: Influenza pandemic preparedness plan). However, there are several major obstacles in producing an adequate vaccine supply during a pandemic:

• Limited production capacity
• Production capability in only a few countries, which will yield an inequitable distribution
• Technological challenges to vaccine development

Limited Production Capacity

For the period 2000 to 2003, global annual influenza vaccine production ranged from approximately 230 million doses of trivalent vaccine (2000) to 291 million doses (see References: Fedson: Pandemic influenza vaccine). Assuming that the pandemic vaccine will be a monovalent vaccine, the capacity would be increased to an estimated 750 million doses each year (see References: WHO: Consultation on priority public health interventions before and during an influenza pandemic).

In the United States, domestic production was estimated at 50 million doses of trivalent vaccine during 2004. This would be equivalent to about 150 million doses of monovalent standard-dose (15 mcg HA) vaccine (see References: Fedson: Pandemic influenza and the global vaccine supply). Another issue is whether one dose or two doses will be needed to confer adequate protection. If two doses are needed, only 75 million people in the United States could be vaccinated during the first year of a pandemic at the current rate of domestic vaccine production.

Decreasing the amount of antigen per dose and using adjuvants to increase immunogenicity could substantially increase vaccine production. However, even with these additional steps, it will likely take many months to produce enough vaccine to cover the world's population at the current rate of capacity (see References: Medema 2004, Fedson 2003).

Production Capability in Only a Few Countries

Most of the world's influenza vaccine is produced in a few countries. These countries are likely to reserve scarce supplies for their own populations during a pandemic, thus leading to an inequitable distribution of vaccine, particularly to developing countries. This issue has relevance for the United States as well, where current domestic vaccine production falls far short of producing adequate vaccine supplies to vaccinate the entire US population. Moreover, the US plan does not address the issue of distributing vaccine to other countries.

Nine companies, located in the following nine developed countries, currently produce influenza vaccine:

• Australia
• Canada
• France
• Germany
• Italy
• The Netherlands
• Switzerland
• The United Kingdom
• The United States

Technological Challenges to Vaccine Development

The manufacture of vaccines derived from pathogenic avian strains poses a number of technological challenges. For example, highly pathogenic avian strains cannot be grown in large quantities in eggs because they are lethal to chick embryos. These strains also pose significant safety issues and would require extensive biocontainment procedures during the manufacturing process.

Several approaches have been suggested to overcome these issues (see References: Stephenson 2004):

• Produce inactivated vaccine from wild-type virus
• Select an antigenically related but nonpathogenic surrogate vaccine strain
• Use baculoviruses to express recombinant hemagglutinin
• Develop DNA-based vaccines
• Use reverse genetics to construct vaccine seed strains that possess attenuated hemagglutinin
• Use reverse genetics to construct attenuated donor strains

The process of reverse genetics has been used for preparing H5N1 seed strains (see References: Webby 2004; WHO: Development of a vaccine effective against avian influenza H5N1 infection in humans). However, whether vaccines made from these seed strains will be immunogenic in humans is not clear, given that candidate vaccines developed against the 1997 H5N1 strain from Hong Kong were poorly immunogenic (see References: Stephenson 2004). It may be that an effective vaccine cannot be developed until a true pandemic strain (reassorted with human influenza viruses) emerges and can be used as the seed virus.

Interpandemic Steps to Facilitate Vaccine Production

During the interpandemic period, a number of steps can be taken to improve vaccine response capability once a pandemic arrives. One set of recommendations includes the following (see References: Fedson 2004: Vaccination for pandemic influenza; a six point agenda for interpandemic years):

• Prepare vaccine seed strains for production. Use of reverse genetics to develop high growth variants can enhance this process.
• Determine the characteristics of a pandemic vaccine and vaccination schedule. This can be done by undertaking clinical trials of pandemic-like candidate vaccines. Such trials should determine the minimal antigenic content per dose needed for an acceptable immune response.
• Consider global registration of pandemic vaccines. A global protocol would allow vaccine produced by any company to be registered in all countries and thereby eliminate regulatory delays on a country-by-country basis.
• Increase the use of influenza vaccines during interpandemic years to bolster manufacturing capacity.
• Document the epidemiology of influenza vaccination. This would help vaccine companies make future plans for vaccine production.
• Address underlying political issues that will affect the global supply of pandemic vaccines. A key issue is the fact that political leaders in vaccine-producing countries will likely prohibit export of domestically produced pandemic vaccine until that country's vaccine demands are met. International agreements to address this problem should be developed before a pandemic occurs.

Because of concerns about the pandemic potential of H5N1, the World Health Organization (WHO) has been working with laboratories in its influenza network to develop vaccines against this subtype (see References: WHO: Development of a vaccine effective against avian influenza H5N1).

• Candidate vaccines were developed during 2003 by network laboratories in London and in Memphis, Tennessee, for protection against the strain that was isolated from humans in Hong Kong in February of that year. However, the 2004 strain is different from that strain.
• In April 2004, WHO made the prototype seed strain for an H5N1 vaccine available to manufacturers (see References: WHO: Avian flu: situation in Thailand; status of pandemic vaccine development).
• The National Institute of Allergy and Infectious Diseases (NIAID) awarded two contracts to support the production and clinical testing of an investigational vaccine based on the prototype seed strain made available by WHO (see References: NIAID 2004).
• The contracts were awarded to Aventis Pasteur of Swiftwater, Pennsylvania, and to Chiron Corporation of Emeryville, California. Each manufacturer is using established techniques in which the virus is grown in eggs and then inactivated and further purified before being formulated into vaccines.
• Clinical trials of candidate H5N1 vaccines should begin in early 2005 (see References: WHO: Avian flu: situation in Thailand; status of pandemic vaccine development).

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Pandemic Preparedness Planning

Although pandemic planning has been ongoing for several years at the global level (through WHO) and in a number of countries, the challenges for preparing for a pandemic are enormous. Even with the best planning efforts, there is no way to adequately prepare for a pandemic given the currently available resources. The challenges include these:

• If an influenza pandemic were to occur in the near future, vaccine for the pandemic strain would not be readily available for a number of months, as noted in the previous section. In addition, supplies of antiviral agents would be extremely limited (see References: Hayden 2004). Therefore, prevention and treatment options would essentially not be available during the initial wave of the pandemic.
• Once a vaccine is available, the current plans do not adequately address how the vaccine will be distributed globally. This is of great concern, since vaccine is only produced by a few countries and those countries are likely to not release vaccine until the needs of their populations are met.
• If the next pandemic strain is highly virulent (such as the 1918 strain) the global death toll could be dramatic. The current plans generally do not address the social, political, or economic issues that would likely be associated with an ongoing influenza pandemic. It is very possible that substantial disruption of basic services (such as health care, food, clothing, provision of utilities [eg, water, electricity], and transportation will occur. Furthermore, international trade will likely be impacted, which could have serious economical and societal consequences.

Global Planning

WHO has taken several steps toward global pandemic influenza planning, including development of a pandemic plan in 1999 (see References: WHO: Influenza pandemic preparedness plan).

In addition, WHO in March 2004 held a meeting, WHO Consultation on Priority Public Health Interventions Before and During an Influenza Pandemic (see References). The consultation was attended by more than 100 experts from 33 countries. Key recommendations made during the consultation are summarized below.

Surveillance

• Assure prompt and transparent reporting of early human cases.
• Develop integrated surveillance systems, such as those for detection of other emerging or epidemic-prone diseases.
• Concentrate on the interpandemic phase, to assure early detection of a pandemic strain.
• Focus on the ability to detect unusual clusters of respiratory diseases as part of an early warning system. Multidisciplinary teams for investigation of such clusters should be developed. Field investigations should include:
• Molecular epidemiology to determine the characteristics of the virus
• Studies on dynamics of human-to-human transmission
• Identification of a reassortment event
• Strengthen the WHO Global Influenza Surveillance Network to ensure collection, testing, and timely transfer of clinical specimens to one of the four WHO collaborating centers for reference and research on influenza.
• Assure that surveillance activities involve collaboration with animal surveillance, since pandemic strains historically arise in animal reservoirs.
• Follow surveillance methodologies suggested by WHO and stratified according to the pandemic phase (as outlined in the consultation document).

Public health interventions

• Since a pandemic would affect multiple sectors within society, a broad range of government departments should be involved in pandemic planning.
• Nonmedical interventions will be the control measures pending adequate supplies of an effective vaccine; examples of measures to consider include:
• Rick communication
• Isolation of cases
• Tracing and management of contacts (early in the pandemic)
• Measures to increase "social distance" (such as closing schools, furloughing nonessential workers, and canceling mass gatherings)
• Limiting the spread of infection by domestic and international travel through steps such as providing information to travelers and recommending that ill persons not travel

Use of antiviral agents

• Most countries will not have access to antiviral agents. Those with manufacturing capacity should consider stockpiling agents in advance.
• Development of an international stockpile should be considered for use in the prepandemic period to delay spread of the pandemic strain.
• Early treatment is considered a more efficient use of resources than prophylaxis.

Vaccine development

• Increasing vaccine use in interpandemic years will enhance production capacity, which is currently inadequate to handle the demands of a global pandemic.
• Since no country will have adequate supplies at the onset of a pandemic, countries should decide in advance on priority groups of vaccination when supplies are limited.
• Public funding should give priority to research on cross-subtype vaccines that confer lasting protection.

The US Pandemic Influenza Plan

The US Pandemic Influenza Preparedness and Response Plan was issued by the Department of Health and Human Services (HHS) in draft form in August 2004 (see References: HHS: Pandemic influenza response and preparedness plan). The plan includes an Executive Summary (most of its content is included in the sections below. In addition, the plan includes these12 annexes addressing various aspects of the plan process:

• Planning Guidance for State and Local Health Departments
• Planning Guidance for Health Care System
• Overview of Influenza Illness and Pandemics
• Surveillance
• Vaccine Development and Production
• Vaccination Strategies, Monitoring, and Safety
• Antiviral Strategies and Use
• Strategies to Limit Transmission
• Communication and Education
• Pandemic Influenza Research
• Lessons Learned from the 1976 Swine Flu Program
• Synergies and Differences in Preparedness and Response for Influenza and Other Infectious Disease Threats

Goals

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

Key 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 United States 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 US 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 WHO, 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 US 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 6 to 8 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 targeted first to priority groups that will be defined on the basis of several factors. These may include the risk of occupational infections/transmission (eg, healthcare 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, zanamivir) also are effective for prophylaxis and treatment of susceptible strains. New data suggest 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 US 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 Strategic National Stockpile (SNS). Analysis is ongoing to define strategies for optimal antiviral use, potential health impacts, and cost-effectiveness of antiviral drugs in the pandemic setting. Results of these analyses will contribute to decisions regarding the appropriate antiviral drugs to maintain in the SNS. Planning by public and private healthcare 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 healthcare 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 healthcare 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 healthcare services. Because of the increased risk of exposure to pandemic virus in healthcare settings, illness and absenteeism among healthcare workers in the context of increased demand will further strain the ability to provide quality care.
• In addition to shortages of hospital beds and staff, equipment and supplies may be in short supply in a pandemic. The disruptions in the healthcare system that result from a pandemic may also have an impact on blood donation and supply.
• Planning by local health departments and the healthcare 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 healthcare personnel. Local coordination can help direct patients to hospitals with available beds and distribute resources to sites where they are needed.
• Healthcare 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 healthcare, 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.

The plan also addresses coordination of the pandemic response. According to the plan, an influenza pandemic will represent a national health emergency requiring coordination of response activities.

• As outlined in Homeland Security Presidential Directive 5 (see References: FEMA), the Department of Homeland Security 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 or Institute of Medicine, or in other forms.

During the interpandemic 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 pandemic vaccine production, and assess potential approaches to optimize vaccine dose and diversify manufacturing.
• Strengthen global surveillance (human and animal), 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 severe acute respiratory syndrome. In addition to coordinating between HHS and the US Department of Agriculture, building and strengthening a global veterinary surveillance network will complement the existing clinical laboratory network organized by WHO.
• Strengthen US 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 (eg, 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 capable of leading 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, easier to administer, and directed against a constant portion of the influenza virus, thus sidestepping the need to develop a new vaccine every year to match the predominant viral strains that are most likely to cause disease. Through 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 increase manufacturers' overall capacity.
• Improve capacity to monitor influenza vaccine effectiveness and 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, public and private healthcare 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, limited public gatherings, and quarantine and isolation.
• Develop materials for various audiences that will inform and educate them about influenza and pandemic influenza.

Planning at the Local Level

In addition to the federal plan, a number of states have developed pandemic influenza plans. Guidance on pandemic planning for state and local health departments is provided in the federal plan as Annex 1 (see References: HHS: Pandemic influenza preparedness and response plan). In addition, the Association of State and Territorial Health Officials (ASTHO) has issued a guidance document for pandemic influenza planning (see References: ASTHO).

The Council for State and Territorial Epidemiologists (CSTE) has links to a number of state plans on their Web site (see References: CSTE).

Infection Control Considerations

Infection control guidelines for pandemic influenza are provided in Annex 2 of the draft Federal Plan (see References: HHS: Pandemic Influenza Preparedness and Response Plan).

Droplets are the major mode of influenza transmission; therefore, the draft Federal plan recommends Droplet Precautions along with Standard Precautions for prevention of transmission in healthcare settings. Airborne precautions are not recommended at this time. The draft Plan also calls for instituting programs of respiratory hygiene and cough etiquette.

Standard Precautions

According to the Federal plan, the following Standard Precautions should be taken for a patient with suspect or confirmed influenza caused by a pandemic strain:

• Wear gloves in hand contact with respiratory secretions or potentially contaminated surfaces is expected.
• Wear a gown if soling of clothes with patient's respiratory secretions is expected.
• Change gloves and gowns after each patient encounter and before touching any noncontaminated items or touching another patient, and perform hand hygiene.
• Decontaminate hands before and after touching the patient, after toughing the patient's environment, or after touching the patient's respiratory secretions, whether or not gloves are worn.
• When hands are visibly soiled or contaminated with respiratory secretions, wash hands with either a non-antimicrobial or an antimicrobial soap and water. Hand hygiene with plain soap or detergent for at least 10 to 15 seconds, under running water is an effective method of removing soil and transient microorganisms. If sinks for hand hygiene are not readily available, alcohol-based agents can be used.
• If hands are not visibly soiled and after glove removal, use an alcohol-based hand rub for routinely decontaminating hands in clinical situations. Alternatively, wash hands with an antimicrobial soap and water.

Droplet Precautions

• Place patient in a private room. When a private room is not available, place the patient in a room with a patient or patients who have active infection with the same microorganism but no other infection (cohorting). In a pandemic it is likely that most patients with suspected influenza will not have a specific laboratory confirmed diagnosis; such patients should be cohorted with other patients who have or may have influenza. If for some reason cohorting is not achievable, at least 3 feet spatial separation should be maintained between the infected patient an other patients and visitors. Special air handling and ventilation are not necessary, and the door may remain open.
• Wear a surgical mask upon entering the patient's room or when working within 3 feet of the patient. Remove the mask when leaving the patient's room and dispose of the mask in a waste container. N95 respirators, which would be recommended for infections with airborne spread such as tuberculosis, are not required for influenza. Logistically, some hospitals may want to implement policy for the wearing of a mask to enter the room.
• Limit the movement and transport of the patient fro the room to essential purposes only. If transport or movement is necessary, minimize patient dispersal of droplets by having the patient wear a surgical mask.

Respiratory Hygiene/Cough Etiquette

The draft Federal Plan indicates that respiratory hygiene/cough etiquette programs should be in place to decrease transmission of influenza. The CDC Web site outlines steps for implementing these programs (see References: CDC: Respiratory Hygiene/Cough Etiquette in Healthcare Settings).

• The following measures to contain respiratory secretions are recommended for all individuals with signs and symptoms of a respiratory infection.
• Cover the nose/mouth when coughing or sneezing.
• Use tissues to contain respiratory secretions and dispose of them in the nearest waste receptacle after use.
• Perform hand hygiene (eg, hand washing with non-antimicrobial soap and water, alcohol-based hand rub, or antiseptic handwash) after having contact with respiratory secretions and contaminated objects/materials.
• During periods of increased respiratory infection activity in the community (eg, when there is increased absenteeism in schools and work settings and increased medical office visits by persons complaining of respiratory illness), healthcare facilities should offer masks to persons who are coughing.
• Either procedure masks (ie, with ear loops) or surgical masks (ie, with ties) may be used to contain respiratory secretions.
• Respirators such as N-95 or above are not necessary.
• When space and chair availability permit, coughing persons should be encouraged to sit at least three feet away from others in common waiting areas.
• When implementing respiratory hygiene programs, healthcare facilities should:
• Ensure the availability of materials for adhering to respiratory hygiene/cough etiquette in waiting areas for patients and visitors.
• Provide tissues and no-touch receptacles for used tissue disposal.
• Provide conveniently located dispensers of alcohol-based hand rub; where sinks are available, ensure that supplies for hand washing (ie, soap, disposable towels) are consistently available.

Additional components of infection control can be found in Annex 2 of the draft Federal Plan.

WHO Infection Control Guidelines for H5N1 Avian Influenza

In March 2004, WHO issued infection control guidelines for preventing transmission of H5N1 influenza in healthcare facilities (see References: WHO: Influenza A (H5N1): Interim infection control guidelines for health care facilities). These guidelines indicate that the following precautions should be implemented when caring for patients with H5N1 influenza:

• Standard precautions
• Droplet precautions
• Contact precautions
• Airborne precautions (including use of high-efficiency masks and negative-pressure rooms when available)

References

ASTHO. Nature's terrorist atack: pandemic influenza. Preparedness planning for state health officials [Full text]

Barry JM. 1918 revisited: lessons and suggestions for further inquiry. In: The threat of pandemic influenza: are we ready? Institute of Medicine. Nov 16, 2004 [Full text]

Capua I, Alexander D. Avian influenza: recent developments. Avian Pathol 2004;33(4):393-404

Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis 2005 Feb;11(2) [Full text]

CDC. Respiratory hygiene/cough etiquette in healthcare settings [Web page]

CSTE. Influenza preparedness state plans [Web page]

Cunha BA. Influenza: historical aspects of epidemics and pandemics. Infect Dis Clin North Am 2004 Mar;18:141-55 [Abstract]

Fedson DS. Pandemic influenza and the global vaccine supply. Clin Infect Dis 2003 Jun 15;36:1552-61 [Full text]

Fedson DS. Vaccination for pandemic influenza; a six point agenda for interpandemic years. Pediatr Infect Dis J 2004 Jan;23(1 Suppl):S74-7 [Abstract]

Fedson D. Pandemic influenza vaccine: obstacles and opportunities. In: The threat of pandemic influenza: are we ready? Institute of Medicine. Nov 16, 2004 [Full text of book]

FEMA. Homeland Security Presidential Directive/HSPD-5: Management of domestic incidents. Feb 28, 2003[Full text]

Glezen WP. Emerging infections: pandemic influenza. Epidemiol Rev 1996;18(1):64-76

Guan Y, Shortridge KF, Krauss S, et al. Emergence of avian H1N1 influenza viruses in pigs in China. J Virol 1996;70(11):8041-46 [Full text]

Hayden FG. Perspectives on antiviral use during pandemic influenza. In: The threat of pandemic influenza: are we ready? Institute of Medicine. Nov 16, 2004 [Full text of book]

Hien TT, Liem NT, Dung NT, et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 2004 Mar 18;350(12):1179-88 [Full text]

HHS. Influenza pandemics: how they start, how they spread, and their potential impact. National Vaccine Program Office [Web page]

HHS. Pandemic influenza response and preparedness plan. Aug 26, 2004 [Full text]

Horimoto T, Kawaoka Y. Pandemic threat posed by avian influenza A viruses. Clin Microbiol Rev 2001;14(1):129-49 [Abstract]

Kaye D, Pringle CR. Avian influenza viruses and their implications for human health. Clin Infect Dis 2005 Jan 1;40(1):108-12 [Abstract]

Keawcharoen J, Oraveerakul K, Kuiken T, et al. Avian influenza H5N1 in tigers and leopards. Emerg Infect Dis 2004 Dec;10(12) [Full text]

Kobasa D, Takada A, Shinya K, et al. Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature 2004 Oct 7;431(7009);703-7 [Abstract]

Li KS, Guan Y, Wang J, et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 2004 Jul 8;430:209-13 [Abstract]

Li KS, Xu KM, Peiris JSM, et al. Characterization of H9 subtype influenza viruses from ducks on Southern China: a candidate for the next influenza pandemic in humans? J Virol 2003 Jun;77(12):6988-94 [Abstract]

Medema JK, Zoellner, YF, Ryan J, et al. Modeling pandemic preparedness scenarios: health economic implications of enhanced pandemic vaccine supply. Virus Res 2004 Jul;103(1-2):9-15 [Abstract]

NIAID. Significant dates in influenza history [Web page]

NIAID. NIAID announces contracts to develop vaccine against H5N1 avian influenza. May 2004 [Press release]

Oxford JS. Influenza A pandemics of the 20th century with special reference to 1918: virology, pathology and epidemiology. Rev Med Virol 2000 Mar-Apr;10(2):119-33 [Abstract]

Peiris M, Guan Y, Markwell D, et al. Cocirculation of avian H9N2 and contemporary "human" H3N2 influenza A viruses in pigs in Southeastern China: potential for genetic reassortment? J Virol 2001;75(20):9679-86 [Abstract]

Reid AH, Taubenberger JK, Fanning TG. The 1918 Spanish influenza: integrating history and biology. Microbes Infect 2001 Jan:3(1):81-7 [Abstract]

Simonsen L, Olson DR, Viboud C, et al. Pandemic influenza and mortality: past evidence and projections for the future. In: The threat of pandemic influenza: are we ready? Institute of Medicine. Nov 16, 2004 [Full text of book]

Stephenson I, Nicholson KG, Wood JM, et al. Confronting the avian influenza threat: vaccine development fro a potential pandemic. Lancet Infect Dis 2004 Aug;4(8):499-509 [Abstract]

Voyles BA. Orthomyxoviruses. In: The biology of viruses. Ed 2. New York, NY: McGraw-Hill, 2002:147

Webby RJ, Perez DR, Coleman JS, et al. Responsiveness to a pandemic alert: use of reverse genetics for rapid development of influenza vaccines. Lancet 2004 Apr 3;363(9415):1099-103 [Abstract]

Webster RG. The importance of animal influenza for human disease. Vaccine 2002;20:S16-20

Webster RG. Predictions for future human influenza pandemics. J Infect Dis 1997 Aug;176(Suppl 1):S14-19 [Full text]

WHO. Avian influenza fact sheet [Web page]

WHO. Avian influenza: situation in Thailand; status of pandemic vaccine development Oct 4, 2004 [Web page]

WHO. Avian influenza—update: implications of H5N1 infections in pigs in China. Aug 25, 2004 [Web page]

WHO. Consultation on priority public health interventions before and during an influenza pandemic [Full text]

WHO. Development of a vaccine effective against avian influenza H5N1 infection in humans: update 4. Jan 20, 2004 [Web page]

WHO. Guidelines for the use of seasonal influenza vaccine in humans at risk of H5N1 infection. Jan 30, 2004 [Web page]

WHO. Influenza A (H5N1): interim infection control guidelines for health care facilities. Mar 10, 2004 [Full text]

WHO: Influenza pandemic preparedness plan: the role of WHO and guidelines for national or regional planning. Geneva, Switzerland. Apr 1999 [Full text]

WHO. Cumulative number of confirmed human cases of avian influenza A(H5N1) since 28 January 2004 [Web page]

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