Pandemic Influenza

Last updated October 3, 2008

Agent
Laboratory Testing for Influenza
General Considerations
Historical Perspective
Pandemics of the 20th Century
Lessons From Past Pandemics
The Pandemic Severity Index
The Current H5N1 Threat
Vaccine Development
Use of Antiviral Agents
Community Mitigation Strategies
Pandemic Preparedness Planning
Hospital Pandemic Preparedness Planning
Infection Control Considerations
References

Note: Information on avian influenza is available in the overviews "Avian Influenza (Bird Flu): Implications for Human Disease" and "Avian Influenza (Bird Flu): Agricultural and Wildlife Considerations" in the Avian Flu section of this site.

Agent

All past influenza pandemics in humans have been caused by influenza A viruses. General information about influenza A viruses (not specific to pandemic strains) is presented in the bullet points below.

Family: Orthomyxoviridae

Enveloped virions are 80 to 120 nm in diameter, are 200 to 300 nm long, and may be filamentous.
They consist of spike-shaped surface proteins, a partially host-derived lipid-rich envelope, and matrix (M) proteins surrounding a helical segmented nucleocapsid (6 to 8 segments).
The family contains five genera, classified by variations in nucleoprotein (NP and M) antigens: influenza A, influenza B, influenza C, thogotovirus, and isavirus.

Genus: Influenzavirus A

The genus consists of a single species: influenza A virus.
Influenza A viruses are a major cause of influenza in humans.
The multipartite genome is encapsidated, with each segment in a separate nucleocapsid. Eight different segments of negative-sense single-stranded RNA are present; this allows for genetic reassortment 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).
The genome consists of 10 genes encoding for different proteins (eight structural proteins and two nonstructural proteins). These include the following: three transcriptases (PB2, PB1, and PA), two surface glycoproteins (hemagglutinin [HA] and neuraminidase [NA]), two matrix proteins (M1 and M2), one nucleocapsid protein (NP), and two nonstructural proteins (NS1 and NS2).
The virus envelope glycoproteins (HA and NA) are distributed evenly over the virion surface, forming characteristic spike-shaped structures. Antigenic variation in these proteins is used as part of the influenza A virus subtype definition (but not used for influenza B or C viruses).

Influenza A virus subtypes:

There are 16 different HA antigens (H1 to H16) and nine different NA antigens (N1 to N9) for influenza A. Until recently, 15 HA types had been recognized, but a new type (H16) was isolated from black-headed gulls caught in Sweden and the Netherlands in 1999 and reported in the literature in 2005 (see References: Fouchier 2005).
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 from avian origin). A recent report suggests that human infections with H9N2 viruses may be more common than previously recognized (see References: Wan 2008). The authors also concluded that H9N2 viruses can evolve extensively and reassort, suggesting that they may be capable of undergoing further adaptation for more efficient transmission among mammals and humans.
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; however, domestic chickens and turkeys are susceptible to severe and potentially fatal influenza.
Certain mammals also are susceptible to influenza. Influenza A viruses have traditionally been known to cause disease in horses, pigs, whales, and seals; however, the range of several influenza A subtypes is expanding to further mammalian species. H5N1 influenza A recently has been shown to infect cats, leopards, and tigers (see References: Keawcharoen 2004; Webster 2006). A recent report demonstrated that calves can be experimentally infected with H5N1 virus (see References: Kalthoff 2008).
Cases of canine influenza have been recognized in the United States and are being caused by H3N8 influenza A, a subtype traditionally found in horses (see References: Crawford 2005).

Influenza A virus subtype strains

Antigenic strain nomenclature is based on: (1) host of origin (if other than human), (2) geographic origin, (3) strain number, (4) year of isolation, and (5) HA and NA type. (Examples are: A/Hong Kong/03/68[H3N2], A/swine/Iowa/15/30[H1N1].)
H5N1 strains have been differentiated into genetic clades, with nonoverlapping case distributions. All human H5N1 strains are grouped in clade 1 and subclades 1 through 3 of clade 2 (see References: WHO 2007: Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as pre-pandemic vaccines).

Classification of influenza A strains by pandemic potential

Strains from past pandemics: "Noncontemporary" strains are those from previous pandemics that pose some degree of risk to the public owing to decreased immunity in the current population. The term is currently used to describe strains from the Asian flu (H2N2).
Nonpandemic strains: These include strains that have recently circulated or are currently circulating in the human population (ie, those belonging to H1N1, H3N2, and H1N2 subtypes).
Potential pandemic strains: Potential pandemic strains must have the following features: (1) an antigenic makeup to which the population is immunologically naive, (2) ability to replicate in humans, and (3) capability to transmit efficiently from human to human. Because of homosubtypic immunity (see below), new pandemic strains are most likely to be of subtypes not previously recognized in human populations. Currently, strains of H5 and H7 subtypes are of greatest concern.
Animal pandemic strains (including avian influenza strains): Animal strains such as H5N1 avian influenza are not considered human pandemic strains unless the above criteria are met, but they have significant potential to evolve into new human pandemic strains through the process of genetic reassortment (see below) or through gradual adaptation to the human host. Most avian strains are not of concern as potential pandemic strains.

Avian influenza

The term "avian influenza" is used to describe influenza A subtypes that primarily affect chickens, turkeys, guinea fowls, migratory waterfowl, and other avian species.
"Avian influenza" is an ecological classification that does not correspond exactly to other classification schemes.
As with other influenza A subtypes, standard nomenclature is used to name strains (eg, A/chicken/HK/5/98 [H5N1]).
Avian influenza strains in domestic chickens and turkeys are classified according to disease severity, with two recognized forms: highly pathogenic avian influenza (HPAI), also known as fowl plague, and low-pathogenic avian influenza (LPAI). Avian influenza viruses that cause HPAI are highly virulent, and mortality rates in infected flocks often approach 100%. LPAI viruses are generally of lower virulence, but these viruses can serve as progenitors to HPAI viruses. The current strain of H5N1 responsible for die-offs of domestic birds in Asia is an HPAI strain; other strains of H5N1 occurring elsewhere in the world are less virulent and, therefore, are classified as LPAI strains. All HPAI strains identified to date have involved H5 and H7 subtypes.
Human infections have been associated with both HPAI and LPAI strains (see References: HHS 2005: Pandemic influenza plan).
Evidence that HPAI strains arise from LPAI strains has led the World Organization for Animal Health (OIE) to classify all H5 or H7 strains as notifiable (see References: Alexander 2003, Capua 2004, OIE 2005).
In the United States, currently only HPAI avian strains and reconstructed 1918 H1N1 strains are regulated as select agents (see Biosafety and Biosecurity, below).
The 1918 influenza pandemic strain (H1N1) appears to be of avian origin (see References: CDC: CDC Resources for Pandemic Flu).

Environmental survival of avian influenza viruses

Viruses remain infectious after 24 to 48 hours on nonporous environmental surfaces and less than 12 hours on porous surfaces (see References: Bean 1982). (Note: The importance of fomites in disease transmission has not been determined.)
Influenza A viruses can persist for extended periods in water (see References: WHO: Review of latest available evidence on risks to human health through potential transmission of avian influenza [H5N1] through water and sewage). One study of subtype H3N6 found that virus resuspended in Mississippi River water was detected for up to 32 days at 4°C and was undetectable after 4 days at 22°C (see References: Webster 1978). Another study found that several avian influenza viruses persisted in distilled water for 207 days at 17°C and 102 days at 28°C (see References: Stallknecht 1990).
Influenza A viruses can be preserved in lake ice and then released when the ice thaws the following spring or, in the case of arctic ice, up to years later. This may lead to temporal gene flow between viruses entrapped during one year and those shed by migrating birds in following years (see References: Zhang 2006).
Recent data from studies of H5N1 in domestic ducks have shown that H5N1 can survive in the environment for 6 days at 37ºC (see References: WHO 2004: Laboratory study of H5N1 viruses in domestic ducks).
Inactivation of the virus occurs under the following conditions (see References: OIE 2002; PHS):

Temperatures of 56°C for 3 hours or 60°C or more for 30 minutes
Acidic conditions
Presence of oxidizing agents such as sodium dodecyl sulfate, lipid solvents, and B-propiolactone
Exposure to disinfectants: formalin, iodine compounds

Laboratory Testing for Influenza

The following general considerations apply to laboratory testing of novel or pandemic influenza strains.

Tests for influenza virus include viral culture, polymerase chain reaction (PCR), rapid antigen testing, and immunofluorescence (IFA). Serologic tests are used to retrospectively diagnose infection.
During a pandemic, recommendations for laboratory testing may be unique and depend on factors such as: (1) availability of reagents and laboratory surge capacity, (2) presence or absence of other influenza strains in the community, (3) level of influenza activity in the community, and (4) treatment considerations.
The sensitivity and specificity of laboratory tests appear to vary with the involved strain, which has implications for emerging variants (see References: Weinberg 2005).
Laboratory tests are required for specific identification of pandemic strains. The most likely ways that a pandemic strain would be detected initially are:

Outbreak investigations or investigation of unexplained death in a previously healthy individual
Influenza surveillance with laboratory testing and characterization of unusual strains
Investigation of unusual laboratory findings
Testing of persons with influenza-like symptoms who meet certain exposure criteria

State and local health departments should be prepared to process or test for the following (if they have the capability, as described below) (see References: HHS 2005: Pandemic influenza plan).

Avian influenza A (H5N1) and other avian influenza viruses
Other animal influenza viruses
New or re-emergent human influenza viruses (such as H2 strains)

Testing during a pandemic (see References: HHS 2005: Pandemic influenza plan):

The Centers for Disease Control and Prevention (CDC) will update protocols and distribute reagents as necessary.
The need for confirmatory testing will diminish as the pandemic progresses. Some level of continued monitoring will be necessary to monitor changes in antigenicity and antiviral susceptibility. The CDC will provide appropriate guidance in such situations.

Reporting and referral (see References: HHS 2005: Pandemic influenza plan)

Clinical laboratories should contact their state or local health departments if they receive specimens from patients with possible novel influenza suspected on the basis of clinical and epidemiologic criteria.
Public health laboratories should send specimens to the CDC if the patient meets clinical and epidemiologic criteria and (1) tests positive for influenza A by reverse transcriptase PCR (RT-PCR) or rapid testing or (2) tests negative for influenza A by rapid testing and RT-PCR is not available. Laboratories without capacity for testing avian strains by indirect IFA or RT-PCR should send untypable influenza isolates to the CDC.
Any unusual subtype should be reported to the CDC through its emergency response hotline (770-488-7100).

Laboratory-based influenza surveillance networks

The World Health Organization (WHO) Global Influenza Surveillance Network (see References)
The CDC National Respiratory and Enteric Virus Surveillance System (NREVSS) (see References)
State or local health department surveillance networks

Detailed information about laboratory testing for avian influenza in humans is available in the overview "Avian Influenza (Bird Flu): Implications for Human Disease" on this site. Topics included in that overview are: specimen collection, biosafety and biosecurity, direct detection methodology, serology, virus isolation by cell culture, and viral susceptibility testing.

Laboratory values that may trigger concern for human pandemic influenza include the following:

Positive test for influenza from a patient with risk factors for avian influenza
Culture: CPE positive or negative; HAd positive; HAI titer low or negative and no other hemagglutinating viruses identified
RT-PCR positive for H5 or H7
RT-PCR positive for influenza A from a conserved target, such as matrix protein, and negative for H1-H3
A four-fold rise in H5-specific antibody titer (acute and convalescent serum samples)

General Considerations

Cross-Immunity

In general, the degree of immunity induced by one strain of influenza virus to a second challenge with another influenza virus is related to the taxonomic distance between the two strains (see References: Epstein 2003). Several terms that characterize the type of immunity are identified below.

Heterologous immunity: Immunization with one type of influenza virus (eg, A, B, or C) does not offer protection from challenge with a different type.
Heterosubtypic immunity (also referred to as "heterotypic immunity"): Immunization with one influenza A virus subtype (eg, H1N1) may offer some protection from challenge with a second influenza A subtype (eg, H5N2). The degree of protection, or lack of protection, is important to the discussion of pandemic influenza and vaccine development.
Homosubtypic immunity: Immunization with one strain within a subtype (eg, A/Hong Kong/03/68[H3N2]) will frequently offer some protection against challenge with a second strain within the same subtype (eg, A/Fujian/447/2003[H3N2]).
Homologous immunity: Immunization with one strain of influenza A virus (eg, A/Fujian/447/2003[H3N2]) offers protection from a second challenge with the same strain.

Antigenic Drift vs Antigenic Shift

"Antigenic drift" refers to the process of small genetic changes that influenza viruses continuously undergo from year to year, which necessitates the development of new vaccines annually. Partial immunologic cross-reactivity between new strains and those they are replacing (ie, homosubtypic immunity) limits morbidity, mortality, and spread in the population.
"Antigenic shift" refers to substantial genetic changes caused by the process of genetic reassortment. Relatively few lineages of influenza A are circulating among humans at any one time, which reduces the likelihood of significant genetic reassortments. However, antigenic shift can occur between human and animal strains, which is what happened with the pandemic strains of 1957 and 1968. It is important to note that not all pandemic strains arise from genetic reassortment. For example, the 1918 pandemic strain apparently did not originate through a reassortment event; rather, it is likely that an avian strain initially infected humans and then adapted gradually to the human population over time to become a pandemic strain (see References: Taubenberger 2005).

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 likely go through. These are outlined in the following table. (Note: In 1999, the WHO developed a set of pandemic phases; these were revised in the new WHO Global Influenza Preparedness Plan that was released in April 2005. The phases identified below are from the 2005 Plan [see References: WHO: WHO global influenza preparedness plan 2005].) The current pandemic phase for H5N1 is phase 3.

WHO Pandemic Phases
Phase	Characteristics of Phase	Rationale
Phase 1	No new influenza virus subtypes have been detected in humans. An influenza virus subtype that has caused human infection may be present in animals. If present in animals, the risk of human infection or disease is considered to be low.	It is likely that influenza subtypes that have caused human infection and/or disease will always be present in wild birds or other animal species. Lack of recognized animal or human infections does not mean that no action is needed. Preparedness requires planning and action in advance.
Phase 2	No new influenza virus subtypes have been detected in humans. However, a circulating animal influenza virus subtype poses a substantial risk of human disease.	The presence of animal infection caused by a virus of known human pathogenicity may pose a substantial risk to human health and justify public health measures to protect persons at risk.
Pandemic Alert Period
Phase 3	Human infection(s) with a new subtype, but no human-to-human spread, or at most rare instances of spread to a close contact.	The occurrence of cases of human disease increases the chance that the virus may adapt or reassort to become transmissible from human to human, especially if coinciding with a seasonal outbreak of influenza. Measures are needed to detect and prevent spread of disease. Rare instances of transmission to a close contact, for example, in a household or healthcare setting, may occur but do not alter the main attribute of this phase (ie, that the virus is essentially not transmissible from human to human).
Phase 4	Small cluster(s) with limited human-to-human transmission but spread is highly localized, suggesting that the virus is not well adapted to humans.	Virus has increased human-to-human transmissibility but is not well adapted to humans and remains highly localized, so that its spread may possibly be delayed or contained.
Phase 5	Larger cluster(s) but human-to-human spread is still localized, suggesting that the virus is becoming increasingly better adapted to humans but may not yet be fully transmissible (substantial pandemic risk).	Virus is more adapted to humans and therefore more easily transmissible among humans. It has spread in larger clusters, but spread is localized. This is likely to be the last chance for massive coordinated global intervention, targeted to one or more foci, to delay or contain spread. In view of possible delays in documenting spread of infection during pandemic Phase 4, it is anticipated that there would be a low threshold for progressing to Phase 5.
Pandemic Period
Phase 6	Increased and sustained transmission among general population.	Major change in global surveillance and response strategy, since pandemic risk is imminent for all countries. The national response is determined primarily by the disease impact within the country.
From WHO: WHO global influenza preparedness plan 2005 (see References).

Historical Perspective

Earliest reports of influenza epidemics date back to 412 BC and were recorded by Hippocrates. A number of epidemics that likely were influenza were described in the Middle Ages, and one that was probably a true pandemic took place in 1510 (see References: Beveridge 1978). Other key historical facts include the following:

One of the earliest recorded pandemics occurred in 1580. Like the 1918 pandemic, this one was particularly severe. It started in Asia and spread to Africa, Europe, and the Americas. In 6 weeks it afflicted all of Europe. Death rates were high; 9,000 of 80,000 people died in Rome, and some Spanish cities were described as "nearly entirely depopulated" by the disease (see References: Beveridge 1978, Patterson 1986).
Ten pandemics have been recorded in the past 300 years (see References: Osterholm 2007: The fog of pandemic preparedness). The time between starting points of these pandemics has ranged from 10 to 49 years, with an average of 24 years.
During the 17th century, localized epidemics were reported, and in the 18th century at least two pandemics occurred (1732-33, and 1781-82).
Five influenza pandemics occurred during the 19th century (1800-02, 1830-33, 1847-48, 1857-58, and 1889-90) (see References: Osterholm 2007: The fog of pandemic preparedness). The 1889 pandemic, known as the Russian Flu, began in Russia and spread rapidly throughout Europe. It reached North America in December 1889 and spread to Latin America and Asia in February 1890. About 1 million people died in this pandemic.

Global influenza surveillance was established in 1947 by the WHO to better understand the epidemiology of influenza and to obtain isolates in a systematic fashion for annual vaccine development (see References: Hampson 1997).

Pandemics of the 20th Century

Three pandemics occurred during the 20th century, caused by an H1, an H2, and an H3 strain. These are outlined in the table below and then briefly summarized. Currently, H1 and H3 influenza strains are circulating in the human population. Scientists have raised concern about the possibility of H2N2 reemerging (also referred to as recycling) in humans, particularly through accidental release of a laboratory strain (see References: Dowdle 2006).

Influenza Pandemics of the 20th Century: Impact in the United States*
Date	Strain	Estimated No. of Deaths in US	Comments
1918-19 (Spanish Flu)	H1N1	500,000	Global mortality may have been as high as 100 million. The virus likely originated in the US and then spread to Europe.
1957-58 (Asian Flu)	H2N2	60,000	The virus was first identified in China; approximately 1 million people died globally during this pandemic.
1968-69 (Hong Kong Flu)	H3N2	40,000	The death rate from this pandemic may have been lower because the strain had a shift in the hemagglutinin (HA) antigen only and not in the neuraminidase (NA) antigen.
*All three pandemics were characterized by a shift in age distribution of deaths to younger populations under age 65 (at least initially); shift was particularly dramatic during the 1918 pandemic (see References: HHS: Q&A; HHS: Influenza pandemics; Kilbourne 2006; Simonsen 2004; Webster 1997).

1918-19 (Spanish Flu)

This pandemic was caused by an influenza A (H1N1) strain. Worldwide, about one third of the world's population was infected and had clinically apparent illness (about 500 million people) and an estimated 50 to 100 million died (see References: Johnson 2002, Taubenberger 2006). 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.

One study projected 51 to 81 million deaths using 2004 population estimates; however, the authors assumed wide variability in death rates by country based on per-capita income and other factors (see Dec 22, 2006, CIDRAP News Story and see References: Murray 2006).
Another report suggests that if a 1918-like pandemic were to occur with increased deaths in the elderly population, over 142.2 million people would die and there would be a gross domestic product loss of US $4.4 trillion worldwide (see References: Osterholm 2007: Unprepared for a pandemic).
Some have suggested that the death toll from a similar pandemic occurring in modern times would be lower owing to improved medical care and public health infrastructure (see References: Morens 2007); however, if attack rates were high, medical and public health systems could quickly become overwhelmed.

The 1918 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 this 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, although the origin of the implicated H1N1 strain still remains a mystery.
This first wave was followed by two additional waves in the fall and winter of 1918-19 that were much more severe (see References: Taubenberger 2006). The 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.
Recorded case-fatality rates (CFRs) 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.
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; Morens 2007). 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 CFRs ranged from 23% to 71% (see References: Barry 2004).

The excess influenza deaths appear to have involved two overlapping clinical-pathologic syndromes (see References: Morens 2007). One pattern was aggressive bronchopneumonia, most likely caused by a secondary bacterial pneumonia. The second pattern was a rapidly evolving severe acute respiratory distress-like syndrome (ARDS). A recent report suggests that secondary bacterial pneumonia was the major cause of death during the1918-1919 pandemic (see References: Morens 2008). The authors state that most deaths resulted from poorly understood interactions between the infecting virus and secondary infections caused by bacteria that colonize the upper respiratory tract. The findings of this study may not be generalizable, however, because the population studied included only patients who had an autopsy performed (see Aug 22, 2008, CIDRAP News story).

In October 2005, the CDC reported that scientists had reconstructed the 1918 pandemic H1N1 strain and tested it in mice (see References: Tumpey 2005). They found that mice infected with the 1918 strain died in as little as 3 days, and mice that survived as long as 4 days had 39,000 times as many virus particles in their lungs as did mice infected with a control influenza virus, a Texas strain of H1N1 from 1991. All the mice infected with the 1918 virus died, while those exposed to the Texas strain survived. Further, the 1918 virus was at least 100 times as lethal as an engineered virus that contained five 1918 genes and three genes from the Texas H1N1 strain. The researchers found that the mice had severe inflammation in their lungs and bronchial passages, findings very similar to those in people who died of the 1918 virus.

Earlier studies in mice using genetically engineered influenza strains similar to the H1N1 1918 pandemic strain suggest that macrophage activation with high levels of cytokine production may have been a key factor in lung damage caused by the pandemic strain (see References: Kobasa 2004). Investigators have postulated that an overly robust immune response inducing a "cytokine storm" may have contributed to the high CFRs seen in younger populations during the 1918 pandemic. Another study recently found that cynomolgus macaques had an atypical host response to infection with the 1918 virus (characterized by dysregulation of the antiviral response), suggesting that the 1918 virus was able to modulate the host immune response (see References: Kobasa 2007).

Recent genetic sequencing of the 1918 strain indicates that the strain was of avian origin and that the strain did not reassort with a human strain (unlike later pandemics), but rather gradually adapted to humans until it could be efficiently transmitted person to person (see References: Taubenberger 2005). Current evidence indicates that the 1918 virus was an avian-like virus derived in toto from an unknown source (see References: Taubenberger 2006). A two-amino acid change in the HA of the 1918 virus was recently shown to abolish transmission among ferrets, confirming the essential role of HA receptor specificity for the transmission of influenza viruses in mammals (see References: Tumpey 2007).

1957-58 (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 CFR in this age-group declined in subsequent years. Globally, approximately 1 million people died during this pandemic.

1968-69 (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 HA antigen only and not in the NA antigen. Although antibodies to NA 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 elderly 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.

Lessons From Past Pandemics

In a report issued in January 2005, WHO officials identified key lessons from the three pandemics of the past century (see References: WHO 2005: Avian influenza: assessing the pandemic threat). These lessons are summarized as follows.

Pandemics behave as unpredictably as the viruses that cause them. During the previous century, great variations were seen in mortality, severity of illness, and patterns of spread.
One consistent feature important for pandemic preparedness planning is the rapid surge in the number of cases and their exponential increase over a very brief time, often measured in weeks.
Apart from the inherent lethality of the virus, its capacity to cause severe disease in non-traditional age groups, namely young adults, is a major determinant of a pandemic's overall impact.
The epidemiologic potential of a virus tends to unfold in waves. Subsequent waves have tended to be more severe.
Virologic surveillance, as conducted by the WHO Laboratory Network, has performed a vital function in rapidly confirming the onset of pandemics.
Most pandemics have originated in parts of Asia where dense populations of humans live in close proximity to ducks and pigs.
Some public health interventions may have delayed the international spread of past pandemics, but could not stop them.
Delaying spread is desirable, as it can flatten the epidemiological peak, thus distributing cases over a longer period.
The impact of vaccines on a pandemic, though potentially great, remains to be demonstrated. In 1957 and 1968, vaccine manufacturers responded rapidly, but limited production capacity resulted in the arrival of inadequate quantities too late to have an impact.
Countries with domestic manufacturing capacity will be the first to receive vaccines.
The tendency of pandemics to be most severe in later waves may extend the time before large supplies of vaccine are needed to prevent severe disease in high-risk populations.
In the best-case scenario, a pandemic will cause excess mortality at the extremes of the lifespan and in persons with underlying chronic disease. Countries with good programs for yearly influenza vaccinations will have experience with the logistics of vaccinations for these populations.

The Pandemic Severity Index

In February 2007, HHS released the "pandemic severity index," or PSI, as a way to grade pandemics. The severity level is initially based on CFR, a single criterion that will likely be known even early in a pandemic when small clusters and outbreaks are occurring. The pandemic severity index levels are:

Category 1, CFR <0.1%
Category 2, CFR 0.1% to 0.5%
Category 3, CFR 0.5% to 1%
Category 4, CFR 1% to 2%
Category 5, CFR >2%

According to this index, the pandemics of 1957 and 1968 both fit into category 2, whereas the 1918 pandemic qualified as a category 5.

The Current H5N1 Threat

According to the WHO, at this time the pandemic alert level for H5N1 influenza is at Phase 3: a new viral subtype is causing disease in humans but is not yet spreading efficiently and sustainably (see References: WHO: Current WHO phase of pandemic alert).

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; WHO 2005: Influenza pandemic preparedness and response):

Since 2003, H5N1 viruses have spread across Asia and into Europe, the Middle East, India, and Africa, with outbreaks occurring in bird populations in more than 60 countries.
In early 2008, the United Nations Food and Agriculture Organization (FAO) reported that the greatest areas of ongoing concern are Indonesia, Bangladesh, and Egypt, where the virus has become "deeply entrenched" (see References: FAO 2008). The potential of exposure and infection of humans is likely to be ongoing in rural areas of these countries, which could enhance the likelihood that a pandemic strain will emerge (see References: Stohr 2005).
H5N1 strains cause severe disease in humans, with a high CFR (reported at over 60%).
Recent genetic sequencing performed on H5N1 viral isolates from Turkey demonstrates that the strains contain two mutations that may make the virus better adapted to humans (see References: Butler 2006). These mutations could potentially enhance transmission from birds to humans and between humans.

Detailed information about H5N1 influenza in human populations can be found in the document on this Web site, "Avian Influenza (Bird Flu): Implications for Human Disease."

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, the WHO has indicated that it will take at least 4 months to develop a vaccine (see References: WHO: WHO global influenza preparedness plan 2005). In addition, 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

Limited global vaccine production capacity exists at this time. (For further information, see the seven-part CIDRAP News series called "The Pandemic Vaccine Puzzle" [see Nov 15, 2007, CIDRAP News story].)

Currently only about 565 million doses of trivalent influenza vaccine containing 15 mcg HA per strain can be produced each year (see References: WHO 2007: Projected supply of pandemic influenza vaccine sharply increases). This is equivalent to about 1.7 billion doses of monovalent vaccine at the same antigen level.
The production capacity could be lower if a pandemic vaccine requires higher levels of antigen.
Similarly, if two doses are needed, the number of people who could be vaccinated will decrease.
For H5N1 vaccine production, WHO officials believe that the amount of antigen needed per dose of H5N1 vaccine may ultimately be about eight times less than trivalent vaccine and that, as a result, global annual production capacity could be as high as 4.5 billion doses of H5N1 vaccine by 2010 (see References: WHO 2007: Projected supply of pandemic influenza vaccine sharply increases). However, these projections may change depending upon the actual amount of antigen needed per dose.
Developing an effective vaccine may require having the pandemic strain in hand, which will mean that a vaccine cannot be produced until the onset of the pandemic. Once a virus is identified, it will take at least 19 weeks to develop the appropriate reagents for an inactivated pandemic vaccine (see References: WHO 2007: A description of the process of seasonal and H5N1 influenza vaccine virus selection and development).
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, assuming 15 mcg HA per dose (see References: 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

One of the goals of the WHO Global Vaccine Action Plan is to establish new vaccine production facilities, particularly in developing countries (such as Indonesia) (see References: WHO 2006: Global pandemic influenza action plan to increase vaccine supply).

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. The seven-part series called "The Pandemic Vaccine Puzzle" (see Nov 15, 2007, CIDRAP News story) contains further details on challenges, as well as solutions-in-progress.

Suggested approaches for overcoming these issues include the use of reverse genetics, which has been used for preparing H5N1 seed strains (see References: Webby 2004; WHO 2004: Development of a vaccine effective against avian influenza H5N1 infection in humans). Reverse genetics provides several advantages in influenza vaccine development (see References: Luke 2006: Vaccines for pandemic influenza; Palese 2006): (1) it allows creation of engineered viruses that are modified to be less virulent, thus eliminating the need for high-level containment, (2) with reverse genetics, a selection system is not needed to derive appropriate reassortant viruses from background parental viruses, (3) it dramatically shortens the timeframe for production of seed strains, (4) it allows for standardization of seed strains to be used in vaccine development, and (5) the process may eliminate the potential for any adventitious agents to enter the manufacturing process.

Other approaches include the following (see References: Stephenson 2004):

Produce inactivated vaccine from wild-type virus
Select an antigenically related but nonpathogenic surrogate vaccine strain
Use other viruses (eg, baculoviruses, adenoviruses) to express recombinant HA
Develop DNA-based vaccines

Another option for consideration is development of influenza vaccines based on cell-mediated immunity. Cell-mediated responses generally focus on internal influenza proteins, which are more conserved and less susceptible to antigenic variation (see References: Thomas 2006). A recent analysis of cross-reactive CD4⁺ and CD8⁺ memory T cell responses to overlapping peptides of influenza A/Vietnam/CL26/2005 (H5N1) and influenza A/New York/232/2004 (H3N2) in healthy individuals demonstrated that CD4⁺ and CD8⁺ T cells isolated from most participants showed cross-recognition of at least one H5N1 internal protein. Matrix protein 1 (M1) and nucleoprotein (NP) were the immunodominant targets of cross-recognition (see References: Lee 2008).

Interpandemic Steps to Facilitate Vaccine Production

In September 2006, the WHO released an action plan to increase pandemic influenza vaccine production capacity (see References: WHO 2006: Global pandemic influenza action plan to increase vaccine supply). The plan outlines the following strategies:

Develop an immunization policy to increase demand for seasonal vaccines.

Develop regional and national plans for seasonal influenza vaccination programs.
Mobilize resources for the implementation of seasonal influenza vaccination programs.

Increase influenza vaccine production capacity.

Increase capacity for inactivated influenza vaccines.

Improve production yield of H5N1 viruses and immunogenicity of prototype H5N1 inactivated vaccine.
Build new production facilities in developing and/or industrialized countries.

Assess formulations of influenza vaccine other than those commonly used for seasonal vaccine.

Conduct clinical trials of adjuvanted vaccines.
Explore the possibility to scale-up production of live, attenuated influenza vaccines.
Further evaluate whole-cell vaccines.

Assess alternative vaccine delivery routes (such as intradermal administration).

Promote research and development of new influenza vaccines.

Enhance protective efficacy and immunogenicity of existing vaccine types.
Develop novel vaccines that induce broad-spectrum and long-lasting immune responses.
Improve evaluation of vaccine performance.

Current Status of H5N1 Candidate Vaccines

The WHO indicated in a statement released on Feb 16, 2007, that progress is being made on the development of prototype H5N1 pandemic influenza vaccines (see References: WHO 2007: WHO reports some promising results on avian influenza vaccines). Sixteen manufacturers from 10 countries are developing prototype pandemic influenza vaccines against H5N1 avian influenza virus. Five of them also are involved in the development of vaccines against other avian viruses (H9N2, H5N2, and H5N3). More then 40 clinical trials involving prototype vaccines have been completed or are ongoing. Even though these findings are encouraging, the WHO also expressed concern about global vaccine production capacity.

Detailed information about H5N1 influenza vaccine development can be found in the document on this Web site, "Avian Influenza (Bird Flu): Implications for Human Disease." Additional information can be found in the seven-part "The Pandemic Vaccine Puzzle" (see Nov 15, 2007, CIDRAP News story).

As of September 2008, three H5N1 influenza vaccines had been licensed:

A Sanofi Pasteur vaccine was licensed by the FDA in April 2007; this vaccine is currently being stockpiled in the United States.
A vaccine produced by GlaxoSmithKline (GSK) was approved by the European Union in May 2008 (see References: GlaxoSmithKline 2008).

In June 2008, Australian authorities approved an H5N1 influenza vaccine made by the Australian-based pharmaceutical company, CSL (see Jun 17, 2008, CIDRAP News story).

A universal vaccine that would be effective against all types of influenza, including emerging pandemic strains, is being developed by the British company Acambis and is being researched by others as well. Such a vaccine would not have to be reengineered each year.

One possible target for a universal vaccine is the relatively conserved M2 homotetramer (see References: Haque 2007).
Acambis announced in early August 2005 that it produced successful results in animal testing (see References: Acambis 2005). The vaccine, known as ACAM-FLU-A, is currently undergoing clinical trials in humans (see Jul 30, 2007, CIDRAP News story). The vaccine focuses on the M2 protein, rather than the surface HA and NA proteins targeted by traditional flu vaccines. The universal vaccine is made through bacterial fermentation technology, which would greatly speed up the rate of production over that possible with culture in chicken eggs; plus, the vaccine could be produced constantly, since its formulation would not change. Still, such a vaccine is several years away from full testing, approval, and use.

Development of Vaccines Against Influenza Viruses Other Than H5N1 That May Pose a Pandemic Threat

In mid-September 2006, Sanofi Pasteur announced that it was beginning a clinical trial of an H7N1 vaccine; the vaccine is a split-virus product grown in cell culture rather than in eggs (see Sep 19, 2006, CIDRAP News story).
Live, attenuated, cold-adapted H9N2 vaccine candidates have been developed that are protective in mice (see References: Fauci 2006).
A phase 1, randomized, double-blind trial of an H9N2 subunit vaccine with and without MF59 adjuvant showed that the adjuvanted vaccine was immunogenic even after a single dose (see References: Atmar 2006).

Stockpiling H5N1 Vaccines and Vaccination Strategies

Currently, the US government has a stockpile of 13 million courses of pre-pandemic H5N1 vaccine (see References: HHS 2008: Pandemic planning update V). By 2011, HHS intends to expand US-based vaccine production capacity to the point that it can generate 600 million doses of a pandemic influenza vaccine (two doses for every American) within 6 months of the time that a reference strain of the actual pandemic virus is developed. To meet this goal, HHS currently is funding six companies to either implement commercial-scale production cell culture methods or expand capacity for conventional manufacturing using chicken eggs.

A WHO report by the director general, issued in November 2007, indicated that the WHO is in the process of developing a pre-pandemic vaccine stockpile. In June 2007, GSK pledged to give 50 million doses of H5N1 vaccine to the WHO, and in June 2008, Sanofi Pasteur pledged an additional 60 million doses of vaccine over 3 years (see Jun 16, 2008, CIDRAP News story). A variety of issues are currently under discussion, such as developing consensus on policy options for use of H5 vaccines in an international stockpile; rules and procedures for the geographical placement, operation (including prioritization of release of vaccine), management, and oversight of a stockpile; and resources needed to maintain the stockpile (see References: WHO 2007: Reports by the Director General: Intergovernmental meeting on pandemic influenza preparedness: sharing of influenza viruses and access to vaccines and other benefits).

In July 2008, HHS issued a guidance document on allocating vaccine during a pandemic (see References: HHS 2008: Guidance on allocating and targeting pandemic influenza vaccine). The vaccination target groups and level of priority within each group (as identified by the tier according to the severity of a pandemic) are outlined in the table below.

Category	Target Group (Estimated Number)	Severity of Pandemic
		Severe	Moderate	Less Severe
Homeland and national security	Deployed and mission critical personnel (700,000)	Tier 1	Tier 1	Tier 1
	Essential support and sustainment personnel (650,000)	Tier 2	Tier 2	Tier 2
	Intelligence services (150,000)	Tier 2	Tier 2	Tier 2
	Border protection personnel (100,000)	Tier 2	Tier 2	Tier 2
	National Guard personnel (500,000)	Tier 2	Tier 2	Tier 2
	Other domestic national security personnel (50,000)	Tier 2	Tier 2	Tier 2
	Other active duty and essential support (1,500,000)	Tier 3	Tier 3	NT*
Healthcare and community support services	Public health personnel (300,000)	Tier 1	Tier 1	Tier 1
	Inpatient healthcare providers (3,200,000)	Tier 1	Tier 1	Tier 1
	Outpatient and home healthcare providers (2,500,000)	Tier 1	Tier 1	Tier 1
	Healthcare providers in long-term care facilities (1,600,000)	Tier 1	Tier 1	Tier 1
	Community support services and emergency management personnel (600,000)	Tier 2	Tier 2	NT*
	Pharmacists (150,000)	Tier 2	Tier 2	NT*
	Mortuary services personnel (50,000)	Tier 2	Tier 2	NT*
	Other important healthcare personnel (300,000)	Tier 3	Tier 3	NT*
Critical infrastructure	Emergency medical services personnel (EMS, law enforcement, and fire services) (2,000,000)	Tier 1	Tier 1	Tier 1
	Manufacturers of pandemic vaccine and antivirals (50,000)	Tier 1	Tier 1	Tier 1
	Communications/IT, Electricity, Nuclear, Oil and Gas, and Water sector personnel (2,150,000)	Tier 2	Tier 2	NT*
	Financial clearing and settlement personnel	Tier 2	Tier 2	NT*
	Critical operational and regulatory government personnel	Tier 2	Tier 2	NT*
	Banking and Finance, Chemical, Food and Agriculture, Pharmaceutical, Postal and Shipping, and Transportation sector personnel (3,400,000)	Tier 3	NT*	NT*
	Other critical government personnel	Tier 3	NT*	NT*
General population	Pregnant women (3,100,000)	Tier 1	Tier 1	Tier 1
	Infants and toddlers, 6 – 35 months old (10,300,000)	Tier 1	Tier 1	Tier 1
	Household contacts of infants under 6 months old (4,300,000)	Tier 2	Tier 2	Tier 2
	Children 3 – 18 years old with high-risk medical conditions (6,500,000)	Tier 2	Tier 2	Tier 2
	Children 3 – 18 years old without high-risk medical conditions (58,500,000)	Tier 3	Tier 2	Tier 3
	Persons 19 – 64 years old with high-risk conditions (36,000,000)	Tier 4	Tier 3	Tier 2
	Persons 65 years and older (38,000,000)	Tier 4	Tier 3	Tier 2
	Healthy adults, 19 – 64 years old (123,350,000)	Tier 5	Tier 4	Tier 4
Abbreviations: NT, Not targeted. Persons not targeted in an occupational group would be vaccinated as part of the general population based on their age and health status. Note:* Estimates are rounded to the closest 50,000. Occupational target group population sizes may change as plans are developed further for implementation of the pandemic vaccination program.


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