Influenza Pandemic: Efforts Under Way to Address Constraints on Using Antivirals and Vaccines to Forestall a Pandemic
Released: 2008-01-22T00:00:00

Letter

Background

WHO, in conjunction with the United States and other governments, has developed an international strategy for forestalling the onset of an influenza pandemic. Elements of this strategy include restricting the movement of people in and out of the affected area, isolation of ill persons, and school closures. Antivirals are also an important element of this strategy. Studies suggest that using antiviral drugs, along with other interventions, to treat infections and prevent illness might contain a pandemic at the site of the outbreak or at least slow its international spread, thus gaining time to put emergency measures in place and begin producing matched vaccines that would be effective in preventing individuals from being infected with the strain of influenza causing the pandemic.

Influenza

Influenza, also called “the flu,” is caused by a virus that primarily attacks the upper respiratory tract—the nose and throat—and sometimes the lungs. Influenza is characterized by cough, fever, headache, and other symptoms and is more severe than some viral respiratory infections, such as the common cold. In almost every year a seasonal influenza virus causes acute respiratory disease in epidemic proportions somewhere in the world. Most people who contract seasonal influenza recover completely in 1 to 2 weeks, but some develop serious and potentially life- threatening medical complications, such as pneumonia. Most healthy adults may infect others 1 day before getting symptoms and up to 5 days after they first develop symptoms. Some young children and people with weakened immune systems may be contagious for more than a week. WHO estimates that seasonal influenza affects about 5 to 15 percent of the world’s population each year, causing 3 to 5 million cases of severe illness worldwide including 250,000 to 500,000 deaths.

There are three types of influenza viruses: A, B, and C. However, only influenza A viruses cause pandemics. Influenza A viruses are further categorized into subtypes according to differences in the “HA” and “NA” proteins that are on the outer surface of the virus. These influenza A subtypes are further characterized into strains. Influenza strains mutate, or genetically change, over time. As strains mutate, new strains of influenza viruses appear and may replace older, circulating strains. When a new strain of human influenza virus emerges, immunity that may have developed after a previous infection or vaccination may not provide protection against the new strain. Small mutations in the influenza virus are the reason why someone who has previously been infected with influenza can still be susceptible to seasonal or common influenza. More substantial changes in the influenza virus can result in the emergence of a pandemic influenza subtype.

Pandemic human influenza is a virulent influenza that causes a global outbreak, or pandemic, of serious illness. It occurs when an existing strain of the influenza virus is replaced by a new influenza A strain to which humans have no immunity, resulting in widespread morbidity and mortality. According to WHO, pandemic influenza can spread to all parts of the world very quickly, usually in less than a year, and can sicken more than a quarter of the global population. Three conditions must be met before an influenza pandemic begins: (1) a new influenza virus subtype that has not previously, or at least recently, circulated in humans must emerge, (2) the virus must be capable of causing disease in humans, and (3) the virus must be capable of sustained human-to-human transmission. The H5N1 virus currently meets the first two of these three conditions but not the third.

The current H5N1 pandemic influenza threat stems from an unprecedented outbreak of H5N1 influenza that first appeared in birds in southeastern China and Hong Kong in 1996 and 1997 and was first detected in humans in Hong Kong in 1997. The virus reappeared in late 2003 and early 2004 and has since spread in bird populations across parts of Asia, Europe, and Africa, with limited infections in humans. From December 1, 2003, to December 11, 2007, H5N1 was detected in animals in 60 countries. According to WHO, the geographical spread of H5N1 in animals in 2006 was the fastest and most extensive of any pathogenic avian influenza virus recorded to date. From January 1, 2003, through December 12, 2007, WHO reported 338 confirmed human cases, including 208 human deaths from the H5N1 virus in a total of 12 countries—a case fatality rate of 62 percent. Scientists and public health officials agree that the spread of the H5N1 virus in birds and the occurrence of infections in humans have increased the risk that this disease may change through adaptive mutation or reassortment into a form that is easily transmissible among humans, resulting in an influenza pandemic.

HHS stated that little is known about how to control a pandemic and that it is important to distinguish between seasonal influenza and pandemic influenza. Current knowledge about how antiviral drugs and influenza vaccines perform is largely drawn from experience with seasonal influenza. HHS stated that how antivirals and vaccines will perform against a pandemic influenza virus cannot be predicted, but as there are currently no better options, the agency has made plans for their use in response to a pandemic.

Vaccines

Vaccines are considered the first line of defense against influenza to prevent infection and control the spread of the disease. Vaccines stimulate immune responses which include causing the body to produce neutralizing antibodies to provide protective immunity to a particular virus strain. After vaccination, the body takes about 2 weeks to produce protective antibodies for that strain. For the one FDA-licensed H5N1 vaccine, two doses administered about 4 weeks apart would be required to provide what is believed to be an adequate immune response based on past experience with seasonal influenza vaccines. When a vaccinated person is exposed to the specific virus proteins in the vaccine, antibodies develop in response that will help either to prevent infection or reduce the severity of the illness caused by infection. To be most effective, an influenza vaccine needs to closely match the circulating influenza strain. However, because influenza viruses undergo minor but continuous genetic changes from year to year, a matched vaccine cannot be developed until the circulating strain has been identified. Generally, the purpose of vaccination is to prevent infection; however, in the event of a pandemic, the purpose could be broadened to include decreasing mortality or morbidity. The impact of such a change could be to increase vaccine availability since a vaccine that is not fully matched to the virus might be available more quickly and still help reduce mortality and morbidity.

In the case of vaccines for seasonal influenza, WHO, CDC, FDA, health officials around the world, and vaccine manufacturers participate in a system that develops and produces vaccines targeted to the influenza strains most likely to be in circulation during the next influenza season. This system collects and analyzes circulating influenza viruses, uses the information to determine the three human strains most likely to circulate in the upcoming year, and formulates and distributes virus reference strains to vaccine manufacturers, who produce seed viruses to manufacture influenza vaccines. Influenza vaccine is produced in a complex process that involves growing viruses in millions of fertilized chicken eggs. Seasonal vaccine production generally takes 6 or more months after virus strains have been selected. The same general system would be used in the event of a pandemic to manufacture a vaccine targeted to the influenza strain causing it.

Influenza vaccines can be categorized into three types: seasonal, pre- pandemic, and pandemic. As discussed in table 1, seasonal vaccines protect against annual (i.e., seasonal) influenza strains. Pre-pandemic vaccines are formulated to match strains of influenza viruses that have had limited circulation in humans but have pandemic potential. However, they are not matched or targeted to the specific pandemic strain that may eventually emerge. Pandemic vaccines are formulated to match a pandemic strain that has already emerged. Influenza vaccines are made either from inactivated (i.e., killed) viruses or from live viruses that have been attenuated (i.e., weakened). Generally, inactivated influenza vaccines are made from parts of the influenza virus rather than the whole virus.

Globally, influenza vaccine production is largely a private-sector activity and vaccine manufacturing is concentrated in Europe and North America, with approximately 90 percent of worldwide production capacity located in these areas. However, there are manufacturers throughout the world, including in Australia, China, and Japan. Some manufacturers have production facilities in more than one country. In some cases, more than one manufacturer may be producing vaccine for distribution in a particular country. For example, there were four manufacturers producing five vaccines for the 2006-2007 influenza season in the United States. In the event of a pandemic, manufacturers would switch production from seasonal to pandemic vaccine, and would use the same facilities to produce the pandemic vaccine as they had used to produce seasonal vaccine. Pre-pandemic vaccines are currently produced only during the 3- to 4-month period when manufacturers are not producing seasonal vaccine.

Antivirals

Antiviral drugs are also used against seasonal influenza in humans to reduce symptoms and complications and could be used in the event of a pandemic. Antivirals can be used to both prevent illness and treat those who are already infected by killing or suppressing the replication of the influenza virus. Antivirals are not reformulated to match a specific influenza strain and could be used from the early phase of an influenza pandemic.

As shown in table 2, two classes of antiviral drugs are currently available for the prevention and treatment of influenza, and two types of drugs within each class have been approved. Amantadine and rimantadine belong to the older class, adamantanes. Tamiflu and Relenza belong to the newer class, neuraminidase inhibitors. Amantadine is given as a capsule, syrup, or tablet, while rimantadine is administered as a syrup or tablet. Tamiflu can be administered as either a capsule or liquid. Relenza is a powder that must be inhaled using a special device. According to CDC, antivirals are about 70 to 90 percent effective for preventing illness in healthy adults; that is, they are about as effective as vaccines, when the vaccine and circulating virus strains are well matched, in preventing illness among healthy adults. For maximal effectiveness in preventing infection, the antiviral must be taken throughout the entire period of a community outbreak. According to current research involving seasonal influenza, if taken within 2 days of the onset of symptoms, these drugs can shorten the duration of the illness by 1 or 2 days, alleviate symptoms, reduce complications and serious illness, and may make someone with influenza less contagious to others. However, it is unknown if antivirals will perform the same for pandemic influenza as they do for seasonal influenza. In addition, influenza virus strains can become resistant to one or more of these drugs, and so they may not always be effective for prevention or treatment.

WHO has stated that the neuraminidase inhibitors are preferred for prevention and treatment of influenza because there is lower risk for adverse events (compared historically to adamantanes), less evidence of drug resistance, and greater therapeutic value associated with these particular antivirals. Of the two currently available neuraminidase inhibitors, WHO strongly recommends the use of Tamiflu. Tamiflu is generally less expensive and easier to ship than Relenza and, because it is given as a capsule or liquid, it is easier to administer.

Pharmaceutical manufacturers are currently producing both brand name and generic versions of antivirals approved for preventing and treating influenza. Tamiflu is produced by Roche, a health care company that sells products throughout the world. Relenza is manufactured by GlaxoSmithKline, another health care company that sells products worldwide. Neither drug is patent protected in all countries, so generic drug manufacturers may produce these drugs where they are not under patent protection. Both amantadine and rimantadine are no longer under patent protection and, consequently, the number of manufacturers that can produce the drug worldwide is not limited by patent restrictions.

U.S. Government Entities Engaged in International Pandemic Influenza Preparedness

HHS, along with the Departments of Agriculture, Defense, and State and the U.S. Agency for International Development, carries out U.S. international animal and pandemic influenza assistance programs. The Department of State leads the federal government’s international engagement on influenza and coordinates U.S. international assistance activities through an interagency working group. The Homeland Security Council is monitoring the U.S. efforts to improve domestic and international preparedness.

HHS provides technical assistance and financing to improve human disease detection and response capacity. HHS received total appropriations specifically available for pandemic-influenza-related purposes in fiscal year 2006 of $5.683 billion. Of this amount, HHS allocated approximately $3.2 billion to vaccines, $1.1 billion to antivirals, and $179 million to international collaboration with the remainder going to such areas as state and local preparedness and risk communications.

The U.S. Agency for International Development provides technical assistance, equipment, and financing for both animal and human health- related activities. In addition, the Department of Agriculture provides technical assistance and conducts training and research programs and the Department of Defense stockpiles protective equipment.

International Strategy to Contain a Pandemic

WHO, in conjunction with the United States and other governments, has developed an international strategy on how to contain an emerging pandemic virus at the site of the outbreak, whether it is H5N1 or another influenza virus with pandemic potential. Containment is a key element of the broad U.S. National Strategy for Pandemic Influenza. The public health community has generally not attempted to contain an initial outbreak of a pandemic-potential strain or to eradicate it while it is still confined to a limited area. WHO has noted that the success of the strategy in halting a pandemic or delaying its spread cannot be assured. However, WHO has stated that given the potential health, economic, and social damage a pandemic can produce, forestalling a pandemic must be tried. Further, WHO notes that should early containment fail, once a certain level of spread of the pandemic virus is reached, no interventions are expected to halt international spread, and the public health response will need to shift to the reduction of morbidity and mortality.

The international containment strategy is based on studies suggesting that efforts, centered on using antiviral drugs to prevent infection as well as treat cases, might contain a pandemic at the site of the outbreak or at least slow its international spread, thus gaining time to put emergency measures in place and develop vaccines. Such a strategy includes the creation of a geographically defined containment zone. According to WHO, the containment zone would be created around the cases where widespread antiviral and nonpharmaceutical countermeasures should be used. The containment zone should be large enough so that all known persons infected by the pandemic virus are located within the zone as well as many of the people in frequent contact with them. Rapid detection and reliable reporting of outbreaks, immediate availability of necessary antivirals for large numbers of people, and the restriction of the movement of people in and out of the affected area (or containment zone) are components of the strategy. Other elements of the strategy include isolation of ill persons, voluntary quarantine of people in contact with these persons, school closures, and cancellation of mass gatherings. These measures are meant to reduce the opportunities for additional human-to-human transmission to occur.

Disease surveillance in animals and humans has a critical role in the success of the international strategy to forestall the onset of a pandemic. The Director of CDC has stated that for optimal response, an emerging influenza pandemic outbreak anywhere in the world must be recognized within 1 to 2 weeks and then be investigated and confirmed within days. Infectious disease surveillance activities include detecting and reporting cases of disease, analyzing and confirming this information to identify possible outbreaks or longer-term trends, exchanging information related to cases of infectious disease, and applying the information to inform public health decision-making. HHS officials have noted that as outbreaks of animal influenza viruses spread and affect people, collaboration between animal and human influenza surveillance systems is needed. Additionally, WHO has stated early detection of animal diseases, which might be transmissible to humans, leads to quicker actions to reduce threats to humans. Alerts of animal outbreaks can provide early warning so that human surveillance can be enhanced and preventive action taken. When effective, surveillance can facilitate (1) timely action to control disease outbreaks, (2) informed allocation of resources to meet changing disease conditions and other public health programs, and (3) adjustment of disease control programs to make them more effective.

Diagnostic tests are an important component of identifying pandemic influenza and putting measures in place to forestall its spread. Diagnostic tests for a range of viruses help assess patients for the presence of H5N1, other emerging influenza viruses, and seasonal influenza. Quick and accurate diagnosis of influenza is essential to early treatment. In addition, accurate, rapid diagnosis enables timely implementation of containment and treatment procedures, and will be critical in identifying the beginning of a pandemic and possibly slowing the spread of the disease. Rapid diagnosis allows more time for equipment and personnel to be mobilized to aid in pandemic response.

As part of the WHO Global Influenza Surveillance Network, individual countries, including the United States, collect and analyze influenza virus samples and submit selected samples to WHO Collaborating Centres for further analysis. These samples allow WHO to perform a number of influenza-related public health activities, including: determining if the virus has acquired human genes or made other tracking the evolution of the virus and its geographic spread, updating diagnostic tests and reagents, identifying potential vaccine strains, and testing to determine if the virus remains susceptible to antivirals.

The success of this network is dependent upon the participation of its members. According to HHS, the network has functioned efficiently in the past for the detection and characterization of newly emergent influenza viruses of epidemic potential.

Uncertain Effectiveness and Limited Availability Would Likely Constrain the Use of Antivirals and Vaccines to Forestall the Onset of a Pandemic

The use of antivirals and vaccines to forestall the onset of a pandemic would likely be constrained by their uncertain effectiveness and limited availability. Weaknesses within the international influenza surveillance system impede the detection of strains, which could limit the ability to promptly administer or develop effective antivirals and vaccines to treat and prevent cases of infection to prevent its spread. The delayed use of antivirals and the emergence of antiviral resistance in influenza strains could limit their effectiveness. A targeted vaccine cannot be manufactured until the pandemic strain has emerged and been identified. The availability of antivirals and vaccines is constrained by existing limitations in their production, distribution, and administration. Current antiviral production capacity is inadequate to reach the number of antivirals WHO estimates will be needed to contain a pandemic. Vaccines targeted to match a pandemic strain are unlikely to be available for prevention of disease at the onset of a pandemic as, according to HHS officials, they would not become available until 20 to 23 weeks following detection of a pandemic. Moreover, most countries do not possess the capacity to distribute and administer these antivirals and vaccines quickly enough to forestall a pandemic.

The Effectiveness of Antivirals and Vaccines in Containing Initial Outbreaks Could Be Constrained by the Limited Capacity to Monitor the Virus and Successfully Treat and Prevent Cases

Antiviral and vaccine effectiveness depends upon their timely application. To achieve timely application, health authorities must be able to detect the virus strain quickly through surveillance efforts and use this information to administer or develop effective antivirals and vaccines. However, weaknesses within the global influenza surveillance system could limit the effectiveness of antivirals and vaccines in treating and preventing cases of infection. In addition, limited support for clinical trials could hinder their ability to improve understanding of the use of antivirals and vaccines against a pandemic strain.

The Effectiveness of Antivirals and Vaccines to Forestall a Pandemic Depends on Influenza Surveillance

An influenza surveillance system that can promptly detect outbreaks would facilitate the timely use of antivirals. The effectiveness of antivirals in containing an initial influenza outbreak of a new strain depends in part on the timely use of the appropriate drug. Experience with seasonal influenza indicates that antivirals are most effective for treatment if started within 48 hours of the onset of symptoms; therefore, rapid detection of human outbreaks of potential pandemic strains is necessary. If an individual is diagnosed too late, antivirals may not be effective. WHO has noted that a critical problem is the tendency of human H5N1 cases to be detected late in the course of the illness. Antivirals used for prevention should be started either before exposure or as soon as possible after initial exposure.

International surveillance is also required to monitor strain evolution for the development of vaccines targeted to a potential pandemic strain or the actual pandemic strain. A well-matched vaccine cannot be ensured until the pandemic virus strain has been identified. According to HHS officials, 20 to 23 weeks are currently required from the detection of a pandemic before a well-matched vaccine can be developed. Consequently, well- matched vaccines are likely to play little or no role in efforts to stop or contain a pandemic, at least in its initial phases. However, an effective surveillance system is necessary to develop a safe and effective pandemic vaccine as soon as possible so that a vaccine is available for later stages of the pandemic.

Another concern is that influenza strains can be resistant to antivirals, rendering them ineffective in treating or preventing infection. Monitoring strain evolution to determine susceptibility or emergence of antiviral resistance is one element of assessing the likelihood that a particular antiviral will be effective. The effectiveness of an antiviral against one strain of seasonal influenza does not mean that it will be effective against an H5N1 strain or another potential pandemic strain. While both classes of antivirals, adamantanes and neuraminidase inhibitors, could potentially be used against a pandemic strain, experts caution against the use of adamantanes without prior indication that the emerging strain is susceptible to them. For example, CDC recommends against the use of adamantanes to treat or prevent currently circulating influenza because strains resistant to adamantanes have emerged. Similarly, WHO recommends only neuraminidase inhibitors be used to respond to H5N1 outbreaks unless neuraminidase inhibitors are not available or local surveillance data show that the H5N1 virus is known or likely to be susceptible to the adamantanes. A high proportion of H5N1 strains circulating in Indonesia, Thailand, and Vietnam have been resistant to adamantanes. Like adamantanes, the effectiveness of neuraminidase inhibitors against potential pandemic strains could also be constrained by the emergence of antiviral-resistant strains of the virus. In Vietnam, a study identified H5N1 strains resistant to Tamiflu, a neuraminidase inhibitor, and a few seasonal influenza viruses—less than .5 percent—have been resistant to Tamiflu. Another study examined the effectiveness of Tamiflu and Relenza, another neuraminidase inhibitor, against H5N1 viruses. The researchers found that there was little variation in the effectiveness of Relenza against all H5N1 viruses studied but that there was variation in the effectiveness of Tamiflu. For example, they reported that one group of H5N1 viruses was 15- to 30-fold less sensitive to Tamiflu than was another group of H5N1 viruses.

Weaknesses in International Influenza Surveillance

According to the U.S. National Strategy for Pandemic Influenza Implementation Plan, international capacity for influenza surveillance still has many weaknesses, including limited influenza sample collection and sharing. Surveillance requires the collection and sharing of virus samples and the genetic sequencing of these samples from both infected humans and animals to monitor if and how a strain is mutating. According to WHO, global influenza surveillance in humans is weak in some parts of the world, particularly in developing countries. Surveillance systems in many of the countries where H5N1 influenza is of greatest concern are inadequate, particularly in rural areas where many cases have occurred. WHO has noted that to increase the likelihood of successfully forestalling the onset of a pandemic, surveillance in affected countries needs to improve, particularly concerning the capacity to detect clusters of cases closely related in time and place. Such clusters could provide the first signal that the virus has begun to spread more easily among humans. If early signals are not identified, the opportunity for preemptive action will be missed. In addition, some countries experiencing H5N1 influenza outbreaks (e.g., Indonesia) have at times not promptly shared human virus samples with the international community, thus further weakening international surveillance efforts.

Similarly, a surveillance network to monitor influenza in animals faces weaknesses. Global animal influenza surveillance can help provide early recognition of viruses with the potential for causing human influenza. Surveillance in animals may indicate how an influenza virus is spreading and evolving. WHO has recommended combining the detection of new outbreaks in animals with active searches for human cases. However, influenza surveillance in animals has weaknesses. For example, definitions of what constitutes an outbreak vary between countries and may be reported as a single infected farm, an affected village, or an affected province. In addition, only the number of outbreaks may be reported rather than more specific information. Moreover, animal disease surveillance is completely lacking in some countries. For example, Djibouti and Uganda have no capacity to collect, transport, and diagnose animal influenza samples. Just as with human influenza samples, there are concerns that animal samples have also not always been shared promptly, or for every outbreak.

According to WHO, few countries have the necessary expertise and facilities to diagnose H5N1. This leads to the need for countries lacking laboratories these facilities to wait until collected samples of a strain are tested by labs outside the country, possibly delaying both timely diagnosis and antiviral administration. Therefore, laboratories must have the necessary information, guidance, and materials to allow them to recognize, store, and safely transport H5N1 samples to more specialized laboratories in other countries. In a previous report, we reported, for example, that Indonesia and Nigeria both had limited capacity to collect, diagnose, or transport influenza in human samples.

Currently, there is not a good way to quickly and easily determine whether a patient has H5N1 or a more common type of influenza. The accuracy of clinical diagnosis of influenza on the basis of symptoms alone is limited because symptoms from illness caused by other pathogens can overlap considerably with influenza. The amount of time required to attain results from diagnostic tests varies from minutes to several days, with accuracy often being the trade-off for rapid results. Existing point-of-care tests can provide results rapidly and determine if the patient is infected with seasonal influenza viruses A or B but cannot identify avian influenza H5N1. A viral culture test can provide specific information on circulating strains and subtypes of influenza viruses in 2 to 10 days but may require longer for more detailed analysis. In addition, the need to conduct viral culture tests in laboratories with enhanced safety levels can also restrict their usefulness. HHS recommends an H5 polymerase chain reaction test, which can be done without the specialized laboratory facilities required by viral culture tests, for the diagnosis of H5N1 influenza. This test is FDA- approved and is used by public health laboratories throughout the United States and in many parts of the world.

Limited Support for Clinical Trials

Limited support for clinical trials could hinder their ability to improve understanding of the use of antivirals and vaccines against a pandemic strain. Clinical trials improve the understanding of effectiveness, timing of administration, duration of treatment, optimal dosage, safety, and the balance of risks and benefits of antivirals and vaccines. Improved understanding gained through clinical trials would assist with updating international guidance on antiviral use. The current estimates on the effectiveness of antivirals in a pandemic are largely based on their use in treating and preventing influenza illness caused by seasonal influenza strains circulating at the times the studies were performed. However, the viral characteristics of a pandemic strain may be different. Similarly, clinical trials are an essential step in vaccine development and are used for testing the safety and effectiveness of vaccines. For instance, clinical trials could test for the optimal dosage of vaccines developed against a potential pandemic strain. However, few governments are assisting vaccine manufacturers with funding and technical support for clinical trials.

Limited Production, Distribution, and Administration Capacity Could Constrain the Availability of Antivirals and Vaccines

The availability of antivirals and vaccines is constrained by limited production, distribution, and administration. Vaccine manufacturers’ liability concerns might also limit their willingness to manufacture these drugs and make them available in certain countries.

Constraints on Antiviral and Vaccine Production

Current antiviral production is inadequate to reach WHO estimates for the number of antivirals needed to contain a pandemic. While WHO has not set a target for national antiviral stockpiles, it stated in 2007 that it is unlikely that sufficient quantities of antivirals will be available in any country at the onset of a pandemic. WHO estimates that the quantity of antivirals required to forestall a pandemic would be enough treatment courses for 25 percent of the population. In addition, there would need to be enough preventative courses to last 20 days for the remaining 75 percent of the population in the outbreak containment zone. While Roche, the primary manufacturer of Tamiflu, has expanded production, it has stated that the demand for Tamiflu will need to further increase before there are any new increases in production.

While vaccination is considered to be the best defense against influenza, it is unlikely that a vaccine targeted to the pandemic strain will be available in time to forestall the onset of a pandemic. HHS has reported that 20 to 23 weeks are currently required from the start of a pandemic to the availability of a well-matched vaccine; WHO expects that once a pandemic strain emerges, it is likely that it will spread globally within approximately 3 months. Figure 1 shows how WHO, its Collaborating Centres around the world, and pharmaceutical manufacturers would proceed to develop and produce vaccines designed to protect against a newly emerged pandemic strain, and how long it would take for the vaccines to become available.

Some health authorities have suggested that increased seasonal vaccination could play a limited role in forestalling the emergence of a pandemic by limiting the opportunities for human and animal influenza strains to combine and form a pandemic strain, but it is likely that the limited availability of seasonal vaccination would limit its role in forestalling an influenza pandemic. Seasonal vaccine would not prevent individuals from becoming infected with animal influenza. However, in the case of an H5N1 strain, promoting seasonal vaccination prior to the emergence of a pandemic strain, particularly among health care workers and others in contact with human cases of H5N1 infection and infected poultry, could reduce the likelihood of H5N1 and seasonal influenza coinfection in humans. Experts fear that such co-infection could lead to the emergence of a reassorted influenza strain that has the transmissibility of the human seasonal strain and the virulence of the H5N1 strain, thus resulting in a pandemic. However, large-scale global seasonal influenza vaccination would be difficult to implement because of the lack of influenza vaccination programs in many countries. Additionally, seasonal vaccination of humans would not prevent influenza reassortment within animals.

According to WHO, current annual global production capacity for trivalent seasonal vaccines is approximately 565 million doses; these doses would only be enough to vaccinate about 9 percent of the world’s population of 6.6 billion people. WHO has also stated that the current demand for and supply of seasonal influenza vaccine is approximately equal. Thus, without additional production, either by current manufacturers scaling up their production or by increasing the number of manufacturers, the supply of seasonal vaccine would not be able to meet the increased demand that would stem from the promotion of seasonal vaccination. In fact, due to limitations in vaccine production capacity, even countries with existing seasonal vaccine programs have experienced shortages. For example, the United States experienced vaccine shortages as recently as the 2004-2005 influenza season due to production problems experienced by one manufacturer.

This limited vaccine production capacity would also limit the availability of a pandemic vaccine in the event of a pandemic since the processes used to manufacture seasonal and pandemic vaccines are similar and the manufacturing would take place in the same facilities. If a monovalent vaccine (that is, a vaccine that contains only one influenza strain) were produced for a pandemic strain, experts estimate that approximately three times the number of trivalent doses could be produced. Consequently, if annual production capacity is sufficient to produce 565 million doses of trivalent vaccine, 1.695 billion doses of monovalent vaccine could be produced each year. However, the actual number of doses that could be produced would depend on a number of factors including how well the virus strain grows in eggs and the dosage required. For instance, if a dose larger than 15 micrograms—the dose required for current seasonal vaccine—was needed, fewer doses could be produced. Testing on a sanofi pasteur H5N1 vaccine approved by FDA in April 2007 indicates that a single 15 microgram dose would not be sufficient to confer immunity. Instead, the testing indicated that 45 percent of individuals who received two 90 microgram doses of this vaccine—or twelve times as much— developed an immune response expected to reduce the risk of getting influenza. If this dosage were required during a pandemic, instead of having the capability to vaccinate 1.695 billion people, only 141,250,000 (one-twelfth as many) could be vaccinated. This would likely be well below global demand, given a global population of 6.6 billion people.

The location of vaccine manufacturing facilities could also limit the role that vaccines would play in forestalling an influenza pandemic. Experts fear that the concentration in a few countries of vaccine production capacity could, in the event of a pandemic, lead to vaccine shortages in countries without domestic manufacturing capacity. According to WHO, 90 percent of vaccine production capacity is concentrated in Europe and North America. Currently, only one manufacturer’s entire seasonal influenza vaccine production facilities are located completely within the United States. There is concern among experts that countries without domestic manufacturing capacity would not have access to vaccines in the event of a pandemic if the countries with domestic manufacturing capacity prohibited the export of vaccine until their own needs were met. Many countries experiencing H5N1 influenza outbreaks, such as Cambodia and Indonesia, do not have domestic manufacturers that produce influenza vaccines, and according to WHO, would require financial and technical support from the international community to create a domestic pharmaceutical infrastructure.

Constraints on Distribution and Administration

Limited global, national, and local-level distribution and administration capacity could restrict the availability of antivirals at the site of outbreaks for use in forestalling the onset of a pandemic. Distribution and administration capacities require plans, delivery networks, facilities suitable for administering the drugs, trained personnel, and funding to get antivirals to where they are needed and administer them promptly. As discussed earlier, experience with seasonal influenza indicates that antivirals are most effective in treating influenza if they are taken within 48 hours of the onset of symptoms. This requires an efficient distribution network to get the drugs to where they are needed.

Antiviral distribution networks are poor or nonexistent in some countries. We previously reported that as of October/November 2005, 10 of 17 countries reviewed did not have distribution plans for the release of antiviral stockpiles and there was insufficient information available to reach conclusions for 4 others. Studies of national pandemic preparedness plans in Europe and the Asia-Pacific region found that most did not adequately address how antivirals would be transported to locations where they are needed and how they would be administered to individuals. Thirteen of the 21 European plans had guidance on priority groups for treatment with antivirals, but none described the process by which individuals belonging to priority groups would be identified. Most of the plans in Asian-Pacific countries did not identify such priority groups. The timely administration of antivirals would also likely be constrained if there is a scarcity of trained professionals as well as packaging and instructions that are printed in languages foreign to those administering the drugs. In addition, countries that depend upon outside sources to provide antivirals might not have these drugs available in time to contain an outbreak. Many countries do not have national stockpiles of antivirals and are dependent on outside sources to provide these drugs for distribution in the event of an outbreak. Antiviral stockpiling is expensive, and it may not be feasible for many countries to establish their own national stockpiles.

Similarly, the availability of vaccines could be affected by limitations in countries’ capacity for distributing and administering vaccines. For example, a lack of supplementary medical supplies (such as syringes) could impede the administration of vaccines. Countries’ experience with seasonal vaccination programs indicates potential problems in the event of a pandemic. IFPMA has noted that many developing countries have insufficient health care systems to deliver vaccines. Most countries have little seasonal influenza vaccine distribution infrastructure and lack financial and human resources to implement national seasonal influenza vaccination programs. In 2005, WHO reported that about 50 of the 193 countries in the world, mainly those that are industrialized and some countries in rapid economic development, offer influenza vaccination to nationally defined high-risk groups. However, even in industrialized nations such as the United States, vaccine distribution and administration issues arise. For example, during the vaccine shortage in the 2004-2005 influenza season, CDC developed a plan to allocate the available vaccine among states. However, the formula for allocating each state’s allocation was imperfect, resulting in some states having more vaccine than needed to cover demand and other states having too little.

Manufacturers’ Liability Concerns

Manufacturers’ concerns regarding product liability in individual countries could also hinder the global availability of vaccines. Experts and vaccine manufacturers have said that the lack of liability protection increases liability concerns for manufacturers, which may hinder their willingness to manufacture and distribute vaccines in countries where they might be held liable for any adverse effects that occurred from their administration. Concerns regarding potential liability for the vaccines could hinder efforts by WHO to get companies to donate vaccines to countries where they are not licensed. Industry representatives have stated that manufacturers would need advance assurance that governments would provide liability protection.

U.S. Government and International Partners’ Efforts Are Under Way to Address Constraints on Use of Antivirals and Vaccines, but Certain Efforts Face Limitations

The United States, its international partners, and the pharmaceutical industry are investing substantial resources in efforts to address the uncertain effectiveness and limited availability of antivirals and vaccines. Efforts to make effective antivirals and vaccines more available include (1) improving disease surveillance on an international scale in order to monitor the evolution of influenza strains and the effectiveness of antivirals and vaccines against those strains, (2) increasing global demand for antivirals and vaccines to encourage production and spur research and development, and (3) increasing global distribution and administration capacity. However, some of these efforts face funding and logistical limitations and will take several years to complete.

Efforts Are Under Way to Improve Surveillance in Order to Increase the Effectiveness of Antivirals and Vaccines

The U.S. government and its international partners are supporting efforts to increase the effectiveness of antivirals and vaccines by improving influenza surveillance. International surveillance is required for monitoring strain evolution in humans and animals to detect the emergence of new influenza strains and evaluate the continued effectiveness of antivirals and vaccines as the virus evolves. Governments, international organizations, manufacturers, and scientists have initiatives under way to improve international surveillance by improving disease surveillance in humans, creating animal surveillance networks, improving animal and human sample sharing and analysis, increasing international collaboration in monitoring influenza strains, and improving diagnostic capabilities.

WHO’s revised International Health Regulations seek to improve worldwide disease surveillance in humans. The revised Regulations were adopted in May 2005 and effective on June 15, 2007, require that member states report all events that constitute a public health emergency of international concern, such as those caused by new and reemerging diseases with epidemic potential like H5N1 influenza. The Regulations set out the basic public health capacities a country must develop, strengthen, and maintain to detect, report, and respond to public health risks and potential public health emergencies of international concern. For example, at the national level a country is required to be able to assess all reports of urgent events within 48 hours. Each country must assess its ability to meet the core surveillance capacities by June 2009 and has until June 2012 to develop these capacities.

Among activities to improve influenza surveillance in animals, in May 2005 the World Organisation for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations (FAO) created the OIE/FAO Network of Expertise on Avian Influenza (OFFLU), an international veterinary counterpart to WHO’s human Global Influenza Surveillance Network. OFFLU supports international efforts to monitor and control H5N1 in poultry and other bird species through the collection and sharing of influenza virus samples from infected animals. Increased animal surveillance could speed the diagnosis and reporting of novel influenza strains. One of OFFLU’s goals is to put influenza sequences in the public domain for the benefit of research and development, and OFFLU is actively supported in this endeavor by the U.S. government. Influenza sequencing reveals complete genetic blueprints of influenza viruses, information which is used to develop vaccines and to monitor the emergence of antiviral-resistant influenza strains. Additionally, sequencing provides information that might indicate that a virus has changed in such a way to become more transmissible among humans. OFFLU collects animal influenza samples and shares them with NIH for sequencing and with CDC for antigenic analysis. NIH sequences the samples and funds the costs of sequencing these samples. NIH then makes the completed sequences available in the public domain. Through its Influenza Genome Sequencing project, NIH makes available to the entire scientific community over the Internet the genetic sequences of human and animal influenza viruses. As of December 13, 2007, 2,807 human and animal influenza viruses have been completely sequenced. In addition to this project, CDC and NIH have provided materials to countries affected by H5N1 to test animal influenza virus strains. In the event of a pandemic, CDC and NIH have also offered them assistance in sequencing influenza viruses.

An additional effort to improve surveillance through sample sharing is the Global Initiative on Sharing Avian Influenza Data, formed in August 2006 by a group of scientists from over 40 countries. Genetic sequence data collected through this initiative will be deposited in a publicly available database and then after a specified period of time will be released automatically to publicly funded databases participating in the International Sequence Database Collaboration or in other publicly available databases. This initiative will work to overcome restrictions which have previously prevented influenza information sharing, with the hope that more shared information will help researchers understand how viruses spread, evolve, and can potentially lead to a pandemic. This initiative is open to all scientists, provided they agree to share their own data, credit the use of others’ data, analyze findings jointly, and publish results collaboratively.

In addition to OFFLU, a surveillance system for animal diseases that are transmissible to humans has also been established and many countries have improved their surveillance of animal diseases. FAO, OIE, and WHO launched the Global Early Warning and Response System for Major Animal Diseases, including Zoonoses (GLEWS) in July 2006 to improve the early warning and response capacity of the three organizations to animal diseases, including those that can spread to humans. GLEWS is the first joint early warning and response system conceived with the aim of predicting and responding to such diseases. WHO has stated that from a public health perspective, early warnings of animal outbreaks that have a known potential to spread to humans will enable the initiation of control measures that can prevent human morbidity and mortality. The United Nations System Influenza Coordinator and the World Bank have reported that many countries have improved their animal disease surveillance systems. They noted that better disease surveillance systems, along with improved laboratory capacity and increased access to epidemiological expertise, account for improved detection of H5N1 and other influenza viruses.

In April 2007, NIH announced that it was awarding $23 million per year for 7 years to establish six Centers of Excellence for Influenza Research and Surveillance. The mission of the centers is to expand NIH’s influenza research program, both in the United States and internationally, to determine how these viruses cause disease as well as how the human immune system responds to them. Specific activities include expanding animal influenza surveillance and studying how pandemic viruses emerge.

Governments, including the U.S. government, and manufacturers are undertaking efforts to increase international collaboration to monitor the evolution of influenza strains. Through a collaborative global network, CDC’s WHO Collaborating Centre is monitoring the H5N1 virus to track its geographic spread and to identify and analyze changes in the virus. CDC is providing funds for the shipment of influenza samples to WHO Collaborating Centres for analysis. As part of its surveillance role, CDC conducts antiviral susceptibility testing on seasonal and novel influenza viruses and has been able to identify changes in the sequence of H5N1 virus samples that could affect their susceptibility to existing antiviral medications. For example, in January 2007 CDC testing found an H5N1 virus sample from Egypt with reduced susceptibility to Tamiflu. FDA, CDC and other WHO Collaborating Centres, other WHO laboratories, and national regulatory authorities have also used information on H5N1 strain evolution to recommend representative strains for use in the development of pre-pandemic vaccines and to develop H5N1 reference viruses which are shared with manufacturers. Manufacturers are also supporting the independent Neuraminidase Inhibitor Susceptibility Network, which includes government officials and works in collaboration with WHO to monitor influenza viruses for any signs of strains that have developed resistance to this class of antivirals.

Concerns regarding the failure of certain countries to share human and animal influenza samples and the availability of vaccines developed from these samples have led to efforts to promote sample sharing. In February 2007, Indonesia announced that it would no longer share H5N1 samples with WHO because the resulting vaccines produced by private companies were unlikely to be available to developing countries such as Indonesia. At times, the Indonesian government has also expressed a desire for royalties from any invention derived from an influenza sample isolated within its borders. In March 2007, WHO said that an agreement had been reached and that Indonesia would resume sharing H5N1 samples immediately. However, sample sharing did not resume until May 2007 when, at the World Health Assembly meeting, 17 developing countries introduced a resolution demanding equitable access to vaccines made from H5N1 samples the countries provide. At that time, Indonesia provided three samples from two patients to WHO. Later at that meeting, the World Health Assembly requested that WHO formulate mechanisms and guidelines aimed at ensuring the fair and equitable distribution of pandemic influenza vaccines at affordable prices in the event of a pandemic. Following this, in June 2007 the health ministers of the Asia- Pacific Economic Cooperation stated they planned to share influenza virus specimens in a timely manner. However, HHS officials told us that concerns remain. In July 2007, HHS reported to us that Indonesia had not shared any seasonal or H5N1 influenza samples since those it sent to WHO in May 2007. HHS also noted that the Asia-Pacific Economic Cooperation agreement is not being followed. A WHO official has also expressed concern. In August 2007, he stated that by not sharing virus samples, Indonesia is endangering the world’s health as well as its own. Also in August 2007, Indonesian health officials stated that the county will continue to withhold H5N1 samples at least until a new virus-sharing agreement is developed at an international meeting in November 2007. Later in August Indonesia sent two samples to CDC for testing, although concerns remain whether Indonesia will share or continue to withhold samples in the future. At the November 2007 meeting, no agreement on sample sharing was reached. Indonesia advocated an accord stating that for every virus sample sent out of a country, there should be an agreement specifying that the sample be used only for diagnostic purposes. Commercial use of the virus would require permission of the country that provided the sample.

Improved understanding of influenza viruses could improve surveillance and, in turn, vaccine development. Scientists at NIH, along with a collaborator at Emory University, have identified mutations that would help a strain of the H5N1 virus spread easily from person-to-person. This knowledge could contribute to better surveillance of naturally occurring influenza outbreaks because efforts could be focused on identifying viruses with mutations that lead to increased transmissibility among humans. This could permit the development of vaccines prior to a pandemic, and possibly help contain a pandemic at its outset.

WHO and CDC are undertaking a number of activities in order to improve diagnostic capability worldwide. WHO reported providing equipment and training to staff working within national laboratories and is providing experts to give hands-on support. At the regional level, it reported enhancing the laboratory network with the facilities and expertise to analyze H5 samples so that every country has access to a regional H5 laboratory. This H5 laboratory network has provided support to countries in shipping samples and providing confirmation of suspected H5N1cases. According to WHO, four laboratories in Africa have been upgraded so that they can conduct H5 diagnosis. For the long term, WHO is working to build and strengthen local H5 diagnostic capability. In addition, CDC officials stated that among its activities the agency provides financial and technical assistance to 35 countries, WHO, and WHO regional offices in order to improve influenza laboratory diagnostic capability. CDC is also providing training for laboratory workers and epidemiologists in order to expand laboratory diagnostic capabilities and develop rapid response teams that could quickly detect, report, and control outbreaks caused by novel influenza viruses. CDC officials have also provided laboratory support and diagnostic reagents to countries investigating H5N1 outbreaks.

Research is being conducted to improve rapid, diagnostic tests for influenza. In order to forestall a pandemic, it is critical to be able to identify people with H5N1 quickly. A reliable, rapid diagnostic test is needed for epidemiological assessments, traveler screening, and clinical care. Currently, rapid tests cannot distinguish between strains and subtypes of influenza viruses. To address this shortcoming, in December 2006, CDC awarded four companies a total of $11.4 million in contracts to develop new viral diagnostic tests with quicker and more reliable results that could be used at, for example, a patient’s bedside or a port of entry (see table 3). CDC hopes for FDA approval and commercialization of these products in 2 to 3 years. In addition, tests designed for large reference and public health laboratories are also being developed. In February 2006, FDA approved a test developed by CDC that identifies H5 but not the strain within 4 hours once testing begins. Previously, it would have taken 2 to 3 days. If the virus is identified as H5, tests are then conducted to identify the strain. FDA has shared this technology with WHO and its Collaborating Centres.

Research is also under way to improve other types of diagnostic tests for influenza. For example, using funding from NIH, scientists at the University of Colorado at Boulder and CDC have developed a test that is based on a single influenza virus gene that could allow scientists to quickly identify influenza viruses, including H5N1. This test offers several advantages over available tests including being based on a gene that, unlike hemagglutinin and neuraminidase, does not mutate constantly. Consequently, the researchers believe that this test will be more useful than other tests because it will provide accurate results even if the hemagglutinin and neuraminidase genes mutate. However, WHO has cautioned that the availability of such tests are at least 4 years away.

Efforts Are Under Way to Increase Demand for Antivirals and Vaccines to Encourage Production and Spur Research and Development

Efforts to expand seasonal vaccination and build national stockpiles of antivirals and pre-pandemic vaccines are under way to encourage increased demand for these drugs. Demand for seasonal influenza treatment drives global production capacity for antivirals and all types of influenza vaccines. Increasing demand through government support provides incentives for manufacturers to develop more effective antivirals and vaccines.

Efforts to Increase Demand to Encourage Production

While the primary benefit of increased seasonal vaccination would be the enhanced protection against seasonal influenza, WHO has stated that increased demand for seasonal vaccines would spur manufacturers to increase their vaccine manufacturing capacity. One of WHO’s goals is to increase seasonal vaccine coverage in countries that already use seasonal vaccine to 75 percent of target populations by 2010, which would require an increase in global vaccine production to 560 million doses to cover use in these countries only. Some countries with seasonal influenza vaccination programs had increased their use of seasonal vaccines prior to WHO setting vaccination goals, thus providing incentives for manufacturers to increase overall vaccine production capacity. In October 2007, WHO stated that seasonal influenza vaccine capacity is expected to rise to 1 billion doses annually in 2010, provided sufficient demand exists.

Increased demand for antivirals and pre-pandemic vaccines also stems from orders placed by countries to build national stockpiles. According to Roche, as of April 2007, more than 80 countries had ordered Tamiflu for their own national antiviral stockpiles. Some countries, including Australia, France, and the United States, are also ordering Relenza to supplement their Tamiflu stockpiles. The United States had 36.6 million neuraminidase treatment courses in its federal stockpiles as of August 6, 2007, consisting of 30.8 million treatment courses of Tamiflu and 5.8 million treatment courses of Relenza. It also had 3.6 million treatment courses of rimantadine, an adamantane, on-hand for a total stockpile of 40.2 million antiviral treatment courses. Approximately 100,000 additional Tamiflu treatment courses and 700,000 additional Relenza treatment courses are currently on order for the stockpile. The U.S. goal at the national level is to have a federal stockpile of 50 million antiviral treatment courses. In addition, states and other entities had stockpiles totaling 12.9 million treatment courses of Tamiflu and 1.6 million treatment courses of Relenza as of August 6, 2007. Similarly, Australia, Japan, the United States, and countries in Europe have been establishing stockpiles of pre-pandemic vaccines. For example, in 2005, sanofi pasteur agreed to produce 1.4 million doses of H5N1 pre-pandemic vaccine for France’s stockpile. It is also providing H5N1 pre-pandemic vaccines for national stockpiling in the United States and Italy. In addition, GlaxoSmithKline Biologicals and Novartis Vaccines and Diagnostics are also producing H5N1 pre-pandemic vaccine for the U.S. national stockpile. The United States has stockpiled enough H5N1 pre-pandemic vaccine to cover about 7 million people. The United States’ goal is to have a pre-pandemic vaccine stockpile of treatment courses for 20 million persons. However, developing countries may not be able to build such antiviral and vaccine stockpiles.

Antiviral manufacturers have expanded their production capabilities. Roche expanded its Tamiflu production so that it could produce 400 million treatment courses of Tamiflu by the end of 2006. Roche noted that this represents an approximate 15 fold increase over its production capacity of 27 million treatment courses in 2004. In April 2007, Roche stated that its production capacity now exceeded government and corporate orders for Tamiflu received to date. To increase capacity, Roche expanded production from one facility to eight Roche sites, including the United States where 80 million Tamiflu treatment courses can now be produced. In addition, Roche now has 19 external manufacturing partners that perform particular functions in the manufacturing process. Roche has also granted sublicenses to selected drug companies in China and India to allow them to produce Tamiflu in its generic form, oseltamivir, which will increase the amount of that antiviral available globally. In Africa, Roche granted a sublicense to a South African company allowing it to produce oseltamivir to increase production and speed up availability of the drug for use against a pandemic strain in Africa. GlaxoSmithKline, the manufacturer of Relenza, is undertaking efforts to boost Relenza production. While less than 1 million treatment courses of Relenza were produced in 2005, GlaxoSmithKline stated in May 2006 that it planned to increase production capacity in its existing facilities in North America, Europe, and Australia. It increased production to 15 million treatment courses in 2006 and plans to produce 40 million treatment courses in 2007. GlaxoSmithKline also stated that it is willing to license other manufacturers to produce Relenza in its generic form, zanamivir. In September 2006, GlaxoSmithKline announced a licensing agreement with a Chinese drug company to produce the antiviral and sell it in China, Indonesia, Thailand, Vietnam, and other developing countries.

Governments and manufacturers are also working to increase the global production of vaccines by helping to build production facilities and supplying the technology and resources necessary to produce influenza vaccines. In September 2006, WHO stated that worldwide vaccine production capacity is expected to increase by 280 million trivalent doses in the next 2 to 3 years.

The U.S. government has offered assistance to countries trying to create the infrastructure necessary for vaccine production. For example, HHS has provided countries with reagents, the chemicals required to assess vaccine effectiveness, and training for testing vaccines. It also works with countries to help them develop their own reagents and tests for use in clinical trials and other research.

WHO’s Global pandemic influenza action plan to increase vaccine supply, dated September 2006, proposes building new production plants in both developing and industrialized countries as one means to increase production capacity.

In October 2006, HHS announced a grant of $10 million to WHO to support influenza vaccine development and manufacturing infrastructure in other countries, while Japan has contributed $8 million. In April 2007, WHO announced that it was awarding grants to six countries to help them develop the capacity to make influenza vaccine. Two of the projects will be in Latin America and four in Asia. Three of the Asian countries receiving grants—Indonesia, Thailand, and Vietnam—have had cases of persons infected with H5N1 influenza. Manufacturers have also committed substantial funds to increase their own vaccine production capacity.

Additionally, sanofi pasteur signed a technology transfer arrangement with the governments of Thailand, Mexico, and Brazil.

In June 2007, HHS awarded a $77.4 million contract to sanofi pasteur and a $55.1 million contract to MedImmune to renovate existing vaccine manufacturing facilities in the United States and to provide warm-base operations for manufacturing pandemic influenza vaccines. In warm-base operations, a facility does not shut down. HHS stated that these changes will increase production capacity and permit year-round production of pre-pandemic influenza vaccines for the national stockpile, which is currently limited to 3 months per year.

In July 2007, sanofi pasteur announced that it had completed construction of a new influenza vaccine manufacturing facility in the United States. It also noted that it was expanding its influenza vaccine manufacturing capacity in France.

Encouraging Further Research and Development

Increased demand through government support has provided incentives for manufacturers to develop more effective antivirals and vaccines. Manufacturers are conducting research on new antivirals and on improving the use of existing antivirals. Manufacturers are also working to improve the effectiveness of vaccines to combat pandemic influenza through such activities as developing pre-pandemic vaccines, examining cell-based production technology, studying substances that can be added to vaccines to improve effectiveness, and conducting research on vaccines that would provide protection against multiple influenza strains. These studies could be used to help define additional studies and resources that might be needed to assess the safety, effectiveness, and risk and benefit of products, and appropriate use of proposed new products or new uses of existing products.

Research on and Development of Antivirals Development of new antivirals is particularly important due to concern over the emergence of antiviral-resistant influenza strains that could render existing antivirals ineffective. Manufacturers are developing and testing new antivirals, and the U.S. government is providing support to manufacturers that are developing new antivirals. In 2005, HHS announced plans to spend $400 million to develop new antiviral drugs. In January 2007, HHS awarded a 4-year $103 million contract to BioCryst Pharmaceuticals, Inc., to support development of a new antiviral, peramivir. Sankyo Co., Ltd., of Japan and Biota Holdings Limited of Australia are working together to develop new antivirals called long-acting neuraminidase inhibitors. These companies have received a $5.6 million grant from HHS to accelerate the development of these antivirals.

In addition to developing new antivirals, governments and manufacturers are exploring ways in which existing antivirals could be used to treat influenza more effectively and efficiently. For example, researchers are examining the potential use of antiviral combination therapy, which would entail the use of more than one antiviral to treat an influenza infection. Combination antiviral therapy may be more effective and could reduce the likelihood that an antiviral-resistant strain might emerge because, for example, there may be less chance that a strain resistant to both antivirals would emerge. Researchers are also examining the use of antivirals with other types of pharmaceuticals. NIH, the Department of Defense, and the Department of Veterans Affairs are collaborating on a study to determine if Tamiflu used in combination with the drug probenecid can stretch the supply of Tamiflu. The aim of these studies is to determine whether the combination of these drugs results in Tamiflu remaining in the body longer, thus reducing the amount of Tamiflu that an individual would need to take and effectively increasing the supply of the drug. NIH has also provided funding to the South East Asian Influenza Clinical Research Network, to improve understanding and clinical management of influenza through clinical research, as well as to increase clinical research capacity in participating countries (Indonesia, Thailand, and Vietnam). One ongoing study will compare the safety and effectiveness of standard- and high-dose Tamiflu in treating animal and severe seasonal influenza in hospitalized children and adults. Planned studies include the evaluation of the safety and tolerability of the long-term use of Tamiflu and Relenza to prevent influenza in health care workers and a study of the safety and effectiveness of using intravenous Relenza for the treatment of H5N1 infection in adults and children.

Research on and Development of Pre-Pandemic Vaccines Manufacturers, sometimes with the assistance of governments, are working to develop pre-pandemic vaccines. These vaccines might provide some protection against a pandemic strain and also give manufacturers experience in producing effective vaccines for a potential pandemic strain. The United States has been the primary government sponsor of these efforts although other countries have sponsored some studies; other studies have been conducted without government support. The United States has supported studies of vaccines developed by Baxter International, Inc., MedImmune, Novartis, and sanofi pasteur.

WHO has reported two ways in which a pre-pandemic vaccine could be used. First, such a vaccine could be used to protect selected populations at risk of being infected by viruses currently circulating among poultry. Second, it could be used to immunize general populations or selected groups (e.g., health care workers) against a potential pandemic strain. However, WHO points out that the pandemic virus may be quite different than what people are immunized against and therefore the pre-pandemic vaccine may not be protective.

Pre-pandemic vaccine might also be used as part of a “prime-boost” series in which two doses of vaccine based on different strains would be given. The first vaccine would be a pre-pandemic vaccine that would prime the immune system for a second vaccine. The second vaccine would match the pandemic strain. It is hoped that together the two doses would result in immunity. However, the data needed to support such an approach have not been fully developed.

In April 2007, FDA licensed the first pre-pandemic vaccine for human use in the United States against H5N1 based on the results of a clinical trial conducted by NIH, although the results revealed limitations. FDA approved the vaccine for the immunization of persons 18 to 64 years of age at increased risk of exposure to the H5N1 influenza subtype. The vaccine, manufactured by sanofi pasteur, will not be marketed commercially. Instead, the vaccine has been purchased by the federal government for inclusion in the United States stockpile for distribution if needed. However, NIH’s clinical trial showed limitations of the vaccine. First, in previously unexposed populations, two 90 microgram doses are needed to elicit the levels of immune responses usually thought to be adequate to provide protection instead of the single 15 microgram dose of seasonal influenza vaccine that is needed for protection against a seasonal influenza strain. Second, even with this larger dosing regimen, vaccination results in an immune response thought to be protective in only 45 percent of those receiving the vaccine. Studies of seasonal vaccines in healthy persons have demonstrated that effectiveness against well-matched strains is 70 to 90 percent. In addition, experts have noted that such a high vaccine dose could result in an unusually high rate of adverse reactions. NIH, along with other federal agencies, sanofi pasteur, and other manufacturers, continue to work on the development of vaccines that will stimulate enhanced immune response at lower doses of vaccine.

GlaxoSmithKline and Novartis have both announced that they have submitted pre-pandemic H5N1 vaccines for approval in Europe.

Research on and Development of Cell-Based Production Technology To speed development and production of new technologies for influenza vaccines, the U.S. government and manufacturers are pursuing the development of cell-based vaccine production technology as an alternative method to current egg-based production. Egg-based vaccine production cannot be scaled up quickly and egg supplies can be compromised in the event of an influenza outbreak. According to HHS, cell-based technology could be scaled up quickly because cells can be frozen in advance and large volumes grown quickly, thus providing surge capacity in the event of a pandemic. In April 2005, HHS awarded a $97 million 5-year contract to sanofi pasteur for development of a cell-based influenza vaccine. Subsequently, HHS awarded more than $1 billion in contracts to accelerate development and production of cell-based production technologies for influenza vaccines within the United States. (See table 4.) HHS officials told us that this funding provided companies with the incentive to invest in this technology. In the past, companies did not want to invest in cell-based production technologies because it would not increase efficiency as both cell- and egg-based production would yield similar amounts of vaccine. FDA issued draft guidance in September 2006 to assist manufacturers in developing cell-based vaccines. In other countries, companies are making similar although smaller investments than in the United States, usually without government support.

Progress has already been made on the development of cell-based influenza vaccines. For example, Solvay Pharmaceuticals received authorization to market its cell-culture influenza vaccine in the Netherlands in 2001. However, this vaccine has not yet been marketed. In June 2007, the European Union approved a cell-culture-derived seasonal influenza vaccine manufactured by Novartis. The company has stated that it expects to submit an application for approval to market the vaccine in the United States in 2008.

Research on and Development of Adjuvants HHS has awarded contracts to manufacturers to research and develop influenza vaccines that use adjuvants. An adjuvant is a substance added to a vaccine to improve its effectiveness so that less vaccine is needed to provide protection. When added to a vaccine, adjuvants can stretch the vaccine supply by decreasing the amount of vaccine needed per person while still providing the same level of protection. Adjuvants have been used in other vaccines, but not in influenza vaccines. GlaxoSmithKline, Novartis, and sanofi pasteur have announced study results that show that adjuvanated influenza vaccines produced possible protective immunity at lower doses than did nonadjuvanated vaccines. For example, Novartis has reported that its adjuvanated vaccine produced a strong immune response against H5N1, H5N3, and H9N2, but that its vaccine without adjuvant produced a poor response. In January 2007, HHS announced that it had awarded contracts totaling $132.5 million to three vaccine manufacturers for the development of H5N1 vaccines using an adjuvant. (See table 5.)

In addition to potentially stretching the vaccine supply, there is evidence that when adjuvants are added to a vaccine, that vaccine might also provide protection against strains to which it is not fully matched. Research by Novartis demonstrated that its H5N3 vaccine generated a better immune response against H5N1 strains with an adjuvant than without it. Similarly, a GlaxoSmithKline vaccine with adjuvant provided protection against two diverse H5N1 influenza strains.

Research on and Development of Universal Vaccines and Other Vaccines That Protect Against Multiple Influenza Strains Current efforts to develop a universal influenza vaccine are intended to address constraints on both the effectiveness and availability of vaccines. A universal vaccine would protect against multiple virus strains. Availability of universal influenza vaccines would eliminate the current process required to reformulate seasonal influenza vaccines each year. Consequently, if vaccines effective against pandemic influenza could be available when a pandemic strain emerged, there would not be a 20- to 23-week period between identification of the pandemic strain and the ability to produce an effective vaccine. The recent threat of a human pandemic arising from H5N1 has spurred new funding for manufacturers currently attempting to develop universal influenza vaccines. In October 2005, a consortium of companies and universities announced that it had received a 2-year $1.4 million grant from the European Union to support the Universal Vaccine project. The aim of this project is to develop an easily-administered nasal vaccine that provides life-long protection against influenza. Manufacturers such as Merck and Cytos Biotechnology are also working to develop a universal vaccine. NIH is working to bring universal vaccine candidates through the pre-clinical development stage.

Despite the recent increase in funding, experts caution that a completely universal influenza vaccine is years away. Therefore, some researchers and manufacturers are developing live attenuated vaccines that might protect against a matched strain as well as mutated strains that typically emerge from year to year. These live attenuated vaccines would not be completely universal, but are easier to develop than universal vaccines and may provide broader protection than current vaccines that match a specific influenza strain. For example, MedImmune’s current seasonal FluMist vaccine, which is a live attenuated vaccine, proved effective in children against the H3N2 strain to which it was fully matched as well as against H3N2 strains for which there was a mismatch in studies in children. However, this may not be the case in adults. Evidence suggests that a live attenuated vaccine was less effective in protecting against mismatched strains in healthy adults than was the inactivated trivalent vaccine. In September 2005, HHS announced that it would work with MedImmune to develop at least one vaccine for each of the 16 identified hemagglutinin influenza proteins. According to experts, it is not clear whether live attenuated virus vaccines matched only for the hemagglutinin protein (e.g., H5 or H7) would work as well against a pandemic strain as would a vaccine matched to the particular strain. However, as in the case of pre-pandemic vaccines, even if limited in their effect these vaccines might help reduce mortality during a pandemic while a fully matched vaccine is developed. HHS officials noted that the protection offered by live attenuated vaccines against multiple strains of different subtypes has yet to be established. It has also been noted that even if an acceptable live attenuated H5N1 vaccine is developed, it could not be used as a pre- pandemic vaccine. There is concern that it could reassort with a circulating seasonal influenza virus and thereby increase its transmissibility among humans.

Similarly, research has been conducted using vaccines made from whole influenza virus rather than just parts of the virus. Studies from two vaccine manufacturers, Baxter and Biken, have independently suggested that whole virus vaccines provide protection against multiple strains of the H5N1 virus and require a smaller dose than do vaccines made from parts of the virus. Consequently, the use of whole virus vaccine might not only increase the number of influenza strains against which one is protected, but also increase the number of doses available.

To Increase Availability, Governments and International Organizations Have Worked with Manufacturers to Improve Distribution of and Administration Capacity for Antivirals and Vaccines

Increasing global availability of antivirals and vaccines includes improving the global capacity for their distribution and administration. These efforts also include establishing global and regional antiviral stockpiles and addressing restrictions that different national regulations place on drug manufacture and approval.

WHO, countries, and pharmaceutical manufacturers have established global and regional antiviral stockpiles to enhance the availability and quick distribution of antivirals to the site of outbreaks. In August 2005, Roche donated 3 million treatment courses of Tamiflu to WHO for a global stockpile to contain or slow the spread of a pandemic at its origin. According to Roche officials, the size of the stockpile was based on studies that indicated that 3 million treatment courses would be sufficient to stop the spread of a pandemic strain at its source. Roche will be responsible for the delivery of Tamiflu from these stockpiles to the international airport closest to the outbreak, where it will transfer the Tamiflu to WHO. It will then be the responsibility of the affected countries to distribute the donated antivirals within their country to contain outbreaks. Subsequently, in January 2006 Roche announced the donation of an additional 2 million treatment courses to WHO for the establishment of regional stockpiles. In March 2007, WHO stated that these drugs are for the use of countries currently experiencing human outbreaks of animal influenza. Supplies from this second donation have already been sent to those countries. Additionally, some countries have taken the lead in funding regional stockpiles. Japan has provided 500,000 treatment courses of Tamiflu for a regional stockpile for Asia. Japan is also funding the delivery of antivirals from that regional stockpile to the capitals of affected Asian nations. Discussions are under way for HHS to assist in this antiviral stockpiling. For example, there are discussions about sharing antivirals from the United States stockpile, but these drugs could be recalled for domestic use if outbreaks could not be contained or if an outbreak occurred in North America. In May 2006, HHS sent a stockpile of approximately 260,000 treatment courses of Tamiflu to Asia to be pre- positioned for international containment efforts in the event of a pandemic influenza outbreak in that region.

The United Nations System Influenza Coordinator and the World Bank reported in December 2007 that individual countries have also purchased or are planning to purchase antivirals but that coverage in many countries remains limited. Sixty-eight percent of countries worldwide have purchased antivirals and an additional 22 percent plan to purchase them. However, the agencies also note that 36 percent of countries report that that their supply of antivirals covers less than 1 percent of their population while another 37 percent report that their antiviral supply covers from 1 to 20 percent of their populations.

Individual countries and WHO are also establishing pre-pandemic influenza vaccine stockpiles. Several industrialized countries, including the United States, have established pre-pandemic influenza vaccine stockpiles to vaccinate critical workforce and primary health care workers at the onset of a pandemic. WHO is working to establish a pre-pandemic vaccine stockpile. Such a stockpile could help to alleviate developing countries’ concerns about their lack of access to H5N1 vaccines developed using virus samples provided by them. In April 2007, a WHO expert committee wrote that there is sufficient scientific support for creating a stockpile of H5N1 vaccine for use in countries without influenza vaccine production capacity or the ability to purchase stockpiles of H5N1 vaccines. The committee noted that there is some evidence that current H5N1 vaccines produce a protective immune response against other H5N1 viruses as well. Following this, in May 2007, the World Health Assembly passed a resolution requesting WHO to establish an international stockpile of vaccines for H5N1 or other influenza viruses of pandemic potential. In June 2007, GlaxoSmithKline announced that it would contribute 50 million doses of its H5N1 vaccine to the stockpile, enough to vaccinate 25 million people. Also in June, WHO stated that three additional companies had indicated their willingness to make some of their H5N1 vaccine available for the stockpile.

In an effort to facilitate access to various vaccines, FDA and its international counterparts, in collaboration with WHO, are developing a standard set of data requirements to support the licensure of pandemic and pre-pandemic vaccines. Each country has its own requirements for the development and licensure of vaccines for human use (which include testing in clinical trials). If demand were to surge as might happen in the event of a pandemic, the time needed to go through the regulatory process to gain approval for a new vaccine could constrain its availability. FDA and its international counterparts, in conjunction with WHO, participate in international working groups that examine regulations for the development and manufacturing of influenza vaccines.

Some governments are also exploring other avenues to speed up their domestic regulatory process to enhance pandemic preparedness. Currently, FDA’s goal is to complete the review of a “standard” application in the United States for vaccine licensure within 10 months. However, the goal for review of a “priority” license application is 6 months. Priority reviews are given to those vaccines that have the potential for providing significant preventive, diagnostic, or therapeutic advancement as compared to existing treatments for a serious or life-threatening disease. In addition, FDA has processes intended to shorten the time needed for commercial development and FDA review in certain circumstances. For example, because it can take many years to determine whether a drug provides real improvement for patients—such as living longer or feeling better—FDA has a process known as “accelerated approval.” Under accelerated approval, applications are reviewed using a substitute measurement of effectiveness that is considered likely to predict patient benefit.

Similarly, the European Union is pursuing approval for pre-pandemic vaccines as a mechanism to expedite approval for a pandemic vaccine. Prior to the onset of a pandemic, these pre-pandemic vaccines undergo safety and effectiveness testing and are submitted for approval. In the event of a pandemic, this approved pre-pandemic vaccine would then be reformulated to match the pandemic virus and expedited approval for the reformulated vaccine would be sought. Because the application would only pertain to a variation on the earlier, approved, pre-pandemic vaccine, regulatory approval is expected to be faster. Both GlaxoSmithKline and Novartis have had pre-pandemic vaccines approved by the European Union under this mechanism. In addition, GlaxoSmithKline, Novartis, and sanofi pasteur have submitted additional vaccines for approval under this process.

Certain Efforts to Increase the Effectiveness and Availability of Antivirals and Vaccines Face Limitations and Will Take Several Years

While efforts are under way to alleviate constraints upon the effectiveness and availability of antivirals and vaccines, certain efforts face limitations and will take several years to complete. The strengthening of animal and human surveillance systems is vital to increasing the effectiveness of antivirals and vaccines. However, according to OFFLU officials, that network lacks sufficient funding to hire staff needed to analyze influenza strains. Officials fear that without this staff, scientists might not continue to submit samples to OFFLU—which are analyzed and presented in public databases—out of concern that they would not be analyzed. FAO, OIE, and WHO have stated that greater support of OFFLU is required in order for it to fulfill its functions. Experts have noted that public access to databases that contain influenza sequence information is vital to understanding the spread and evolution of influenza viruses and, therefore, to the research and development of influenza treatments.

International support for clinical trials—necessary for developing and evaluating the effectiveness of antivirals and vaccines—is largely provided by only four countries: the United States, Australia, Japan, and the United Kingdom. The United States supports clinical trials for antivirals and vaccines being developed by global manufacturers, but experts state that more widespread and consistent international support is needed. Clinical trials are also required to test effectiveness and cross-protection provided by pre-pandemic vaccines. The United States, Australia, Japan, and the United Kingdom have provided the most support for pandemic vaccine development. However, only the United States provides substantial support to both domestic and international manufacturers for such trials. According to IFPMA representatives, the United States’ efforts are the primary governmental source for funding clinical trials for these vaccines.

Increasing demand for vaccines is likely to continue to pose difficulties because a number of countries will still need to balance concerns about a potential pandemic against other existing public health concerns. Low demand for vaccines to treat seasonal influenza is due in part to the low priority placed on seasonal influenza by many countries. As discussed earlier, current global demand for seasonal influenza vaccines is lower than global need, which is the amount required to cover individuals under medical guidelines for influenza vaccination. Manufacturers have been reluctant to invest in the development and production of vaccines due to this low demand and disincentives such as low profits. One reason for low demand is that seasonal influenza programs compete with many other public health priorities for limited budgets in developing countries. For example, Indonesia, one of the countries experiencing human H5N1 outbreaks, is also dealing with other diseases as well as the aftermath of a tsunami, volcanic eruptions, and earthquakes. Some developing countries are willing to implement seasonal influenza vaccination programs but require outside funding to do so. One objective of WHO’s Global pandemic influenza action plan to increase vaccine supply is to increase seasonal vaccine use. According to WHO, a minimum of $300 million is required to do this. Similarly, efforts to increase vaccine production capacity can also be problematic. Citing Vietnam as an example, NIH officials told us that countries may have been too overwhelmed with H5N1 outbreaks to accept offers of assistance to develop vaccine production infrastructure.

Although efforts are under way to increase antiviral and vaccine manufacturers’ production capacity by building new facilities, these new facilities are not expected to be ready to produce antivirals and vaccines for several years. According to manufacturers, it will take at least 5 years to build new vaccine manufacturing facilities and receive regulatory approval. WHO stated that it will take the six countries that received grants to develop vaccine production capacity at least 3 to 5 years to begin producing vaccine. Additionally, Roche granted sublicenses to selected drug companies in developing countries for the production of generic versions of Tamiflu. However, these agreements will not immediately alleviate any shortages due to the complicated production process for Tamiflu. Roche has estimated that it would take 2 to 3 years for a new facility to produce Tamiflu on a large scale. It has also stated that, even with all the materials necessary for production available, it takes 6 to 8 months to produce Tamiflu. Similarly, GlaxoSmithKline has stated that it would take a minimum of 6 to 9 months to increase production capacity for Relenza. WHO has stated that it is unlikely that sufficient quantities of antivirals will be available in any country at the onset of a pandemic. Further, in November 2006, Roche stated that because of high demand and long manufacturing lead times for Tamiflu, it is highly unlikely that it would be able to fill large Tamiflu orders on short notice. Demonstrating the importance of demand in driving production capacity, Roche announced in April 2007 that it planned to reduce Tamiflu production because it now exceeded demand for the drug. Roche officials stated that if demand were to increase, it would take 4 months to return the production level to 400 million treatment courses annually.

Although global, regional, and national stockpiles of antivirals are being established, little progress has been made in improving the capacity for distributing the stockpiled antivirals to the site of outbreaks around the world, particularly within developing countries. According to Asian Development Bank officials, the logistics of distributing antivirals in the event of a pandemic would be of greater concern than the limited supply of antivirals. Although the cost and logistics of transporting antivirals from a stockpile to a country’s capital are addressed to some extent by WHO and those countries and manufacturers that have donated antivirals, issues of transportation from the capital to a province or distant region remain unaddressed by many national governments. WHO has established protocols for countries to request Tamiflu for containment purposes from its global stockpile. Roche, the donor of the WHO global stockpile, will deliver the drugs to the international airport nearest the crisis and hand them over to WHO. National authorities would then be responsible for the storage, transportation, and administration of those drugs within their borders. To do so effectively, governments must have plans in place prior to an outbreak as well as adequate resources to implement them. The U.S. government has assisted countries in developing such plans. In June 2007, WHO officials reported that over 178 countries have drafted or finalized their preparedness plans. However, WHO has noted that not all plans have incorporated its rapid containment protocol.

Agency Comments and Our Evaluation

HHS, the Department of State and WHO provided comments on a draft of this report. The comments from HHS and the Department of State are reproduced in appendixes I and II. WHO provided comments via e-mail and stated that the report was comprehensive and useful.

In its comments, HHS said that we had lost the larger context of all efforts with respect to pandemic preparedness and that HHS’s antiviral and vaccine strategies and implementation plans are not captured. Expressing concern about our focus on antivirals and vaccines, HHS said that these are only one piece of the agency’s broader scope of work on this topic. It cautioned that the use of antivirals and vaccines in response to a pandemic is part of a larger, integrated whole, so viewing them outside of the broader context is likely to raise other questions and issues. HHS said that we were assuming that antivirals and vaccines are the only tools necessary to forestall a pandemic. HHS commented on the uncertainty of success associated with measures such as stockpiling antivirals, stating that one must not assume that establishing antiviral stockpiles has solved the problem. HHS noted that if a potential pandemic is identified early, efforts at containment should and will be attempted. It further commented that if containment fails, the effort may still have the effect of slowing the pandemic’s rate of spread while if it succeeds, a pandemic may be at least temporarily averted. In its comments, HHS stated that as a preventive health measure only a vaccine will have the capability of dramatically changing the course of an influenza pandemic.

We do not agree that we have lost the larger context of efforts to prepare for a pandemic. This work was done in response to a congressional request that we study the role that antivirals and vaccines could play in forestalling a pandemic. While this was the focus of this engagement specifically, we are well aware that antivirals and vaccines are just two of many possible measures that could be taken in response to an influenza pandemic. As HHS notes in its comments, we have issued other reports on various aspects of pandemic preparedness (see the Related GAO Products section of this report) and we have ongoing work on numerous other aspects of this issue. We stated on page 2 of the draft report provided to HHS for comment that antivirals and vaccines may play a role in forestalling a pandemic, but we did not suggest that they were the only available response measures. Nonetheless we have added language to the report to make it clearer still that antivirals and vaccines are just two of a variety of available countermeasures that are being contemplated by WHO, HHS, and other agencies charged with the responsibility of protecting the public in the event of a pandemic. However, a discussion of the full range of possible responses to an influenza pandemic currently being contemplated by HHS and other organizations and agencies is beyond the scope of this report.

HHS also expressed concern with our discussion of “forestalling” a pandemic, suggesting that the premise that a pandemic can be forestalled is not one widely held by the public health or scientific community and is misguided and misleading. They said that few believe that a developing pandemic can be stopped in its tracks. In elaborating on this point, HHS suggested that the concept that antivirals and possibly vaccines might be used to stop an incipient pandemic or to slow the spread should be explicitly stated instead of using the word forestalled in a way that is very likely to be misinterpreted. They note that theoretically, the only way to truly forestall a human pandemic would be to eliminate the avian reservoir from which a future pandemic is likely to emerge.

In the draft of this report provided to HHS for comment, we defined the word “forestalling” to mean “preventing or at least delaying.” We use this term to suggest that, while preventing a pandemic would be the desired result of any response effort, delaying the pandemic would perhaps be the more likely yet still desired result. It is not clear why the level of concern expressed by HHS in its comments on our use of the word “forestall” is being raised at this time. We issued a report in June 2007 that discussed efforts to forestall an influenza pandemic, including the word “forestall” in the report title, on which HHS provided written comments. At that time, HHS expressed no concern with the term. In addition WHO has used the word in describing its efforts to respond to a pandemic and our definition is consistent with WHO’s use of the term.

Moreover, we fail to see significant differences in the meaning of the word “forestall” as compared to other terms and concepts contained in other parts of HHS’s comments on this report and other public comments. For example, in its comments, HHS discussed a goal to “minimize the impact” of a pandemic. They expressed the desire that we explicitly state the concept of “stopping or slowing the spread of” an incipient pandemic, rather than using the word forestall, defined as “prevent or delay,” which HHS believes is likely to be misinterpreted by the readership. Later in its comments, HHS stated that a pandemic may be “temporarily averted” or slowed. HHS stated in its letter that a vaccine could “dramatically change the course” of a pandemic. While we believe that these concepts are consistent with our use of the term forestall when describing efforts to respond to a pandemic in such a way as to avert, slow, mitigate, or change the course of a pandemic, we have revised the report and defined forestall to mean containing, delaying, or minimizing the impact of the onset of a pandemic. We have also added discussion to the report to further clarify our use of the term, making it clear that success in these efforts is uncertain and that it is unlikely that a pandemic can be entirely prevented.

HHS provided other general comments on the structure and organization of the report. HHS expressed concern that we have provided an inadequate amount of information about influenza diagnostic tests. They said that our emphasis on OFFLU is out of proportion to the role it plays in recognizing when a new virus with pandemic potential has begun to spread in humans. They further suggest that we do not adequately distinguish between seasonal, pre-pandemic, and pandemic vaccines. Finally, HHS stated that some information in the draft is out of date and that they corrected many factual errors in their technical comments.

We have evaluated HHS’s other comments on the structure and organization of the report. Both their general and technical comments suggested that we have overemphasized some issues while underemphasizing others. They also touched upon areas where HHS does not believe that we adequately distinguished between various aspects of influenza response; for example, HHS commented that we do not adequately distinguish between seasonal and pandemic influenza but also noted that much of what is believed to be true about pandemic influenza is based upon experience with seasonal influenza. We made changes to the report where HHS’s general and technical comments could enhance clarity and completeness. However, this report was intended to describe the challenges and limitations of efforts to respond to an impending pandemic using antivirals and vaccines; it was not intended to capture a complete inventory of the most current scientific knowledge and developments regarding these two countermeasures. In some cases, rapid scientific advances may have outpaced the timing of this report such as, for example, the initiation of a new area of research not specifically identified in the report. In other cases, there is no consensus on the appropriate use and likely results of various medical countermeasures, including different types of antivirals and vaccines.

Further, while we updated the report to reflect changes that occurred while the draft report was with the agencies for comment, we disagree with HHS that the draft contained many factual errors. In its comments, HHS updated the information in the report in several areas, provided additional information on some points, and suggested different areas of emphasis in others. HHS suggested different wording in several instances that would have made our description of certain concepts extremely technical and not easily understood by persons not expert in the field. In those instances, we often chose not to make the change suggested by HHS. There were few instances of corrections of facts. Moreover, in a meeting discussing the draft, an HHS official was complimentary of the accuracy and completeness of the report.

The Department of State suggested in its comments that the report should be restructured to separate discussion of antivirals and vaccines. The comments state that these medical countermeasures are very different from each other in their application, utility, and the challenges the U.S. government faces in development and production of sufficient quantities. They further commented that while the report extensively discusses the challenges in production of adequate quantities of medical countermeasures, it does not give adequate consideration to the challenges of establishing protocols that would guide the international community in the use of whatever vaccines and antivirals are available. They also suggested that our use of the word “forestall” is somewhat ambiguous and should be clarified.

While we did not separate the discussion of antivirals and vaccines as the Department of State suggested, we revised the draft to ensure that discussion of antivirals and vaccines are clearly distinguished from one another. While antivirals and vaccines are very different from each other, we believe that the issues involved in identifying where they are needed, manufacturing sufficient quantities, shipping them to where they are needed, and administering them safely, are similar enough to merit discussing them together. We agree that the issue of establishing protocols to guide the international community in the use of antivirals and vaccines is an important one. However, this issue was discussed in the draft report and the Department of State did not articulate in its comments what information needs to be added.

The Department of State’s concerns about our use of the word “forestall” are unclear. In making this comment, the Department of State suggests that we refer to the North American Plan for Avian and Pandemic Influenza, approved by the United States, Canada, and Mexico. The comments quote the plan, which states that “The North American Plan will enhance collaboration in order to … prevent or slow the entry of a novel (pandemic) strain of human influenza to North America.” We fail to see the meaningful difference between the words, “prevent or slow” in the plan and “prevent or delay,” which is the meaning of the word “forestall.” However, as stated earlier, we added discussion to the report to clarify our use of the word “forestall.”

We incorporated technical comments provided by HHS, the Department of State, and WHO, as appropriate throughout the report.

As arranged with your offices, unless you publicly announce the contents of this report earlier, we plan no further distribution of it until 30 days after its issue date. At that time, we will send copies of this report to the Secretary of Health and Human Services, the Secretary of State, the Commissioner of the U.S. Food and Drug Administration, the Director of the Centers for Disease Control and Prevention, the Director of the National Institutes of Health, the Director of the Office of Global Health Affairs, the Special Representative on Avian and Pandemic Influenza at the U.S. Department of State, and to interested congressional committees. We will also make copies available to others upon request. In addition, the report will be available at no charge on GAO’s Web site at http://www.gao.gov.

If you or your staff have any questions about this report, please contact Marcia Crosse at (202) 512-7114 or crossem@gao.gov or David Gootnick at (202) 512-3149 or gootnickd@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made major contributions to this report are listed in appendix III.

Appendix I: Comments from the Department of Health and Human Services

Appendix II: Comments from the Department of State

Appendix III: GAO Contacts and Staff Acknowledgments

GAO Contacts

Acknowledgments

In addition to the contacts above, Thomas Conahan, Assistant Director; Celia Thomas, Assistant Director; Robert Copeland; Etana Finkler; David Fox; Cathy Hamann; R. Gifford Howland; Michael McAtee; Jasleen Modi; Syeda Uddin; and George Bogart made key contributions to this report.

Related GAO Products

Influenza Vaccine: Issues Related to Production, Distribution, and Public Health Messages. GAO-08-27. Washington, D.C.: October 31, 2007.

Influenza Pandemic: Opportunities Exist to Address Critical Infrastructure Protection Challenges That Require Federal and Private Sector Coordination. GAO-08-36. Washington, D.C.: October 31, 2007.

Influenza Pandemic: Further Efforts are Needed to Ensure Clearer Federal Leadership Roles and an Effective National Strategy. GAO-07-781. Washington, D.C.: August 14, 2007.

Influenza Pandemic: DOD Combatant Commands’ Preparedness Efforts Could Benefit from More Clearly Defined Roles, Resources, and Risk Mitigation. GAO-07-696. Washington, D.C.: June 20, 2007.

Influenza Pandemic: Efforts to Forestall Onset Are Under Way; Identifying Countries at Greatest Risk Entails Challenges. GAO-07-604. Washington, D.C.: June 20, 2007.

Avian Influenza: USDA Has Taken Important Steps to Prepare for Outbreaks, but Better Planning Could Improve Response. GAO-07-652. Washington, D.C.: June 11, 2007.

The Federal Workforce: Additional Steps Needed to Take Advantage of Federal Executive Boards’ Ability to Contribute to Emergency Operations. GAO-07-515. Washington, D.C.: May 4, 2007.

Financial Market Preparedness: Significant Progress Has Been Made, but Pandemic Planning and Other Challenges Remain. GAO-07-399. Washington, D.C.: March 29, 2007.

Influenza Pandemic: DOD Has Taken Important Actions to Prepare, but Accountability, Funding, and Communications Need to be Clearer and Focused Departmentwide. GAO-06-1042. Washington, D.C.: September 21, 2006.

Influenza Pandemic: Applying Lessons Learned from the 2004-05 Influenza Vaccine Shortage. GAO-06-221T. Washington, D.C.: November 4, 2005.

Influenza Vaccine: Shortages in 2004–05 Season Underscore Need for Better Preparation. GAO-05-984. Washington, D.C.: September 30, 2005.

Influenza Pandemic: Challenges in Preparedness and Response. GAO-05-863T. Washington, D.C.: June 30, 2005.

Influenza Pandemic: Challenges Remain in Preparedness. GAO-05-760T. Washington, D.C.: May 26, 2005.

Flu Vaccine: Recent Supply Shortages Underscore Ongoing Challenges. GAO-05-177T. Washington, D.C.: November 18, 2004.

Emerging Infectious Diseases: Review of State and Federal Disease Surveillance Efforts. GAO-04-877. Washington, D.C.: September 30, 2004.

Emerging Infectious Diseases: Asian SARS Outbreak Challenged International and National Responses. GAO-04-564. Washington, D.C.: April 28, 2004.

Global Health: Challenges in Improving Infectious Disease Surveillance Systems. GAO-01-722. Washington, D.C.: August 31, 2001.

Flu Vaccine: Supply Problems Heighten Need to Ensure Access for High- Risk People. GAO-01-624. Washington, D.C.: May 15, 2001.

Influenza Pandemic: Plan Needed for Federal and State Response. GAO-01-4. Washington, D.C.: October 27, 2000.