Influenza Pandemic: Efforts Under Way to Address Constraints on Using Antivirals and Vaccines to Forestall a Pandemic
Published: 2007-12-21T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: Pandemic influenza poses a threat to public health at a time when the United Nations' World Health Organization (WHO) has said that infectious diseases are spreading faster than at any time in history. The last major influenza pandemic occurred from 1918 to 1919. Estimates of deaths worldwide if a similar pandemic were to occur have ranged between 30 million and 384 million people. Individual countries and international organizations have developed and begun to implement a strategy for forestalling (that is, containing, delaying, or minimizing the impact of) the onset of a pandemic. Antivirals and vaccines may help forestall a pandemic. GAO was asked to examine (1) constraints upon the use of antivirals and vaccines to forestall a pandemic and (2) efforts under way to overcome these constraints. GAO reviewed documents and consulted with officials of the Departments of State and Health and Human Services (HHS), international organizations, and pharmaceutical manufacturers. WHO commented that the report was comprehensive and useful. HHS stressed that vaccines and antivirals must be viewed in a larger context. State and HHS commented that the term "forestall" is ambiguous and misleading. However, GAO has used the word in a way that is consistent with WHO's use of the term.
section_title: What GAO Found
paragraphs: The use of antivirals and vaccines, two elements of the international strategy to forestall a pandemic, could be constrained by their uncertain effectiveness and limited availability. To use antivirals effectively, health authorities must be able to detect a pandemic influenza strain quickly through surveillance and diagnostic efforts and use this information to administer antivirals. The effectiveness of antivirals could be limited if they are used more than 48 hours after the onset of symptoms or by the emergence of strains resistant to antivirals. Unlike antivirals, vaccines are formulated to target a specific influenza strain in advance of infection. The effectiveness of vaccines in forestalling a pandemic could be limited because such a targeted pandemic vaccine cannot be developed until that strain has been identified. Due to the time required to identify the virus and develop and manufacture a pandemic vaccine--20 to 23 weeks according to HHS--such vaccines are likely to play little or no role in efforts to forestall a pandemic in its initial phases. The availability of antivirals and vaccines in a pandemic could be inadequate due to limited production, distribution, and administration capacity. WHO has stated that it is unlikely that sufficient quantities of antivirals will be available in any country at the onset of a pandemic. The distribution and administration capacity for antivirals and vaccines is limited in some countries by poor or nonexistent delivery plans and networks, a lack of facilities for administering the drugs, and small numbers of personnel trained to administer them. The United States, its international partners, and the pharmaceutical industry are investing substantial resources to address constraints on the availability and effectiveness of antivirals and vaccines. Efforts are under way to improve influenza surveillance, including diagnostic capabilities, so that outbreaks can be quickly detected. Increased demand and government support has led manufacturers to increase research into more effective antivirals and vaccines. Manufacturers are developing new antivirals to combat influenza. New methods for developing vaccines are being studied in order to reduce the amount of vaccine that is needed and to increase the number of strains against which it is effective. Pre-pandemic vaccines, which are formulated to target influenza strains that have the potential to cause a pandemic, are being developed. However, these vaccines may or may not be effective against the pandemic strain that ultimately emerges. To overcome limitations on the availability of antivirals and vaccines, manufacturers are working to increase production at existing facilities and build new facilities. To address constraints on the distribution and administration of antivirals, stockpiles are being established to allow faster delivery of antivirals to countries experiencing outbreaks. WHO is also working to establish stockpiles of pre-pandemic vaccines. Additionally, other efforts also face limitations. For example, increasing production capacity of vaccines and antivirals will take several years as new facilities are built and necessary materials acquired.

section_title: Letter
paragraphs: An influenza pandemic—caused by a novel strain of influenza virus that is  An influenza pandemic—caused by a novel strain of influenza virus that is  virulent and highly transmissible among humans—would be of global  virulent and highly transmissible among humans—would be of global  significance. While some scientists and public health experts believe that  significance. While some scientists and public health experts believe that  the next influenza pandemic could be caused by a strain of the H5N1 avian  the next influenza pandemic could be caused by a strain of the H5N1 avian  influenza virus (also known as “bird flu”) that is currently circulating in  influenza virus (also known as “bird flu”) that is currently circulating in  parts of Asia, Europe, and Africa, it is unknown when an influenza  parts of Asia, Europe, and Africa, it is unknown when an influenza  pandemic will occur, where it will begin, or whether an H5N1 strain or  pandemic will occur, where it will begin, or whether an H5N1 strain or  another strain would be the cause. Pandemic influenza poses a grave  another strain would be the cause. Pandemic influenza poses a grave  threat to global public health at a time when the United Nations’ World  threat to global public health at a time when the United Nations’ World  Health Organization (WHO) has said that infectious diseases are spreading  Health Organization (WHO) has said that infectious diseases are spreading  faster than at any time in history. Of the three pandemics of the twentieth  faster than at any time in history. Of the three pandemics of the twentieth  century, the most deadly was the pandemic of 1918-1919 in which  century, the most deadly was the pandemic of 1918-1919 in which  scientists estimate that there were 50-100 million deaths worldwide,  scientists estimate that there were 50-100 million deaths worldwide,  including at least 675,000 in the United States, making it among the most  including at least 675,000 in the United States, making it among the most  deadly events in human history. The U.S. government has estimated that as  deadly events in human history. The U.S. government has estimated that as  many as 2 million U.S. citizens could die in the next pandemic. If an  many as 2 million U.S. citizens could die in the next pandemic. If an  influenza pandemic were to occur on the same scale as the 1918-1919  pandemic, estimates of deaths worldwide have ranged between 30 million  and 384 million people.
The concern regarding an influenza pandemic has prompted the United  States, other governments, and international organizations such as WHO  to develop and begin to implement an international strategy to respond to  the threat of an influenza pandemic. The international strategy comprises  local, national, regional, and global strategies, which include a variety of  countermeasures designed to contain or delay a pandemic or to minimize  its impact once it emerges. Included among the elements of these  strategies aimed at forestalling a pandemic (that is, containing, delaying,  or minimizing the impact of) are antivirals and vaccines. Both could  potentially be used to prevent infection and, in the case of antivirals, to  also treat infected individuals.
The important role that antivirals and vaccines could play in containing or  limiting the spread of a pandemic has led to questions regarding their use.  For example, antivirals and vaccines could be needed in greater quantities  than ever before. As agreed with your offices, we are reporting on (1) the  constraints upon the use of antivirals and vaccines to forestall the onset of  a pandemic and (2) the efforts under way to overcome these constraints.
To report on these issues, we reviewed documents and consulted officials  from the Departments of Health and Human Services (HHS) and State,  WHO, the Asian Development Bank, and pharmaceutical manufacturers.  Within HHS, we examined documents and consulted officials from the  Office of the Secretary, the Centers for Disease Control and Prevention  (CDC), the Food and Drug Administration (FDA), and the National  Institutes of Health (NIH). We obtained information from the International  Federation of Pharmaceutical Manufacturers & Associations (IFPMA),  including information about influenza vaccine development projects  initiated by members of its Influenza Vaccine Supply International Task  Force. We reviewed reports published by the Institute of Medicine  focusing on pandemic influenza. In addition, we interviewed experts and  attended academic symposia on pandemic influenza and the challenges to  addressing its threat. We determined the data on the funding of antiviral  and vaccine research as well as the data on the manufacturing, use, and  availability of antivirals and vaccines were sufficiently reliable for the  purposes of this report. Our goal in collecting the information in this  report was to provide a picture of ongoing efforts by the U.S. government,  other national governments, international organizations like WHO, and  industry to prepare for a pandemic. This often involved reporting technical  information on the research and development on antivirals and vaccines.  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. This  report was not intended to provide the most complete, current, or  definitive discussion of scientific developments and knowledge  concerning the use of antivirals and vaccines. We have, instead, sought to  report information that is necessary to understand the challenges faced by  the U.S. government and others in their efforts to develop measures  involving antivirals and vaccines in efforts to forestall a pandemic. We  conducted our work from January 2006 through December 2007 in  accordance with generally accepted government auditing standards.
In recent related work, we examined the extent to which U.S. agencies and  their international partners have assessed pandemic risk by country and  prioritized countries for international assistance. In addition, we examined  the steps that U.S. agencies and their international partners have taken to  improve global preparedness to forestall a pandemic. This work was also  conducted in accordance with generally accepted government auditing  standards.
subsections: section_title: Background
paragraphs: 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.
subsections: section_title: Influenza
paragraphs: 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.
section_title: Vaccines
paragraphs: 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.
section_title: Antivirals
paragraphs: 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.
section_title: U.S. Government Entities Engaged in International Pandemic Influenza Preparedness
paragraphs: 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.
section_title: International Strategy to Contain a Pandemic
paragraphs: 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.
section_title: Uncertain Effectiveness and Limited Availability Would Likely Constrain the Use of Antivirals and Vaccines to Forestall the Onset of a Pandemic
paragraphs: 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.
subsections: section_title: 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
paragraphs: 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.
subsections: section_title: The Effectiveness of Antivirals and Vaccines to Forestall a Pandemic Depends on Influenza Surveillance
paragraphs: 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.
section_title: Weaknesses in International Influenza Surveillance
paragraphs: 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.
section_title: Limited Support for Clinical Trials
paragraphs: 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.
section_title: Limited Production, Distribution, and Administration Capacity Could Constrain the Availability of Antivirals and Vaccines
paragraphs: 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.
subsections: section_title: Constraints on Antiviral and Vaccine Production
paragraphs: 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.
section_title: Constraints on Distribution and Administration
paragraphs: 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.
section_title: Manufacturers’ Liability Concerns
paragraphs: 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.
section_title: U.S. Government and International Partners’ Efforts Are Under Way to Address Constraints on Use of Antivirals and Vaccines, but Certain Efforts Face Limitations
paragraphs: 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.
subsections: section_title: Efforts Are Under Way to Improve Surveillance in Order to Increase the Effectiveness of Antivirals and Vaccines
paragraphs: 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.
section_title: Efforts Are Under Way to Increase Demand for Antivirals and Vaccines to Encourage Production and Spur Research and Development
paragraphs: 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.
subsections: section_title: Efforts to Increase Demand to Encourage Production
paragraphs: 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.
section_title: Encouraging Further Research and Development
paragraphs: 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.
section_title: To Increase Availability, Governments and International Organizations Have Worked with Manufacturers to Improve Distribution of and Administration Capacity for Antivirals and Vaccines
paragraphs: 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.
section_title: Certain Efforts to Increase the Effectiveness and Availability of Antivirals and Vaccines Face Limitations and Will Take Several Years
paragraphs: 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.
section_title: Agency Comments and Our Evaluation
paragraphs: 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.
section_title: Appendix I: Comments from the Department of Health and Human Services
section_title: Appendix II: Comments from the Department of State
section_title: Appendix III: GAO Contacts and Staff Acknowledgments
subsections: section_title: GAO Contacts
section_title: Acknowledgments
paragraphs: 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.
section_title: Related GAO Products
paragraphs: 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.