Influenza Vaccine: Federal Investments in Alternative Technologies and Challenges to Development and Licensure
Published: 2011-06-27T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: Production delays for the 2009 H1N1 pandemic vaccine using the current egg-based production technology heightened interest in alternative technologies that could expand the supply or accelerate the availability of influenza vaccine. Within the federal government, the Department of Health and Human Services (HHS) and the Department of Defense (DOD) support the development of technologies that can be used in producing influenza vaccines. HHS's Food and Drug Administration (FDA) reviews licensing applications for new vaccine, and the Department of State is the U.S. diplomatic liaison to the international entity that declares worldwide pandemics. GAO was asked to review federal activities for the development of alternative technologies used in producing influenza vaccine. This report examines (1) federal funding from fiscal year 2005 through March 2011 for alternative technologies and the status of manufacturers' efforts, (2) challenges to development and licensure identified by stakeholders, and (3) how HHS is addressing those challenges. GAO reviewed HHS and DOD documents and funding data. GAO also interviewed stakeholders, including manufacturer representatives, industry associations, and other experts on challenges to development and licensure. GAO interviewed HHS officials on how they are addressing those challenges.
section_title: What GAO Found
paragraphs: From fiscal year 2005 through March 2011, HHS and DOD provided about $2.1 billion in funding for the development of alternative technologies that could potentially expand the supply or accelerate the availability of influenza vaccine. Specifically, HHS and DOD have funded two alternative production technologies--cell-based and recombinant technologies, which produce vaccine in cells instead of eggs--and adjuvants, which can reduce the amount of vaccine needed to stimulate an immune response. HHS's funding supports the development of a new influenza vaccine using alternative technologies with the goal of manufacturers submitting licensing applications to FDA. DOD's funding supports the research and development of a technology that can make various vaccines, including influenza vaccines. HHS awarded $1 billion in contracts to manufacturers to develop cell-based technology, with manufacturers making progress toward licensure. HHS and DOD funded $296.5 million in contracts and $86.9 million in technology investment agreements, respectively, for the development of recombinant technology. HHS also awarded about $152 million in contracts for the development of adjuvanted influenza vaccines. Two manufacturers receiving HHS funds plan to submit licensing applications for their adjuvanted vaccines to FDA within the next 2 years. Some stakeholders said low demand, high research and development costs, and regulatory challenges can hinder the development and licensure of new vaccines using alternative technologies. For example, despite the United States using more seasonal vaccine than any other country, some stakeholders told us that low vaccination rates can decrease incentives for manufacturers to develop new influenza vaccines using alternative technologies because there is not sufficient demand for new products. Some stakeholders said high research and development costs can also decrease manufacturers' incentives; however, HHS noted that increased investments in this area have generated a significant interest in this type of research and development. Some stakeholders also told us that some of FDA's guidance documents are not sufficiently comprehensive. FDA officials told us that their guidance documents cannot cover all possible scenarios; thus, they regularly meet with manufacturers to discuss issues and provide advice. HHS is addressing challenges in the development and licensure of new influenza vaccines using alternative technologies. For example, HHS intends to fund the establishment of specialized facilities that will provide support and expertise to manufacturers. Additionally, through FDA, HHS plans to facilitate the review of licensing applications for new influenza vaccines using alternative technologies and to enhance FDA's staff expertise. HHS, DOD, and the Department of State reviewed a draft of this report. In commenting on a draft of this report, HHS and DOD agreed with GAO on its findings. The Department of State did not provide comments. HHS provided suggestions to clarify the discussion.

section_title: Letter
paragraphs: Influenza, in both its seasonal and pandemic forms, is an ongoing public  health concern. Seasonal influenza may begin as early as August and  generally diminishes by April in the northern hemisphere. It has been  associated with 3,000 to nearly 50,000 deaths each year in the United  States in recent decades, according to the Department of Health and  Human Services’s (HHS) Centers for Disease Control and Prevention  (CDC). Pandemic influenza, which periodically causes a global outbreak  of serious illness with the potential for many more deaths than seasonal  influenza, has occurred four times in the past 100 years. In the late 1990s  and early 2000s, detection of the H5N1 avian influenza (also known as  “bird flu”) virus in animals raised concerns among experts that it or  another influenza virus might mutate into a strain that could lead to a  human influenza pandemic. The recent 2009 H1N1 influenza pandemic  reinforced the need to be prepared for future influenza pandemics.
The federal government, specifically HHS and the Department of Defense  (DOD), funds the research and development of alternative technologies  that can be used in producing human influenza vaccines as a part of its  pandemic influenza preparedness efforts. According to HHS, HHS’s and  DOD’s funding represents virtually all of the federal government’s  investment in this type of research and development. Vaccines are  considered the first line of defense against seasonal and pandemic  influenza, as they can prevent infection and control the spread of the  disease. Furthermore, influenza vaccines are—along with diagnostic tools  and treatments such as antiviral drugs—a type of medical countermeasure  that can be used to protect the population during public health  emergencies. In 2005, HHS issued the HHS Pandemic Influenza Plan  (Plan) for responding to an influenza pandemic. One of the goals stated in  the Plan is to have sufficient domestic capacity to produce enough  pandemic vaccine to cover the United States’ population within 6 months  of a pandemic declaration. These global declarations are made by the  United Nations’ World Health Organization, to which the Department of  State is the United States’ diplomatic liaison. HHS also laid out its intent  to support the development of new influenza vaccines using alternative  technologies that could help achieve this goal. DOD plays an active role in  pandemic influenza preparedness in order to maintain the military’s  readiness and ongoing military operations abroad, such as stockpiling  antiviral drugs for use during a pandemic and developing other  countermeasures. In addition to ensuring the military’s readiness, DOD’s  pandemic preparedness goals include being able to support U.S.  government efforts to save lives, reduce human suffering, and slow the  spread of infection.
Challenges in the production of 2009 H1N1 pandemic vaccines caused  fewer doses of vaccine to be available early in the pandemic than  manufacturers had initially estimated; this heightened interest in the status  of vaccine technologies that provide alternatives to egg-based technology.  Egg-based technology is used to make all influenza vaccine currently  licensed for the U.S. market by the Food and Drug Administration (FDA),  the agency within HHS responsible for licensing and regulating influenza  vaccines for the U.S. market. It is a well-established technology that has  been in use for decades; however, it has demonstrated certain limitations  in speed and efficiency in producing influenza vaccine as evidenced in the  delay in producing the 2009 H1N1 pandemic vaccine supply. Given the  limitations of egg-based technology and the vulnerability of chicken flocks  to infectious diseases, the federal government has funded the development  of alternative technologies that can be used to produce new influenza  vaccines. Vaccines produced using these alternative technologies may be  used during the annual influenza season or during a pandemic in order to  respond faster or to create a greater supply than is possible with the  current technology and production capacity. New influenza vaccines using  alternative technologies are being pursued by influenza vaccine  manufacturers that have egg-based influenza vaccines currently licensed  for marketing and distribution in the United States or internationally, as  well as by manufacturers that currently only have products in  development. No influenza vaccines using alternative technologies have  yet been licensed in the United States.
You asked us to review the federal government’s actions regarding the  research and development of alternative technologies that can be used in  producing new influenza vaccines. In this report, we examine (1) federal  funding from fiscal year 2005 through March 2011 in alternative  technologies that can be used in producing influenza vaccines and the  status of manufacturers’ efforts, (2) the challenges identified by  stakeholders to the development and licensure of influenza vaccines using  alternative technologies, and (3) how HHS is addressing challenges to the  development and licensure of influenza vaccines using alternative  technologies.
To examine federal funding from fiscal year 2005 through March 2011 in  alternative technologies that can be used in producing influenza vaccines  and the status of manufacturers’ efforts, we reviewed documents  pertaining to HHS’s and DOD’s funding for this purpose. According to  HHS, HHS’s and DOD’s funding represents virtually all of the federal  government’s investment in this type of research and development. We  reviewed documents from HHS on its funding from fiscal year 2005  through March 2011. These documents included semiannual reports  prepared by HHS that were submitted to Congress on the department’s  contracts to develop influenza vaccines using alternative technologies. We  also interviewed HHS officials who oversee contracts with manufacturers  to assist with the research and development of influenza vaccine for the  federal government. We reviewed HHS’s proposals for funding the  research and development of these technologies and interviewed HHS  budget officials to discuss and clarify the department’s efforts.  Additionally, we reviewed information from DOD on its technology  investment agreements from fiscal year 2005 through fiscal year 2010. We  interviewed DOD officials on the department’s support of alternative  technologies and the status of these development efforts. To assess the  reliability of HHS’s contracting data, we reviewed published data across  multiple years to ensure relative consistency and interviewed  knowledgeable officials to clarify questions regarding the department’s  funding. For DOD, we compared data on its funding provided by different  sources within the department. We also asked officials about its data  sources and how the department validates its data. Although we did not  independently verify the information provided by HHS or DOD, based on  our reviews of the data and interviews with federal officials, we concluded  that these data were sufficiently reliable for the purposes of our work.  Additionally, to better understand these technologies we conducted site  visits to three influenza vaccine manufacturing facilities, each utilizing a  different production technology, and attended national conferences on  influenza vaccine research and development.
To examine challenges to the development and licensure of influenza  vaccines using alternative technologies, we interviewed a judgmental  sample of stakeholders, which included representatives from industry  associations and manufacturers and other experts. Specifically, we  interviewed 15 representatives of the vaccine industry, including those  from three associations that represent pharmaceutical manufacturers—the  Biotechnology Industry Organization, the International Federation of  Pharmaceutical Manufacturers & Associations, and the Pharmaceutical  Research and Manufacturers of America. We also interviewed officials  representing 12 vaccine manufacturers—which included those  manufacturers pursuing the research and development of influenza  vaccines using alternative technologies, as well as those that have chosen  to forgo such research and development—about the factors influencing  their decisions. Of these 12 manufacturers, 8 have received funding from  HHS to pursue the research and development of influenza vaccines using  alternative technologies, and 1 received funds from DOD. Additionally, we  interviewed a judgmental sample of 12 other experts in vaccine technology  on challenges to research and development and licensure. We selected  these other experts, in part, based on recommendations from an initial  round of interviews with members of associations representing  researchers and scientists, such as the American Society for Microbiology  and the Infectious Disease Society of America. Other experts we  interviewed included those from provider groups—specifically the  American Academy of Pediatrics, the American Congress of Obstetricians  and Gynecologists, and the American Medical Association. We interviewed  representatives from these provider groups about the public’s and  providers’ concerns about influenza vaccine safety and their  understanding of alternative technologies. We also reviewed peer- reviewed journal articles and federal reports on challenges to the  development and licensure of influenza vaccines using alternative  technologies, including HHS’s medical countermeasure review and the  President’s Council of Advisors on Science and Technology’s (PCAST)  report on influenza vaccine production. We also interviewed officials  representing manufacturers with influenza vaccines licensed for use in  other countries and officials from the Department of State, the diplomatic  liaison to the United Nations’ World Health Organization—the  international body that declares worldwide pandemics.
To examine how HHS is addressing challenges to the development and  licensure of influenza vaccines using alternative technologies, we  interviewed HHS officials on their assessments of challenges to research,  development, and licensure identified by stakeholders. We also  interviewed HHS officials on their efforts to address these challenges,  including plans to use funds available for this purpose. Additionally, we  reviewed federal documents, such as a report by FDA on its plans to  improve its oversight of new products, including influenza vaccines using  alternative technologies.
We conducted this performance audit from March 2010 through June 2011  in accordance with generally accepted government auditing standards.  Those standards require that we plan and perform the audit to obtain  sufficient, appropriate evidence to provide a reasonable basis for our  findings based on our audit objectives. We believe that the evidence  obtained provides a reasonable basis for our findings based on our audit  objectives.
subsections: section_title: Background
paragraphs: Influenza is a contagious respiratory illness caused by a number of  different influenza virus strains and can range in severity from mild to  lethal. Symptoms can include cough, muscle or body aches, and fatigue.  Vaccination is the primary method for preventing infection with strains of  the influenza virus and controlling the disease. In order for a vaccine to  be most effective, it needs enough well-matched antigen to stimulate a  protective immune response, antigen being the active substance in a  vaccine that provides immunity by causing the body to produce protective  antibodies to fight off a particular influenza strain. The vaccine’s antigen  needs to be derived from a strain that is well-matched to a specific  influenza strain—in wide circulation in humans—so that the antibodies  formed in response to the vaccine protect against infection from that  strain. Because multiple influenza strains are in constant circulation,  seasonal vaccine is produced and administered annually to protect against  the three influenza strains expected to be most prevalent that year (i.e., a  trivalent vaccine). In contrast, the 2009 H1N1 pandemic vaccine was  formulated to match the single pandemic-causing strain (i.e., a monovalent  vaccine).
subsections: section_title: Federal Government’s Role in the Research and Development of Alternative Technologies and the Licensure and Regulation of Influenza Vaccines
paragraphs: Within the federal government, HHS is the department responsible for  leading and coordinating preparedness and medical response activities to  public health emergencies, per the 2006 Pandemic and All-Hazards  Preparedness Act. Additionally, as the principal department for  protecting the public’s health, HHS is the primary department funding the  research and development of influenza vaccines. HHS enters into  contracts with manufacturers for the development of new influenza  vaccines using alternative technologies. DOD also makes some  investments through its technology investment agreements for the  research and development of alternative technologies that can be used in  producing influenza vaccine as part of its preparedness efforts in order to  maintain the military’s readiness. Manufacturers with which these  agencies have entered into contracts or technology investment agreements  include large-scale influenza vaccine manufacturers that have vaccines  licensed for use in the United States and internationally as well as  manufacturers that currently only have vaccines in research and  development. Influenza vaccines—both seasonal and pandemic—are  biological products. Within HHS, FDA is the federal agency responsible for  the licensure and regulation of biological products for use in the U.S.  market (see app. I for additional information on the research and  development and review of licensing applications for new influenza  vaccines in the United States). These responsibilities include issuing  guidance for existing and new vaccines and consulting with manufacturers  on the development of their new vaccines, such as on how manufacturers  conduct clinical trials required for licensure of new vaccines. Until FDA  has approved its licensing application, no manufacturer can market its  biological product in the United States. Table 1 summarizes the federal  government’s role in the research and development of alternative  technologies and the licensure and regulation of influenza vaccines.
section_title: HHS Efforts to Enhance Domestic Production Capacity to Expand the Supply or Accelerate the Availability of Influenza Vaccine
paragraphs: Given its responsibilities for national seasonal influenza and pandemic  preparedness and response, HHS has an interest in enhancing domestic  production capacity—that is, enhancing the nation’s overall infrastructure  for influenza vaccine production—and expanding the supply or  accelerating the availability of influenza vaccine. HHS began awarding  contracts to enhance domestic production capacity for the current egg- based technology as early as fiscal year 2005. Since fiscal year 2005, HHS  has supported a program to ensure a year-round, secure, domestic egg  supply; prior to this funding, manufacturers maintained a 9-month supply  of eggs—enough for production only during the influenza season without  any additional capacity for emergencies, such as an influenza pandemic.
Despite HHS’s initial efforts to maintain a year-round egg supply, other  events have occurred that highlighted the need for HHS to increase  domestic production capacity for influenza vaccine and to support the  introduction of influenza vaccines produced using alternative  technologies. First was the unexpected loss of almost half of the influenza  vaccine supply because of potential contamination during the 2004–05  season and the reliance on two domestic influenza vaccine manufacturers  to supply enough vaccine for that year. Second was the recognition by  HHS that one of the greatest challenges to preparing for an influenza  pandemic and implementing its strategy for using vaccines was the lack of  production capacity within the United States. As we noted in prior work,  the lack of U.S. production capacity is cause for concern among experts  because it is possible that countries without domestic production capacity  will not have access to influenza vaccine in the event of a pandemic if  countries where vaccine is produced prohibit the export of the pandemic  vaccine until their own needs are met. As a result, HHS continued its  funding of egg-based technology for the production of influenza vaccine to  enhance domestic production capacity using this technology. For  example, in fiscal year 2007, HHS entered into contracts with two  manufacturers for the retrofitting of existing domestic egg-based  production facilities for the production of pandemic influenza vaccine.  Some of the completed facilities were used in the 2009 H1N1 pandemic,  and according to HHS, when all the retrofitting is complete, one of these  facility’s production capacity will double and the other will triple. Third,  concerns about strains of the H5N1 virus that had reemerged in the early  2000s, and continues to cause severe infection in humans, further  prompted interest in alternative technologies to egg-based technology for  producing influenza vaccine. Strains of the H5N1 virus have infected  chicken flocks and other poultry, resulting in the culling of these flocks,  raising concern that the egg supply for influenza vaccine was at risk. Thus,  HHS began a more concerted effort to fund the research and development  of influenza vaccines using three alternative technologies. Specifically,  HHS has funded the development of vaccines using two alternative  production technologies—cell-based and recombinant technologies—and  vaccines using a third alternative technology—antigen-sparing technology  (adjuvants).
Each of these three alternative technologies has the potential to expand  the supply or accelerate the availability of both seasonal and pandemic  influenza vaccines (see app. II for a description of the production process  for influenza vaccine using the current, egg-based technology). Expanding  the supply or accelerating the availability of influenza vaccine is  particularly important when there is a perceived shortage of seasonal  vaccine—when vaccine is not available and demand is highest—or during  a pandemic when demand increases because of increased risk of disease  and death. Expanding the supply or accelerating the availability of  influenza vaccine can be done in two ways. The first is to increase the  overall amount of vaccine available at the end of the production process;  the second is to speed up the production process itself by, for example,  reducing or eliminating step(s) in the process. Table 2 describes these  three alternative technologies and their potential to expand the supply or  accelerate the availability of influenza vaccines (see app. III for more  information on these alternative technologies).
section_title: HHS Funding for the Development of Influenza Vaccines Using Alternative Technologies
paragraphs: In fiscal year 2005, with funds available from that year’s appropriation,  HHS funded the research and development of an influenza vaccine  produced using cell-based technology. Following the release of the Plan,  numerous additional appropriations became available for the acquisition  and development of pharmaceutical interventions for pandemic-related  purposes, including approximately $3.2 billion dedicated for vaccines.  HHS has since used these funds, as well as funds available from previous  appropriations, for multiyear contracts for the development of influenza  vaccine using cell-based technology, recombinant technology, and  adjuvants. In response to the 2009 H1N1 pandemic, Congress provided  HHS with a supplemental appropriation to prepare for and respond to an  influenza pandemic. In addition to making $1.85 billion immediately  available to HHS, the 2009 supplemental appropriation made $5.8 billion  available contingent upon one or more presidential notifications to  Congress. In August 2010, after the 2009 H1N1 pandemic had ended, HHS  notified Congress of its plan to direct some of the remaining funds toward  pandemic and related preparedness activities. Specifically, HHS proposed  spending $1.98 billion in a variety of vaccine-related activities, including  the development of alternative technologies, such as recombinant  technology. According to HHS, it also uses funding available from annual  appropriations, such as its fiscal year appropriations for 2009 and 2010, for  pandemic-related activities.
section_title: The Federal Government Has Provided about $2.1 Billion in Funding for the Development of Alternative Technologies that Can Be Used in Producing Influenza Vaccines, and Manufacturers Are Demonstrating Progress Toward Licensure
paragraphs: From fiscal year 2005 through March 2011, the federal government  awarded approximately $2.1 billion in contracts and technology  investment agreements for the research and development of cell-based  and recombinant technologies and adjuvants, which can be used in  producing influenza vaccines. Manufacturers are demonstrating progress  toward licensure.
subsections: section_title: HHS Has Primarily Funded the Development of Cell- Based Technology, with Two Manufacturers Completing Clinical Trials and One Manufacturer Constructing a Domestic Facility
paragraphs: In fiscal year 2005, HHS awarded the most funding through contracts to  manufacturers to develop cell-based technology. With these funds, two  manufacturers are demonstrating progress toward licensure of a vaccine  by completing clinical trials required to file for licensure with FDA, and  one of these two manufacturers has also constructed a domestic cell- based influenza vaccine facility. HHS awarded contracts to six  manufacturers—one manufacturer in fiscal year 2005 and five  manufacturers in fiscal year 2006—worth a total of approximately   $1 billion for the development of an influenza vaccine produced using cell- based technology (see table 3). According to HHS, it awarded multiple  contracts because it expected some attrition by manufacturers as the  development of new influenza vaccines progressed. Cell-based technology  has the potential to increase the overall amount of vaccine available at the  end of the production process. As of March 2011, two of the manufacturers  to which HHS had awarded contracts—DynPort Vaccine Company LLC  (with Baxter International Inc.) (DynPort/Baxter) and Novartis Vaccines  and Diagnostics Inc. (Novartis Vaccines)—have completed clinical trials  required to file for licensure with FDA. While Novartis Vaccines  anticipates submitting a licensing application for its seasonal influenza  vaccine using cell-based technology to FDA in 2011, DynPort/Baxter  anticipates submitting its licensing application to FDA in 2012.  Additionally, GlaxoSmithKline plc (GlaxoSmithKline) is currently  conducting clinical trials with its adjuvanted cell-based pandemic  influenza vaccine, and MedImmune, LLC is conducting preclinical studies  in animals on its cell-based pandemic influenza vaccine. The remaining  two contracts with sanofi pasteur and Solvay Pharmaceuticals were  terminated by HHS.
In addition to the six contracts awarded for the research and development  of cell-based influenza vaccine, HHS also entered into a $486.6 million  contract with Novartis Vaccines in fiscal year 2009 for the construction of  a cell-based influenza vaccine production facility in the United States to  enhance domestic production capacity. According to HHS, Novartis  Vaccines completed construction of this facility in November 2009 and will  have qualified the facility for producing pandemic vaccine using cell-based  technology, if needed, by the end of 2011. HHS expects the new facility to  provide at least 25 percent of the needed domestic production capacity for  pandemic vaccine. This facility also has the capacity to produce seasonal  and adjuvanted influenza vaccine as well as other biological products that  use this technology for other infectious diseases.
section_title: HHS and DOD Have Funded the Research and Development of Recombinant Technology, and One Manufacturer Has Submitted a Licensing Application to FDA
paragraphs: In fiscal year 2009, HHS awarded contracts to manufacturers for the  research and development of recombinant technology. Recombinant  technology has the potential to increase the overall amount of vaccine  available at the end of the production process and speed up the  production process itself, in part, because unlike egg-based and cell-based  technologies, it does not depend on the replication of the influenza virus  for production. In fiscal year 2009, HHS entered into a $34.5 million  contract with Protein Sciences Corporation (Protein Sciences) for the  continued development of recombinant technology for use in producing an  influenza vaccine. According to HHS, if Protein Sciences’ recombinant,  seasonal influenza vaccine is shown to be safe and effective through  clinical trials, the contract requires the company to establish enough  domestic manufacturing capacity to provide finished vaccine within   12 weeks of the beginning of a pandemic and to produce at least 50 million  doses of pandemic vaccine within 6 months of the beginning of a  pandemic. In May 2011, HHS extended its contract with Protein Sciences  for 2 years with $46.8 million of additional funding.
In February 2011, HHS awarded two additional contracts for the research  and development of pandemic influenza vaccines using recombinant  technology. HHS awarded contracts to Novavax, Inc. (Novavax) for   $97.3 million and VaxInnate, Inc. (VaxInnate) for $117.9 million each for a  3-year period. According to HHS, if the manufacturer and department  mutually agree, each respective contract may be extended for an  additional 2-year period, resulting in contract amounts totaling   $179.1 million for Novavax and $196.6 million for VaxInnate (see table 4).
In contrast to HHS’s contract awards specifically designated for influenza  vaccine described above, DOD’s funding efforts have been more generally  targeted toward the research and development of technologies that could  be used in producing these vaccines. For example, in fiscal year 2010,  DOD entered into technology investment agreements with manufacturers  and research institutes—totaling approximately $86.9 million—for the  research and development of recombinant technology through a DOD  initiative called Blue Angel. The Blue Angel initiative is intended to  accelerate ongoing programs that would potentially assist the federal  government in providing a governmentwide response to an influenza  pandemic. Under the Blue Angel initiative, DOD supported the initial  testing of a production process using recombinant technology to produce  antigen—the active substance in a vaccine that stimulates the production  of protective antibodies—using the 2009 H1N1 pandemic strain.  According to DOD, although the initiative did not result in a finished  vaccine, the first batch of antigen was produced within 30 days of  receiving information on the pandemic-causing strain.
section_title: HHS and DOD Have Also Funded the Research and Development of Adjuvanted Influenza Vaccines, and Two Manufacturers Are Demonstrating Progress toward Licensure
paragraphs: Since fiscal year 2007, HHS has also awarded contracts for the research  and development of an adjuvanted influenza vaccine. Adjuvants have the  potential to increase the overall amount of vaccine available at the end of  the production process by enhancing the immune response, thereby  reducing the amount of antigen needed per vaccine dose. Two  manufacturers have demonstrated progress toward licensure of their  vaccines by completing clinical trials. HHS awarded three contracts  totaling $152 million to GlaxoSmithKline, Novartis Vaccines, and Intercell  AG for the research and development of an adjuvanted influenza vaccine  (see table 5). Of the three manufacturers awarded contracts,  GlaxoSmithKline anticipates submitting a licensing application for its  adjuvanted egg-based pandemic influenza vaccine to FDA for review in  2011, while Novartis Vaccines anticipates submitting a licensing  application for its adjuvanted egg-based seasonal influenza vaccine to FDA  for review in 2012. According to HHS, Intercell AG’s clinical trials did not  achieve the desired result and were ended.
In addition to its awards through contracts with manufacturers, HHS also  provided $4 million in funding to the National Institutes of Health (NIH)— an agency within HHS—for H5N1 “mix-and-match” studies starting in  March 2008. According to HHS, these studies are designed to determine  whether the adjuvant from one manufacturer can be safely and effectively  combined with the antigen from another manufacturer in the case of a  public health emergency, such as an influenza pandemic. The ability to  combine the antigen from one manufacturer with the adjuvant from  another manufacturer could increase the overall vaccine supply during a  pandemic. The preliminary preclinical studies in animals with a H5N1  vaccine were completed in early 2009 in preparation for clinical testing by  NIH. However, NIH delayed its work on the H5N1 vaccine to conduct  clinical trials testing the unadjuvanted and mix-and-match 2009 H1N1  pandemic vaccine as part of HHS’s response to the pandemic. According  to NIH officials we spoke with, NIH resumed work on the H5N1 mix-and- match studies in May 2011; officials anticipate completing clinical trials for  these studies in 2012.
DOD has also funded the development of adjuvants for use with influenza  vaccine. In fiscal year 2009, DOD entered into a technology investment  agreement for $3.3 million with the Infectious Disease Research Institute.  According to DOD, the department is currently awaiting the results of  completed animal studies using an adjuvanted vaccine.
section_title: Some Stakeholders Identified Challenges to the Development and Licensure of Influenza Vaccines Using Alternative Technologies
paragraphs: Some stakeholders and federal reports identified three primary challenges  to the development and licensure of influenza vaccines using alternative  technologies: low demand, high research and development costs, and  regulatory challenges.
subsections: section_title: Some Stakeholders Said Low Demand Hinders the Development of Influenza Vaccines Using Alternative Technologies
paragraphs: Some stakeholders told us that low demand because of low vaccination  rates hinders manufacturers’ willingness to develop seasonal influenza  vaccines using alternative technologies. According to CDC, during the  2009–10 influenza season, national vaccination rates reached an estimated  41 percent of the population aged 6 months or older for the seasonal  vaccine, and an estimated 27 percent for the separate 2009 H1N1 pandemic  vaccine. Each influenza season more vaccine is produced than is actually  used, even in years where there has been a perceived shortage of influenza  vaccine because of challenges in the production process. Data from CDC,  FDA, and the American Medical Association confirm that—despite an  increase in the total amount of influenza vaccine produced and distributed  since at least 2001—more doses of seasonal vaccine are produced than  distributed each year, including in years when there were few licensed  manufacturers or a perceived vaccine shortage (see table 6). This excess  vaccine expires and is destroyed at the season’s end as it will not be useful  for the next influenza season, when a new vaccine will need to be  formulated using the three influenza strains expected to be most prevalent  that year. Additionally, despite the increase in influenza vaccine  production and distribution and the United States using more seasonal  vaccine than any other country, 5 of 12 manufacturer representatives, 1 of  3 industry association representatives, and 2 of 12 other experts we  interviewed said that this low demand decreases incentives for  manufacturers to develop new seasonal influenza vaccines using  alternative technologies.
Stakeholders told us that there are a number of reasons why demand for  seasonal influenza vaccine is low. For example, two experts stated that  patients commonly do not view seasonal influenza as a serious disease,  and another expert and an industry association representative stated there  is a need for more patient education on the safety of influenza vaccine to  overcome patient and provider hesitancy. Researchers have also found  that patients and providers have concerns about influenza vaccine. One  manufacturer representative also noted that the current influenza vaccine  is less effective for certain populations, such as the elderly, which also  decreases demand. We have previously reported that according to CDC, a  recommendation from a physician or other health care provider is the  most important factor in an individual’s decision to get vaccinated.  Additionally, a recent review of survey data found that health care  professionals were cited as one of three most important sources of  information in making decisions about children’s vaccines by 85 percent of  parents surveyed. CDC has made efforts to encourage providers to  recommend vaccination to their patients. However, despite these efforts,  available data suggest that getting providers to recommend vaccination for  their patients has been difficult. CDC told us that it is working closely  with numerous partners to implement an influenza vaccine  communication plan utilizing multiple forms of media to reach the general  public as well as specific target populations.
HHS officials acknowledged the challenge of low demand for seasonal  influenza vaccine; however, they said manufacturers remain interested in  pursuing the development of new influenza vaccines using alternative  technologies. For example, according to department officials,  manufacturers have more than two dozen influenza vaccines in  development, and many of these manufacturers have received funds from  HHS.
section_title: Some Stakeholders Said High Research and Development Costs Decrease Incentives for Developing Influenza Vaccines Using Alternative Technologies
paragraphs: Some stakeholders said that high research and development costs required  for the development of influenza vaccines can decrease manufacturers’  incentives to pursue new influenza vaccines using alternative  technologies. Six of the manufacturer representatives we spoke with said  that research and development costs are high. Furthermore, five  manufacturer representatives we spoke with noted that clinical trials in  particular contributed to high research and development costs. For  example, a representative for one manufacturer we spoke with noted the  significant costs associated with the research and development of its  currently licensed egg-based influenza vaccine, estimating that his  company has spent $400 million alone on clinical trials. One small-scale  manufacturer conducting clinical trials for a new influenza vaccine using  an alternative technology estimated that it spends $150,000 per day on  these trials and other expenses as it moves toward applying for licensure.  In addition, PCAST—a presidential advisory council—found in a recent  report on influenza vaccine research and development that constructing a  cell-based influenza vaccine production facility could cost more than   $1 billion and it could take over 30 years to recover the investment.
Access to capital is important to manufacturers because of these high  research and development costs. A manufacturer representative and an  industry association representative that we spoke with told us that  manufacturers’ difficulties in raising capital to finance research and  development costs deterred or slowed the development of new influenza  vaccines produced using alternative technologies. One manufacturer  representative told us that in the current economic market it has been  challenging for his firm to find investors. Three other manufacturer  representatives noted that their decision making is also influenced by  perceptions of whether the benefits of a new influenza vaccine will offset  these high research and development costs by increasing production  efficiency or supporting higher prices for the new product compared to  the current vaccine. HHS told us that it has worked to address this issue  through its funding for influenza vaccines using alternative technologies  and that its support of manufacturers’ efforts has helped to change the  return on investment such that manufacturers have more incentive to  pursue the development of new influenza vaccines using alternative  technologies. Additionally, HHS noted that increased investments in this  area have generated a significant interest in this type of research and  development.
section_title: Some Stakeholders Identified Regulatory Challenges That Hinder the Development of Influenza Vaccines Using Alternative Technologies
paragraphs: Some stakeholders identified two regulatory challenges to the  development of influenza vaccines using alternative technologies. First,  some stakeholders and recent federal reports identified weaknesses in  FDA’s “regulatory science” capacity—that is, its ability to utilize resources,  such as staff expertise, to develop new tests and measures to assess the  safety, efficacy, quality, and performance of FDA-regulated products, such  as influenza vaccines. Three manufacturer representatives, one industry  association representative, and three experts told us that regulatory  science weaknesses at FDA create challenges in the review of new  product licensing applications, including those for new influenza vaccines.  In particular, stakeholders told us that FDA’s staff expertise in alternative  technologies affects its ability to work with manufacturers developing new  influenza vaccines using these technologies, and that limited staff  expertise is a challenge to efficient communication. A manufacturer  representative told us that FDA’s ability to conduct its own research is  important in understanding the science manufacturers present in licensing  applications, but noted that some of FDA’s research programs have been  cut in recent years thereby hindering its ability to gain needed experience.  An industry association representative told us that manufacturers pursuing  the development of some influenza vaccines using alternative technologies  sometimes find it difficult to find FDA staff who can answer their  questions. One expert said that many experienced senior leaders in FDA’s  biologics division—where licensing applications for new vaccines are  reviewed—have left the agency in recent years; therefore, reviewers are  less familiar with these alternative technologies. This expert said this lack  of familiarity can make it more difficult for manufacturers to work with  reviewers to explain the technology to them.
Some recent federal reports have echoed stakeholders’ concerns about  FDA’s regulatory science capacity. According to a recent HHS report, FDA  needs to be able to conduct applied research in order to better incorporate  advances in life sciences research and knowledge into the regulatory  process. In order to make that possible, the report states that FDA needs  greater staff expertise and infrastructure. In addition, a 2007 report  prepared for the FDA Science Board—an FDA advisory group—found that  the development of products based on new science cannot be adequately  regulated by FDA because of a lack of capacity to review new  technologies. However, FDA officials told us that they are not aware of  actual examples of lack of expertise within the agency and that their staff  consists of highly qualified scientists. Furthermore, FDA officials noted  the continuing education that staff members engage in to maintain their  proficiency in technological advances as well as the quality of FDA’s  research programs. The agency said it has the scientific and regulatory  experience to adequately assess the safety and effectiveness of vaccines  for use in the United States, but as noted later in this report, it continues to  fund improvements in regulatory science capacity and staff expertise.
Some stakeholders also identified a second challenge, namely that FDA’s  written guidance and consultation with manufacturers on some of the  requirements for licensure of new influenza vaccines using alternative  technologies is not sufficiently comprehensive. They noted that FDA’s  guidance documents do not include all of the various scenarios  manufacturers may encounter. Additionally, one manufacturer  representative said it can take months to arrange a formal meeting with  FDA officials. Another manufacturer representative noted that FDA often  conducts its discussions with manufacturers in stages, which can limit  their ability to plan for long-term issues. According to stakeholders, this  lack of detail and incremental approach can hinder manufacturers’  abilities to plan their research and development efforts, including those for  new influenza vaccines, because they are uncertain as to what  requirements they must meet in order to obtain licensure. For example,  two manufacturer representatives said that it is unclear what size clinical  trials will be required for influenza vaccines using alternative technologies  because the guidance documents available are not specific enough in  laying out these requirements. In addition, PCAST found in a recent report  on influenza vaccine research and development that there is currently  uncertainty about the regulatory pathway for recombinant influenza  vaccines and recommended that guidance be developed on areas including  criteria for formulation, safety, immunogenicity, and efficacy. Also, one  manufacturer representative told us that his company was repeating  clinical trials for an adjuvanted vaccine that had already been performed  in Europe because the company had been unaware of certain FDA  requirements for data that are not typically required for similar vaccines or  by regulatory authorities in other countries. The manufacturer  representative noted that this situation could have been avoided if FDA  had provided a more complete explanation of the requirements in this  regard.
FDA officials acknowledged that its guidance documents are high level,  explaining that specific instructions are unique to the product as guidance  documents cannot cover all possible scenarios. In its comments, HHS  officials noted that FDA’s guidance is intended to provide a regulatory  framework, adding that guidance cannot be specific to individual  manufacturing processes because these processes are trade secrets.  Because of their inability to be very specific in guidance documents, FDA  officials told us that they regularly meet with manufacturers developing  vaccines using alternative technologies to discuss various issues and  provide advice. They also noted that the agency has a good record of  achieving its goals on meeting with manufacturers within a specific time  frame, adding that officials often consult with manufacturers in other  ways, such as participating in teleconferences. Additionally, FDA officials  said that it is necessary to consult with manufacturers in stages because  their review is an iterative process. They explained that it is not always  apparent what requirements may be necessary for a late phase of clinical  trials because such decisions are based, in part, on results from earlier  trials the manufacturer has completed. Furthermore, FDA noted that it has  approved many vaccines for other diseases that used alterative  technologies, such as adjuvants, and these manufacturers were able to  successfully develop and license their products using FDA’s guidance.  Finally, FDA has published guidance on criteria for the formulation, safety,  immunogenicity, and efficacy for vaccines using recombinant technology,  and one manufacturer has submitted a licensing application for its  influenza vaccine using this technology. According to HHS, part of this  guidance, which is available on FDA’s Web site, is related to clinical trials  and is specific to clinical data needed to support the licensure of pandemic  influenza vaccines.
section_title: HHS Is Addressing Challenges in the Development and Licensure of Influenza Vaccines Using Alternative Technologies
paragraphs: HHS has expanded its recommendations for seasonal vaccination to a  larger population and has released a 10-year strategic plan to address  national immunizations. HHS also plans to assist manufacturers with high  research and development costs by funding the establishment of  specialized facilities. In addition, HHS plans to fund the enhancement of  regulatory science capacity and FDA’s staff expertise to address  challenges that may hinder the licensure of new influenza vaccines using  alternative technologies.
subsections: section_title: HHS Has Expanded Its Vaccination Recommendations for Seasonal Influenza to a Larger Population and Has Released Its Strategy for National Immunization, Which It Expects Could Eventually Increase Demand for Vaccine
paragraphs: HHS has expanded its recommendations for seasonal influenza  vaccination to a larger population and has released its 10-year strategy to  enhance immunization rates in the United States, which it expects could  eventually increase demand for influenza vaccine. In August 2010, HHS  announced that it was expanding its vaccination recommendations for the  2010–11 influenza season from specific target groups based on personal  risk from the disease to all persons aged 6 months and older. According to  HHS, its expanded recommendations simplify the public health message to  providers and to the public on who should be vaccinated against seasonal  influenza. Because the 2010–11 influenza season is the first for which the  recommendations are in place and the first influenza season after the 2009  H1N1 pandemic, HHS is also evaluating vaccination rates from this season  for changes from previous years. For example, preliminary data from CDC  suggest an increase in vaccination rates against seasonal influenza among  children aged 6 months to 17 years. According to CDC, vaccination rates  for this population increased by 6.7 percentage points, or from   42.3 percent during the 2009–10 influenza season to 49 percent, as of  February 2011. Officials noted that currently, only about 40 percent of  Americans are vaccinated against seasonal influenza. HHS added that  eventually demand for seasonal vaccine could increase by approximately  32 percent—or 100 million people—as a result of the expanded  recommendations. Additionally, a rise in immunization rates for seasonal  influenza vaccine could result in an increase in the market for this vaccine  of approximately $3 billion annually, according to HHS.
In February 2011, HHS released its updated national immunization  strategy, which outlines, in part, the department’s efforts to address low  vaccination rates for influenza. This strategy, called the National Vaccine  Plan, lays out HHS’s efforts to enhance aspects of vaccines and  vaccination rates against infectious diseases and provides a  comprehensive plan for U.S. vaccine and immunization efforts from  childhood to adulthood. As we have noted above, several stakeholders  we spoke with cited a lack of provider and public education and concerns  regarding the safety of vaccines as factors affecting the demand for  influenza vaccine. The National Vaccine Plan has been updated to reflect  experiences from the 2009 H1N1 pandemic and describes various goals,  such as enhancing provider and public education on vaccines and vaccine  safety and assisting providers and the public with making informed  decisions regarding vaccination. HHS also plans to develop a  corresponding implementation plan that will include measurable  indicators so the department can assess its progress in achieving the goals  of the National Vaccine Plan; HHS anticipates releasing this  implementation plan later in 2011. Additionally, HHS launched a new Web  site, www.vaccines.gov in the spring of 2011 as another way of educating  providers and the public on vaccines and vaccine safety.
section_title: HHS Plans to Assist Manufacturers with High Research and Development Costs by Funding the Establishment of Specialized Facilities to Provide Support and Expertise
paragraphs: HHS plans to assist manufacturers with high research and development  costs by supporting the establishment of two or three privately owned  facilities called Centers for Innovation in Advanced Development and  Manufacturing that will provide support and expertise to manufacturers.  HHS indicated that it intends to enter into contracts to partially fund the  construction of new facilities or the retrofitting of existing facilities using  approximately $478 million available from various appropriations.  Although not the primary purpose of these facilities, according to HHS,  one benefit of these specialized facilities is that they could reduce smaller,  less-experienced manufacturers’ research and development costs by  providing needed resources and knowledge about manufacturing, and  reduce the technical risks of researching and developing medical  countermeasures, such as influenza vaccine produced using alternative  technologies. These facilities are primarily intended to provide, on a  routine basis, core services that include the advanced development and  manufacturing of chemical, biological, radiological, and nuclear medical  countermeasures. These specialized facilities may also be used in an  emergency to make pandemic influenza vaccine produced using  alternative technologies, such as recombinant technology. HHS noted  that smaller, less-experienced manufacturers often lack the staff and other  resources to address technical issues—such as those related to  production, quality control, and licensure—resulting in delays and higher  costs, which could cause an effort to fail. These specialized facilities  would have the resources to provide manufacturers with the necessary  staff, technical resources, and expertise to address these delays that can  result in higher costs or effort failures.
According to HHS, these facilities might also reduce the total cost of the  federal government’s contracts with manufacturers. By using these  specialized facilities for vaccine production, the costs associated with  producing these initial vaccine doses, such as those for use in clinical  trials, could be included in the facilities’ operating budgets rather than in  manufacturers’ research and development contracts, thereby reducing the  total amount of these contracts. According to HHS, the enhanced  production capacity from these facilities could also help manufacturers  with which HHS has contracts avoid production delays. These specialized  facilities could also allow smaller, less-experienced manufacturers to  focus more on developing new influenza vaccines using alternative  technologies rather than on production and licensure issues. HHS  anticipates awarding competitive contracts to establish these facilities in  2011 or 2012.
section_title: HHS Intends to Enhance Regulatory Science at FDA to Facilitate the Review of Licensing Applications for Influenza Vaccines Produced Using Alternative Technologies
paragraphs: HHS has announced plans to spend $170 million available from its fiscal  year 2009 and fiscal year 2010 annual appropriations, in part, to facilitate  FDA’s review of licensing applications for influenza vaccines produced  using alternative technologies and for other medical countermeasures.  Specifically, HHS intends to enhance regulatory science at FDA, that is,  the development of new tests and methods to assess the safety, efficacy,  quality, and performance of FDA-regulated products, such as influenza  vaccines. According to HHS’s report, The Public Health Emergency  Medical Countermeasures Enterprise Review, improvements in  regulatory science at FDA will help strengthen the agency’s review of  licensing applications. In October 2010, FDA released a report outlining a  proposed framework for advancing regulatory science using the funding  intended by HHS for this purpose. According to FDA, improvements in  regulatory science would focus on transitioning products more efficiently  through review from initial concepts to licensed products. In its report,  FDA identified areas in which it would focus that would potentially assist  it in reviewing licensing applications for products more quickly, including  during an influenza pandemic or other public health emergency.
In its October 2010 report, FDA proposes additional efforts that could  enhance staff expertise in reviewing licensing applications for new  vaccines using alternative technologies. For example, FDA intends to  initiate a program to help recruit experts in emerging technologies to work  as researchers and reviewers throughout the agency. FDA is also initiating  the creation and support of Centers of Excellence in Regulatory Science to  conduct applied regulatory science research both independently and in  collaboration with the agency. According to FDA, this additional research  will enhance staff expertise with emerging technologies.
FDA has issued guidance to the industry on various aspects of vaccine  production, such as on the selection of cells as a medium for producing  vaccines and the clinical data needed for licensure of pandemic influenza  vaccines. FDA officials noted that developing guidance relies on  experience, which takes time to acquire, adding that they plan to continue  to make themselves available to manufacturers to consult with and advise  them on various aspects of the vaccine development process, including on  conducting clinical trials and safety assessments.
section_title: Agency Comments
paragraphs: HHS, DOD, and the Department of State reviewed a draft of this report.  HHS and DOD provided written comments, which we have reprinted in  appendixes IV and V, respectively. The Department of State did not  provide comments. HHS also provided technical comments, which we  have incorporated as appropriate.
In its comments, HHS stated that it agreed on the importance of expertise  and research to the development of influenza vaccines produced using  alternative technologies—cell-based and recombinant technologies and  adjuvants. HHS also noted that the department has made significant  contributions to advancing such expertise and research, as reflected in the  collaboration within the department as well as with influenza vaccine  manufacturers during the 2009 H1N1 pandemic. For example, HHS  described how the Biomedical Advanced Research and Development  Authority, FDA, and NIH worked with manufacturers producing both the  seasonal and pandemic influenza vaccine. After approving seasonal  vaccines from six manufacturers during the summer of 2009, FDA  approved pandemic vaccines from four manufacturers in September 2009,  and a pandemic vaccine from a fifth manufacturer in November 2009. HHS  also described work done that allowed for influenza vaccine to be  produced more rapidly. For example, FDA developed a technique to  assess the sterility of vaccine, reducing the time for testing from 14 days to  5 days.
HHS’s written comments also noted the department’s concern that our  description of challenges identified by stakeholders could be construed as  an endorsement of them. However, as stated in our objectives, scope, and  methodology, we examined challenges identified by stakeholders to the  development and licensure of influenza vaccines produced using  alternative technologies, and we believe our report clearly attributes these  statements to the stakeholders. In response to industry concerns, HHS  stated that FDA has an excellent record of responding to industry within  agreed-upon time frames under applicable law and that FDA’s guidance  documents cannot be specific to individual manufacturing processes  because these processes are trade secrets. HHS also stated that FDA  provides clear guidance to manufacturers regarding the size of clinical  trials and meets with sponsors of new vaccines at key stages of the  product development process to provide further guidance that is informed  by earlier trials.
In its comments, DOD agreed with the contents of the draft and noted that  it had no substantive or administrative issues with the draft report.
We are sending copies of this report to the Secretaries of HHS, DOD, and  State and to interested congressional committees. The report also is  available at no charge on the GAO Web site at http://www.gao.gov.
If you or your staff have any questions about this report, please contact me  at (202) 512-7114 or crossem@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 VI.
section_title: Appendix I: The Research, Development, and Review of Licensing Applications for New Influenza Vaccine in the United States
paragraphs: The research, development, and review of licensing applications for new  influenza vaccine for the U.S. market involve several stages.  Manufacturers producing a biological product, of which influenza vaccines  are one type, must submit a licensing application for review by the Food  and Drug Administration (FDA) in order to market their vaccine in the  United States. If FDA approves the application, the vaccine will be  licensed for use in the United States. As shown in figure 1, this process can  take, on average, a little over 10 years to complete.
section_title: Appendix II: Influenza Vaccine Production Process Using Egg-Based Technology
paragraphs: Both seasonal and pandemic influenza vaccines for the U.S. market are  produced using egg-based technology—a complex process that involves  growing seed strains in millions of fertilized chicken eggs. As shown in  table 7, this process involves a sequence of steps that can take  approximately 4 to 5 months to complete.
section_title: Appendix III: Egg-Based and Alternative Technologies for Use with Influenza Vaccines
paragraphs: Both seasonal and pandemic influenza vaccines for the U.S. market are  produced using egg-based technology—a complex process that involves  growing seed strains in millions of fertilized chicken eggs. The antigen for  an egg-based influenza vaccine—the active substance in a vaccine that  provides immunity by causing the body to produce protective antibodies  to fight off a particular influenza strain—is derived from strains well  matched to the strains in wide circulation. In order for a vaccine to be  most effective, it needs to contain enough antigen to stimulate a protective  immune response.
subsections: section_title: Egg-Based Technology
paragraphs: Egg-based technology has been used to produce influenza vaccine for  several decades. Department of Health and Human Services (HHS)  officials we spoke with described it as a “tried and true” production  technology with which regulators and manufacturers are familiar. This  technology utilizes fertilized eggs as the medium for producing the  vaccine. Additionally, several decades of safety and efficacy data on the  influenza vaccine produced using egg-based technology are available.
However, the timeliness of vaccine production is hindered, in part, by egg- based technology’s reliance on seed strain development and growth.  Another factor affecting the production timeline is the amount of antigen  produced per egg. For example, during the 2009 H1N1 pandemic, vaccine  delivery was delayed, in part, because of poorer yields of antigen per egg  than expected. Also, the amount of influenza vaccine that can be produced  depends on the manufacturer’s egg supply. It generally takes 12 to   18 months to establish an egg supply large enough to meet the demands of  either seasonal or pandemic influenza. Some experts we spoke with  expressed concern that despite keeping chicken flocks producing the eggs  in secure conditions to prevent contamination, these flocks are at risk of  infection by, for example, the H5N1 avian influenza virus (also known as  “bird flu”).
section_title: Alternative Technologies for Use with Influenza Vaccines
paragraphs: Alternative technologies that can be used in producing influenza vaccines  include alternative production technologies—such as cell-based and  recombinant technologies—as well as the use of adjuvants. While various  alternative technologies are in development, in this report we focus on  these three because these are the alternative technologies the federal  government has primarily funded.
These three technologies have the potential to expand the supply or  accelerate the availability of both seasonal and pandemic influenza  vaccines. Expanding the supply or accelerating the availability of influenza  vaccine is particularly important during times of a perceived seasonal  vaccine shortage—when vaccine is not available and demand is highest— or during a pandemic when demand increases because of increased risk of  disease and death. Expanding the supply or accelerating the availability of  influenza vaccine can be done in two ways. The first is to increase the  overall amount of vaccine available at the end of the production process;  the second is to speed up the production process itself by, for example,  reducing or eliminating step(s) in the process.
subsections: section_title: Cell-Based Technology
paragraphs: The key potential benefit to cell-based technology is the ability to increase  the overall amount of vaccine available at the end of the production  process. This technology for influenza vaccines typically relies on the use  of well-established cell lines, such as those originally derived from the  kidney cells of monkeys or canines. These cells can exponentially increase  in number, allowing for the rapid expansion of the medium used for  influenza vaccine production. Additionally, cells can be stored in freezers  and prepared for use within days or weeks for large-scale production  demands. Vaccines using cell-based technology are licensed for use in the  United States for use against other infectious diseases, such as polio. Both  seasonal and pandemic vaccines using such technology are also licensed  in other countries, such as those in the European Union, including  Germany and Spain. Cell-based seasonal and pandemic vaccines are also  licensed for use in Iceland and Norway.
Despite the potential benefits of cell-based technology, there are  challenges associated with its use. Similar to egg-based technology, cell- based technology relies on seed strain development and growth to obtain  the influenza vaccine’s antigen. For example, during the 2009 H1N1  pandemic, manufacturers had low production yields in both eggs and cells  when they started vaccine production, which resulted in limited supplies  for delivery to the public. Also, cell-based technology has not yet been  licensed for use with influenza vaccine for the U.S. market. Additionally,  few manufacturers have established domestic production capacity for  influenza vaccine using this technology, and construction costs for cell- based facilities are high. For example, the construction costs for Novartis  Vaccine and Diagnostics Inc.’s cell-based facility in Holly Springs, North  Carolina, were over $1 billion, of which HHS funded approximately   40 percent and the manufacturer funded the remaining 60 percent.
section_title: Recombinant Technology
paragraphs: Recombinant technology potentially increases the overall amount of  vaccine available at the end of the production process and speeds up the  production process itself. First, this technology can also utilize specialized  cells—from mammals or from other sources, such as from bacteria, yeast,  insects, or plants—that can exponentially increase in number as the  medium for influenza vaccine production, allowing for the rapid expansion  of the medium used for influenza vaccine production. Recombinant  technology also has the potential to speed up the production process  because it does not rely on the development and growth of a seed strain to  obtain the influenza vaccine’s antigen. Instead, antigen is derived from the  protein(s) on the surface of the influenza virus or from the virus’s genes.  Recombinant technology is currently used in U.S.-marketed vaccines  against other diseases, such as hepatitis B and the human papillomavirus,  so FDA has experience reviewing licensing applications for vaccines  produced using this technology.
However, influenza vaccine using recombinant technology has not yet  been licensed for use in the United States. Although some influenza  vaccine has been produced for use and is currently being used in clinical  trials, influenza vaccine has not yet been produced on a large scale using  this production technology. One manufacturer, Protein Sciences  Corporation, has submitted a licensing application to FDA for a  recombinant seasonal influenza vaccine, but some experts we spoke with  said it is unlikely we will know the benefits of this technology in producing  influenza vaccine for several years.
section_title: Adjuvants
paragraphs: Adjuvants’ antigen-sparing capability has the potential to increase the  amount of vaccine available at the end of the production process.  Adjuvants—which can be used with influenza vaccines produced using  egg-based, cell-based, or recombinant technologies—can enhance the  immune response, thereby reducing the amount of antigen needed per  vaccine dose. By reducing the amount of antigen needed per vaccine dose,  adjuvants could increase the overall influenza vaccine supply. Adjuvants  have other benefits beyond potentially accelerating the delivery of  influenza vaccine (see table 8).
Seasonal influenza vaccines administered with adjuvants are licensed for  use in other countries for targeted populations, such as the elderly.  Adjuvants are licensed for use with seasonal influenza vaccine in other  countries, such as those in the European Union, including Belgium and  Italy. Adjuvanted seasonal influenza vaccines are also licensed for use in  Argentina, Columbia, Hong Kong, Mexico, the Republic of South Africa,  New Zealand, and Thailand. Adjuvants were also used with the 2009 H1N1  pandemic vaccine in other countries. These other countries include  Canada and Malyasia.
Although adjuvants have been used in other vaccines licensed for the U.S.  market—such as in vaccine against tetanus—FDA has not approved a  licensing application for a seasonal influenza vaccine using this technology  in the United States; adjuvants were also not used in the U.S. supply of  2009 H1N1 pandemic vaccine. Some experts have noted potential  concerns regarding the safety of repeated, annual administration of  adjuvants in healthy populations—such as young adults—in a seasonal  influenza vaccine.
section_title: Appendix IV: Comments from the Department of Health and Human Services
section_title: Appendix V: Comments from the Department of Defense
section_title: Appendix VI: GAO Contact and Staff Acknowledgments
subsections: section_title: GAO Contact
section_title: Staff Acknowledgments
paragraphs: In addition to the contact named above, Thomas Conahan, Assistant  Director; George Bogart; Cathleen Hamann; Mariel Lifshitz; Gay Hee Lee;  John Rancourt; and Kristal Vardaman made key contributions to this  report.
section_title: Related GAO Products
paragraphs: Influenza Pandemic: Monitoring and Assessing the Status of the  National Pandemic Implementation Plan Needs Improvement.   GAO-10-73. Washington, D.C.: November 24, 2009.
Influenza Pandemic: Gaps in Pandemic Planning and Preparedness  Need to Be Addressed. GAO-09-909T. Washington, D.C.: July 29, 2009.
Influenza Pandemic: Continued Focus on the Nation’s Planning and  Preparedness Efforts Remains Essential. GAO-09-760T. Washington, D.C.:  June 3, 2009.
Influenza Pandemic: Sustaining Focus on the Nation’s Planning and  Preparedness Efforts. GAO-09-334. Washington, D.C.: February 26, 2009.
Influenza Pandemic: HHS Needs to Continue Its Actions and Finalize  Guidance for Pharmaceutical Interventions. GAO-08-671. Washington,  D.C.: September 30, 2008.
Influenza Pandemic: Efforts Under Way to Address Constraints on  Using Antivirals and Vaccines to Forestall a Pandemic. GAO-08-92.  Washington, D.C.: December 21, 2007.
Influenza Vaccine: Issues Related to Production, Distribution, and  Public Health Messages. GAO-08-27. 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: Efforts to Forestall Onset Are Under Way;  Identifying Countries at Greatest Risk Entails Challenges. GAO-07-604.  Washington, D.C.: June 20, 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.
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.
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.