Influenza is characterized by cough, fever, headache, and other symptoms and is more severe than some viral respiratory infections, such as the common cold. 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. On average each year in the United States more than 36,000 individuals die and more than 200,000 are hospitalized from influenza and related complications. Vaccination, administered annually to provide protection against particular influenza virus strains expected to be prevalent that year, is the primary method for preventing seasonal influenza and its more severe complications. After vaccination, the body takes about 2 weeks to produce the antibodies that protect against infection. Traditionally CDC has recommended vaccination begin around October each year. However, because influenza seasons most often peak in January or February, in most years vaccination in December or later can still be beneficial. As shown in figure 1, the influenza season peaked in January or February in nearly two-thirds of the past 30 seasons. Two types of vaccine are recommended for protection against seasonal influenza in the United States: (1) an inactivated virus vaccine injected into muscle or (2) a live attenuated vaccine administered as a nasal spray. The injectable vaccine—which represents the vast majority of influenza vaccine administered—can be used to immunize healthy individuals aged 6 months and older and those at increased risk of complications or more likely to require medical care, including high-risk individuals. The live attenuated vaccine, in contrast, is approved for use only among healthy individuals aged 2 through 49 years who are not pregnant. This live attenuated vaccine represented less than 3 percent of the vaccine doses produced for sale in the United States for the 2006–07 influenza season. Because of fluctuations in the most prevalent virus strains of seasonal influenza, a new influenza vaccine is produced each year. Seasonal influenza vaccine is produced by manufacturers each year in a lengthy and complex process that involves a sequential set of steps (see fig. 2):1. Virus Strain Selection: In late winter each year, FDA determines the three influenza virus strains assessed to be most likely to cause serious illness in the United States the following influenza season. One or two of the three strains selected for inclusion in the vaccine are usually new compared to the prior season. For example, for the 2000–01 influenza season and all but one of the subsequent seasons, FDA has changed at least one strain selected for the vaccine—that is, at least one selected strain has differed from the strains included in the previous season’s vaccine. For one season, the 2003–04 season, FDA selected the same three influenza virus strains for the vaccine that were included in the prior season’s vaccine. 2. Production and Purification: Manufacturers and FDA obtain samples of each of the three selected virus strains from one of the World Health Organization Collaborating Centres. The manufacturers then inject the virus samples of each selected strain into separate batches of fertilized eggs to amplify the amount of virus. The viruses grown at this stage are called seed viruses and are tested by FDA. After manufacturers develop an appropriate seed virus for each of the three virus strains, these seed viruses are injected into millions of fertile chicken eggs and allowed to replicate. Producing these fertile eggs is more difficult than producing eggs grown for human consumption and FDA requires that the fertile eggs meet particular sanitation and other requirements. Each virus strain is grown separately inside the eggs over the course of several days, after which it is harvested, inactivated, and purified. 3. Testing, Filling, and Packaging: Using biological materials provided by FDA, manufacturers and FDA test the virus strains produced by the manufacturers to determine the purity and yield of the virus and to ensure that the potency of the virus is sufficient for immunization. The three virus strains are then combined to create the vaccine for that season. Once the vaccine is created, manufacturers fill vaccine doses into vials and syringes. Labels are applied denoting the vaccine lot number and expiration date. FDA may conduct additional testing before officially releasing each lot for distribution; according to FDA, the agency typically releases a lot within 3 weeks, provided the lot has satisfied FDA standards. 4. Shipping to Customers: Manufacturers ship released vaccine to customers, which can include medical supply distributors, physicians, hospitals, state and local health departments, and mass immunizers. The vaccine must be kept refrigerated within a prescribed temperature range. Vaccine production generally takes 6 or more months after virus strains have been selected, according to vaccine manufacturers, and vaccines for certain influenza virus strains have been difficult to mass-produce. Manufacturers are currently pursuing new production technologies, which may allow for more robust and reliable influenza vaccine production and may speed up the production process. For example, One such production technology involves growing the influenza virus in cells rather than chicken eggs. While eggs must be ordered up to 1 year in advance for egg-based production, cells used in cell-based production are more readily available, allowing for faster start up of vaccine manufacturing—the required amount of cells can be produced from frozen cells in a few days to weeks. In addition, cell-based production may present fewer contamination problems than egg-based production. Another technology under development makes seed viruses using genetic techniques rather than through the current trial-and-error process in which the virus strains are grown and sampled for the desired characteristics. This technology may allow for more reliable production of seed viruses— an essential step in the vaccine production process. Technology resulting in the development of a universal vaccine that would be effective against multiple virus strains would eliminate the need for current processes required to reformulate seasonal influenza vaccine each year. As a result, vaccine could be produced and available at any time of the year. However, despite recent increases in funding, a completely universal influenza vaccine may be years away. Manufacturers aim to make influenza vaccine available before the fall vaccination period when demand for vaccination has traditionally been the highest. At the end of the influenza season unused doses expire and cannot be used in subsequent years. For example, more than 18 million doses left over from the 2006–07 influenza season expired in 2007. Accordingly, manufacturers seek to match their vaccine production to expected demand for the vaccine so that no doses remain unsold at the end of the influenza season. Manufacturers sell vaccine directly to providers who administer vaccine, including physicians, hospitals, pharmacies, federal agencies, state and local health departments, and mass immunizers. In addition, manufacturers sell vaccine to medical supply distributors, who in turn sell it to providers and other customers such as other medical supply distributors. Providers administer vaccinations in a variety of locations, including physicians’ offices, public health clinics, nursing homes, and nonmedical locations such as workplaces and retail stores. Millions of individuals receive influenza vaccinations through mass immunization campaigns in these nonmedical settings, where organizations such as visiting nurse agencies under contract administer the vaccine. The number of manufacturers of seasonal influenza vaccine for the U.S. market and the number of doses produced and distributed have changed over the past seven seasons (see table 1). For the 2007–08 influenza season, six U.S.-licensed manufacturers are expected to produce an estimated 132 million doses of seasonal influenza vaccine. Since influenza vaccine production and distribution are largely private- sector activities, HHS and other federal entities have limited authority to control influenza vaccine production and distribution. CDC administers a number of programs to help make vaccines, including influenza vaccine, affordable for low-income and other populations. For example, under CDC’s Vaccines for Children program, vaccines are provided free of charge for certain children 18 years of age or younger, including those who are Medicaid-eligible, uninsured, or those without insurance coverage for vaccinations. CDC also reserves stockpiles of certain vaccines for use in the event of a vaccine shortage or disease outbreak. For each influenza season, ACIP, after consulting with CDC, makes recommendations on who should be targeted for vaccination and, in some years, has modified its annual recommendations after issuing them in order to address vaccine shortage, such as during the 2004–05 season. For the 2007–08 season, ACIP recommends vaccination for two categories of individuals: (1) high-risk individuals—that is, those persons at increased risk for medical complications or more likely to require medical care, such as children aged 6 to 59 months, pregnant women, persons aged 50 years or older, and persons with certain chronic conditions; and (2) close contacts of those at high risk—that is, persons who live with or care for persons at high risk, such as family members and health care workers. According to ACIP, approximately 73 percent of the U.S. population is included in one or more of these target groups. However, not everyone in these recommended target groups receives a vaccination each year—only an estimated one-third of them received vaccination, according to CDC estimates. For the 2007–08 season, in addition to recommending that providers vaccinate individuals in high-risk and other target groups, ACIP recommends that all persons, including school-aged children, who want to reduce the risk of becoming ill with influenza or of transmitting influenza to others should be vaccinated. Several factors may affect the quantity of vaccine produced for a given season and when it reaches providers who administer the vaccine. These factors include: challenges in manufacturing a new vaccine each year; limitations in the production capacity of manufacturers; and demand for vaccine by providers and patients that fluctuates throughout the season. For an individual provider, additional factors, including the route the vaccine takes from the manufacturer to the provider, can affect how much and when a particular provider receives vaccine. Manufacturing challenges inherent to the production of a new seasonal influenza vaccine each year include the necessity of adhering to a relatively inflexible and sequential process involving multiple players, difficulties growing new virus strains, and problems associated with maintaining safety and quality-control practices to produce a sterile vaccine.