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By Linda Bren
Seasonal influenza is among America's most lethal killers, according to the Centers for Disease Control and Prevention (CDC), because the virus infects so many people—5 percent to 20 percent of the U.S. population every year. Most people who get this contagious respiratory illness caused by the influenza virus recover in a week or two without complications. But each year, more than 200,000 people have complications severe enough to send them to the hospital. And another 36,000 die each year from seasonal influenza.
Ninety percent of the deaths occur in those ages 65 and older, but the highest rates of infection occur in children. And healthy children younger than 2 years are as likely to land in the hospital because of influenza as those over 65.
"Vaccination remains the single most effective preventive measure available against influenza, and can prevent many illnesses and deaths," says Jesse Goodman, M.D., director of the Food and Drug Administration's Center for Biologics Evaluation and Research (CBER). Yet each year, millions of Americans choose to take a chance and forgo influenza vaccination.
Public health officials urge those eligible for vaccination to receive it and remind people that although influenza vaccination begins in September or October each year, vaccine continues to be available in November, December, and later, and immunization during those months is still beneficial.
The CBER regulates vaccines for use in the United States and is responsible for their safety and effectiveness.
Vaccine is available to anyone who wants to reduce his or her chances of getting influenza, with a few exceptions, but the CDC strongly recommends it for the following groups of people:
Since no influenza vaccine is approved for children younger than 6 months of age, families should use a strategy known as "cocooning," says William Schaffner, M.D., professor and chairman of the Department of Preventive Medicine at Vanderbilt University School of Medicine in Nashville, Tenn. "They should provide a cocoon, or zone of protection, around that very vulnerable young child by vaccinating all the other people in the family, including grandma and granddad who come in for visits, and out-of-home caregivers. "
Infection-fighting antibodies develop about two weeks after vaccination.
Studies have shown that influenza vaccine is 70 percent to 90 percent effective in healthy adults younger than 65. In older people, children, and those with chronic illnesses, the vaccine may not necessarily prevent influenza, but it can reduce the severity of the symptoms and the risk of complications if they do get sick.
Vaccination in people older than 65 reduces the likelihood of hospitalization for influenza-related complications by 30 percent to 70 percent. And for those living in nursing homes or other long-term care facilities, the vaccine is up to 80 percent effective in preventing death from influenza.
The FDA has licensed two types of influenza vaccine for use in the United States: the "shot" and the inhaled vaccine.
The shot contains inactivated, or killed, viruses and is given with a needle in the arm. The inhaled vaccine contains live viruses that are weakened and is administered into the nose with a sprayer. The influenza shot can be given to those 6 months of age and older, including healthy people and those with medical conditions. The inhaled vaccine is approved only for healthy people between the ages of 5 years and 49 years, excluding pregnant women.
Some people may get a mild fever, body aches, and fatigue for a few days, but you can't get influenza from the influenza shot, says Karen Midthun, M.D., the deputy director for medicine in the FDA's Center for Biologics Evaluation and Research. "No vaccine is 100 percent effective. So you may get the flu soon after you received the vaccine, before it could be expected to protect you. It does not mean the shot gave you the flu."
In addition to the influenza shot, an inhaled influenza vaccine is approved by the FDA. The inhaled vaccine does not cause influenza in healthy people, the only group for which it's approved.
Preparing for the influenza season each year is a time-critical, highly orchestrated, collaborative effort between the FDA, the CDC, the National Institutes of Health (NIH), the World Health Organization (WHO), vaccine manufacturers, and the health care community.
One of the biggest challenges in the process is to produce a new vaccine every year, says Jesse Goodman, M.D., director of the CBER. "Because the virus mutates, each year's vaccine may be different from the preceding year."
The process begins in late January or early February when an FDA advisory committee meets to recommend which three strains of the virus should be included in the vaccine, based on data from WHO laboratories in more than 80 countries. The FDA makes the final decision on which strains will be included in the vaccine for the U.S. population.
Once the strains are selected, the FDA, CDC, or other WHO collaborating centers can produce reference influenza viruses that are adapted to high growth in eggs. The reference influenza viruses are provided to the licensed vaccine manufacturers to generate the "seed virus" for further manufacturing influenza vaccine.
Manufacturers inject the seed viruses into fertilized chicken eggs, which contain a nutrient in which the virus multiplies.
The manufacturer harvests and purifies the virus from the egg and applies chemical treatments to kill (inactivate) the virus so that it cannot transmit infection. These treatments are done for each of the three strains, which are tested and retested by both the manufacturer and the CBER before being blended into the three-virus strain vaccine.
The CBER produces and provides manufacturers with antiserum, which they use to test vaccine potency for each influenza strain.
Manufacturers ship sample vials of vaccine from each lot, along with their test results, to the CBER for "lot release." The CBER reviews the test results as well as performs its own tests to ensure the accuracy of the manufacturers' tests and the vaccine's safety and effectiveness before releasing each lot for distribution.
Some lots of vaccine may be released as early as July, but manufacturing usually continues until October or later in order to produce and test the large volume of vaccine required for the U.S. population.
It takes about six months to complete influenza vaccine production—from egg to vial—each season. Throughout the process, the FDA discusses technical and manufacturing issues with the companies and inspects each company's facility and manufacturing processes while it is making vaccine.
Selecting the influenza virus strains each year, preparing the vaccine, and manufacturing and distributing millions of doses all must be precisely timed to make the vaccine available for the influenza season. Any problems encountered during the process may cause delays or shortages. In addition, because the number of companies that make influenza vaccine for the United States is small, a production problem with any company can substantially affect the overall supply.
Manufacturers have projected making about 100 million doses of influenza vaccine for the 2006–2007 season in the United States, but these projections could change as manufacturing continues. The projected supply is 16 percent more than the 2005–2006 season's 86 million doses and 40 percent more than the 2004–2005 season's 61 million doses. Demand has usually been around 70 million to 75 million doses.
Government agencies monitor the vaccine market, but do not control it. Distributing and administering influenza vaccine is mostly a private sector enterprise. The CDC and state and local health departments work to influence distribution through collaborations and recommendations so that vaccine reaches the people most at risk, including older people, health care workers, nursing homes residents, young children, and expectant mothers.
Vaccine distribution is a complex process involving manufacturers, wholesalers, distributors, purchasers, and providers. Some manufacturers sell directly to providers, others work exclusively with wholesalers, and some use both methods of distribution. Since there is no coordinated system that manufacturers and distributors use to deliver vaccines, some health care providers receive their vaccine before others.
Sometimes, vaccine is in short supply early in the season, but there is leftover vaccine at season's end. How much vaccine is produced and distributed plays a role, but so does timing, says Christine Layton, Ph.D., M.P.H., of RTI International, a nonprofit firm in Research Triangle Park, N.C. "The peak demand for flu vaccine is in October and November, when only about 50 percent of the vaccine has been delivered. But it's not until January, generally speaking, that all the vaccine has been available to providers."
And it's usually not until January or later that the influenza disease season peaks in the United States, according to the CDC. The FDA and the CDC support extending vaccination throughout the influenza season, into January and February.
Scientists and public health experts are looking for ways to boost the production of influenza vaccine and make it available more quickly to more people. And researchers are looking at new technologies that could be used to produce vaccine, not just for seasonal influenza, but for a pandemic—a worldwide outbreak of serious illness.
One of the technologies researchers are using is cell culture production, which allows a virus to grow and multiply in living animal cells instead of eggs. Cell-based vaccines could help meet surge capacity—making a lot of vaccine in a short time period—in the event of a shortage or a pandemic.
With cell culture production, cells can be frozen and stored, and then thawed out and used to produce more vaccine as needed—a speedier process than acquiring millions more fertilized eggs. Like the current method of influenza vaccine production, the safety of vaccines produced in cell culture would be thoroughly evaluated by the FDA.
In May 2006, Health and Human Services Secretary Mike Leavitt announced the department's investment of more than $1 billion in contracts with five companies to develop influenza vaccine made from cell culture.
Researchers also are looking at recombinant vaccines, made by genetic engineering, for influenza prevention. The gene from a specific influenza protein is isolated from the influenza virus, cloned, and grown in yeast or other cells to create large amounts of the protein. The protein produced is purified and then used to make vaccine. When the vaccine is injected into a person, the body's immune response to the recombinant protein protects against infection by the naturally occurring virus.
Researchers also are experimenting with substances that enhance vaccine effectiveness (adjuvants) to make current vaccines more potent. "If you could double the potency, the current technology could make twice as many doses, which would make 50 percent of the doses available sooner," says George Curlin, M.D., M.P.H., an infectious diseases researcher and adviser on vaccine clinical trials at the National Institute of Allergy and Infectious Diseases. Studies supported by the NIH are under way using adjuvants as a "dose-sparing" technology.
Another area of research is a universal vaccine. This one-shot-fits-all vaccine would protect people for years against all strains of influenza anywhere in the world. Although universal vaccine research has been going on for decades, says Curlin, "nothing seems like it's available right around the corner, but there are clinical trials starting."
The FDA has worked to streamline the vaccine approval and licensing process to encourage new vaccine development and to make vaccines available for use sooner. In March 2006, the agency published recommendations, in the form of two draft guidelines, to aid manufacturers in developing vaccines for both seasonal and pandemic influenza. The guidelines give specific approaches that vaccine developers can follow to show the safety and effectiveness of new vaccines, and they provide flexible, regulatory pathways for getting vaccines on the market.
One of these pathways is the accelerated approval process, which can reduce the development time for a new vaccine. For an application that does not use the accelerated approval pathway, a company must show that a vaccine actually prevents influenza, which requires waiting to see whether people in studies get sick or not. For accelerated approval, if the manufacturer demonstrates that within weeks after vaccination, adequate levels of protective antibodies are made in the blood that the FDA believes may prevent influenza, then this approach may be acceptable. If the accelerated approval approach is used, further studies are required after approval to make sure that the vaccine actually prevents influenza.
The accelerated approval pathway was critical in allowing the rapid approval in 2005 of Fluarix, a new influenza vaccine and the first vaccine of any kind approved using the FDA's accelerated approval process.
The FDA has corresponded with the major manufacturers of influenza vaccine in the world to stimulate interest in producing vaccine for the U.S. market. This outreach resulted in one additional vaccine product approval for the 2005–2006 season, and the possibility for others in future influenza seasons.
The FDA is also undertaking efforts to aid development of influenza vaccines using new technologies. To accomplish this goal, the CBER is using various approaches to reach a broad audience, such as convening an advisory committee meeting to discuss the use of novel cell substrates for making influenza vaccine, and having frequent interactions with vaccine manufacturers to provide both scientific and regulatory guidance. In addition, the CBER is participating in and leading meetings with industry, regulatory authorities of other nations, and stakeholders concerning the development of influenza vaccine.
Getting an annual influenza vaccination continues to be the first line of defense against seasonal influenza. But antiviral drugs—started within the first two days of experiencing influenza symptoms—can shorten the time influenza lasts.
The FDA has approved four antiviral prescription drugs to treat influenza: Tamiflu (oseltamivir), Relenza (zanamivir), Symmetrel and generics (amantadine), and Flumadine and generics (rimantadine).
All of these drugs also are approved to prevent influenza, but they are not substitutes for influenza vaccine. The CDC recommends that the drugs be used in specific circumstances, for example, in combination with the vaccine to help control influenza outbreaks in institutions such as nursing homes where people at high risk for complications from influenza are in close contact with each other. The antiviral drugs should not be used, however, in people who receive inhaled influenza vaccine until at least two weeks after vaccination. In addition, people should not get vaccinated within two days of stopping the use of antiviral drugs.
The drugs may be prescribed by a doctor to prevent influenza in place of vaccine in certain people, such as those who are allergic to eggs, the medium used to grow the virus for the vaccine.
Influenza viruses can rapidly develop resistance to certain drugs. Because of recent evidence that many circulating influenza viruses are resistant to amantadine and rimantadine, the CDC has recommended that these drugs not be used to treat or prevent influenza in the United States at this time.
The Centers for Disease Control and Prevention recommends the following good health habits to help prevent getting influenza:
www.fda.gov/oc/opacom/hottopics/flu.html
This article has been condensed from the original article as it appears in FDA Consumer magazine and edited for the FDA Web site. The print version of FDA Consumer is available by subscription.