Influenza Virus Vaccine, H5N1

Date of Approval: April 17, 2007
Company: Sanofi Pasteur Inc.
Treatment for: Prevention of H5N1 Influenza (Avian Influenza)

The U.S. Food and Drug Administration (FDA) has licensed Influenza Virus Vaccine, H5N1, the first avian influenza vaccine for humans in the U.S.

Sanofi pasteur, in collaboration with the National Institutes of Health, submitted a Biologics License Application to the FDA for this H5N1 vaccine. The licensure serves as a first key step in achieving the government's goal of stockpiling vaccine intended to protect those who are at increased risk of exposure to the H5N1 influenza virus contained in the vaccine during the early stages of a pandemic.

The licensure of this vaccine was based on a clinical trial conducted by the National Institute of Allergy and Infectious Diseases. This trial evaluated the safety and ability to generate an immune response of this vaccine when administered in two 90 �g/ml doses in healthy adults 18 through 64 years. The study, which was completed in 2005, showed that the vaccine elicited an immune response against the H5N1 virus and was associated with mild side effects.

Source: Sanofi Pasteur Inc.

Influenza Virus Vaccine, H5N1 - Questions and Answers

What is the Food and Drug Administration (FDA) announcing?

FDA is announcing the licensure of the first vaccine in the United States for humans against the H5N1 influenza virus, commonly referred to as avian influenza or "bird flu." This inactivated influenza virus vaccine is indicated for immunization of persons 18 through 64 years of age who are at increased risk of exposure to the H5N1 influenza virus subtype contained in the vaccine. This vaccine is derived from the A/Vietnam/1203/2004 influenza virus. The vaccine is manufactured by sanofi pasteur Inc. of Swiftwater, PA and has been purchased by the federal government for inclusion within the Nation's National Stockpile.

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The approval and availability of this vaccine is an important step in enhancing the Nation's readiness against a possible pandemic and enhances our ability to protect those at increased risk of exposure to the H5N1 virus.

What is avian influenza?

Avian influenza - the "bird flu" - is a virus that infects wild birds (e.g., ducks and gulls) and domestic poultry (e.g., chickens and turkeys). There are numerous different strains of avian influenza; however, most do not cause illness in people. Only influenza A viruses naturally infect birds. Wild birds are the natural host for all subtypes of influenza A virus. In general, wild birds do not get sick when they are infected with influenza virus, but some avian viruses can cause serious disease and death in wild birds. However, domestic poultry, such as turkeys and chickens, can get very sick and die from avian influenza. H5N1 is a newer, more recent strain of avian influenza, and is currently the main cause of concern among the scientific and medical community with regard to its potential to cause a pandemic. The H5N1 strain can infect birds, other animals and people.

What is an influenza pandemic?

An influenza pandemic is a global outbreak of disease that occurs when a new influenza virus appears in the human population, causes serious illness, and then spreads easily from person to person. It can sweep across a country and around the world in a very short time. Like the seasonal influenza many people get every year, pandemic influenza will probably spread by infected people coughing or sneezing or by touching something with the influenza virus on it and then touching their mouth or nose. Unlike seasonal influenza, people will have little immunity to the virus that causes a pandemic. An influenza pandemic will likely cause more severe illness, even death, and affect more people than seasonal influenza.

It is difficult to predict when the next influenza pandemic will occur or how severe it will be. In the past century, pandemics occurred in 1918-1919, 1957-1958 and 1968-1969.

The H5N1 strain of the avian influenza virus has caused the largest number of reported cases of severe disease and death in humans of any avian influenza viruses and is a potential candidate for starting the next pandemic.

Wherever and whenever an influenza pandemic starts, everyone around the world is at risk for getting the disease. Countries might delay arrival of the virus through measures such as border closures and travel restrictions, but these measures are not likely to totally protect the population.

Has anyone been diagnosed with avian influenza?

There have not been any human cases of avian influenza in the United States or North America, but there have been cases in other parts of the world such as Asia and Africa. According to statistics provided by the World Health Organization, from 2003 through April 11, 2007, there have been 291 laboratory-confirmed cases in humans, of whom, 172 died. Each additional case provides the virus an opportunity to improve its ability for human-to-human transmission and develop into a pandemic strain. But right now, there is no pandemic influenza in the world.

Is avian influenza more serious than seasonal influenza?

Yes. H5N1 or avian influenza has some of the standard seasonal influenza symptoms such as high fever, headache, and muscle aches, but people quickly become seriously ill and pneumonia, difficulty breathing, and multi-organ failure have been common among people who have been stricken with H5N1 influenza.

How well does the influenza virus vaccine, H5N1, work?

One multi-center, randomized, double-blinded, placebo-controlled, dose-ranging study in healthy adults, 18 to 64 years of age, investigated the safety and immunogenicity of the vaccine. A total of 103 healthy adults received a 90 microgram dose of the vaccine by injection, followed by another 90 microgram dose, 28 days later. In addition, there were approximately another 300 healthy adults who received the vaccine at doses lower than 90 micrograms and a total of 48 who received placebo by injection.

Of the various doses tested, the study showed that the 90 microgram dose had the better immune response, meaning that at this particular dose, the vaccine induced the most antibodies in the blood against the H5N1 influenza virus strain. The 90 microgram two-dose regimen produced levels of antibodies expected to reduce the risk of getting H5N1 influenza in 45% of those who received it. Although the remaining individuals did not develop this level of antibody, current scientific information on other influenza vaccines, suggests that less than optimal antibody levels may still have the potential to help reduce disease severity and influenza-related hospitalizations, and deaths.

Why didn't the clinical trial include more people?

FDA recognizes that a limited number of people were studied in the clinical trial. The study was designed by the National Institutes of Health (NIH) as an exploratory study to look at the amount of antibodies generated in humans from various doses. Because the results showed promise for providing protection against the H5N1 influenza virus and helping with national preparedness for influenza pandemic, sanofi pasteur submitted a Biologics License Application to FDA.

Although each 90 microgram dose required to stimulate the immune response was twice the amount that is used in the seasonal influenza vaccine, the manufacturing process and vaccine formulation for the H5N1 vaccine is the same as that of sanofi pasteur's US licensed seasonal vaccine, which has a long record of safety and effectiveness.

It is fortunate to have this vaccine during this "inter-pandemic" phase. The benefit of having a licensed vaccine against a potential pandemic influenza virus strain, even with limited data, outweighs the risk of having no vaccine at the time of an inevitable influenza pandemic.

What are the risks associated with the vaccine?

The vaccine was generally well-tolerated by the recipients in the study, with pain and tenderness at the injection site, headache, general ill feeling, and muscle pain being the most common complaints. However, because the number of people studied was small, rare safety events may not have been identified, but given the potential risk of a pandemic, this is the only vaccine currently available and its benefits outweigh its risks. In addition, sanofi pasteur has agreed to work with the U.S. government to gather additional information on the safety and effectiveness of the vaccine should it be used in the event of a pandemic.

How will FDA monitor the safety of a pandemic influenza vaccine if it is used?

Post-licensure monitoring of vaccine safety involves identification of possible adverse effects of vaccination, followed by evaluation of these "signals" for a possible causal link with vaccines. Systems currently available to conduct vaccine safety monitoring include the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD). Adaptation of these systems for use during a pandemic may be required. Other large automated databases of encounter and/or claims data that might be useful for pandemic influenza vaccine safety monitoring include those of the Centers for Medicaid & Medicare Services, Veterans Affairs, Department of Defense, and private insurance groups not currently part of the VSD. The FDA and the Centers for Disease Control and Prevention (CDC) are evaluating these systems for potential to contribute to the monitoring of pandemic influenza vaccine safety. If the pandemic vaccine is administered primarily through public health departments, a registry of vaccinees, with common identifiers allowing researchers to determine the vaccination status of those with adverse events (AE), may need to be established.

What if a pandemic is declared and the influenza virus strain of the pandemic is different than the influenza virus strain in this vaccine?

No one can predict which influenza virus subtype (strain) will cause the next pandemic. Several factors affect the effectiveness of influenza vaccines. One major factor is the degree to which circulating strains and influenza vaccine strains are similar. If the pandemic virus strain is substantially different from the H5N1 virus contained in the vaccine, it is unlikely that the existing vaccine would be effective. It is possible that the next influenza pandemic will be caused by a strain of influenza that does not belong to the H5N1 subtype. Both of these scenarios would require development of a new vaccine. If the influenza pandemic strain turns out not to be a perfect match with the vaccine strain, it does not necessarily mean that the vaccine can't be used; studies have shown that influenza vaccine may provide some immunity against strains that are somewhat different.

The goal of pandemic preparedness is to develop additional vaccines and vaccination strategies that will be ready for use against various strains that have the potential to cause a pandemic.

Does the vaccine contain thimerosal?

Yes, thimerosal, a mercury containing compound, is used as a preservative in the vaccine. Because the vaccine is supplied in a multi-dose vial; it is necessary to have a preservative to prevent the growth of bacteria and fungus in the event that the vaccine is accidentally contaminated, as might occur with repeated puncture of multi-dose vials.

Will the vaccine be available to anyone who wants it?

No, the manufacturer has stated that the vaccine won't be available to the public commercially, meaning it can't be obtained from a doctor's office. It has been purchased by the federal government for inclusion within the country's National Stockpile, for distribution by the Department of Health and Human Services in case it is ever needed.

Why is the vaccine for inclusion within the National Stockpile and not being made available to all Americans?

The production capacity of the United States currently is not sufficient to make vaccine rapidly available for the entire population. Inclusion of this vaccine in the National Stockpile will ensure that when it is needed, those who are designated as priority recipients, will have vaccine available to them. Other vaccines are also being developed to meet the Nation's needs against influenza pandemics.

Even though it will be in the Stockpile, can people who may be at risk of exposure to H5N1 influenza virus, such as travelers to infected regions of the world, poultry workers, or first-responders get the vaccine?

At this time, immunization is not recommended for populations that may be at risk of exposure to H5N1 influenza virus. Through its Interagency Pandemic Vaccine Prioritization Working Group, the federal government is working to decide who will get the vaccine earliest in a pandemic.

Why does the approved indication not include children or elderly?

It is not uncommon for new vaccines to be tested in a healthy adult population and then once further information is gathered about benefits and risks, additional testing is done in other populations such as children and the elderly. FDA is expecting information on these particular populations to be submitted in the near future and will evaluate those results.

How is the vaccine administered?

It is administered as a two-dose regimen. One 90 microgram dose is given intramuscularly, in the upper arm, and a second 90 microgram dose is given in the same manner, 28 days later.

Is it possible to become infected with avian influenza from the H5N1 vaccine?

No. The vaccine is made from killed influenza viruses, and they cannot cause influenza infection.

Will the annual shot for influenza protect people against pandemic influenza?

No, current annual influenza vaccines include three influenza viruses, A subtypes H3N2 and H1N1 viruses, and one B virus. A vaccine made from these viruses would not provide protection against a different influenza A subtype virus (such as H5N1).

It is important to continue to get the influenza shot every year as this is the best way to prevent illness from the seasonal influenza virus.

Where can I get more information on avian influenza and actions that can be taken to prepare for a pandemic?

Information can be found at www.flu.gov. This website provides one-stop access to U.S. Government avian and pandemic flu information and is managed by the Department of Health and Human Services.

Influenza Virus Vaccine, H5N1 - Highlights of Prescribing Information

These highlights do not include all the information needed to use Influenza Virus Vaccine, H5N1, safely and effectively. See full prescribing information for Influenza Virus Vaccine, H5N1.

Indications and Usage

Influenza Virus Vaccine, H5N1, is an inactivated monovalent influenza virus vaccine, indicated for active immunization of persons 18 through 64 years of age at increased risk of exposure to the H5N1 influenza virus subtype contained in the vaccine.

Dosage and Administration

Immunization consists of two 1 mL (90 �g) intramuscular injections, a 1 mL dose given on day 1 followed by another 1 mL dose given approximately 28 days later (window 21 to 35 days).

Dosage Forms and Strengths

Each 1 mL dose contains 90 micrograms (�g) of influenza virus hemagglutinin (HA) of strain A/Vietnam/1203/2004 (H5N1, clade 1).

Suspension in a 5 mL multi-dose vial, contains thimerosal, a mercury derivative (approximately 50 �g mercury/dose), added as a preservative.

Contraindications

None

Warnings and Precautions

History of a hypersensitvity reaction to chicken or egg proteins or life-threatening reactions to previous influenza vaccinations.

If Guillain-Barr� syndrome (GBS) has occurred within six weeks of vaccination with influenza vaccine, the decision to give Influenza Virus Vaccine, H5N1, should be based on careful consideration of the benefits and risks.

Immunocompromised persons may have a reduced immune response to Influenza Virus Vaccine, H5N1.

Adverse Reactions

Most common (>10%) adverse reactions are pain at injection site, headache, malaise, and myalgia.

Drug Interactions

Do not mix with other vaccines in the same syringe or vial.

Immunosuppressive therapies may reduce the immune response to Influenza Virus Vaccine, H5N1.

Use in Specific Populations

Safety and effectiveness have not been established in pregnant or lactating women, and in pediatric and geriatric populations.

Patient Counseling Information

Patients, parents or guardians should be fully informed by their health care provider of the benefits and risks of immunization with Influenza Virus Vaccine, H5N1. When educating vaccine recipients and guardians regarding the potential side effects, clinicians should emphasize that Influenza Virus Vaccine, H5N1, contains non-infectious particles.

Patients, parents or guardians should be instructed to report any serious adverse reaction to their health care provider.

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