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February 2007

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QUESTIONS AND ANSWERS
Avian Influenza Trials


As part of the federal government’s efforts to prepare for a possible pandemic involving avian influenza (bird flu), the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is supporting the development and testing of candidate avian influenza vaccines. The Institute has initiated a series of clinical trials to evaluate these vaccine candidates. This set of questions and answers pertains to these clinical trials of H5N1 and H9N2 influenza vaccines.

1. What is H5N1 avian influenza (bird flu), and why is it of concern to public health officials?

The H5N1 virus is one of 16 different known subtypes of influenza virus. All influenza viruses (human and avian) are of significant concern to public health officials because these viruses can mutate rapidly and have a tendency to acquire genes from flu viruses that infect other animal species. In addition, some H5N1 viruses are highly pathogenic, meaning they can cause severe disease and death in humans.

In the past decade, highly pathogenic avian influenza A viruses, specifically H5N1 viruses, have caused widespread sickness and death in domestic and wild bird populations around the world. As the spread of H5N1 infection among birds increases, so does the opportunity for H5N1 to be transmitted directly from birds to humans. When an influenza virus “jumps” species from an animal, such as a chicken, to infect a human, the result is usually a “dead-end” infection that cannot easily spread further in the human population. However, mutations in the virus could develop that allow efficient human-to-human transmission.

As of January 12, 2007, H5N1 has infected 265 humans worldwide, resulting in the death of more than half of the infected individuals. (For up-to-date numbers, see the World Health Organization Web site at http://www.who.int/csr/disease/avian_influenza/country/en/index.html.) While human cases remain relatively rare and are largely the result of direct virus transmission from infected birds, a few suspected cases of human-to-human transmission have been reported. The severity of disease and the potential for sustained and efficient human-to-human spread has caused great concern among public health officials and provided a major incentive to accelerate developing a human vaccine for avian influenza.

If avian and human influenza viruses were to simultaneously infect a person or animal, the two viruses might swap genes. The result could be a new virus that is readily transmissible between humans and against which humans would have no natural immunity. Such an event could trigger a worldwide influenza pandemic.

2. Why is this influenza virus called H5N1?

Subtypes of influenza virus are named according to two specific proteins, hemagglutinin and neuraminidase, that appear on the surface of the virus. Hemagglutinin allows the virus to “stick” to a cell and initiate infection, while neuraminidase enables newly formed viruses to exit the host cell. Currently, there are 16 known variants of hemagglutinin protein and 9 known variants of neuraminidase proteins. This particular subtype of influenza virus has hemagglutinin type 5 and neuraminidase type 1, so it is known as H5N1.

3. What vaccines are being tested?

In 2004, NIAID awarded two contracts for production and clinical testing of investigational vaccines against H5N1. Both sanofi pasteur (Swiftwater, PA) and Chiron (Emeryville, CA) are producing vaccines made from inactivated H5N1 viruses for NIAID to test in clinical trials. Under these contracts, sanofi pasteur has already delivered more than 8,000 doses to NIAID; Chiron has delivered more than 1,000 doses.

Also in 2004, NIAID directed Chiron Corporation to produce 40,000 doses of an experimental H9N2 vaccine. This strain of avian influenza infected two children in Hong Kong in 1999.

For more information on avian influenza clinical trials, see ClinicalTrials.gov.

4. Where and how was the H5N1 reference virus used to produce these vaccines developed?

The H5N1 reference virus (the strain used to produce the H5N1 vaccines for NIAID’s clinical trials) was developed by researchers at St. Jude Children’s Research Hospital, Memphis, TN, using a technique known as reverse genetics. NIAID provided this H5N1 reference virus to both sanofi pasteur and Chiron in spring 2004 for vaccine production.

5. When did NIAID begin testing the H5N1 vaccines? What were the results?

The first clinical trial began in April 2005; it tested the H5N1 vaccine produced by sanofi pasteur in 451 healthy adults ages 18 to 64. This trial, which is completed, evaluated the safety of the vaccine and its ability to generate an immune response (immunogenicity). A report published in the March 30, 2006 issue of The New England Journal of Medicine showed that two doses of the 90-µg dosage H5N1 candidate vaccine generated the highest immune response among those dosages tested.

6. What other vaccine trials have been conducted?

A trial to evaluate the safety and immunogenicity of the sanofi pasteur H5N1 vaccine in persons 65 and older began in October 2005. A similar trial in children ages 2 through 9 years old opened in January 2006. Immunogenicity data for both elderly and pediatric trials are expected in early 2007.

NIAID also supported a trial to evaluate the safety and immunogenicity in healthy adults of a Chiron/Novartis H9N2 vaccine combined with an adjuvant known as MF59. Adjuvants are substances that are added to a vaccine to improve the immune response to the vaccine. A report published in Clinical Infectious Diseases in November 2006 showed that a good antibody response was generated among the lowest dosage of the adjuvant-containing H9N2 vaccine. Studies also showed that a single dose of vaccine with adjuvant was as good as two doses of unadjuvanted H9N2 vaccine.

NIAID is also interested in the development of other vaccine technologies including alternative strategies to egg-based vaccine production. Through a subcontract with Baxter International (Deerfield, IL), NIAID is supporting trials of a whole-virus H5N1 candidate vaccine that was produced using the company’s vero-cell-based technology platform. This strategy produces high yields of influenza virus without the addition of any animal-derived serum.

Additionally, in December 2006, scientists with the NIAID Vaccine Research Center (VRC) in Bethesda, MD, launched the first clinical trial of a DNA vaccine designed to prevent H5N1 avian influenza. Unlike conventional flu vaccines, administered as a weakened or killed form of the virus, the DNA vaccine designed by VRC scientists contains no infectious material but only portions of the influenza virus’ genetic material. Once inside the body, the DNA instructs human cells to make proteins that act as a vaccine against the virus.

7. Are there studies evaluating how to optimize the vaccine supply if necessary?

Yes, NIAID studies are evaluating various strategies to optimize a limited vaccine supply. NIAID has completed a Phase I trial to evaluate the response to intradermal (under the skin) administration of the sanofi pasteur H5N1 vaccine; the purpose of the study is to determine if a smaller intradermal dose may be as immunogenic as a larger dose administered intramuscularly (see question 8). NIAID also is conducting H5N1 and H9N2 vaccine trials with adjuvants.

8. What did the results show in the trial evaluating intradermal response of the sanofi H5N1 vaccine?

All dose regimens of inactivated influenza A/H5N1 vaccine administered intradermally and intramuscularly were safe and well tolerated for all study participants. It was concluded that at the doses tested there was no clear advantage with regard to immunogenicity of intradermal administration when compared with intramuscular administration. Additional studies of H5N1 vaccine delivery are under consideration.

9. What is status of the NIAID adjuvant trials of aluminum hydroxide and MF59?

NIAID is evaluating the H5N1 vaccine with aluminum hydroxide adjuvant in two studies in healthy adults and healthy elderly. These trials are being conducted at NIAID’s Vaccine and Treatment Evaluation Units (VTEUs). These trials are designed to investigate the safety, reactogenicity and dose-related immunogenicity of an investigational inactivated influenza A/H5N1 vaccine when given alone or combined with aluminum hydroxide. NIAID is also assessing safety and dose-related immunogenicity of H5N1 vaccine adjuvanted with aluminum hydroxide or MF59 in healthy adults in a separate trial.

10. Where are these clinical trials being conducted?

NIAID has initiated a series of clinical trials of H5N1 candidate vaccines. These clinical trials are being conducted at NIAID’s Vaccine and Treatment Evaluation Units (VTEUs). This network of university research hospitals across the United States conducts Phase I and II clinical trials to evaluate candidate vaccines for infectious diseases. Not all VTEUs are involved in every trial of H5N1 vaccines; rather, various VTEUs are involved in different stages of this series of clinical trials. NIAID’s VTEU sites are as follows:

  • Baylor College of Medicine, Houston, TX
  • University of Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
  • Saint Louis University Health Sciences Center, St. Louis, MO
  • Harbor UCLA Research and Education Institute, Los Angeles, CA
  • University of Maryland School of Medicine, Baltimore, MD
  • University of Rochester School of Medicine and Dentistry, Rochester, NY
  • Vanderbilt University Medical Center, Nashville, TN

The trial in healthy adults was initiated at three VTEU sites: the University of Rochester; the University of Maryland; and the University of California, Los Angeles (UCLA). The trial in elderly subjects is taking place at four sites: UCLA; University of Cincinnati; University of Rochester; and Vanderbilt University. The pediatric trial is being conducted at three VTEUs: the University of Maryland, UCLA; and Saint Louis University.

11. What vaccine formulations are being tested?

Currently, NIAID is testing a range of concentrations, known as dosage levels, of the sanofi pasteur H5N1 and the Chiron/Novartis H9N2 vaccines to evaluate safety and immunogenicity.

12. Can the H5N1 or H9N2 vaccines under study give me the flu?

No, you cannot get the flu from receiving an inactivated H5N1 or H9N2 vaccine.

13. How will we know if the H5N1 or H9N2 vaccine will work in the event of a real pandemic?

A major objective of these clinical trials is to evaluate the immune response generated by an H5N1 or H9N2 vaccine made from an inactivated form of the same virus. The immune response is determined by measuring levels of infection-fighting antibodies in those vaccinated, to see whether the antibodies reach a level that scientists think should be able to provide protection.

14. If the H5N1 virus currently circulating mutates considerably before the vaccine is ready for the public, will it still be effective?

We know that flu viruses change over time (a process known as “antigenic drift”). However, in response to the increasing number of H5 cases reported in early 2004, public health officials deemed it critical to move ahead quickly and select one of the available human H5 viruses for vaccine production. If a distinct H5N1 virus should suddenly emerge, an additional new vaccine against that strain may be needed. Ultimately, the experience gained by manufacturers in producing the current H5N1 vaccine should make us better prepared for the next time.

15. What is the difference between vaccines and antiviral drugs?

Influenza vaccines are given as a preventive measure to elicit a protective immune response in the body. When immunized, the body is poised to remember this virus and can better fight an infection caused by it. Antiviral drugs, on the other hand, are medicines given to people either prophylactically to prevent influenza or therapeutically once they are already infected.

16 Are drugs effective in treating avian influenza in humans?

Data from the World Health Organization’s Global Influenza Surveillance Network indicate that the recently circulating H5N1 strains are susceptible to two antiviral drugs approved for use in the United States to treat human influenza infections—oseltamivir (sold as Tamiflu) and zanamivir (sold as Relenza). However, these medicines need to be started early enough—usually within the first two days of infection—to be effective.

Many of the recently circulating H5N1 influenza viruses have been shown to be resistant to two older, inexpensive antiviral drugs—rimantadine and amantadine. Scientists are studying how the H5N1 viruses became resistant to these older drugs and carefully watching for any signs of resistance to the newer drugs.

17. Is the H5N1 vaccine the same as the seasonal flu shot?

No. The seasonal flu vaccine contains two strains of the most recent form of influenza A as well as one strain of influenza B. These strains have widely circulated in humans for a number of years.

The NIAID clinical trials are testing a vaccine made with the H5N1 strain of influenza that mainly infects birds and other small animals. The H5N1 strain is highly lethal to both birds and humans—more lethal than the seasonal flu. The process used to manufacture the sanofi pasteur H5N1 influenza vaccine is similar to that used to make the seasonal influenza vaccine that is licensed for use in the United States each year. Because the processes are similar, the FDA will more easily be able to evaluate this candidate H5N1 vaccine than if it were made with an entirely new process.

18. By what mechanism is pandemic flu most likely to arrive in the United States?

Migratory birds, the poultry trade, and human travel are among the possible mechanisms that experts believe could introduce pandemic flu into the United States. Public health officials are monitoring these and other possible mechanisms as priorities for the health of the nation.

19. How can I get into a clinical trial of this vaccine?

Persons interested in participating in a clinical trial of candidate H5N1 vaccines can monitor www.ClinicalTrials.gov for ongoing and upcoming clinical trials information.

20. Are there plans to make the vaccine available to the public?

The Department of Health and Human Services (HHS) Pandemic Influenza Plan includes information about influenza pandemic preparedness and populations that will be considered to receive vaccinations during a pandemic. For more information, visit www.pandemicflu.gov.

Media inquiries can be directed to the NIAID News and Public Information Branch at 301-402-1663, niaidnews@niaid.nih.gov.


NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Last Updated January 30, 2007