Preliminary results from clinical trials testing two different pandemic flu vaccine approaches — one a prime-boost strategy using different subtypes of H5N1 vaccines, the other an H5N1 vaccine delivered into the skin (intradermal) rather than the muscle — will be presented at the 44th Annual Meeting of the Infectious Diseases Society of America being held in Toronto Oct. 12-15. The presentations are scheduled for a late-breaker session on Friday afternoon, Oct. 13th.

Funding for the trials comes from the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health. Reporters may call the NIAID News Office at 301-402-1663 to speak with NIAID Director Anthony S. Fauci, M.D., who is available to comment and provide perspective on these preliminary findings.

Preliminary Results Suggest Priming Boosts Immune Responses to Variant H5N1 Vaccine

Presentation time: Late-Breaker Session, Friday, Oct. 13, 2006, 5:00 p.m.
Presenter: Nega Ali Goji, M.D., University of Rochester Medical Center, Rochester, NY

If a pandemic influenza strain was identified, it would likely take several months to make a vaccine against it, and stimulating protective immunity with the vaccine would likely require more than one dose. Giving people two doses of H5N1 influenza vaccine as a pandemic is evolving would be logistically difficult, however, so researchers have been urgently investigating alternative strategies.

One such alternative is to prime people ahead of time with a related vaccine so that only a single dose of vaccine is required when the pandemic emerges. A team of researchers led by University of Rochester Medical Center investigators Nega Ali Goji, M.D., and John J. Treanor, M.D., recently tested this hypothesis. They compared the immune response to a single 90-microgram dose of one variant of avian flu vaccine in two groups of adults: those who had received a different variant of H5N1 avian flu virus vaccine some eight years earlier and those without pre-exposure to any H5N1 virus or vaccines.

In late 1997-98, soon after the first case of direct bird-to-human transmission of an H5N1 flu virus occurred in Hong Kong, NIAID funded the production of an experimental vaccine made from the Hong Kong virus and tested it in a small clinical trial conducted at the University of Rochester in healthy adults (see reference). Thirty-seven individuals who received two doses of the Hong Kong H5N1 vaccine in that trial served as the “primed” population in the current study.

The booster dose in the current study — an experimental inactivated H5N1 virus vaccine produced for NIAID by sanofi pasteur, the vaccines business of the sanofi-aventis Group of Paris — is based on an H5N1 flu virus from Vietnam. The Hong Kong virus is related to the Vietnam virus but belongs to clade 3, which refers to its branch on an evolutionary tree of the H5N1 viruses in Asia, while the Vietnam virus belongs to clade 1.

In their trial, the Rochester team found that more than twice as many of the individuals who had received the priming dose of clade 3 H5N1 vaccine responded with substantial antibody levels to a single dose of clade 1 H5N1 vaccine than did those with no prior H5N1 exposure. Dr. Treanor says that these early but promising data indicate that priming with an antigenic variant vaccine before a pandemic occurs may be one strategy used to help control a pandemic.

“These preliminary findings need to be confirmed in larger studies, but they offer the intriguing possibility that pre-pandemic priming with existing H5N1 vaccines may boost the immune response to a different H5N1 vaccine tailor-made years later to thwart an emerging human influenza pandemic,” says Dr. Fauci.

Third Dose of Intramdermal H5N1 Vaccine Well-Tolerated but does Not Improve the Immune Response

Presentation Time: Late-Breaker Session, Friday, Oct. 13, 2006, 5:15 p.m.
Presenter: Shital M. Patel, M.D., Baylor College of Medicine, Houston, TX

Previous studies have suggested that lower dosages of seasonal flu vaccine given intradermally may work as well as higher dosages of the same vaccine given intramuscularly, enabling public health officials to “stretch” available doses of vaccine in a time of shortage. To test this principle with an H5N1 pandemic flu vaccine, NIAID initiated a vaccine trial to compare immune responses generated by an H5N1 vaccine given by the intradermal or the intramuscular route. The H5N1 vaccine formulations were produced for NIAID by sanofi pasteur.

Wendy Keitel, M.D., Shital M. Patel, M.D., and their Baylor College of Medicine colleagues conducted the trial. Results of their initial two-dose study among 100 participants indicated that antibody responses among volunteers given 3 or 9 micrograms of vaccine intradermally were similar to the antibody responses seen among volunteers given 15 micrograms intramuscularly: 4 percent, 5 percent, and 12 percent of volunteers, respectively, had a significant increase in antibody levels after two doses. Those given 45 micrograms by the intramuscular route, however, showed a significantly higher response rate: 56 percent of volunteers in this group responded.

In the current study, the Baylor team enrolled 77 healthy adults between the ages of 18 and 40 who had previously received two doses of the same vaccine one month apart and gave them a third dose of vaccine 6 months later to see if it boosted their antibody response. The participants, again divided into four groups, received either 3 or 9 micrograms intradermally or 15 or 45 micrograms intramuscularly. The dosages of vaccine were limited by the formulations available.

According to Dr. Patel, a quarter or less of the participants in the study groups given the vaccine intradermally or intramuscularly at 15 micrograms had a significant antibody response after the third dose, while nearly two-thirds of the volunteers in the group that received 45 micrograms intramuscularly had a similar response. For each dosage by either route of administration, the results show that giving a third dose of the vaccine 6 months later increased antibody titers to levels similar to those achieved after the first two doses.

“This small pilot study demonstrates that multiple doses of an inactivated H5N1 vaccine given by either the intradermal or the intramuscular route are safe and well tolerated,” says Dr. Fauci. “It also provides a strong rationale for testing higher dosages of H5N1 vaccine given intradermally.” Plans are under way to directly compare the immune responses generated by vaccinating either into the skin or into the muscle with an H5N1 vaccine containing higher levels of the same amount of antigen.

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (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. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.