H5N1 vaccine trial shows limited benefit

Mar 30, 2006 (CIDRAP News) – The first experimental US vaccine for H5N1 avian influenza yielded only modest results in its first clinical trial, generating an adequate immune response in slightly more than half of participants who received a heavy dose, scientists report.

Fifty-four percent of volunteers who received two doses totaling a dozen times the standard dose of seasonal flu vaccine had an immune response that was considered protective, according to the report in today's New England Journal of Medicine. Those who received smaller doses were less likely to show an adequate immune response.

On the positive side, the vaccine triggered almost no serious side effects, even at the highest doses. The results are in line with some preliminary findings reported last summer.

But the findings underscore the huge gap between existing vaccine production capacity and the likely need for vaccine in a pandemic. In an editorial accompanying the report, vaccine expert Dr. Gregory Poland of the Mayo Clinic writes that all the world's vaccine producers could make only enough of the vaccine for about 75 million people if the high dose that yielded best results in the study were used.

"We have a long way to go," commented Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), as quoted by the Associated Press. The NIAID funded the vaccine trial.

The trial was conducted last year at NIAID-supported centers at the University of Rochester in New York state, the University of Maryland School of Medicine in Baltimore, and Harbor–University of California–Los Angeles Medical Center in Los Angeles. John J. Treanor, MD, of the University of Rochester was the first author.

The vaccine is based on an H5N1 virus isolated from a Vietnamese patient in 2004. The hemagglutinin and neuraminidase genes from that virus were spliced together with genes from another flu virus strain commonly used in vaccines, the report says. In addition, the hemagglutinin gene was modified to make it harmless to birds so the virus could be grown in eggs. The vaccine was made by Sanofi Pasteur, but the company was not involved in the study.

The researchers recruited a total of 451 healthy adult volunteers. They were randomly assigned to receive a placebo or one of four doses of the vaccine: 7.5, 15, 45, or 90 micrograms (mcg). Each volunteer received two doses, the second one 28 days after the first.

The study was done in two stages, the first one involving 118 volunteers. After they received their two doses and monitoring showed no safety concerns, the other 333 volunteers were vaccinated in the second stage.

The researchers used a neutralizing antibody titer of 1:40 (signaling a fourfold or greater increase in antibody titer) as the criterion for an adequate immune response. Of the 99 volunteers who received the 90-mcg dose, 54% reached this level (95% confidence level, 43% to 64%). Smaller percentages of volunteers in the lower dose-groups had this level of immune response: 43% in the 45-mcg group, 22% in the 15-mcg group, and 9% in the 7.5-mcg group.

The volunteers reported few significant side effects, according to the report. They described 84% of symptoms as mild, and there were no serious allergic reactions. Systemic symptoms such as fever and headache were not significantly more common in the vaccine groups than the placebo group. One volunteer suffered a rash, which faded after a few weeks.

The results indicate that two 90-mcg doses of the vaccine "would probably have an acceptable tolerability profile and could be effective in preventing H5 influenza in healthy adult recipients," the authors write. "Elderly people, persons with impaired immunity, or children may have a different response, and trials of the vaccine in these populations are in progress.

"Production of the vaccine and this clinical trial are important steps toward control of a pandemic, and the current vaccine would probably be acceptable for licensure, if needed. However, the need for a vaccine with a total dose of 180 micrograms would pose a considerable barrier to rapid production of a supply that would be adequate to meet the world's requirements should a pandemic occur. Therefore, dose-sparing approaches should be pursued aggressively."

In the editorial, Poland says the results show that the immunogenicity of the vaccine is "poor to moderate at best." He adds that current annual global production capacity for flu vaccine is estimated at 900 million 15-mcg doses. This means that, at a dose level of 180 mcg, only 75 million people, or 1.25% of the world population, could be fully immunized with the H5N1 vaccine, and only about half of them would actually have protection.

In addition, Poland comments that the vaccine might not be effective against more recent strains of H5N1 virus. Researchers have identified an Indonesian clade, or subgroup, of H5N1 viruses that differs antigenically from the Vietnamese clade on which the vaccine is based. The US government recently announced plans to develop a vaccine based on the Indonesian strain of H5N1 virus, called clade 2.

Infectious disease expert Michael T. Osterholm, PhD, MPH, said the study was well-designed and yielded important information. "Unfortunately, that information supports our earlier concerns that both the antigen requirements and the immunogenicity of an H5N1 vaccine mean that if H5N1 becomes the next pandemic strain in the next several years, vaccine will play a limited or almost nonexistent role in such a pandemic worldwide," Osterholm told CIDRAP News.

As he has before, Osterholm called for a "Manhattan Project–like investment" to develop a flu vaccine that could be produced before the emergence of a pandemic train. He is director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of the CIDRAP Web site.

Poland comments in his editorial that the government has funded studies of more than 30 candidate vaccines for potential pandemic flu strains. These include vaccines with adjuvants (immune-boosting chemicals) to increase potency and live, attenuated vaccines, which could provide cross-protection against different viral subtypes.

The study authors write that other possible dose-sparing approaches under consideration include injecting vaccine just under the skin (intradermally) instead of into muscle and "prepriming" the immune system by including an H5 component in the annual flu vaccine.

Despite the limitations revealed by the study, flu vaccine expert Dr. William Schaffner of Vanderbilt University said the vaccine represents progress. "My impression is we are better off having stockpiled this vaccine than none," he told the Associated Press. He added that the vaccine should be viewed as "the first strong step in a long journey."

Treanor JJ, Campbell JD, Zangwill KM. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 2006 Mar 30;354(13):1343-51 [Full text]

Poland GA. Vaccines against avian influenza—a race against time (editorial). N Engl J Med 2006 Mar 30;354(13):1411-13 [Full text]

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