Robert Roos - News Editor

Nov 11, 2008 (CIDRAP News) – A vaccine designed to offer protection against many strains of influenza viruses appeared safe in low doses and triggered a satisfactory immune response in a phase 1 clinical trial, the vaccine's developer announced recently.

The vaccine, made by VaxInnate Inc., Cranbury, N.J., targets the M2 protein of influenza A viruses, a surface protein that differs little among different strains of type A. Existing flu vaccines target hemagglutinin (HA), a flu surface protein that often mutates, making it necessary to change the vaccine each year to cover the predominant strains in circulation. A vaccine targeting a protein found in all or most flu strains could reduce or eliminate the need to change the vaccine each year.

The company reported the results in an Oct 26 press release and at the Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America (ICAAC/IDSA) meeting, held Oct 24-28 in Washington, DC.

"VaxInnate's M2e universal flu vaccine candidate has passed a critical initial test," David Taylor, MD, the company's chief medical officer, said in the news release. "We're encouraged by these data, which demonstrate that the vaccine is safe and elicits potent immune responses at doses below a microgram [mcg] of vaccine antigen, and does so without the use of conventional adjuvants."

Fewest events at lowest doses
The phase 1 trial was a double-blind study designed to test the safety and immunogenicity of four different doses of the vaccine: 0.3, 1, 3, and 10 mcg. It was conducted in Galveston, Tex., and Lenexa, Kan.

In the trial, 60 healthy volunteers between the ages of 18 and 49 received one of the four doses or a placebo in two injections 28 days apart, the company reported. Safety was assessed 1 and 7 days after immunization, and immune response was examined 7, 14, and 28 days after each dose. Seroconversion was defined as a serum IgG and anti-M2e antibody value of at least 0.174 mcg per milliliter and a fourfold increase in antibody titer.

The two lowest doses were safe and well-tolerated in all the volunteers; they yielded an immune response in 18 of 24 volunteers after the first dose and in 23 of 24 after two doses, VaxInnate said. However, the two highest doses "were associated with the presence of flu-like symptoms in some of the subjects."

"Given the strength of the antibody responses and the absence of significant adverse reactions at the two lowest doses (0.3 and 1.0 mcg), VaxInnate intends to continue development and clinical evaluation of the vaccine candidate at doses of 1.0 mcg and less," the company said.

Christine Turley, MD, primary investigator in the study, said in the release that the results for the two lowest doses "suggest that the M2e vaccine candidate could be a promising and much-needed new option for prevention or attenuation of influenza A disease." She is director of clinical trials and clinical research in the Sealy Center for Vaccine Development, University of Texas Medical Branch (UTMB), Galveston.

The vaccine consists of the ectodomain of the M2 protein, fused to flagellin, a bacterial protein. The company uses recombinant bacteria to produce the vaccine, a technique that the company says is faster than conventional egg-based production or cell-culture production.

Flagellin interacts with the immune system's toll-like receptors, which serve in human immune cells as sentries to detect pathogens and mount a general defense, according to VaxInnate. This initial defense stimulates an adaptive immune response that includes production of pathogen-specific antibodies, the company said.

'Encouraging but not definitive'
Dr. Kristin Nichol, an experienced flu immunization researcher who was not involved with the study, described VaxInnate's results as promising but advised a wait-and-see attitude. She is associate chief of staff for research at the Minneapolis VA Medical Center.

"The notion of a universal influenza vaccine or any kind of influenza vaccine that reduces the need for annual vaccination or provides better or more reliable protection against influenza viruses—that will be very useful to us," she said. "Until a vaccine goes all the way through phase 3 clinical trials and we have good evidence about actual protection, the verdict is out. But certainly there are a number of kinds of vaccines in development, such as this one, that are exciting with regard to the prospect of a more universal kind of vaccine."

Nichol said the measures of immune response used by VaxInnate are reasonable and generally correlate with actual protection, but do not guarantee it. "It's encouraging but not definitive until we see the clinical protection data," she said.

Plans for targeting type B
The M2e vaccine targets influenza A but not influenza B, the other major type. Type A viruses generally cause more severe illness than type B. Seasonal flu vaccines normally target two type A subtypes—H1N1 and H3N2—and one type B strain, all of which typically circulate each season.

While acknowledging that the M2e vaccine would not cover type B viruses, VaxInnate's Taylor told CIDRAP News that the company also hopes to develop a second-generation universal vaccine that would target both A and B. Meanwhile, he suggested possible uses for the M2e vaccine by itself, assuming it is successful.

"Should M2e be shown to be protective for influenza A, it’s possible that other universal antigens could be developed for influenza B," Taylor said in an e-mailed statement. "In the developing world, where influenza vaccine is not available, M2e could be a cost-effective way to provide influenza A coverage.

"VaxInnate is working to develop a second-generation universal vaccine that has M2e and another conserved antigen that will address influenza B strains, as well as influenza A strains. Efficacious universal vaccines for influenza that cover both A and B strains could potentially replace the more standard HA vaccine in some markets and market segments, even in the developed world."

Taylor also said that in countries where conventional seasonal flu vaccines are available, the M2e vaccine could be used in combination with them to provide increased protection in case the strains in the seasonal vaccine don't match well with circulating strains.

He also commented that VaxInnate is developing seasonal flu vaccines in which its recombinant-bacteria technology is used to make both the A and B components. A vaccine targeting a Solomon Islands strain of H1N1 is currently in clinical testing, and a type B vaccine may become available next year, he said.

The Bill and Melinda Gates Foundation supported the M2e vaccine trial with a $9.5 million grant to UTMB to improve control of flu in the developing world, the company said.