Vical Plans Clinical Testing of Anthrax Vaccine by Year-End 2003

SAN DIEGO -- Vical Incorporated announced today that the company intends to begin human testing of an anthrax DNA vaccine by year-end 2003.

Vical, in collaboration with Ohio State University (OSU), has demonstrated effectiveness of DNA vaccine formulations in protecting rabbits against lethal inhalation challenge with aerosolized Bacillus anthracis. This research has been supported, in part, by a grant from the U.S. National Institute of Allergy and Infectious Diseases (NIAID), as announced in July 2002. In addition, Vical has submitted an application for a Phase II Small Business Innovation Research (SBIR) grant to support, in part, the clinical development of the vaccine.

"Anthrax has been identified as a leading bioterrorism agent," said Vical's president and CEO, Vijay B. Samant, "and the recognized shortcomings of the currently licensed anthrax vaccine make development of an alternative vaccine an attractive opportunity for Vical. We believe that approval of this vaccine would be based on the FDA's two-animal rule, which requires demonstration of effectiveness in two animal species in addition to safety in humans, and that development costs using this regulatory pathway should be moderate compared with conventional clinical trials."

Vical's chief scientific officer, David C. Kaslow, MD, said, "Our anthrax vaccine team advanced this program from initial concept to evaluation of effectiveness in a stringent challenge model in less than 10 months, and held a pre-IND meeting with the FDA in December 2002. Results with multiple formulations of the vaccine in murine and rabbit challenge models have been encouraging and we intend to begin a safety and immunogenicity study in human volunteers before year-end 2003. Based on demonstrated protection in a rabbit challenge model," added Kaslow, "we believe that we can develop a safe and effective DNA vaccine for anthrax that will validate the potential advantages of our proprietary vaccine technologies while addressing a pressing public need."

Kaslow continued, "First, the key anthrax immunogens have been identified, and we have verified in small animal studies that they can be delivered effectively by formulated DNA. Our technology allows us to readily combine two immunogens, Protective Antigen (PA) and Lethal Factor (LF), that together may provide broader protection than the currently licensed anthrax vaccine or proposed single recombinant protein vaccines. Second, our cationic lipid formulated DNA delivery technology has established an excellent safety profile in previous clinical studies, and an important goal of this program is to extend that safety profile to vaccine applications. Third, another important goal of this program is to demonstrate that DNA vaccines can induce protective antibodies in humans and can do so with fewer injections than the currently licensed vaccine, offering a potentially shorter time to protection; and finally, the potential stability of plasmid DNA formulations may offer advantages in handling and storage, which would be important considerations for stockpiling."

Vical scientists developed formulated DNA vaccines encoding detoxified forms of two proteins produced by anthrax bacteria, Protective Antigen (PA) and Lethal Factor (LF), that combine to form lethal toxin (Letx), which contributes to the morbidity and mortality of anthrax. The vaccine formulations were tested in mice for their ability to produce anti-PA, anti-LF, and Letx-neutralizing antibodies.

In collaboration with OSU, selected formulations were then tested for immunogenicity in rabbits. Groups of rabbits including vaccinated and control animals then were challenged by metered inhalation with aerosolized anthrax spores using established procedures at Battelle Memorial Labs, and observed for lethal anthrax infection. Effectiveness data from this small animal testing are being presented today at the American Society for Microbiology (ASM) meeting, "Future Directions for Biodefense Research: Development of Countermeasures," in Baltimore, Md.

Results from the rabbit study for cationic lipid formulated DNA vaccines indicated that:

-- All PA DNA vaccine formulations stimulated anti-PA immune responses

equal to or greater than the currently licensed vaccine;

-- All rabbits immunized with PA DNA vaccine formulations, either alone

or in combination with LF DNA vaccination, survived the inhalation

challenge, indicating protection equivalent to the currently licensed

vaccine;

-- All unvaccinated control rabbits died two to four days after

challenge, validating the study procedures and confirming the severity

of inhalation anthrax infection; and

-- LF DNA vaccination stimulated anti-LF immune responses and, even when

used alone, provided rabbits with partial protection against the

inhalation challenge, suggesting a potential second means of

protection and supporting its inclusion as a component of a bivalent

anthrax vaccine candidate advancing into human testing.

"Our research efforts to date have been encouraging and our path forward is clear," noted Kaslow. "With appropriate guidance from FDA on the new two-animal rule, effectiveness testing could potentially be accomplished using accepted animal challenge models without the expense or ethical difficulties of conducting large clinical efficacy trials in humans before market approval."

Anthrax is a serious infectious disease most frequently occurring in hoofed mammals, but also affecting humans exposed to the spore-forming Bacillus anthracis. Bacterial spores can survive for extended periods and become active upon gaining access to a host. Human infection with anthrax spores can occur after exposure through a cut or abrasion on the skin or through ingestion of contaminated meat, but the most serious risk is through inhalation.

Inhalation anthrax results in death for 90 percent to 100 percent of those exposed, if not treated promptly. Symptoms typically appear within a week of exposure, and may be misdiagnosed as a common cold or flu. Bacterial spores travel from the lungs to the lymph nodes, where they begin to grow. Eventually, they spread into the circulatory system and throughout the body, causing widespread internal bleeding and organ failure. People who work with animals or process animal products are at greatest risk of naturally acquired infection. The greatest potential threat for most people is the inhalation of anthrax spores used in biological warfare or in a bioterrorist attack.

The toxic effects of anthrax infection are the result of three proteins produced by the bacteria: edema factor (EF), lethal factor (LF) and protective antigen (PA). PA couples with either EF or LF and allows these toxins to penetrate and kill host cells, releasing large numbers of bacteria into circulation.

In a review of the currently licensed anthrax vaccine, the Institute of Medicine (IOM) of the National Academy of Sciences concluded, "the production, testing and licensure of a new vaccine requiring fewer doses and producing fewer local reactions is needed." (1) Treatment for proven or suspected anthrax infection involves a long course of antibiotic therapy beginning as soon as possible after diagnosis or suspected exposure. Antibiotics used against anthrax work by killing the bacteria to prevent further production of the toxic proteins. They do not eliminate proteins that accumulate before treatment, and do not offer residual protection against infection after the treatment course has been completed.

(1) Institute of Medicine. An Assessment of the CDC Anthrax Vaccine

Safety and Efficacy Research Program. Washington, DC: National

Academy Press, 2002.

Source: Vical Incorporated

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