Anthrax Vaccine Moves Into Clinical Trials

By Karen Fleming-Michael
Special to the American Forces Press Service

FORT DETRICK, Md., July 9, 2003 - The next-generation anthrax vaccine, based on a decade of work at the U.S. Army Medical Research Institute of Infectious Diseases, is now moving into not one, but four clinical trials.

The group at the institute did the legwork for the current vaccine candidates by singling out which protein in Bacillus anthracis - the bacterium that causes anthrax - signals the body to produce immunity to the disease.

Early studies established definitively that the protein called "protective antigen" was just the component the vaccine would require, said Dr. Arthur Friedlander, a senior scientist at USAMRIID who directed the group's long- term effort. After discovering the protein, researchers took the gene that codes for protective antigen and used recombinant DNA technology to try to produce the protective antigen in three expression systems: bacteria, yeast and viruses.

Ultimately, the team found bacteria was the best for producing the protein, and decided to grow the protective antigen in a non-disease causing strain of B. anthracis. The resulting recombinant protective antigen, or rPA, should provide a high degree of safety in a vaccine because it's just one building block, a single protein of the organism that can produce an immune response.

Researchers then proved it was effective in the best animal model available, the non-human primate. "What we did was identify it, purify it to a very high degree and showed that this protein by itself was protective in the most relevant animal model of human inhalational anthrax," Friedlander said.

To date, two clinical trials that use the B. anthracis- based rPA are underway. VaxGen, based in Brisbane, Calif., started its clinical trials at Baylor College of Medicine, Texas; Emory University School of Medicine in Atlanta; Johns Hopkins University in Baltimore and Saint Louis University Health Sciences Center. The test is under a contract from the National Institute of Allergy and Infectious Diseases.

In a collegial effort, the National Institute of Allergy and Infectious Diseases, USAMRIID and the Joint Vaccine Acquisition Program have undertaken a Phase I clinical trial at the University of Maryland using a version of the original USAMRIID formulation manufactured at the National Cancer Institute Frederick, Md.

The University of Maryland trial will help advance the development of the other vaccines, said Dr. Lydia Falk, director of the Office of Regulatory Affairs, in the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases.

"We can begin to compare the responses we see in humans to what had been observed in animals," she said. "That's a critical part of the development of these vaccines. The more preliminary investigative work that we can do, the more it benefits the entire field. Our hope is that the information we gain will be able to add to those building blocks that would lead to an accelerated development plan."

The formulation being used in that trial won't be pushed toward Food and Drug Administration licensing. "The product that is available and the one that was used during USAMRIID's preclinical studies had the rPA protein in one tube and an aluminum adjuvant in another tube, and before you injected it, you mixed the two," Falk said. "That's not an easy formulation to take to licensure." However this trial design will determine the value of including an adjuvant in the final vaccine formulation.

Two companies are currently using rPA grown in E. coli to create their next generation anthrax vaccine candidates. An rPA vaccine from the UK-based Avecia, under a contract with the National Institute of Allergy and Infectious Disease, will soon start Phase I clinical trials.

The second company, Dynport Vaccine Company, LLC, which licensed its rPA product from Avant, began its Phase I clinical trial April 28. The trial is being conducted by the Henry M. Jackson Foundation in Rockville, Md., which routinely pursues vaccines for HIV for the military.

Because the foundation had an HIV vaccine candidate that used rPA as one of its two components "we decided to reprioritize our activities and commit to evaluating this protective antigen after the anthrax mail attacks in October 2001," said Dr. Merlin Robb of the Henry M. Jackson Foundation, the principal investigator for the foundation's clinical trial. "(The rPA) was ready to go into humans to evaluate it for an anthrax indication. We sensed that it was a higher national priority."

Although the rPA vaccines are on an advanced development path toward Food and Drug Administration licensure, USAMRIID scientists still lend their expertise to vaccine manufacturers and the National Institute of Allergy and Infectious Diseases.

"Their contributions can't be overstated," said Dr. Ed Nuzum, the project officer providing technical oversight for the two National Institute of Allergy and Infectious Diseases contracts with Avecia and VaxGen. "Because of the work done at USAMRIID, as well as its counterpart in the United Kingdom, the Defence Science and Technology Laboratories, the rPA-based vaccine candidates are the most advanced second generation anthrax vaccines."

USAMRIID's early development work regarding animal studies and assay development will also be critical for developing animal models for Food and Drug Administration approval under the "Animal Rule." The rule, effective in July 2002, permits use of data from animal studies when efficacy studies of new drugs or biological products against chemical, biological, radiological or nuclear substances in humans is impossible because of the rarity of the disease or because human exposure to potentially lethal agents, like anthrax, is unethical.

"This is the first test case of the concept of licensing a vaccine based on animal efficacy data and trying to correlate that with the human immune response," Friedlander said.

Nuzum said he thinks the rPA vaccines are potentially the best vaccines to be going forward for licensure under the animal rule largely because of the work done at USAMRIID and DSTL. "The data, models and assays really are essential to the foundation for the work we're doing now," he said.

Editor's note: Fleming-Michael is a reporter at Fort Detrick.

	Dr. Arthur Friedlander, left, and his team at the U.S. Army Medical Research Institute of Infectious Diseases helped establish that the protein called "protective antigen" in Bacillus anthracis causes the body to produce an immune response. Photo by Larry Ostby.
	High resolution photo.