Bioterrorism Threat Rekindles Vaccine Research: Current Studies at IITRI Target Avian Influenza and Smallpox

Biodefense is changing the vaccine development picture. The national emphasis on biodefense in the last six or seven years includes government support of vaccine development, which is encouraging pharmaceutical companies to renew their efforts in this area.

"What's happening now is that, because of bioterrorism concerns, as well as avian influenza, we're starting to see a need for additional vaccines," says Louis E. Holland, II, Ph.D., manager of IITRI's Microbiology and Molecular Biology Division. "The government is showing renewed interest in fostering vaccine development." In two programs supported by the National Institute of Allergy and Infectious Diseases (NIAID), IITRI is conducting research on the safety and efficacy of vaccines against avian influenza and smallpox.

Smallpox Vaccines Use Attenuated Virus

The first study, "Evaluation of Candidate Smallpox Vaccines in Immune-Deficient Mouse Models," will assess the safety and immune-response potential of candidate vaccines. Strains of mice bred to lack natural immunity will be used as the test system. At various time points following administration of the vaccine, the treated mice will be monitored for adverse reactions and blood level concentrations of live virus.

The smallpox vaccines under evaluation use various strains of live vaccinia virus, an attenuated, "pox"-type virus related to smallpox. "Through serial passaging in laboratory conditions, variants of vaccinia have been selected that trigger the same immune response as smallpox, but lack the same pathogenicity as the true wild type," Dr. Holland explains. "With an attenuated virus, you get some virus growth in the test system, so you develop an immune response, but you don't develop the pathogenic response, or the pathogenic response is substantially reduced." Performed in IITRI's restricted biosafety level 2 (BSL-2) laboratories, this study will weigh the safety of the candidate vaccines against their ability to induce an immune response.

Avian Influenza Vaccine Uses Subunit Approach

The second contract, "Influenza A H5N1 Inactivated Subunit Vaccine Repeat Toxicology Study in Rabbits Following Three Intramuscular Administrations," will examine immune response endpoints following vaccine administration. The vaccine uses selected proteins from the H5N1 virus, the strain responsible for the deadly form of avian influenza.

Rather than using the actual virus, a subunit vaccine works by administering only those viral proteins that are responsible for causing an immune response. "Upon administration of the vaccine, the host is exposed to the specific immunogenic proteins without any actual virus infection occurring," Dr. Holland explains. "With this approach, you eliminate the concern of what happens when the virus replicates. You have less worry of disease, but the down side is that the subunits may not give you as complete an immune response as you need," Dr. Holland says. This study will help researchers determine whether the experimental vaccine provides sufficient protection against the disease.

Vaccine Development Rises from Plateau

In the two decades prior to the biodefense push, vaccine development was on the decline. Vaccines for many common infections, such as mumps, measles, rubella, small pox and polio, were already available. Those viruses are relatively stable in genetic terms. "In those cases, you have the right virus materials to use as either an inactivated or an attenuated strain which can induce a good immune response and be very effective in preventing subsequent infections," Dr. Holland says. Diseases that had been affecting much of the population were under control. Thus, the market shrank dramatically, as did the profit margin for companies investing in vaccine development.

Diseases that continued to afflict the population presented a more daunting challenge to vaccine developers. Pathogens such as human immunodeficiency virus (HIV), for example, are highly variable and change dramatically during their replication. "It is extremely difficult to generate a vaccine against a virus that is constantly mutating to that degree at that rate," Dr. Holland says. The common cold has remained similarly elusive, but for a different reason. In this case, many different viruses cause the same condition, making the development of an effective vaccine, thus far, impossible.

Potential liabilities further discouraged pharmaceutical companies from pursuing vaccine development. When the threat of target diseases receded as a result of routine vaccination, occasional adverse reactions to the vaccines overshadowed their health benefits in the popular mind, deterring businesses from continuing in this area.

Due to current national health and safety concerns, the demand for vaccine development is again on the rise. Government agencies are increasing funding for research and considering measures to limit risk for private companies. "There's a push now to try to get some legislation that may limit the liability to some extent," Dr. Holland says, "which will encourage companies to start moving back in the direction of vaccine development."

IITRI Combines Symbiotic Capabilities

IITRI is uniquely qualified to support government and commercial sponsors in their vaccine development efforts. IITRI is one of a limited number of testing facilities that combines expertise in toxicology, virology, immunology and bacteriology together in the same building. In addition, Dr. Holland explains, "IITRI is one of only a few laboratories in the country that is capable of performing aerosol studies; and with the recent completion of our new biosafety level 3 facility, we can conduct aerosol studies using highly pathogenic bacteria and viruses." These studies include the assessment of experimental drugs or vaccines intended for aerosol administration, as well as research involving aerosol challenge with infectious pathogens. Dr. Holland points out that "being able to couple our staff's varied expertise with the ability to perform aerosol studies provides us with unique capabilities to assist government organizations or industrial groups that are involved with vaccine development."