Targeted Genetics Corp. secured added financial backing to advance its investigational viral-vector AIDS vaccine into the clinic.

The International AIDS Vaccine Initiative will provide up to $5.6 million, funding earmarked for regulatory filing and eventual Phase I trials. The partnership, which also includes the Columbus Children's Research Institute at Children's Hospital in Columbus, Ohio, began in February 2000 to develop the recombinant adeno-associated virus-based (rAAV-based) vaccine.

The Seattle-based company plans to begin clinical studies later this year to test the product's safety.

"We have made excellent progress, and we are right on track to initiate clinical trials in the second half of this year," Pervin Anklesaria, Targeted Genetics' vice president of product development, told BioWorld Today. Though she said specific trial design details are not yet complete, the studies eventually would be held in southern and eastern Africa, where the most prevalent virus subtypes are being targeted with the vaccine.

In return for its funding, the New York-based vaccine organization has stipulated that if a vaccine is successfully developed, it would be priced substantially lower in developing countries than in industrialized countries. Targeted Genetics believes its approach through rAAV lends itself to creating a cost-effective HIV vaccine.

"We believe that our vaccine is based on very sound rationale and is cost effective because the kind of immune response we can stimulate is very robust," Anklesaria said. "We get that in one shot, which in itself is cost effective. Our manufacturing process also is designed to be very scalable, and as we make improvements and scale up the process I believe we can get economics of scale and therefore reduce the cost of goods."

Targeted Genetics has developed its gene delivery approach as an alternative to protein delivery. The company has based its HIV vaccine on AAV, a small, stable virus not known to cause disease in humans despite its exposure to a majority of the population. The naturally occurring form of the virus contains only two genes, both of which are removed in developing rAAV vaccines.

"We have taken out all of the viral genes, and the only genetic information that is in there from the virus is about 145 nucleotides required for packaging," Anklesaria said. "The other pieces of the nucleotide are all pieces of the HIV virus."

Genes encoding HIV proteins are inserted into the AAV backbone and administered as a vaccine. Targeted Genetics said that once the vaccine has entered a cell and been activated, the cell is capable of expressing HIV-specific antigens and eliciting an immune response.

"In a murine model, we have demonstrated that most of the viral vaccine DNA exists as an episome; it does not integrate into the host chromosome," Anklesaria said. "It behaves very much like the plasmid, is very safe and is nonreplicating. And with a single injection, at a very reasonable dose in primate studies, we can get a very robust and sustained immune response."

Targeted Genetics said it has demonstrated protective antibody and T-cell responses against simian immunodeficiency virus (nonhuman primate form of HIV) using rAAV vaccines in preclinical studies. Delivery of SIV genes with an rAAV vector also results in decreased viral load when vaccinated animals are challenged with virulent SIV. More recent rabbit data on the preclinical evaluation of an rAAV-based Clade C HIV vaccine will be presented at the Keystone AIDS vaccine conference at the end of this month in Banff, Alberta.

Anklesaria pointed to the vaccine's preclinical safety record, its delivery in a single injection and its ability to elicit responses among T cells in the humeral arm of the immune system as advantageous over other vaccines in development.

Whitehouse Station, N.J.-based Merck & Co. Inc., in partnership with the HIV Vaccine Trials Network and Vical Inc., has entered Phase I trials in the U.S. to study a DNA and adeno-based vaccine constructed from HIV subtype B. San Diego-based Vical also is testing a DNA-based vaccine made from HIV subtype B in Phase I trials with the National Institutes of Health in Bethesda, Md. London-based GlaxoSmithKline plc, in partnership with the HIV Vaccine Trials Network, has advanced into Phase I trials a protein-based vaccine constructed from HIV subtype B.

Another protein-based approach, developed by Brisbane, Calif.-based Vaxgen Inc., has produced the only candidate to enter Phase III efficacy trials. But AidsVax B/B, which targets two strains of HIV subtype B, faired poorly in an initial assessment. The candidate did not show a statistically significant reduction in HIV infection within the study population as a whole. Specifically, the reduction of infection among the more than 5,000 volunteers from the U.S., Canada and the Netherlands who received at least three doses was 3.8 percent (p=0.76). (See BioWorld Today, Feb. 25, 2003.)

An ongoing Phase II trial, studying AidsVax B/E in 2,500 injection drug abusers in Thailand, continues in partnership with the Thai government. Results from the latter are expected late this summer or fall.

A Phase III prime-boost trial involving 15,000 Thai volunteers is not yet under way.

Targeted Genetics has run into trouble of late as well, though from the financial side of operations. Near the end of last year the company cut 67 of its 120-employee work force in an effort to extend its current operating capital for at least another year. It reported about $17 million in cash at the time. Just four months earlier, a prior round of job cuts lowered its then-175-person staff to about 120. (See BioWorld Today, Dec. 18, 2002, and Aug. 8, 2002.)

But development efforts continue in addition to the AIDS vaccine. Targeted Genetics' other gene-based products include its lead clinical product targeting cystic fibrosis to which Targeted Genetics regained full rights after its partner, Slough, UK-based Celltech Group plc, decided to terminate a four-year-old agreement. (See BioWorld Today, Dec. 8, 2002.)

While Targeted Genetics continues to focus on its HIV vaccine and cystic fibrosis programs, as well as a rheumatoid arthritis program, the company is seeking partnerships for its hemophilia and cancer programs. Targeted Genetics said more specific details on such programs would be released later this week as part of its year-end earnings report, including plans to submit regulatory filings later this year to get the rheumatoid arthritis program into clinical trials.

Targeted Genetics' stock (NASDAQ:TGEN) gained 17 cents Tuesday, or 40.5 percent, to close at 59 cents.