November 1, 2008 (Vol. 28, No. 19)

Genocea Biosciences Focuses on the Rapid and Accurate Identification of Antigens

Big pharmaceutical companies generally shy away from vaccine development because it takes even longer to take new vaccines to market than it does new drugs. Also, profits tend to be lower on vaccines.

Genocea Biosciences a biotechnology startup in Cambridge, MA, has created a novel, high-throughput technology to speed the discovery of new vaccine antigens. The company focuses on vaccines for diseases caused by intracellular pathogens, such as chlamydia, malaria, and tuberculosis, which are not readily detected and destroyed by the immune system. The two-year-old company, whose name refers to its ability to screen an ocean of genes, has caught the attention of the global vaccine industry.

Genocea won the “Best Vaccine Startup” award at the World Vaccine Congress in April. A panel of international judges chose Genocea from more than 60 entries, based on the strength of its technology and pipeline and the reputation of its staff.

Then, in June, Genocea announced a collaboration to find a better vaccine to fight Streptococcus pneumoniae (pneumococcus) with PATH, an international, non-profit group that seeks solutions to improve world health. Although current vaccines are highly effective in preventing pneumococcus, the leading cause of death in children younger than age five, better vaccines that cover all pneumococcus serotypes are needed to protect children worldwide.

No Gene Unturned

Genocea’s high-throughput discovery platform identifies antigens for any pathogen in just a few weeks. Each antigen is rapidly screened against libraries of T cells known to provide protection. By identifying the best antigens early in the process, researchers can save years and millions of dollars in research costs.

Darren Higgins, Ph.D., a molecular geneticist at Harvard Medical School and scientific founder of Genocea, spent 10 years perfecting the technology. The platform screens every protein in a pathogen’s genome for its capacity to invoke an immune response.

“Our platform is a full-proteome unbiased way to let the human immune system tell us what’s causing the immunogenic response,” says Robert Paull, CEO and cofounder of Genocea in 2006.

Almost all approved vaccines on the market target B cells that make antibodies. In contrast, Genocea focuses on killer and helper T-cell responses, which are particularly suited for seeking and suppressing hidden intracellular pathogens that escape antibody detection. Intracellular pathogens often cause prolonged, debilitating infections, rather than rapidly killing infected victims.

“Genocea’s technology is best suited for going after intracellular pathogens that previously were intractable to work on for vaccine development,” Paull says.

The company is building a pipeline for new types of vaccines for infectious agents that previously stumped pharmaceutical companies. The platform can also be used to find antigens associated with cancer cells or autoimmune disorders.

The high-throughput screening system removes the guesswork involved in designing vaccines. The speed of the technology allows researchers to produce, express, and target all of the hundreds or thousands of proteins in a pathogen to test as potential antigens.

This thoroughness of screening differentiates Genocea from other groups who rely on bioinformatic or in-silico screens to detect sets of outer membrane or other key proteins based on past experience. Genocea’s approach leaves no gene unturned. “Sometimes we find proteins of unknown function that ultimately are the ones you want to use in a vaccine,” says Paull. The best targets can be combined to produce multivalent vaccine formulations to test in animal models.

Overall, the system consists of expressing all genes of a pathogen in E. coli to build a library of all possible antigens. Blood samples are then collected from people infected with that pathogen to test the antigens and select those with the highest probability of protecting humans against that disease. Finally, proof-of-concept experiments are performed in animal models to confirm immunogenicity.

Most other vaccine researchers start with mouse models and tease out mouse antigens with the hope that they will work in humans. “We flip that model on its head,” adds Paull.

A unique patented aspect of Genocea’s method includes cytolysins—a series of special proteins that are engineered to control the presentation of Class I or II major histocompatibility complexes. This immunological screening tool, when combined with the antigen libraries and human blood samples, speeds the discovery of antigens.

Breakthroughs made by Genocea in cellular immunology, in combination with the high-throughput screening platform technology for T-cell antigens, places Genocea in a class of its own for vaccine antigen discovery. Several vaccines are in the R&D stage, with one for Chlamydia trachomatis farthest along.

Chlamydia, an intracellular bacterial pathogen, is the leading cause of sexually transmitted disease worldwide. Three million Americans are infected with chlamydia each year, and 92 million cases are diagnosed worldwide yearly. Chlamydia infections can progress to infertility or blindness, and the annual healthcare costs of chlamydia exceed $2 billion in the U.S. alone. No vaccine currently exists for chlamydia.

Genocea licensed 14 antigens to chlamydia that were discovered in the laboratory of Higgins at Harvard Medical School. Studies show that T cells are critical for protecting against chlamydia, and subsequent experiments show that T cells specific for the novel antigens protect against chlamydia infections.

A vaccine for chlamydia likely will be the first to enter clinical trials in about two years, according to Paull.

The company has attracted world-class vaccine talent, including George Siber, M.D., former CSO at Wyeth Vaccines. “We’re attracting industry titans who become aware of what we’re doing,” states Paull.

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