Bypassing HIV’s ‘decoy zone’

GHENT, Belgium—In an effort to develop a third generation of AIDS vaccines, Algonomics has been selected to partner with the International AIDS Vaccine Initiative (IAVI) to modify an HIV protein in order to improve immune responses elicited by vaccine candidates that include the protein as an insert. Algonomics was chosen, says company CEO Phillipe Stas, because it has technology that will be useful in AIDS vaccine development by "scrapping off" parts of the Gag protein that have prohibited it from being protective as an AIDS vaccine.

In its natural state, the HIV Gag protein has not generated immune responses that are sufficient to keep HIV in check in the body. By modifying the protein in a rational way using its patented Epibase screening tool, Algonomics hopes to provoke the immune system to develop stronger and more effective responses.

The Epibase tool is currently widely applied for the immunogenicity screening and optimization of biotherapeutics, such as therapeutic antibodies, biosimilars and vaccines, Mr. Stas notes. The computer-based platform focuses on T-cell epitope identification and estimates to what extent a given therapeutic protein may lead to an immune response in patients. The uniqueness of Epibase resides in its capability to identify the T-cell epitopes specific for HLA types covering most of the human population, including Caucasian, Asian, African and Hispanic, extending to the majority of HLA sub-types for which little or no experimental data is available.

All therapeutic proteins show some level of immunogenicity, a side effect where the patient recognizes the drug as a foreign substance. This causes the patient's immune system to mount a defense against the therapeutic drug, resulting in significant reduction of efficacy and a rapid clearance of the drug from the circulation. The process is driven by the presence of T-cell epitopes in the protein—fragments binding to HLA receptors and inducing a T-cell response.

Explaining how and why her organization chose to collaborate with Algonomics, IAVI's director of new alliances Dr. Hansi Dean says, "We apply several different criteria. Technology must be very innovative and address a question of critical importance. Beginning in the pre-proof-of-concept stage where there is higher risk, a program must demonstrate results in 12 to 18 months." IAVI's boasts an extensive research and development infrastructure, which includes a network of labs worldwide, three consortia comprised of leading AIDS researchers and a network of state-of-the-art clinical research centers and supporting programs. Dr. Dean notes that her organization's day-to-day role depends on the specific project but that it frequently provides scientific input and expertise to partners who are new to HIV research.

"Emerging data based on the natural response of long-term non-progressors suggests that they have cellular immune responses targeted toward the conserved region of the protein that generates T-cell responses," Dr. Dean observes. Conversely, when a vaccine is injected that targets the variable region of the virus it fails to be knocked out. "Our goal is bypass the 'decoy zone' of the virus," Stas states.

A vaccine that protects against HIV infection will most likely need to stimulate both arms of the immune system, generating both neutralizing antibodies and cellular immune response. To date, no vaccine candidate to date has been able to generate an effective and robust T-cell response that reduces viral load or protects against HIV infection. The redesign of the HIV gag protein is expected to result in a broader immune response against the protein.

If this project succeeds, additional HIV proteins used in HIV vaccine candidates will be considered for modification to further optimize immune responses.

The project is being funded through IAVI's Innovation Fund, targeted primarily to small- and medium-sized biotechnology companies. The fund finances nascent technologies that could help solve some of the main technical and scientific hurdles facing AIDS vaccine science and ultimately lead to the development of novel candidates. The fund has an initial three-year commitment of $10 million, half of which will be financed by a $5 million grant to IAVI from the Bill & Melinda Gates Foundation.