LifeGuide

[Treatment Horizons]

What if a preventative vaccine for humans could neutralize multiple strains of HIV and provide cross-coverage? One traditional HIV vaccine approach has been to elicit antibodies that recognize envelope proteins, proteins on the outer surface of the HIV cell that are needed for infection to occur. But these proteins vary from strain to strain, making a vaccine that is effective against one strain ineffective for another. However, interim study results from a Phase I clinical trial of the HIV vaccine formulation DP6-001, presented at the AIDS Vaccine 2005 International Conference in Montreal, suggests that headway is being made to produce an immune response against more than one strain.

“We believe the technology is a very solid one,” says Jack Barber, Senior VP of Drug Development at CytRx Corporation, which has licensed the candidate vaccine. DP6-001 is currently being researched under the guidance of principal investigator Jeff Kennedy, MD, at the University of Massachusetts Medical School, which developed the vaccine along with Advanced BioSciences Laboratories, Inc. “It’s a simple yet well-designed vaccine approach.”

Over the course of the five-injection protocol, DP6-001—as an HIV DNA + protein vaccine—addresses what might be thought of as the two branches of the immune system: the cellular and the antibody component. The first three injections, given over three different times, are composed of elements of HIV’s DNA, some of which codes for the envelope protein. (The vaccine is not derived from a live virus so there’s no chance of infection.) These DNA elements are taken up by the body’s cells, converted into envelope antigens (antibody stimulators), and presented to the immune system, which then thinks the body is infected with HIV and produces antibodies and directs T cells toward infected cells. In this case, the immune system thinks the body is infected by multiple strains of HIV for the vaccine developers “purposefully invented a cocktail of pieces of the virus, a subunit vaccine that came from multiple strains of HIV, isolated from the five major clades from throughout the world.” These injections are followed by two separate boosts with corresponding HIV envelope proteins to amplify the immune response to the envelope antigens.

Says Barber: “Historically, DNA vaccines generate very good cell-mediated immune responses, but they don’t generate good antibody responses. Conversely, protein-based subunit vaccines generate very potent antibody responses, but they don’t generate good cell-mediated responses. What the team has really done is put the two together. The hope was that we would get a good, balanced cell-mediated and antibody response.”

The vaccine was tested in three groups of healthy volunteers: Group A received the DNA vaccine under the skin; Groups B and C received the DNA vaccine intramuscularly; and Group C received a six-fold higher DNA dose compared with Groups A and B. All three groups were then boosted with the mixture of envelope protein antigen produced by the first three injections. The DNA component of the vaccine was shown to stimulate T-cell immune responses, even at its lowest dose. Protein boosting induced antibody responses comparable to the levels generated in HIV-positive individuals. Additionally, antibodies were generated to all five envelope antigens in the vaccine. Significantly, sixteen of the twenty-two subjects tested to date have produced antibodies with neutralizing activity against the multiple strains of HIV tested. Since the date has not yet been unblinded, it is not yet known if one of the three groups responded better than any other. DP6-001 was found to be well-tolerated, with mild skin reactions as the most common adverse events. Additional in vitro testing of the subjects’ serum with cultures of live HIV is still ongoing, but so far the serum has been found to have antibodies that neutralize the HIV from three different strains.

Future development rests on the successful completion of the Phase I trial. And the next questions to be addressed will come from the unblinded results: “We see immune responses in people but we don’t know yet whether [they are the result of] the low dose or the high dose; or whether it’s the intradermal or intramuscular injections.”

Chael Needle wrote about the latest innovation in resistance analysis for the September issue.

October 2005