Therapeutic Vaccine Shows Encouraging First Results in Chronically Infected Monkeys

By Patricia Kahn, Ph.D.*

On the final afternoon of the meeting, Julianna Lisziewicz of the Research Institute for Genetic and Human Therapy (Washington, DC) presented encouraging preliminary data on a therapeutic vaccine used together with structured treatment interruption in chronically infected monkeys—among the first hints of success in immune treatment of chronic infection (Abstract #ThPpA2128).

DermaVir is a DNA vaccine designed to target dendritic cells (antigen-presenting cells which are key players in the immune response). The monkey version contains nearly a full genome (env from SHIV89.6P plus the remainder of SIVmac251 genome) except for the integrase gene, so virus can neither replicate nor integrate into host cells—yet it presents the immune system with a nearly full spectrum of HIV antigens expressed under their natural promoter. The DNA is formulated into particles through the addition of PEI (polyethylenimine)—a polymer known to gene therapy aficionados as an enhancer of DNA uptake and expression—with sugar (mannose) molecules tacked on, giving the particles some resemblance to bacterial pathogens.

Immunization is done simply by exfoliating the skin lightly and applying the vaccine topically. Lisziewicz believes that particles enter the local Langerhans cells (immature dendritic cells), which then migrate to the lymph nodes, since the researchers can detect viral RNA and protein expression a day later in the lymph node dendritic cells. This pathway, she says, does not activate pre-existing immunological memory but stimulates naïve T-cells—a difference to most other therapeutic vaccines.

Lisziewicz presented two separate studies in chronically infected monkeys. The first, a small pilot study, involved 7 animals infected 14 months earlier with SIVmac251, all with late-stage AIDS. Three began receiving continuous HAART treatment, while 4 were put on an STI regime (3 weeks on HAART, 3 weeks off) for six cycles. STI led to rapid suppression of virus during treatment, resulting in prolonged survival of 3 monkeys (the fourth one died). But it failed to lower viral loads during the “off” period—that is, virus quickly rebounded to roughly the same level each time. At that point, one dose of DermaVir was added to the HAART treatment just prior to interruption, and this modified STI regime continued for three more cycles.

The effect of DermaVir was dramatic: Median viral load dropped by 3 logs (1000-fold) during each subsequent interruption and was undetectable after the third round, when all treatment was discontinued. Virus eventually rebounded in two of the three animals, with one surviving for another 6 months, another for 12 months, and the third at 18 months (shortly after the Barcelona meeting). Immune monitoring showed that, in each cycle, the numbers of HIV-specific CD8-positive cells increased (measured by intracellular cytokine staining for interferon-gamma, with whole-inactivated SIV virions as the test antigen).

Lisziewicz then reported on a larger, randomized study of 26 monkeys infected with SIVmac251 six months before the trial’s start. The study had four arms: control (no treatment), STI-plus DermaVir, STI-only and DermaVir-only, all treated for 33 weeks (encompassing 6 cycles of STI and concluding shortly before Barcelona).

Once again, three rounds of STI plus DermaVir brought viral loads down to undetectable levels, and ICC analysis at 33 weeks showed increased levels of HIV-specific CD4- and CD8 cells. DermaVir alone somewhat blunted viral load but was much less effective than the combination with STI. Drug treatment without DermaVir was ineffective at long-term control of virus replication in 5 of 7 monkeys but showed short-term suppression of viremia in one, while the seventh animal is still controlling viral load (and remains virus-negative) at 8 weeks post-treatment (including post-Barcelona follow-up time).

Also since the Barcelona talk, virus has rebounded in several of the DermaVir + STI animals, Some animals remain virus-negative at about 8 weeks of follow-up.

“DermaVir is a therapy, not a cure,” says Mark Lewis (Southern Research Institute, Frederick), whose group did the primate work. “But so far it seems to have some benefit. There’s definitely something there. It’s an evolving story, though,” he adds, noting that future studies will shift to combining DermaVir with continuous (rather than interrupted) HAART, to improve reconstitution of the immune system and avoid the potential emergence of drug resistance. Another challenge, he says, will be to tease apart the effects of DermaVir from those of HAART.

Plans are now underway to test DermaVir in humans through the US AIDS Clinical Trials Group (ACTG), as Lisziewicz reported in concluding her Barcelona talk. (Toxicity studies in swine revealed no safety issues, other than transient irritation at the vaccination site.) A Phase I trial, which she hopes will start in early 2003, will look at safety and immunogenicity of DermaVir at three doses in 24 HIV-infected volunteers on HAART, who have CD4 counts above 350/mm3 and viral loads below 50 copies/ml for at least 6 months. Participants will remain on continuous HAART treatment.

*Patricia Kahn, Ph.D., is editor of the IAVI Report.