HIV-1 Vaccine Proving Safe, Immunogenic in Humans

SEATTLE—A new HIV-1 vaccine that uses a replication-defective adenovirus vector has proved to be safe, well tolerated, and immunogenic to date in an ongoing phase I trial, according to research presented at the 9th Conference on Retroviruses and Opportunistic Infections (abstract 12). Emilio Emini, PhD, senior vice president of vaccine research at Merck Research Laboratories, presented the results.

"The clinical goals of our vaccine effort are to develop a vaccine that will lessen the likelihood of persistent virus infection or, should infection occur, lead to the establishment of a clinically significant lowered virus load," Dr. Emini said. "The other potential use of these vaccines is that, in HIV-infected individuals, in combination with HAART, the elicited immune responses could mitigate the effects of previously established HIV infection."

The Merck vaccine development effort is focusing on the cellular response (specifically the CD8 and CD4 cellular responses) to HIV-1, because intensive vaccine efforts to date have not been able to produce a strong, broadly reactive, virus-neutralizing antibody response, Dr. Emini said.

The development of a vaccine designed specifically to elicit a cellular immune response is a novel area of research, according to John Shiver, PhD, senior director and head of viral vaccine research at Merck Research Laboratories. "There are no other vaccines for other disease targets that intentionally produce killer lymphocytes against a virus," he said.

In an estimated 5 years of preclinical research at Merck, two HIV-1 vaccines have emerged as viable candidates and are currently being tested in humans: a naked DNA vaccine and a replication-defective adenovirus vector vaccine. Both vaccines carry DNA encoding the HIV-1 gag structural protein with the clade B gene sequence, Dr. Emini said.

The gag protein was selected after assessing cellular immune responses in HIV-1 infected individuals in North America, Brazil, Thailand, and Malawi. The tests showed that the response to HIV-1 is most consistently and most strongly directed against the gag protein, followed by the pol and nef proteins.

Clade B is one of the three most common clades (genetic variants) of HIV-1 worldwide, although data from the same international population revealed considerable cross-reactivity of the cellular immune response, Dr. Emini noted.

A Potential Problem

A potential limitation of the adenovirus vector vaccine is the presence of preexisting immunity to adenovirus, which might attenuate the vaccine’s effectiveness, Dr. Emini said. He noted that an estimated 30% of individuals in North America have preexisting adenovirus-neutralizing antibodies at a titer of 1:200 or higher.

In the ongoing trials, the Merck team is testing two approaches for overcoming this problem: using a prime-boost approach (prime with the DNA vaccine and boost with the adenovirus vector vaccine) and using a higher dose of the adenovirus vector vaccine alone.

Preliminary Results

Dr. Emini discussed preliminary results from the phase I trials of the two vaccines in HIV-1-uninfected volunteers. In both trials, cellular immune responses are being assessed with the ELISPOT assay, which detects peripheral blood mononuclear cells that produce gamma-interferon after an in vitro challenge with HIV-1 proteins.

In the DNA vaccine trial, 7 (21%) of 34 HIV-1-uninfected volunteers in a low-dose group and 16 (42%) of 38 in a high-dose group have had cellular immune responses after four doses, and adverse events have been sporadic and mild.

"We take comfort from these data suggesting that, in fact, the immune system in these individuals is seeing the DNA vaccine and that hopefully the immune system will be suitably primed so that when we do come back later with an adenoviral vector, we will see a suitable boost," Dr. Emini said.

In the adenovirus vaccine trial data presented, 6 (67%) of 9 HIV-1-uninfected volunteers given 10⁸ vector particles and 4 (57%) of 7 given 10⁹ vector particles have had cellular immune responses after three doses; 5 (56%) of 9 given 10¹⁰ vector particles have had such responses after only two doses. The adverse events to date have been transient malaise, body aches, and injection site reactions.

The mean magnitude of the cellular immune response achieved with the adenovirus vaccine has been at least twice as great as that achieved with the DNA vaccine. Importantly, the responses to the adenovirus vaccine have persisted for at least 16 weeks after the third dose and show some degree of cross-clade reactivity, Dr. Emini noted.

Finally, stratification of the vaccinees according to titer of preexisting adenovirus-neutralizing antibody suggested that lower doses are effective in volunteers without preexisting immunity, and that higher doses appear to be effective for circumventing preexisting immunity.

The ongoing trials of the two vaccines will eventually include an estimated 600 volunteers, both HIV-1-uninfected and HIV-1-infected, and are expected to be completed in 2003, Dr. Emini said.

The research marks progress toward the national goal of an effective HIV vaccine by 2007 set by former President Clinton, but it will take a considerable amount of time to accumulate and analyze data from these and other trials, Dr. Shiver told ONI in an interview. "I think there is certainly some agreement that progress has been made toward that goal, but an actual effective vaccine within 4 more years is probably not going to happen," he said.