A Piggyback Attack

Ertl's group is developing a vaccine based on delivering HIV genes via a viral vector, a chimpanzee strain of adenovirus (J Virol, 78:7392-9, 2004). In mice and monkeys, it "really gives a decent amount of immunity," Ertl says.

To make the vaccine, Ertl's team removes the adenovirus' E1 protein, which abolishes replication to prevent infection. Several HIV genes can be inserted in the vector and, once the vector gets into the host, it replicates once, resulting in expression of the HIV proteins. These proteins cause a cellular immune response in which the proteins activate a T-cell attack, rather than prompting the development of neutralizing antibodies, which is the way most vaccines work.

The vector approach for vaccines is relatively novel. "The only viral vector that is being used and licensed is the vaccinia rabies glycoprotein vector that we throw out of planes to vaccinate raccoons in the United States and foxes in Europe," Ertl says. The vaccine is delivered through ketchup-packet sized sacks and covered with fishmeal, which the animals ingest.

In spite of, or perhaps because of, its nontraditional approach, an adenovirus vector vaccine appears to be the furthest along in development against HIV. Independent of Ertl, Merck has begun Phase II human clinical trials on a human strain of adenovirus-5 vector vaccine that contains HIV genes for the proteins gag, pol, and nef (Nature, 415:331-5, 2002). Merck's previous trials were successful in showing safety and immunogenicity. John Shiver, vice president of Merck Research Labs, says nearly 90% of subjects with low preexisting immunity to adenovirus make an immune response to the vaccine.

That preexisting immunity could cause problems, says Wayne Koff, senior vice president for research and development at the International AIDS Vaccine Initiative. Existing antibodies from previous exposures to adenovirus could neutralize the vaccine. In some developing countries, more than 80% of individuals can have preexisting immunity to adenovirus 5, says Koff. "The question is, will that have a negative effect?" Ertl says that because she switched to working on the chimpanzee strain of adenovirus seven or eight years ago, "we have what they don't have, which is the advantage of not having preexisting immunity."

Ertl's vaccine is at least two years away from human clinical trials, and Shiver says potency could be compromised with a chimpanzee strain of the vector. As it is, all monkeys immunized with Merck's vaccine do become infected after being challenged with SIV (J Virol, 79:15547-55, 2005). Shiver says he is still encouraged, because the vaccine reduces viral load considerably and could still have benefits to people infected with HIV, and potentially to transmission rates. "If it does something, no matter how well, there's a chance we could make it work better," Shiver says.

The National Institute for Allergy and Infectious Diseases (NIAID) also has an adenovirus vector vaccine in the works, and it expects to launch Phase IIB human clinical trials this year. The vector is the same strain as Merck's and also has the HIV gag and pol proteins. The difference is that patients receive a plasma DNA prime, with several additional HIV genes, including envelopes, and an adenovirus vector boost. "Hopefully it's more globally applicable," says Alan Fix, chief of the Vaccine Clinical Research Branch in NIAID's AIDS division.?

Shiver says he expects data from Merck's vaccine in 2009, and "these should give a definitive word on whether cellular immunity has a protective effect against HIV infection."

Editor's note (September 25, 2007): The Merck vaccine trials described in this article have been suspended as of September 21. Read an update here.