A first shot of hope

The breakthrough in the race to find an Aids vaccine could be at hand. David Baltimore, who oversees US efforts, will discuss provocative new findings in California this weekend. Tim Cornwell reports.

Forty million people worldwide may be infected by the HIV virus by the end of this year. About 12 million have died of Aids, and the disease could reduce the gross domestic product of the worst affected African countries by as much as 10 per cent. During his tenure, Ronald Reagan's surgeon general hoped vainly for the development of a vaccine against the illness within two years. In 1997, President Clinton set a target of ten.

An Aids vaccine, to replace the costly cocktail of treatments now offered to only the wealthiest victims of this 20th-century disease, has become a Holy Grail of scientific research. "I will not answer the question of when we will have an Aids vaccine," says David Baltimore. "Because it is so hard to predict."

Nearly two decades after the disease was first identified, efforts to find an Aids vaccine have drawn a blank. The San Francisco company VaxGen has reportedly spent $30 million of investors' money on three years of field tests. Thousands of people at high risk of infection from HIV have volunteered for a vaccine trial that most scientists believe will fail.

Baltimore, recently appointed head of the California Institute of Technology, comes to the meeting of the American Association for the Advancement of Science wearing his hat as chief of the US steering committee on Aids vaccine research. A Nobel prizewinner whose career was nearly ruined by false charges of scientific malfeasance levelled at a co-author, Baltimore still bears the scars of what he calls that "slight hiatus". Though he emerged a "somewhat stronger person", he grimly remembers a time when "people were uninterested in what I had to say, because there was a cloud hanging over me".

Now plenty of people will be waiting to hear what Baltimore has to say about an Aids vaccine. In 1994 the US National Institutes of Health cancelled its field trials of vaccines after disappointing lab test results. Calls for their resumption in the name of human rights sparked a row last year. Baltimore, however, is typically outspoken in putting the need to develop a "deep knowledge" of the HIV virus ahead of the need to test vaccines that, he says, will produce the wrong antibodies.

But Baltimore will brief colleagues at the AAAS meeting on findings that have sent a ripple of excitement through the Aids research community. Work by Jack Nunberg, at the University of Montana, and Peter Kim, of the Whitehead Institute at the Massachusetts Institute of Technology, "offers the hope that there are new ways of inducing antibodies that previous vaccines have not tried," Baltimore says. Nunberg's work in particular suggests that it may be possible to target the Aids virus at the point at which it enters a human cell.

There have been many false starts in the quest. Established methods for making a vaccine from a virus proved useless against the tricky newcomer. "Giving the virus credit for its ability to counter our attempts to inhibit it has always turned out to be the right thing to do," Baltimore observes.

Nonetheless, Nunberg returned from presenting his results at a Colorado Aids conference this month having, as he describes it, "walked into a whirlwind". "Our work perhaps breaks a logjam that had existed since 1993. It was an outstanding question whether any vaccine could elicit antibodies that would neutralise a primary HIV isolate. Our work definitively answers that as a 'yes'," Nunberg says.

Groping for an analogy to describe his work, Nunberg borrows from Nasa terminology. In the human body, the Aids virus approaches a cell like a space shuttle docking with its space station. As the shuttle opens, Nunberg says: "it exposes its inner docking machinery, the space station does the same, there is this intricate dance, this intricate message, then a tube opens up so that the contents of the space shuttle can enter the contents of the space station. Previous vaccines have targeted the space shuttle as it is flying, with all the doors closed. What we are targeting are those docking mechanisms."

Nunberg worked from the basis that as the virus approaches the cell, it reorganises itself and, in that transient state, may be susceptible to an effective antibody. He brought together cells expressing HIV envelope protein and cells expressing cellular receptors then froze the process using formaldehyde.

The fusion process exposed regions of HIV molecules not open to attack at other times in the infection cycle. Nunberg then injected a vaccine of the molecules into mice that had been genetically engineered to focus their immune response on HIV to see if they would start making antibodies - and they did.

In the mice, the vaccine elicited proteins that attacked the virus's envelope protein, ie its docking mechanism. The antibodies neutralised 23 of 24 strains of the virus - including variant strains from Africa, India, Thailand, the US and Europe. The NIH now plans tests in rhesus monkeys.

Baltimore, practising restraint, notes that Nunberg's work is still "black box" research, unreplicated work resting on one publication. Nunberg concurs: "This is a basic research finding. I don't think the cell vaccine at present suggests a definitive path to the clinic. It needs more research to develop a more practical formulation."

But it is a measure of the interest it has aroused that at least three laboratories are now pursuing the research. In Baltimore's judgement, it is "one of the few breakthroughs there has been since we've known about the virus. It certainly gives us something new to do".