The STEP vaccine trial may, like another ‘failed’ trial, the SMART trial, generate a considerable amount of knowledge about HIV infection and vulnerability.
But it failed in its primary aim. After the STEP presentations, Ron Desrosiers of the New England Primate Research Centre at Harvard University and Neal Nathanson of the University of Pennsylvania mounted an elegant two-handed demolition of the entire current philosophy of HIV vaccine research, both saying that vaccine research had to go back to basic science and change its philosophy of generating similar ‘pipeline products’ to be tested in wasteful and expensive human trials.
Desrosiers said that the enormous genetic diversity of HIV, its ability “to replicate unrelentingly despite everything the immune system can throw at it”, the fact that the immune system cannot protect against superinfection, and the fact that we do not currently know what constitutes an immune response to HIV, all persuaded him that at the current time an effective HIV vaccine “is not feasible”.
We should not be surprised the Merck vaccine failed, he said, because strictly-designed monkey studies had already shown it was not protective; it also contained only one single genetic sequence of each of its three HIV antigens, compared with the thousands of variants HIV could throw up. For similar reasons, he believed that none of the products in the current vaccine pipeline stood any reasonable chance of showing efficacy.
He said that repeated trial failures might have serious ramifications both in terms of ‘donor fatigue’ – which could reduce funding for basic science as well as efficacy trials – and ‘volunteer fatigue’ in affected communities.
He accused the US National Institutes of Health, the largest single funder of HIV prevention technologies, of “losing its way” in its vaccine research strategy. And he said that advocates who bemoaned the lack of pharmaceutical company interest in vaccines were misled.
“The discoveries that are going to lead to a successful vaccine have not been made yet,” he said. “The drug companies know this, which is why, with the exception of Merck, they have not got involved. Once an HIV vaccine does become possible, pharma will jump on development and research.”
He urged a return to basic discovery research, and instanced work being done with artificial viral vectors that actually generate broadly neutralising antibodies against HIV (beginning to be recognised as essential in a vaccine) themselves, instead of trying to stimulate the body to make them.
Neal Nathanson, though less robustly, broadly agreed. He said that he and other researchers had long ago defined HIV as a virus “that defies vaccination”. He too urged a return to basic science such as the devising of genetic assays to search for broadly neutralising antibodies, and said that the marginal effects seen so far in lowering HIV viral load in human volunteers did not justify further large human studies such as the imminent PAVE study.
He ended on a note of optimism, saying that HIV could be controlled even in the absence of a vaccine, and citing Botswana as a country that was not only becoming able to treat all its citizens who needed antiretrovirals, but was also beginning to achieve reductions in HIV incidence.