32 Years

Why Can't We Find an AIDS Vaccine?

Don't celebrate this week's promising-seeming AIDS vaccine trial yet—there's a reason we haven't found one.

Getty,Boston Globe

The latest installment in the familiar "AIDS vaccine is just around the corner" saga was presented this week by scientists writing in Nature. The vaccine specialists reported an unprecedented improvement in nine of 16 rhesus monkeys infected with a simian virus similar to HIV, called SIV, who received the novel vaccine.

The finding is heady stuff – if duplicated, this would represent one of the most effective approaches yet demonstrated. But there is a big “however” to the news. It is control of the simian virus. In monkeys. And just nine monkeys at that. The news is the umpteenth "‎breakthrough" in HIV in the 32 years of the epidemic. Indeed, vaccine control of HIV got off to a wildly optimistic start when Margaret Heckler, head of Health and Human Services under Ronald Reagan, announced in 1984, when the viral cause was identified, that we should have a vaccine for prevention within just two years.

She is not the only optimist in the long line of people working hard in pursuit of an AIDS vaccine. In 1991, American scientists reported a promising vaccine in the prestigious New England Journal of Medicine. They gave a different vaccine to 30 patients with early HIV and showed a rise in CD4 cell count in about half – results that never were duplicated. And President Bill Clinton, speaking in 1997, challenged scientists to create an effective AIDS vaccine within the same length of time – 10 years – that his idol, President Kennedy, had implored scientists of the 1960s to place an American man on the moon.

Clinton’s push (and the accompanying dollars) led to genuine excitement in the HIV vaccine field. The excitement met reality in 2007, however, when the lead vaccine candidate in the trial, called the Step trial, proved not only ineffective but dangerous. Vaccine recipients actually had a higher rate of infection, prompting rapid closure of the trial. But work has pushed on. In the darkness that followed the failure of the Step trial came results from a less widely advertised and seemingly less promising vaccine, called RV 144, in volunteers in Thailand. A modest benefit was shown and additional examination of results has identified a specific immune response that seems to predict a clinical response – a place, finally, maybe, for scientists to set up shop. The finding was so exciting that one group, despite the dismal track record of past predictions, declared that the world should have a real HIV vaccine by 2019.

The reasons for the long hard road to an AIDS vaccine have been addressed repeatedly and increasingly by scientists in the field. There are countless explanations, as there are with any unsuccessful campaign. However, an important difference between HIV and other infections now prevented by vaccine is this: Unlike, say, measles, no one has recovered from HIV. Many are living with the infection but no one, without the assistance of medicine, can control the virus. Leaving aside a few remarkable cases where a bone marrow transplant has led to apparent cure, everyone else with HIV has chronic ongoing infection; to stop antivirals is to see a predictable and almost immediate rebound of high viral levels throughout the bloodstream. In contrast, most people with natural measles recover from measles – the body has a natural path to completely effective and durable immunity. This natural immunity showed scientists where and how to look for an effective vaccine. But with HIV, the lack of a natural model of immune control has deprived us of our most important lead.

Plus the "AIDS vaccine" actually is two very different vaccines. One is the traditional vaccine given to people without infection to prevent infection. Just like the measles shot and the hepatitis shot and the flu shot, the goal is prevention, pure and simple. This is being developed for the billions of uninfected people. But a different "AIDS vaccine" is seen as part of the treatment armamentarium for the 35 million people who currently are infected. This is a very different use of vaccination that only in recent years has been embraced by the scientific community. Granted, Pasteur himself sought a rabies vaccine to treat people with active rabies and Robert Koch tried to develop a series of shots to control TB in those already suffering from that disease. But HIV represents the first modern attempt to use the vaccine-based manipulation of the immune system to improve a person's natural response to the already-established infection. Interestingly, therapeutic vaccination is an exciting field in oncology right now; the same approach of vaccine-induced augmentation of a patient's own immune system is being tried in prostate, breast, and numerous other cancers.

The Thai RV144 vaccine is a preventative vaccine while the newest candidate reported this week in the nine rhesus monkeys is a therapeutic vaccine. The latter one is remarkably clever, splicing a bit of simian virus DNA onto the back of a completely different virus – cytomegalovirus or CMV – that knows its way to every corner of the body. By exploiting CMV’s natural tricks, the scientists have achieved a durable suppression and – perhaps – eradication of SIV.

Despite the gust of excitement most scientists are keeping their emotions in check. The battle between scientific caution and the screaming need for human hope is the oldest one in medicine. Scientists who talk big are called out by colleagues as grandstanders; those who are too dark seem Eyeore-like and perhaps a tiny bit cruel. There is no easy middle for patients or doctors to occupy where hope is maintained but in proportions appropriate to the latest news.

But those who are forever pessimistic should bear in mind that in the mid-1990s, the parade of “breakthroughs” that turned out to be duds was quite comparable in the field of medications for HIV. Then the protease inhibitor class of drugs changed the disease almost immediately from a predictably fatal infection to a chronic disease requiring daily care, similar to diabetes. Eventually one of these many vaccine “breakthroughs” will turn out to be the one, the one that leads to global control of the HIV epidemic, a disease that has killed 30 million people in the last 32 years. Unfortunately, none of the current products in hand today will be the promised history-maker.