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Will we ever have an HIV vaccine?

Here’s the seventh piece from my new BBC column

For around 30 years we have lived under the spectre of HIV. In the early 1980s, the mysterious appearance of symptoms that would later be known as AIDS led to unprecedented efforts to unmask the cause. On 23 April 1984, Margaret Heckler, the US Secretary of Health and Human Services, told the world that scientists had identified the virus that was the probable cause of AIDS. She was correct. She also said that a vaccine would be “ready for testing in approximately two years.” She was wrong.

Despite 28 years of research, there is still no vaccine that provides effective protection against HIV, and in that time around 25 million people have died of HIV-related causes. To understand why creating a vaccine is so hard, you need to understand HIV. This is no ordinary virus. Scientists who study it speak of it with a mix of weary frustration and awed reverence.

The virus is the most diverse we know of. It mutates so rapidly that people might carry millions of different versions of it, just months after becoming infected. HIV’s constantly changing form makes it unlike any viral foe we have tried to thwart with a vaccine. “Almost every vaccine that’s been developed protects against a small number of strains,” says Gary Nabel, Director of the Vaccine Research Center at the US National Institute of Allergy and Infectious Diseases (NIAID).

Vaccines train the immune system to recognise part of a virus, creating a long-term armada of antibodies that seek and destroy the invader, should it ever show its face. For HIV, the most obvious target is gp120, the surface protein that it uses to attach itself to human cells. But gp120 also constantly changes shape, making it difficult to recognise. It also comes in clusters of three that are shielded by bulky sugar molecules, hiding it from the immune system.

On top of that, HIV targets immune cells, the very agents that are meant to kill it. And it can hide for years by shoving its DNA into that of its host, creating a long-term reservoir of potential infection.

So, creating an HIV vaccine is like trying to fire a gun at millions of shielded, moving targets. Oh, and they can eat your bullets.

Uphill struggle

So far, nature has provided little reassurance that a vaccine against HIV is even possible. For virtually every other microbe, there are people who naturally recover from their infections. “Nature itself provides the proof-of-concept experiment. It has told you that the body can inherently do this,” says Anthony Fauci, an immunologist who heads NIAID. But when it comes to HIV, “we have the astounding reality that, with more than 30 million people living with the virus, there is not a single documented case of someone mounting an immune response to completely eliminate the virus from their body.” Some people have the right genetic qualities to keep the virus in check, but no one clears it.

Given these challenges, it should be no surprise that vaccine research has been, to quote one researcher, a “Sisyphean onslaught of disappointments. Only three potential candidates have made it through clinical trials. Vaxgen’s AIDSVAX vaccine, consisting of two fragments of the gp120, failed to provide any protection. Merck’s v520 vaccine, consisting of a harmless cold virus carrying three HIV genes, fared even worse. It was meant to marshall immune cells called T-cells to kill off infected cells. It failed. Worse still, the trial had to be stopped early because vaccinated people seemed to be more susceptible to infections, for reasons we still do not fully understand.

The only sliver of success came in 2009. A Thai trial of more than 16,000 people – the largest one yet – had been testing a combination of two vaccines: a bird virus containing three HIV genes, which was meant to prime the immune system, and a tweaked version of the AIDSVAX vaccine to act as a booster. Since both vaccines had failed individually, critics argued that the trial was a waste of time and money. But to many people’s surprise, the combination reduced the risk of infection by 31% – a statistically significant effect, though too low for a useable vaccine. (For comparison, the measles and polio vaccines are around 95% effective).

Some scientists were sceptical about the results, noting that the protection was short-lived and confined to people at low risk of infection. Others saw a ray of hope after years of frustration, a sign that a vaccine is in principle possible. Either way, the trial was confusing, especially since the vaccines did not reduce the levels of virus in infected people. Scientists are still trying to work out why the vaccine had any effect at all.

Renewed hope

But despite the muted results from existing trials, scientists in the field are unfazed. The reason, according to Wayne Koff from the International AIDS Vaccine Initiative, is that since the Thai results were announced, “the field that has begun to undergo a renaissance.”

It turns out that many HIV patients carry secret weapons – “broadly neutralising antibodies” – that can attack a wide range of HIV viruses. For these patients, it is too late. Their infections are already in full swing and the virus can mutate around their defences. But the discovery proved that HIV’s vaunted diversity is not the roadblock for vaccines that many scientists feared. If we taught the immune system to make these antibodies early, we could destroy the virus before it gained a foothold.

It is possible to isolate the right antibodies because we now know the shape of HIV’s surface proteins, down to the atomic level. Nabel used this knowledge to identify parts that stay the same while the rest of the virus shifts and mutates. These non-mutating regions are likely to be vital areas that cannot change without causing problems. He searched patients’ blood to find antibodies that target these conserved regions, and cells that make those antibodies. In 2010, he found three: two of which could neutralise 90% of HIV viruses. Other scientists, such as Dennis Burton of the Scripps Research Institute, have made similar discoveries using similar methods.

Nabel’s vision is a cocktail of these super-antibodies that target different parts of the virus, cutting off its evolutionary escape routes. He hopes to start clinical trials of his first-generation antibodies by early 2013, and he says is close to producing a second-generation of even heavier hitters that he thinks are two to three years away from early trials.

Vaccine researchers are also working on ways of stimulating our T-cells to kill infected cells at an early stage. This was the strategy behind Merck’s failed v520 vaccine, but scientists have since found better ways of smuggling viral genes into cells, and targeting them at the tissues most likely to be infected first. Both approaches would be complementary: “I think we would need a combination of broadly neutralising antibodies and a broad and robust T-cell response,” says Koff.

Compelling need

There is no telling when, or indeed if, these strategies will yield results, but what is certain is that the need for a vaccine will not diminish. There are many ways of preventing HIV infection, including condoms, microbe-killing gels, and the use of treatments as soon as people get infected. “We’d be going in the right direction with the tools we already have,” says Fauci. “But if we added a vaccine to the toolkit, even if it wasn’t 90% effective, you could have a major additive effect. There really is a compelling need for one.”

It may seem frustrating that decades of research have yielded nothing that satisfies this compelling need. But everything in the pipeline has depended on a steadily accumulating knowledge of the virus over those years. And as much as we know about the virus, and our immune response to it, there is still a great deal to learn. Also consider this. It took 47 years to create a vaccine for polio after the microbe behind it was identified. The measles vaccine took 42 years. The hepatitis B vaccine was a positive sprint at 16 years. “Twenty-eight years isn’t an inordinate amount of time,” says Fauci.

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Image by Dr. A. Harrison; Dr. P. Feorino

9 thoughts on “Will we ever have an HIV vaccine?

  1. That virus that Heckler announced as the probable cause of AIDS was HTLV-III (“a true member of the HTLV family”) which was supposedly identified by Robert Gallo (with supposed – but actually non-existant – 48 isolates). The actual cause of AIDS was called LAV back then (which was later renamed HIV-1) which was identified by Montagnier and Barre-Sinoussi – hence the reason these two got the Nobel and not Gallo. So no, she was not correct, on either accounts.

  2. It is a travesty that you describe the vaccine failure without describing the success of PEP and PrEP. Nor do you bother to mention the impact of rapid treatment on dramatic reductions in infectivity, resulting in sharp declines in “community infectivity.” They prove – if anybody looks at it – highly successful means to curbing the epidemic, even if they fail to create antibodies. Stopping and preventing the spread of the virus cures the epidemic, if not the disease itself, and the rapid decline in new cases where universal health care is available and promoted – Massachusetts and British Columbia particularly, but also New York and San Francisco – underscore how HIV is a “community health” concern rather than merely 1:1 random infections. If you can stop infectivity – which we now can – we’ve created a “community vaccine” without vaccinating everybody.

  3. Echoing Joe’s comment, something that isn’t mentioned in this article is the phenomenal effect that cheaper, more accessible ARV drugs have had. Although they aren’t a ‘cure’, they make the HIV virus a chronic, manageable illness rather than being quickly fatal and dramatically reducing transmission risks. For all George Bush’s other political failings, he deserves credit for his President’s Emergency Plan for Aid Relief which has saved countless of lives by making these drugs available to millions of HIV victims.

  4. @Joe and Oli – While I appreciate the comments, this piece was not about whether we’ll beat the HIV epidemic. It was specifically about the vaccine. Yes, other measures are important, and I tried to hint towards that in the penultimate paragraph, but ultimately, they would be the subject of a different article. It’s tough enough to get the details of the vaccine quest down in 1,200 words without also branching out into other measures.

  5. I met Dr. Don Francis when I worked at Vaxgen and still fondly recall his passionate energy. He had the Joseph Campbell quote “Joyful participation in the sorrows of the world. ”
    hand written in script and pinned to his wall. I am thankful for men such as him that devote their life solving to these complex problems.

  6. I haven’t heard any news since last summer, but a company called Koronis is seeing results in using the virus’ tendency to mutate against it. Instead of trying to block transcription, they encourage it and introduce multiple errors that mutate the virus to death, so to speak. I’m not directly in the field, but with something this promising as a potential CURE, it surprises me that we’re not hearing more about it.

  7. From an HIV vaccine researchers perspective: Recent successes give hope that a vaccine is possible, and provide clues as to how we can build on that success. However, it will require us to dissect the mechanisms of how our vaccines work and to understand what immune responses will actually protect from HIV-1 infection (such as neutralizing antibodies). We now know that if neutralizing antibodies are present prior to exposure to HIV-1, they can provide protection from infection. As the article mentions, broadly neutralizing antibodies occur naturally in some HIV-1 infected subjects, providing hope that if we understood how such subjects were able to develop them, we could learn how to elicit such antibodies by vaccination. At Seattle BioMed, the Stamatatos Lab has been on the forefront of broadly neutralizing antibodies for many years, conducting one of the first large scale studies designed to understand how such antibodies are developed (Sather et al., 2009. J. Virology). Since then, we have continued to lead the field, making discoveries about the timing of when these antibodies are developed and characterizing the state of the immune system when they begin to emerge (Mikell, et al., 2011. PLoS Pathogens). Coupled with our advances in HIV-1 immunogen design, these discoveries have provided a foundation of understanding that allows us to continue to produce and evaluate pre-clinical HIV-1 vaccine candidates that are designed to elicit broadly neutralizing antibodies. Those who dedicate their lives to the eradication of HIV-1 recognize that success will not come quickly and easily, but will come from innovation, foreward thinking, and strong science. So, will we ever have an HIV-1 vaccine? Researchers at Seattle BioMed respond to that question every day with a resounding: YES!!

  8. Last year Scientists in La Jolla discovered a compound (LJ001) that kills all Envelope viruses without damaging the host cell this compound could lead to a broad spectrum anti viral drug, since that discovery there has not been 1 mention of this compound anywhere and doesn’t seem to be on anyone’s radar, I wonder why?

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