On 23 April 1984, Margaret Heckler, the then US Secretary of Health and Human Services, announced to a packed press conference that scientists had discovered the virus that caused acquired immune deficiency syndrome (AIDS). She went on to express the hope that a vaccine would be developed within two years.
Thirty-two years later and AIDS-related illnesses have claimed at least 30 million lives. In 2015, around 2.1 million people were newly infected with the virus and approximately 1.1 million people died as a result of the disease. Globally, the rate of infections and deaths have declined over the years thanks to the use of antiretroviral therapy and reduced spread of the human immunodeficiency virus (HIV) responsible for the disease; however the availability of treatment and impact of the disease vary widely across the world. It is widely acknowledged that the most effective way to end the HIV pandemic would be to develop and roll out an effective protective vaccine.
Biggest biomedical challenge of our generation
Even at the time, immunologists who heard Heckler’s infamous prediction about how long it would take to develop an HIV vaccine knew it to be wildly optimistic. More than three decades on, much more is known about the myriad of devious ways through which HIV evades the body’s natural defences and the scale of the task faced by those trying to beat it.
For a start, because no-one has ever fully cured themselves of HIV infection, researchers cannot simply imitate the immune responses of those who have spontaneously recovered, as they have done with many other infections. HIV is highly genetically variable, both replicating and mutating more rapidly than many other viruses. On top of this, the virus is surrounded by a dense coat of sugars that stop immune system antibodies locking on and identifying it as an enemy. “It’s one of the biggest biomedical challenges of our generation,” says Professor Robin Shattock of Imperial College London.
The hunt for an effective HIV vaccine has come in three phases. The high point of the first phase, based on using simple viral proteins to induce antibodies with the aim of disabling the virus, came with the launch of trials of AIDSVAX in 1998 and 1999. This was the first HIV vaccine to enter full-scale efficacy testing. Disappointingly no evidence of protection was found and the AIDSVAX trials ended in 2003.
The discovery around 1990 that CD8 killer T cells play a key role in controlling HIV shortly after infection by killing infected cells led scientists to wonder whether a similar response could be induced by vaccination before infection. The high point for this second phase in the hunt for a vaccine came with the launch of the STEP trial of an adenovirus (Ad5) vector vaccine encoding three synthetic HIV genes in 2004. Again optimism turned to disappointment in 2007 when it became clear the candidate vaccine neither prevented HIV infection nor reduced the amount of virus in those already infected.
A helping hand
One of the characteristics that makes HIV hard to combat is its ability to take over a host’s CD4 helper T cells and then turn them into factories to generate copies of itself. The virus accesses the helper T cells via a surface glycoprotein called CD4 and co-receptors CCR5 and CXCR4.The identification of these mechanisms was of fundamental importance in narrowing the focus of those working on HIV.
Dr Daniel Douek’s group at the National Institute of Allergy and Infectious Diseases at the National Institutes of Health in Bethesda, USA, showed in 2004 that HIV infection causes the rapid depletion of the majority of these CD4 T cells in the gut, and that levels don’t recover. Douek and colleagues later showed HIV infection can cause damage to the gut barrier, thereby allowing microbes to cross it. Douek says this helps explain the systemic immune system activation known to be a key driving force in HIV disease progression.
"Many scientists now belive that rather than deploying a single silver bullet against HIV, the best hopes of success in the hunt for an effective vaccine lie in a combined assault"
These insights have led Douek (who originally trained in the UK before moving to the States) to look more closely at the role of the mucosal tissue that lines cavities in the body and surrounds internal organs. Most recently, he has been looking at the importance of lymph nodes as sites of HIV replication and maintenance. Shattock and others have shown that it is predominantly CD4 T cells in the mucosa that are the first cells to be infected. He and others are investigating whether boosting immune responses in the mucosa could stop the virus in its tracks.
A new approach
The failure of the STEP trial in 2007 led many in the field to move away from efforts to produce vaccines by stimulating killer T cell activity. However, recently there has been renewed confidence in such an approach since 2013 when it was reported that nine of 16 rhesus monkeys given a vaccine and then infected with simian immunodeficiency virus (SIV), a close relative of HIV, were able to completely clear the virus. The vaccine is based on a form of cytomegalovirus (CMV), a common member of the herpes virus family, which had been modified to include SIV genes. It works by training the immune system to recognise and attack SIV infected cells.
Professor Louis Picker of the Vaccine and Gene Therapy Institute at Oregon Health and Science University in Beaverton, Oregon, who leads the CMV work, has carried out other animal trials but has been unable to achieve protection levels above 50–60%. He believes that this could be because SIV is more virulent than HIV, and that higher levels of efficacy may be possible in humans. CMV is thought to be carried by 50–80% of adults in the UK, and in most cases doesn’t cause any obvious symptoms.
Picker is, of course, aware that previous approaches to tackling HIV that have shown promise in animals have later failed to have an effect in humans. Nonetheless, recruitment of around 75 people for safety trials of an attenuated human CMV-based HIV vaccine began in June.
Neutralising HIV variability
Another of HIV’s trump cards is its ability to evade detection by immune system antibodies through its sheer variability. Around the same time as researchers were dissecting the disappointing AIDSVAX and STEP results, it was discovered that a small percentage of infected patients, known as ‘elite controllers’, produced broadly neutralising antibodies (bNAbs) capable of acting against multiple strains of HIV-1 (the most common type of HIV). Although the virus in these subjects was already resistant to these antibodies, the finding demonstrated that humans are capable of producing them in response to natural infection and stimulated efforts to design vaccines based on triggering the production of bNAbs. “We know these antibodies can be made in infected humans,” says Shattock. “The question of how we get non-infected individuals to make them as a preventative vaccine has fuelled a whole raft of advanced immunological research.”
Those seeking to answer this question include a team led by Professor Michel C. Nussenzweig at the Rockefeller University in New York. Last year his group published evidence that a cloned bNAb called 3BNC117 significantly reduced the amount of HIV in the blood of infected patients. It lost most of its effectiveness within 28 days in some patients, suggesting the virus had mutated to evade detection, however there are hopes that cocktails of bNAbs could overcome resistance.
Meanwhile research published in July by researchers at Duke University in Durham, USA, showed individuals capable of producing high levels of bNAbs against HIV also often have higher levels of antibodies that attack the body’s own cells (called autoantibodies), fewer regulatory T cells and higher levels of memory T follicular helper cells. This provides important clues to advance our understanding of the basic biology of bNAb induction and enhances the prospects of future efforts to develop a vaccine based on stimulating their production.
Targeting the envelope spike
Today, scientists seeking to identify bNAbs benefit from recent advances in the fine mapping of the structures on the outside of the virus. Its genetic material and protective protein shell are surrounded by an external envelope that includes glycoproteins, which together form an ‘envelope spike’ that allows it to bind to and enter host cells.
“The more structural information you have, the better you can design immunogens to mimic what is on the virus spike to induce neutralising antibodies,” says Professor John Moore, a British immunologist at Cornell University’s medical school in New York.
What makes mimicking the HIV envelope spike difficult is that it undergoes a series of rearrangements to enable it to carry out its functions. In 2013, Moore’s group produced the first stabilised recombinant envelope protein compound capable of inducing antibodies against itself. “It was the first time somebody has been able to induce strong neutralisation against HIV,” says Shattock.
Moore says the advance was aided by the development in recent years of advanced electron microscope technology at the Scripps Research Institute in La Jolla, California, as this allowed his group to properly visualise the proteins they were making. He also warns that there is still a lot of work to be done if their breakthrough is to benefit patients. “The neutralising response we can induce is of narrow specificity, which is of no real value in an HIV vaccine because the virus is so variable. The goal now is to broaden the response and induce bNAbs,” he says. “That’s not a trivial exercise.”
A combined assault
Many scientists now believe that rather than deploying a single silver bullet against HIV, the best hopes of success lie in a combined assault to induce both bNAbs and killer T cells – what many see as the third phase in the hunt for an effective vaccine. This was the approach taken by what has been called the fi rst ‘successful’ HIV vaccine trial, the results of which were published in 2009. The trial – called RV144 – combined two previous vaccines that had shown no efficacy on their own. The fi rst was AIDSVAX, and the second was ALVAC-HIV, a modified, recombinant canarypox virus that expresses multiple HIV proteins.
Researchers at the US Military HIV Research Program vaccinated one group of Thai volunteers with the vaccine and another control group with a placebo in 2003, and then tested them for HIV over three years ending in 2006. They found that those who received the vaccine were 31% less likely to become infected than those given a placebo.
Another of HIV’s trump cards is its ability to evade detection by immune system antibodies through its sheer variability
This level of protection is not high enough to justify its use and opinions have varied as to how much promise the ‘Thai trial’ approach offers for the future; however efforts are ongoing to fi nd ways to boost the protection RV144 provides. “That was a very important milestone,” says Douek. “It’s not quite the light at the end of the tunnel, but it showed there is at least a tunnel you can start going down.”
An international problem with an international solution
The combination strategy is also at the heart of the European Aids Vaccine Initiative, launched in October last year to pool the efforts of research groups at 22 institutions in nine EU countries, Australia, Canada and the US to develop new candidate HIV vaccines that can be taken through to human trials within fi ve years. Known as EAVI2020, the collaboration is led by Imperial College London and is backed by €23 million from the European Commission. Some EAVI2020 researchers are working on synthetic envelope vaccines to induce bNAbs, while others are seeking to build on Picker’s work, designing vaccines that trigger broad T cell responses by targeting conserved parts of the virus that are unable to mutate. The plan is demonstrate the effectiveness of the best candidates for both approaches in human studies and combine them into one, hopefully effective, vaccine.
Whether the growing hopes that this ‘third generation’ combined approach to the problem of developing a HIV vaccine will prove to be successful or another false dawn remains to be seen. The repeated dead ends, failures and frustrations that researchers have faced since efforts to fi nd an HIV vaccine began in the 1980s have primed them to be sparing in their optimism. And yet, paradoxically, it is also a characteristic that is practically a pre-requisite for working in the field. “I know a lot of very clever people who are working on this problem, and I know we’ll make progress,” says Douek. “I don’t know how long it will take, but I do know we’ll succeed.”
This article was written by Nic Fleming as part of the BSI's report '60 years of immunology: past, present and future'. This article is licensed under Creative Commons Attribution-NoDerivative Licence (CC BY-ND 4.0). Additional permissions may need to be sort from image licence owners.