HIV vaccine conference opens in most promising research atmosphere for years

Gus Cairns
Published: 07 October 2013

The 13th – and last – AIDS Vaccine 2013 Conference opened today in Barcelona in an atmosphere of low-key excitement, with recent research findings to be presented at the conference, signposting new pathways towards the ultimate goal of a preventive vaccine for HIV.

A vaccine won’t happen tomorrow. One renowned researcher, Crucell’s Jerald Sadoff, who has been involved in the development of vaccines to diseases ranging from flu to hepatitis A, told a pre-conference workshop that he still did not expect a licensed HIV vaccine for ten years, and IAVI’s best guess is twelve years. But recent studies have elucidated the complexities of the body’s response to HIV and the way vaccines can change it with much more clarity than before.

Dr Anthony Fauci, Director of the US National Institute of Allergies and Infectious Diseases (phoning in to the opening press conference due to the US federal shutdown) asked the question: with HIV infections falling by 30% in the last eight years and the expanding availability of antiretroviral therapy and pre-exposure prophylaxis, why did we need a vaccine? The answer, he said, was because of the difficulty of people’s adherence and their retention in care.

“Ending the epidemic in the absence of a vaccine is a daunting challenge because it’s so difficult to maintain the continuum of care,” he said.

Treatment as prevention also involved getting people to test, he added, and putting and maintaining people on therapy was challenged by social and cultural factors, such as homosexuality being illegal in 76 countries.

Fauci outlined three main research pathways that the last few years’ research had opened.

How do antibody responses work?

HIV is a unique virus and progress towards a vaccine has been slow because, unlike in most other infections, although the body does develop immune response to the virus, there has never been a documented case where that immune response has led to a spontaneous remission of infection. HIV can change faster than the immune system, and mutates its way round the body’s responses to keep on replicating.

HIV’s weak point is the moment it enters the body. Fewer than one in a hundred exposures to the virus, even in anal sex, may result in infection and in recent years it has become clear that the majority of infections may involve a single virus crossing between people – not a single strain of virus, but a single viral particle. If a vaccine could generate a bodily state that involved a response broad enough to stop a wide variety of viruses getting across, this would be an ideal situation.  It had been thought that such a ‘sterilising’ (infection-stopping) vaccine like this might require the generation of rare, hard-to-engineer ‘broadly neutralising’ antibodies that take years to develop in the body.  

However, the unexpected success of the RV 144 vaccine trial had turned this schema upside down, as the efficacy seen (which, though short-lived, was real) was due to ordinary non-broadly neutralising antibodies.

Four years later, this trial’s result  – which was so unexpected that one of the manufacturers had gone bankrupt and no more vaccine could be made, thus delaying development – is still not fully understood, but may depend on the antibody response ‘waking up’ other parts of the immune system in a process called antibody-dependent cellular cytotoxicity.

A version of the RV 144 vaccine tailored for South Africa rather than Thailand has now been developed and will be taken forward in a series of trials to see if it works and to understand how – though Mitchell Warren of AVAC added, in a pre-conference workshop, that there were also plans to carry it forward in gay men in Thailand.

Broadly neutralising antibodies

The second research direction was to investigate ways of persuading the body to produce the previously mentioned broadly neutralising antibodies (bnAbs). These are unusual antibodies that develop slowly, over a period of years, in about 20% of people with HIV. They are very unlike the antibodies that are quickly developed in response to an infection, having long ‘prongs’ that reach through the sugar-coated fuzz that HIV coats itself in and block essential, highly conserved (unchanging) parts of the viral surface from interacting with cells. 

If we can find ‘superantigens’ – selections of specially immune-stimulating parts of HIV – that force the body to develop bnAbs more quickly, we would have a very powerful vaccine. We may be able to reverse-engineer these superantigens from broadly neutralising antibodies or force them to evolve in the test tube, in a process called affinity maturation. An alternative, as Penelope Moore of the South African Institute for Communicable Diseases acknowledged, might be to give the vaccine to children well before the age of sexual debut so they have time to develop the bnAbs.

The paradoxical properties of CD8 vaccines

The third direction is to continue developing vaccines that develop the second branch of the acquired immune system – the CD8-cell or cytotoxic T-lymphocyte (CTL) response. Research into CTL-stimulating vaccine sagged after the failure of the STEP trial, especially since later research showed that the CTL response it stimulated actually enhanced HIV infection, either because it caused uninfected cells to change into a more vulnerable type or, according to UK vaccine developer Andrew McMichael, because unhelpful immune responses out-competed helpful ones.

More recently, however, new CTL-stimulating vaccines that mimic chronic infection have produced interesting results in animal studies: they did not stop infection but appeared instead to be capable of eliminating infections by slowly killing off HIV-infected cells. Aidsmap.com has written an analysis of the CTL vaccine based on mimicking infection by a combination of HIV genes and the shell of cytomegalovirus (CMV) elsewhere, describing how it seems to work, but new CTL vaccines based on HIV genes combined with the shingles virus Varicella zoster (VZV) and the Kaposi’s sarcoma virus, HHV-8, will be presented at the conference.

Helen Rees, Director of the Wits Reproductive Health and HIV Institute in South Africa, commented that a broadly effective HIV vaccine might have to balance the effects of the two types of vaccine: it might have to include components that reduced vulnerability to HIV infection at one time point and actually enhanced it at another, combined with different components that reduced it at that point, in order to take advantage of the different rates at which different types of immunity develop.

Co-ordinating our research

The renewed prospect for the development of a vaccine in the context of the development of other new HIV prevention modalities – such as the extension of antiretroviral (ARV) therapy, pre-exposure prophylaxis and, possibly, topical microbicides – also poses scientific and ethical dilemmas.

Robin Shattock of London’s Imperial College asked how the research community would reconcile the need for double-blinded, placebo-controlled vaccine trials – which depend on a certain incidence of HIV infection in the population happening in order to show the vaccine is working – with the political and ethical imperative to roll out HIV testing, male circumcision and ARV-based methods. Would vaccine trials have to become impossibly large as we drive down HIV incidence by other means?

Shattock will be a co-chair of the next large conference to feature AIDS vaccine research. As mentioned at the start of this piece, AIDS Vaccine 2013 is the last international conference looking solely at this prevention method. The need to work on developing HIV prevention methods in a co-ordinated and combined way, so that they can reinforce each other rather than compete, has led to the decision to stop having conferences devoted to separate prevention methods and instead have an annual HIV Research for Prevention Conference, with the first one happening in Cape Town in South Africa in October 2014. By that time, we may already have a clearer vision of how to develop an HIV vaccine, long seen as the most elusive – but ultimate – goal of HIV prevention research.