A cure for HIV would almost inevitably have to involve a vaccine to improve the body’s natural ability to control HIV, a seminar on European HIV cure research heard recently. The STEPS seminar, held by the European AIDS Treatment Group (EATG) ahead of the 16th European AIDS Conference (EACS) in Milan last month, also heard that, in the words of Giulio Maria Corbelli, EATG member and European Community Advisory Board chair, “Cure research reminds us of the importance of patient involvement from the very earliest phases of the development of treatment and prevention.”
The cure: an elusive goal
Giulia Marchetti of the University of Milan opened the seminar with a general introduction to HIV vaccines, and particularly therapeutic ones.
She drew attention to an uncomfortable paradox in HIV cure. On the one hand, there are cases like the “Mississippi Baby” and the “Boston patients”, where someone is treated within hours of infection, or where cancer patients had what appeared to be their entire immune system replaced. In these cases, despite repeated assays failing to find even the slightest trace of HIV DNA buried inside cells, the virus came back from somewhere.
And yet we have the case of Timothy Ray Brown, now a decade into what appears to be a cure. We have elite controllers, who seem to be able to control their HIV viral load spontaneously, and we have “post-treatment controllers” such as those in the VISCONTI cohort and ones reported from Germany and France, that suggest that some people who receive early treatment may later be able to spend prolonged periods off treatment. These have been spontaneous cases, and we don’t as yet know why this happens to some people and not others.
In terms of attempting to deliberately induce viral control off therapy, we have been able to prolong the period a handful of patients can stay off therapy without viral rebound in one therapeutic vaccine trial, though others have been disappointing, and we have tantalising early results from vaccines and drugs in animal trials and in the test tube that indicate drug-free viral suppression for long periods, and even complete cure, may be possible.
Correlates of efficacy – how do we know what will work?
It is, however, still almost impossible to predict in advance what approach may work. Dr Felipe Garcia of the University of Barcelona Hospital is also one of the collaborating researchers in the European HIV Vaccine Alliance.
He told the seminar: “The problem with HIV vaccines is that what protects is not able to control and what controls is not able to protect.”
What he meant was that on the one hand, so-called broadly neutralising antibodies and vaccines that generate them – B-cell vaccines – may be able to completely block onward infection of cells by HIV, but tend to lose efficacy quickly as HIV is usually able to mutate enough to develop resistance to them, though one, PRO 140, has produced sustained viral load suppression for over a year. Experiments with combinations of ready-made broadly neutralising antibodies, including ones of novel design, showed more efficacy in human and monkey studies, but these were still passively introduced antibodies, used like drugs: the challenge was to produce a vaccine that could induce the body to make them.
Vaccines that stimulate the cellular immune response of cells to HIV – T-cell vaccines – could potentially generate a much longer-lasting immune response to HIV, but so far that response has been too weak and too narrow, at least in human studies, to produce more than a slight reduction in viral load, typically a threefold to tenfold (0.5 to one log) reduction in the size of the ‘reservoir’ of HIV-infected cells. A trial in monkeys produced much more sustained viral load reductions to the extent of producing an apparent cure in about half of them, but this vaccine may be tricky to adapt to humans.
Garcia quoted one mathematical model that suggested that an immune response would have to produce an ongoing ten thousand-fold drop in infected cells (4 logs) in order to produce lifelong remission.
He added that a more fundamental problem in vaccine trial design was that we still had no real correlates of immunity. Assays that have predicted efficacy in other vaccines in the past – such as the amount of interferon-gamma produced by cells – fail to do so for HIV vaccines. “After an immune response is validated by a trial,” said Garcia, “then I can tell you it’s a surrogate.”
Correlates of efficacy or immunity emerged from large-scale clinical trials, he said. But the problem in vaccines was that trials were very expensive – the RV144 trial, the only phase III study to find efficacy so far, had involved 16,000 participants and had cost €100 million. Multiple trials were needed to find an effective HIV vaccine, and it is estimated that over 35,000 volunteers will be required per year for phase I–III HIV vaccine trials worldwide to achieve this goal.
A better way is needed to select novel vaccine candidates for development, he said, and therapeutic vaccinations offered a way as trials of them did not need too many people. Even so, in a previous trial in which he had been involved, RISVAC02, 3056 volunteers had been screened to find 41 eligible candidates of whom 30 had eventually been enrolled.
Finally, because of the lack of surrogates, at present vaccine trials must assay and analyse a vast array of different proteins in case one of them turns out to be the crucial surrogate of efficacy. In a dendritic-cell vaccine trial Garcia was the principal investigator for, the activity of over 50,000 molecules was evaluated.
This all added up to a formidable task for vaccine researchers. However, by combining approaches, the chances of generating a ‘hit’ when it came to a truly effective immune response were increased.
Strategies recently had included the following:
- Latency-reversing agents such as PD-1 antagonists that prolonged the natural immune response to HIV and stopped the body ‘locking away’ HIV in the cellular reservoir.
- HIV Conserv vaccines that focused on generating immune responses to the particular parts of the virus it could least afford to change and discarded less-relevant responses.
- Combining vaccines with cytokines: these are specific cell-signalling molecules such as IL-15 and CXCR5 which are able to ferry vaccines and drugs into ‘sanctuary sites’ such as the lymph node follicles where HIV is normally able to replicate in cells that are shielded from immune-system surveillance.
- Dendritic-cell vaccines.
Garcia had taken a particular interest in the latter. He explained: “Dendritic cells are the first line of defence in infection. They capture foreign molecules and present them to immune system cells as antigens. You need to target dendritic cells because if these cells don’t say to the body ‘you are infected’, the body doesn’t know it.
“The problem with HIV is that it has developed a loop in its membrane that allows whole live viruses to attach to the dendritic cell which then ferries them to the lymph nodes as a ‘Trojan Horse’. But this does mean that if we develop a vaccine that attaches to dendritic cells, it could generate a strong cellular immune response in the lymph nodes, which is where it needs to be.”
The European HIV Vaccine Alliance is a consortium of 39 partners from eleven countries in Europe plus four in sub-Saharan Africa and the US. It is pursuing a number of different preventative vaccine strategies including improved viral vectors, modified versions of HIV envelope proteins and dendritic-cell vaccines.
Garcia is also a lead investigator in the 14-site HIVACAR consortium. This involves three different therapeutic vaccine strategies that will be used in HIV-positive people separately and in combination. Firstly, vaccine antigens will be developed that are targeted not only at the conserved parts of the virus (iHIVARNA) but also designed with individuals’ own HIV virus’s gene profile in mind – (HIVACAR – truly individualised vaccines). Secondly, the vaccines will be followed by injections of broadly neutralising antibodies. Thirdly, messenger-RNA molecules (already used as experimental cancer drugs) will be injected after the HIV antigens and antibodies. These will be used to sensitise dendritic cells to the HIV antigens and further stimulate an immune response that will – it is hoped – kill off the HIV-infected cells in sanctuary sites that other strategies have failed to do.
And these vaccine components will all be given intranodally – that is, injected into individual lymph nodes – in the hope that taking the vaccine right to the site of HIV integration and replication will kick-start a stronger immune response to HIV that, it is hoped, will dampen down HIV replication to the point where individuals can be taken off antiretroviral therapy.
The HIVACAR protocols are in phase I/II trials – that is, evaluated for safety and immunogenicity – and then the most promising strategies will be taken forward into dosing trials – with results expected in 2021.
The Cure symposium also heard from the RIVER trial, part of the UK-based CHERUB consortium. This study is combining initial inoculations with vector-based vaccines with subsequent doses of the drugs called HDAC inhibitors to see if the two strategies together work better together. HDAC inhibitors, which reawaken the quiescent HIV reservoir cells, were among the first drugs tried as HIV cure agents but while they did reverse viral latency, they did not produce a useful diminution in the size of the viral reservoir. It is hoped that by priming the immune system to recognise the virus that is produced by the ‘woken’ reservoir cells, this diminution will be achieved. RIVER involves 50 volunteers in six sites in England and is due to announce results next year.
The symposium also heard an update on the ICISTEM cohort of cancer patients who have been given bone-marrow transplants (the cure approach similar to that given to Timothy Ray Brown and the Boston patients) but this has largely been reported in our summary of the HIV Cure symposium at the IAS conference in July this year.
Involving the community
Finally, as Felipe Garcia told the symposium, no HIV cure research is complete unless it also involves community collaboration and research into the psychosocial impact of cure studies.
“Any innovative therapeutic approach in HIV infection has ethical, economic, and psychosocial consequences,” he said.
“In HIVACAR, a detailed study about these aspects will be conducted, involving both participants in the clinical trial and the greater community of people living with HIV. Results will be disseminated to people living with HIV, policy makers and the general public in Europe to better inform their future decisions.”
Fred Verdult is a person living with HIV in the Netherlands who has used his experience in advertising and marketing to conduct a number of community opinion surveys and publicity events for HIV cure research and its potential.
He presented the results of one survey that showed that 72% of a group of 457 people with HIV felt it would be “very important” to them personally if there was a cure for HIV and only 6% thought it would not be important. When asked what was the biggest disadvantage of living with HIV, by far the most widely cited (by 91%) was the risk of possible adverse health effects in the future – either side-effects due to long-term antiretroviral therapy, or health problems due to chronic infection. Fewer people cited actual adverse effects happening right now but they were still a consideration for a majority (66%), as was the risk of, or anxiety about, infecting someone (also 66%).
Verdult said that the question of when to interrupt treatment remained a major ethical problem in HIV cure research – a dilemma already being pondered by ICISTEM. But there was also the inequalities involved. Ethically, if there had to be a choice of which people should benefit first from an HIV cure, it should logically be chronically infected people who had suffered most for years with immune suppression and suboptimal HIV therapy (“First in, first out”). However, these were likely to be the most difficult people to cure, so, with the exception of cancer patients, cure research had largely concentrated on the most recently infected people with intact immune systems (“Last in, first out”). Was this fair, he asked.
Finally, there is the issue that treatment as prevention and pre-exposure prophylaxis (PrEP) might be at the point of succeeding in producing large reductions in HIV incidence worldwide. If it did, scientific and funders’ interest in cure research might slacken. He urged a step-up in the pace of cure research now, so as not to lose a “window of opportunity”.
By Gus Cairns