tag:theconversation.com,2011:/us/topics/hvtn-702-22995/articlesHVTN 702 – The Conversation2017-11-30T08:48:29Ztag:theconversation.com,2011:article/881842017-11-30T08:48:29Z2017-11-30T08:48:29ZDesigner proteins: the new generation of HIV vaccines being put to the test<figure><img src="https://images.theconversation.com/files/196907/original/file-20171129-29110-1acq34r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>South Africa has made tremendous advances in providing lifesaving antiretroviral therapy for HIV infected people. The country has the largest treatment programme in the world. </p>
<p>Despite this, the HIV epidemic continues to ravage key populations, especially young women. In 2016 there were more than <a href="https://www.spotlightnsp.co.za/2016/08/31/new-hiv-infections-sa-declining/">270 000 new infections</a> in South Africa – a figure which has been fairly consistent in recent years. </p>
<p>This continued spread of the disease suggests that treatment will not ultimately end this epidemic. An HIV vaccine remains an urgent need.</p>
<p>Many HIV vaccines have already been tested, using approaches that have led to effective vaccines for other infectious diseases. A trial in <a href="https://www.ncbi.nlm.nih.gov/pubmed/25341006">Thailand in 2009</a> was the first HIV vaccine to show some protective effect. But the 31% protection it offered was too low to warrant a wider roll out. </p>
<p>Follow-up trials to try and confirm the results in the Thai trial are now underway, including a large scale study of 5 400 volunteers in South Africa.</p>
<p>While the world waits for the outcomes of these trials, researchers have turned to new strategies based on lessons learnt from studying the immune system of HIV-infected people. For example, researchers now know, in extraordinary detail, how the immune system of some HIV-infected people is able to make rare antibodies, called broadly neutralising antibodies. </p>
<p>When tested in the laboratory these antibodies are able to block various strains of HIV from across the world. These are precisely the types of antibodies that a vaccine should ideally elicit. And scientists are using their findings as a roadmap to develop the next generation of HIV vaccines.</p>
<p>Three new vaccine concepts, all based on cutting edge protein engineering, will shortly, or have already entered human trials and have the potential to revolutionise the HIV vaccine field.</p>
<h2>Kickstarting the immune system</h2>
<p>All humans have millions of B cells in their bodies that produce antibodies and protect them from an infection. But only a small number of these B cells have the potential to produce the broadly neutralising antibodies that fight the HIV virus. </p>
<p>In the first new concept, high-tech nanoprotein engineering has enabled scientists to develop a designer protein called eOD-GT8. The protein is specifically engineered to trigger these rare B cells, and turn them into the broadly neutralising antibodies. </p>
<p>In <a href="http://www.sciencedirect.com/science/article/pii/S0092867415006868">studies in mice</a>, this “designer” protein was able to kickstart the process and set the immune system down the right pathway to fight the virus. </p>
<p>Over the next year eOD-GT8 will be tested in small-scale trials in humans to determine whether targeting these rare B cells is an effective way to generate the right kind of HIV antibodies.</p>
<h2>Making a good mimic of HIV</h2>
<p>A second challenge in HIV vaccine design has been to make a good mimic of the HIV proteins that broadly neutralising antibodies recognise. </p>
<p>This approach, of presenting the immune system with a close mimic of viral proteins, has been the basis of most vaccines, including the polio and hepatitis vaccines.</p>
<p>But the challenge with the HIV protein that is targeted by broadly neutralising antibodies is that it rapidly falls apart when it is produced in a laboratory. As a result, it is not a good mimic. For the past 10 years, scientists have tried to come up with new ways of preserving the complex structure of this HIV protein. </p>
<p>Only recently, using an African virus isolated many years ago, vaccine researchers have finally learned how to biologically “glue” this envelope protein together using chemical bonds, resulting in a good mimic of the protein as it exists on the virus. </p>
<p>This stable protein, called BG505.SOSIP has shown promise in <a href="https://www.ncbi.nlm.nih.gov/pubmed/26089353">vaccine studies</a> in monkeys, where we now see better antibodies than with previous proteins. </p>
<p>BG505.SOSIP will also soon be tested in small-scale trials in Africa and the US to see whether humans also recognise this protein, and make antibodies that would be able to block virus infection. </p>
<h2>Training the immune system</h2>
<p>The third new approach is based on how antibodies and HIV change over time in infected people. Research in South Africa and in the US has shown that antibodies become “broader” over many years, through an “arms race” between the virus and the immune system. As antibodies attempt to stop the virus, it mutates to escape and changes its coat. </p>
<p>Newly emerging antibodies learn to recognise the different coats the virus has tried. In doing so, some antibodies become experts at recognising every form of HIV. Eventually this leads to antibodies able to recognise viruses from across the world, the broadly neutralising antibodies that vaccines aim to elicit.</p>
<p>In a trial that started in August, scientists in the US are using this knowledge to vaccinate volunteers with four different coat proteins representing viral changes, in the same order seen in an HIV infected person. The hope is that this will train the immune system to recognise many different viruses, so that in the event of a future virus exposure, these antibodies will provide broad protection against HIV infection.</p>
<h2>Towards an AIDS-free future</h2>
<p>The next two years will therefore be a critical phase for HIV vaccines. Not only will we learn whether more traditional approaches, such as the Thai vaccine, can be improved enough to roll out. </p>
<p>We will also learn whether these three entirely new concepts, the result of years of research by scientists across the world, can reshape the HIV prevention landscape and, hopefully, take us closer to ending the HIV pandemic.</p><img src="https://counter.theconversation.com/content/88184/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Penny Moore receives funding from the National Research Foundation, the South African Medical Research Council and the US National Institutes of Health.
</span></em></p><p class="fine-print"><em><span>Lynn Morris receives funding from the South African Medical Research Council, the National Research Foundation, the US National Institutes of Health and the Bill and Melinda Gates Foundation. She is a member of the Board of the Global HIV Vaccine Enterprise.</span></em></p>Three new HIV vaccine concepts which rely on high-tech designer proteins are being trialled to see if they can stop the virus.Penny Moore, Reader and DST/NRF SARChI Chair of Virus-Host Dynamics, National Institute for Communicable Diseases, CAPRISA Research Associate, University of the WitwatersrandLynn Morris, Medical Scientist at the National Institute for Communicable Diseases; Research Associate at CAPRISA; Research Professor in the School of Pathology, University of the WitwatersrandLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/679872016-11-01T13:32:51Z2016-11-01T13:32:51ZExplainer: the how, what and why of the latest HIV vaccine trial<figure><img src="https://images.theconversation.com/files/144042/original/image-20161101-8691-1jgg4qi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p><em>As the global quest for an HIV vaccine continues, Linda-Gail Bekker explains the significance of the <a href="http://m.news24.com/news24/SouthAfrica/News/hiv-vaccine-historic-trial-begins-20161029">latest large-scale trial</a> underway in South Africa.</em> </p>
<p><strong>What’s the significance of the trial for the global fight against HIV?</strong></p>
<p>The world needs an HIV vaccine. Our prevention toolbox is better than it has ever been. But there is increasing recognition that the world needs to scale up primary HIV prevention.</p>
<p>Effective vaccination is the poster child for prevention – it is the thing we are missing. If we can get that we can talk about eliminating HIV across the world. </p>
<p>It is fantastic that once again a vaccine is being put into the field. The only way scientists can really learn and understand human immunity is through human clinical trials. I think everyone agrees that laboratory and animal research can only take us so far. </p>
<p>There has been a decrease in the incidence of HIV in some parts of the world. The best news is the impressive downturn in mother-to-child-transmission. </p>
<p>But this is an epidemic that needs constant surveillance because it is still on the rise in many parts of the world. We cannot be complacent. Reduction rates in adult infections are stalling. We are not on course to meet the targets set for 2030 to get the epidemic under control. </p>
<p>But we shouldn’t hang everything on getting a vaccine, as important as that is. The world also needs a primary prevention revolution. If we are really intent on getting the epidemic under control by 2030, we need a call to prevention action while working hard on a definitive vaccine. </p>
<p><strong>What does the trial entail? How will it be done?</strong></p>
<p>This trial – HVTN 702 – is based on a trial from <a href="http://www.aidsmap.com/The-RV144-trial/page/2028003/">Thailand in 2009</a> which showed a 31% reduction in HIV after three years. It is important to note that after 12 months the vaccines showed 60% efficacy. </p>
<p>In the South African study we are hoping to increase the potency and durability of its effect to reach at least a 50% reduction in HIV infection after three years. </p>
<p>There will be 5400 participants aged between 18 and 35 (the most at risk age group) at 15 sites across South Africa. And there are two vaccine products in the regime. The participants will get five shots over the first year. Some of the shots include just one product and some involve both products. The shots are given into the muscle of the upper arm by injection, much like a tetanus or measles vaccine.</p>
<p>This is an efficacy trial. The main question it will answer is: does the vaccine work? To get to this question, the trial is designed so that half of the cohort will get a sham vaccine and half will get a real vaccine, with neither research site staff nor participant knowing which. The cohort will then be followed up after three years when the number of infections in each cohort will be counted.</p>
<p>At that point we will ask whether more infections occurred in the one cohort compared to the other. We will then be able to conclude whether and by what margin the vaccine has been able to prevent HIV infections. That will give us an indication of the vaccine’s efficacy.</p>
<p>This trial also follows an initial “lead in” safety and immunogenicity trial (<a href="http://www.aids2016.org/Media-Centre/The-Latest/Press-Releases/ArticleID/62/New-vigour-in-HIV-vaccine-research-evident-at-AIDS-2016">HVTN100</a>) of the vaccine regimen conducted last year with 252 people in six sites in South Africa. This gave the green light for the HVTN 702 trial. </p>
<p><strong>How is this trial different from the one in Thailand?</strong></p>
<p>The vaccine being used in South Africa is very similar to the one used in an earlier trial in Thailand <a href="http://www.aidsmap.com/The-RV144-trial/page/2028003/">(RV144)</a>. The virus products in that vaccine – RV144 – were designed to reflect the HIV that is circulating in Thailand (subtype BE). In the last five years scientists have modified the inserts in the vaccine to be compatible to the subtype of the virus circulating in southern Africa (subtype C).</p>
<p>Apart from the different inserts, scientists have also changed the adjuvant, which is an agent often used with vaccines to give the immune system an additional boost. In Thailand the adjuvant alum was used. In South Africa we are using a well known adjuvant called MF59, which is also widely used in the flu vaccine. </p>
<p>The last thing we are doing differently in this trial is that the South African participants will receive an additional vaccine boost at 12 months. In Thailand everyone got all their boosts within the first six months. </p>
<p><strong>When will first results be known? And then what happens?</strong></p>
<p>It will take us 12 to 18 months to accrue participants. The study will end when all participants have completed three years of the vaccination regime. </p>
<p>During the three years there will be opportunities for a special safety committee to look at the data in an “unblinded” fashion to check whether we have a winner early on, whether the trial is not going to yield any meaningful results or if there are important safety concerns. </p>
<p>This is important because if the vaccine is shown to be working we will be able to move towards licensing the vaccine for HIV.</p>
<p>In addition, the minute we know it works we would want to do bridge studies in other parts of Africa and then in other parts of the world. </p>
<p><strong>Why is this trial being done in South Africa?</strong></p>
<p>The trial is a partnership between a number of entities, vaccine developers and funders, including the South African Medical Research Council. Southern Africa was chosen as the trial site because of the very high burden of infection in the region.</p>
<p>It is important to see if we can get a vaccine that works in the world’s toughest region. </p>
<p>Up to 300 young women get infected with HIV in South Africa every day. The overall prevalence in South Africa is 19.2% but we know there is a wide range across areas and some populations are more affected than others.</p>
<p>South Africa has <a href="http://www.unaids.org/en/regionscountries/countries/southafrica">7 million people with HIV</a>, almost <a href="http://www.avert.org/professionals/hiv-around-world/sub-saharan-africa/overview">one-fifth</a> of the global HIV positive population. It treats more people than any other country with anti-retrovirals, consuming one-quarter of global generics.</p><img src="https://counter.theconversation.com/content/67987/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Linda-Gail Bekker receives funding from a number of academic funding agencies including the NIH (USA). She is currently the President of the International AIDS Society.</span></em></p>For the next five years South Africa will be leading one of the latest large-scale trials for a vaccine for HIV.Linda-Gail Bekker, Professor of medicine and deputy director of the Desmond Tutu HIV Centre at the Institute of Infectious Disease and Molecular Medicine, University of Cape TownLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/511622015-11-29T13:54:53Z2015-11-29T13:54:53ZTwo trials signal pivotal point in fight against the AIDS epidemic<figure><img src="https://images.theconversation.com/files/103444/original/image-20151127-11640-t9nnyb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A women gets an HIV test. Sub-Saharan Africa accounts for the majority of the HIV deaths annually. </span> <span class="attribution"><span class="source">World Bank Collection/flickr</span></span></figcaption></figure><p><em>Foundation essay: This article is part of a series marking World Aids Day. Our foundation essays are longer than usual and take a wider look at key issues affecting society.</em></p>
<p>There is no doubt that the crisis caused by the HIV pandemic requires urgent and bold steps. While the roll-out of anti-retroviral therapy has had a significant impact on the epidemic, there are still 1.5 million deaths and two million new <a href="http://www.unaids.org/en/resources/campaigns/HowAIDSchangedeverything/factsheet">HIV infections</a> globally every year. In South Africa alone, there are <a href="http://www.unaids.org/en/regionscountries/countries/southafrica">more than six million</a> people living with HIV. Only 42% of these people are being treated with anti-retrovirals. </p>
<p>In the long-term, the use of anti-retrovirals to control the HIV epidemic is unrealistic. Our best hope for an AIDS-free future is the development of a vaccine. Two major clinical trials are set to begin in South Africa in 2016. Both seek to test whether antibodies, which circulate in blood and are part of our natural defence to infection, can prevent new HIV infections. </p>
<p>The first trial, called HVTN 702, relies on the classical approach of active immunisation. Here a vaccine designed to mimic an infection causes the body to make antibodies to HIV. </p>
<p>The second trial, called AMP or antibody-mediated protection, will run in parallel to the first trial. It will use manufactured antibodies that are infused into the body. This approach, called passive immunisation, has been employed for over a 100 years to treat a variety of infectious diseases. This has only recently become an option for HIV. This trial is unprecedented in HIV prevention research.</p>
<p>We are at a pivotal stage in HIV vaccine development. Conducting two large scale efficacy trials in the region of the world with the highest HIV prevalence heralds a new more aggressive approach to tackle what is our most serious public health threat. </p>
<h2>Active vaccination</h2>
<p>The HVTN 702 vaccine trial was inspired by the results of an earlier trial – <a href="http://www.aidsmap.com/The-RV144-trial/page/2028003/">RV144</a> – conducted in Thailand. This trial showed a modest 31% efficacy and provided the first ever indication that a vaccine against HIV may be possible. </p>
<p>This vaccine is now being tested in southern Africa, but it has been tailored to match the viruses circulating in this region. There are also other modifications that are intended to improve on the efficacy of the vaccine which will hopefully facilitate its licensure. </p>
<p>The vaccine comprises two components that stimulate the body’s disease fighting immune helper cells as well as antibodies. </p>
<p>The first, a cellular response, uses a harmless canarypox virus that has been engineered to carry small pieces of HIV. This tricks the body into thinking it is under attack so that it mounts an immune response to HIV. </p>
<p>For the other component – the antibody response – soluble protein derived from the outer envelope coat of the virus are recreated in the laboratory, and used to elicit antibodies to HIV. In RV144, individuals who developed antibodies to a small fragment of envelope called the variable region 1 and 2 (V1V2) had a reduced risk of HIV infection. As such, these immune responses are used to benchmark future trials. </p>
<p>Since the trial in South Africa is using a newly configured vaccine, it first needs to undergo safety and immunogenicity testing. As such, a small trial involving 252 healthy people at low risk of HIV infection is currently taking place.</p>
<p>If the results look promising then HVTN 702, the large efficacy trial that will be done in high-risk individuals, will proceed. For this, more than half the participants in the small safety trial must have V1V2 binding antibodies and HIV-specific helper cell responses. </p>
<p>The decision to go ahead with HVTN 702 will be made in the first quarter of 2016. If this happens, 5400 people will be enrolled at various clinical sites across South Africa. Half the participants in the trial will receive the vaccine, while the other half will receive a placebo, which contains no HIV components. Neither the participants nor the study co-ordinators will know who received the vaccine or placebo. This is known as a double-blinded randomized clinical trial, or RCT and is the “gold standard” for assessing whether a product actually works. </p>
<p>The participants will be followed for up to three years for evidence of HIV infection. If there are significantly fewer infections in those who received the vaccine, it will be considered efficacious and may be licensed. If the vaccine is able to reduce the number of infection by at least 50% it will be considered suitable for general use. It will also be expected to have a major impact on the HIV epidemic.</p>
<h2>Gaining new ground</h2>
<p>While HVTN 702 takes place, the antibody-mediated protection (AMP) trial will be conducted concurrently in the region. This trial will test a related but different concept: whether a pre-formed antibody (called VRC01), which was cloned from an antibody-producing cell isolated from an HIV-infected individual, can prevent HIV infection after it has been transferred into the body. </p>
<p>To participate in this trial, 1500 healthy HIV negative women who are at high risk of HIV infection will receive intravenous infusions every two months for 20 months. </p>
<p>This is also a randomized controlled trial and women will be split into three groups. The first 500 women will receive VRC01 at the higher dose while 500 will receive a lower dose of the antibody. The remaining 500 women will receive a placebo. The volunteers will be studied for over two years with HIV infection as an end-point. During the trial, they will be counselled on safe sexual practises.</p>
<p>Unlike the binding antibodies which are induced by vaccination, VRC01 is a broadly neutralizing antibody. This antibody targets the part of the viral envelope that is needed to bind and infect human cells (similar to a lock and key). Since it targets an essential part of the viral life cycle, this antibody shows excellent coverage and is able to block infection of the majority of global viruses, including those circulating in South Africa. VRC01 has already been shown to be safe in humans and to prevent infection in monkeys. </p>
<p>The purpose of this trial is to provide important proof-of-concept that broadly neutralizing antibodies can prevent HIV infection in humans. Although no vaccine has yet been able to stimulate these types of antibodies, many believe that a highly efficacious vaccine will depend on this. </p>
<p>In addition, this trial will provide an important benchmark for HIV vaccines by revealing the dose of antibody needed to protect an individual from HIV infection. If the trial is shown to work, it will open options to use antibodies as drugs to prevent HIV infection, which is similar to <a href="http://www.cdc.gov/hiv/basics/prep.html">pre-exposure prophylaxis</a> or PreP. </p>
<p>There is also the possibility in future of using more potent antibodies or combinations of antibodies or those engineered for improved efficacy and longevity. The use of gene therapy is also being explored. In this case antibody genes are inserted into a vector which then becomes a local antibody-producing factory inside the body.</p><img src="https://counter.theconversation.com/content/51162/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lynn Morris receives funding from the South African Medical Research Council, the National Research Foundation, the US National Institutes of Health and the Bill and Melinda Gates Foundation. She is a member of the Board of the Global HIV Vaccine Enterprise. </span></em></p><p class="fine-print"><em><span>Penny Moore receives funding from the National Research Foundation, the South African Medical Research Council, the Poliomyelitis Research Foundation and the US National Institutes of Health. </span></em></p><p class="fine-print"><em><span>Nono Mkhize and Zanele Ditse do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Two major clinical trials will be conducted in South Africa in 2016 to test ways of preventing new HIV infections.Lynn Morris, Medical Scientist at the National Institute for Communicable Diseases; Research Associate at CAPRISA; Research Professor in the School of Pathology, University of the WitwatersrandNono Mkhize, Medical Scientist, National Institute for Communicable DiseasesPenny Moore, Reader and DST/NRF SARChI Chair of Virus-Host Dynamics, National Institute for Communicable Diseases, CAPRISA Research Associate, University of the WitwatersrandZanele Ditse, Medical Scientist, National Institute for Communicable DiseasesLicensed as Creative Commons – attribution, no derivatives.