By – Professor Lynn Morris, Professor Carolyn Williamson & Dr Kathy Mngadi
We are at a pivotal point in the pursuit of a vaccine against HIV. Two large efficacy trials will begin in 2016, both aimed at testing whether antibodies can protect against HIV infection.
The first is a classical vaccine approach based on active immunization while the second will test a passively administered broadly neutralizing antibody. Results from these trials are expected in 3-4 years’ time at the earliest.
There have also been significant advances in the laboratory that are delivering new vaccine concepts which are being fast-tracked for testing. On the eve of AIDS 2016 we reflect on the progress we have made, since we last met in Durban in 2000, towards the development of the ultimate game-changer for the HIV epidemic: an HIV vaccine.
New vaccine trials in populations at risk of HIV infection
A major global effort has focused on building on the success of the first partially effective vaccine that was tested in Thailand in 2009, which protected 31% of people from HIV infection. Although protection has been linked to the presence of antibodies that bind to a part of the viral envelope (known as variable loop 2 or V2), the reason why this vaccine worked is still under investigation. HIV is a highly diverse virus and so the Thai vaccine was redesigned to target clade C viruses that are dominant in southern Africa.
The trial will recruit 5 400 people in South Africa at risk of HIV infection, who will receive a total of five vaccinations over a year. The vaccine is comprised of two parts, a canarypox vector prime (ALVAC) and a protein boost, both of which contain fragments of HIV that stimulate the body to mount an immune response to HIV.
If, after 3 years, at least 50% of people are protected, the vaccine will be considered successful and rolled out for general use. Even at this level of protection, this vaccine could have a significant impact on the epidemic. The decision to move forward with this vaccine was dependent on results from a smaller trial showing that it is safe and able to stimulate the right kinds of immune responses. As all criteria were met, the large vaccine trial known as HVTN 702 was given the green light in April 2016 and will start in November of this year.
It has taken seven years of planning and the formation of the Pox-Protein Public-Private Partnership (P5) to get to this point. P5 comprises the South African Medical Research Council, the National Institute of Allergy and Infectious Diseases (NIAID), the HIV Vaccines Trial Network (HVTN), the Bill and Melinda Gates Foundation, the US Military HIV Research Program and vaccine manufacturers (Sanofi Pasteur and GSK). A similar plan to test this vaccine in large efficacy trials is also planned for Thailand using the original vaccine that is based on circulating strains in that country.
Another vaccine, developed by Janssen Pharmaceuticals and which showed encouraging results in animal studies, is also on track for large scale testing in humans (possibly in 2017). This vaccine will also use a prime boost approach, however, in this case, it will comprise an Adenovirus 26 (Ad26) vector and a protein boost. The vaccine contains mosaic HIV genes that are designed to target viruses from around the world and will be evaluated in southern and east Africa, as well as in Asia.
Other promising vaccines that are still in the animal phase of testing include a cytomegalovirus-based vector, which persists for a long time following vaccination and induces an extraordinarily large number of cellular immune responses. An HIV vaccine based on VSV that was used to make the successful Ebola vaccine is also under development.
Ramping up to AMP
Probably the most remarkable development in the vaccine space has been the advent of passive immunization for HIV prevention.
This new approach was made possible as a result of the discovery of broadly neutralizing antibodies that have the ability to kill a large number of HIV viruses from different clades. A vaccine with high efficacy is likely to require antibodies with this kind of activity, but to date no vaccine has managed to do this. However, the isolation of these antibodies from infected people, and the ability to make them in large quantities in the laboratory, has allowed us to directly test this.
This is the concept behind the ‘AMP’ (antibody mediated protection) study, which started in the Americas and Africa in 2016 and will enrol a total of 4 200 people at risk of HIV infection. This trial is being done as a collaboration between the HVTN and the HIV Prevention Trials Network (HPTN). A monoclonal antibody, called VRC01, will be directly infused into the bloodstream of human volunteers to determine whether it can protect against HIV infection and what levels of antibody are needed. The antibodies will decay over time, and repeated infusions will be needed to keep the levels high enough to provide protection.
The use of antibodies as passive immunisation is a well-established approach to provide protection from other infectious diseases such Rabies and Respiratory Syncytial Virus. This monoclonal antibody, while providing invaluable information for vaccines, is not planned as an end-product as there is a pipeline of better, more potent antibodies which can be used alone, or in combination to increase the chances of killing more viruses.
Other modes of antibody delivery, including subcutaneous injections and gene therapy, are also being explored. It is important to remember that passive immunization provides temporary protection, unlike a vaccine which generally gives life-long protection.
How basic research is helping us make better vaccines
Until now, a major hurdle in the development of an HIV vaccine has been the inability to make proteins that look like those on the virus particle and are suitable for manufacture. The trimeric viral envelope spike which is the target of neutralizing antibodies is a highly complex protein that has eluded structural biologists for decades. With new technologies this puzzle has finally been solved and initial studies in animals have shown that these laboratory-generated envelope proteins do induce better neutralizing antibodies. There is a major push to test these proteins in small experimental trials to see if they can stimulate neutralizing antibodies in human volunteers.
How to elicit broad and potent neutralizing antibodies remains the biggest challenge in vaccine research. This is because HIV has devised cunning ways to avoid detection by the immune system. It has an extraordinary ability to mutate and in addition the HIV envelope cloaks itself with sugars (glycans) making it difficult for antibodies to reach vulnerable sites. This plasticity allows HIV to continually evade the neutralizing antibody response, like a perpetual game of cat and mouse.
Furthermore, only some HIV-infected people make broadly neutralizing antibodies after many years into the infection. This, together with the unusual features of HIV antibodies, highlights how difficult it is for the human immune system to make these types of protective antibodies.
Several landmark studies in the last few years by a number of research groups around the world have provided clues as to why and how some HIV infected people make broadly neutralizing antibodies. These studies were only possible because of HIV infected people enrolling into studies and continuing to participate in them for long periods of time.
Perhaps one of the most important clues is the need for the immune system to see and adapt to variation in the viral epitope that is the target of broadly neutralizing antibodies. What that means for vaccination strategies is that we may need to make and test a whole series of vaccines that vary slightly from each other and that drive the antibody response along the pathway towards neutralization breadth. In other words we need to mimic viral evolution by vaccination. This is unprecedented in the history of vaccination and would obviously make the manufacture and delivery of such a vaccination approach more complex.
The journey of vaccine discovery
Even though an HIV vaccine remains elusive, we have come a long way since Durban 2000. Unlike vaccines for Ebola (and possibly Zika), HIV presents a far bigger scientific challenge. That we still do not have an effective HIV vaccine despite tremendous efforts is testimony to the inherent difficulties in doing this. The next decade is likely to bring more significant advances and we await the outcome of the two large efficacy trials with anticipation. Successful products would, without doubt, bring about a major paradigm shift in the fight against the global AIDS epidemic.
* Professor Lynn Morris is the Head of HIV Research at the National Institute for Communicable Diseases.
*Professor Carolyn Williamson is the Head of the Division of Medical Virology at the Institute of Infectious Disease and Molecular Medicine, Professor at University of Cape Town.
*Dr Kathy Mngadi is Honorary Lecturer in the School of Laboratory Medicine and Medical Science at the University of KwaZulu-Natal