What is the current state of research on HIV prevention, at the end of 2017, 1 year after the last edition of the HIVR4P conference? What are the main aspects of the research?
There are 2 main aspects. One is the search for a prophylactic vaccine. The second, which has been making very rapid progress recently and which is essential, is passive prophylaxis based on Pre-exposure prophylaxis (PrEP). The latter currently relies on the use of Truvada but many trials are currently in progress or have been completed, which aim to explore the use of injectable treatments. The other avenue of exploration involving a passive prophylaxis relies on the use of broad-spectrum neutralizing antibodies. PreP is currently the most advanced path because it has already been proven to be effective in several phase 2–3 trials. Nevertheless, the medium- and long-term vision concerning the vaccine options is much clearer than it was in the past with, for example, the creation of a new phase 2–3 preventive trial that began in 2016 in South Africa, the HVTN 702 trial,1 which follows a vaccination regimen very similar to the one in the Thai RV144 trial. This trial relies on the induction of non-neutralizing antibodies, which were shown to be protective in the RV144 trial.2,3 Other clinical trials intended to explore different strategies, which already seem promising, will also be starting. These strategies rely on the induction of neutralizing antibodies or cellular immunity.4
What are the characteristics of the vaccine trial in South Africa?
The only clinical trial of an HIV vaccine that has yielded interesting results to date is the RV144 trial2 (a trial combining the use of a canary pox vector coding for the gag, pol, and env and gp120 envelope proteins, which reduced infections by 31.2% 3.5 years after vaccination). This trial was conducted in Thailand using a combination of recombinant viral vectors and envelope proteins made from viral strains identical to those circulating in Thailand. The question was then raised of the reproducibility of the results of this trial and its transposition elsewhere in the world, particularly in Africa. This was implemented in several stages.
After the RV144 trial, a number of correlates of protection were described, that is, immune responses that were associated with protection against infection in this trial and based primarily on the induction of non-neutralizing antibodies.3 The first step was to see whether this type of strategy could induce the same type of immune response in African populations, whose genetic background is different. This was validated in the HVTN 097 trial. Then, taking the same type of vaccine combination, it was necessary to use vaccines developed from viral strains present in Africa but no longer in Asia, and to confirm that this association was immunogenic. This was also validated in the HVTN 100 trial. After the positive results obtained in these 2 trials, a phase 2-B trial was conducted, that is, we went on to analyze whether the vaccination strategy protects against infection. One of the problems of the RV 144 trial is the short duration of the protection. It is relatively long at 1 year (60%) but falls steadily over time. As such, the scheme of the HVTN702 trials was amended slightly with later booster shots in the hope of obtaining more prolonged protection. All in all, the HVTN702 trial is based on the same type of vaccine strategy but with a slightly more complex scheme to obtain a potentially more long-lasting response.
Vaccine trials are currently taking place, or have recently taken place, in France and Europe: what is their position in relation to these 2 large-scale movements in Asia and Africa, the relationship between which you make very clear?
To put it simply, there are currently 3 main avenues of research from an immunological point of view. The first avenue that we shall discuss is the post-RV144 trials, which aim to induce non-neutralizing antibodies. The second aims to induce broad-spectrum neutralizing antibodies. Neutralizing antibodies are the type of antibodies that one usually seeks to induce after vaccination. They act by preventing infection of the target cells and therefore, when they are present, very effective protection is induced. The problem with HIV infection is that this type of antibody must be able to neutralize all the viral strains, which are very diverse. It was long thought that it would be impossible to develop vaccines with such a capacity. However, we now know that such antibodies can be generated during natural infection. The problem is to use a vaccine to reproduce this induction, which requires a complex process with multiple interactions between the virus and the immune system that would need to be reproduced with a vaccination strategy.5 We are really in a very early phase here, with research essentially performed on animal models. Finally, there is one last, rather advanced, approach based on the use of a vaccine that induces a cellular response. This vaccine is being developed by the team of Louis Picker and relies on the use of a vaccine vector derived from the Cytomegalovirus virus.6 They will soon move on to the first phase-1 trials in humans with the aim of assessing the tolerance of this type of vaccine. Other avenues are of course currently under study. It would be difficult to describe them all but in general, what will change is not the immunological target, which will still be the target of the 3 avenues described above, but the type of antigen, the manner of presentation, the number of injections, the types of adjuvant used, etc. Everything being done outside the HVTN 702 trial is at an early stage of phase 1 or phase 2 for the purpose of examining immunogenicity. We are still in the relative early phases; we are still conducting immunological studies. We will not be looking at how to prevent the infection but just at the immunological efficacy of the vaccine strategies.
Let us return to the first question and look at it from a different angle: how can we assess the importance of these areas of research today from a financial point of view, given the number of researchers and research networks?
We can clearly see that research on drug prophylaxis receives an enormous amount of support, which it did not have a few years ago. It is quite important at the present time for several reasons. First of all, when PreP is effective, its efficacy is quite remarkable. The absence of efficacy in certain populations seems to be clearly linked to a problem of adherence7 and not to a fundamental, intrinsic defect in what we are using, as is the case in the context of a vaccine. An enormous amount of investment can therefore be expected in the social sciences to understand how to improve adherence to this type of strategy. Finally, the use of the available drugs in an injectable form, with one dose every month or every 2 months, should improve compliance to a great extent.
If we examine the cost of the strategies, the vaccine has the advantage that it only requires several injections to be effective over the long term. PreP, however, must be used daily, or very regularly in the case of intermittent PreP. The arrival of generics in Western countries should reduce the cost enormously. However, PreP remains effective for populations who are at a high risk of infection.8
When a vaccine trial is conducted, the main costs are related to (1) the development of the vaccine, (2) the study of its immunogenicity, and (3) the practical execution of the trial. Only the latter cost is important in a trial to evaluate PreP. The drug is already known and available, and it is not necessary to study the immune response; so, the cost is minimal. To date, PreP has demonstrated its efficacy in high-risk homosexual populations. It is therefore necessary to evaluate its effectiveness in other populations where the incidence of the disease is lower. That can be interesting. In terms of investment in clinical research, vaccine research and PreP research are at about the same level, but the cost of vaccine development is much higher.
Who are the main donors of funds today?
HIV vaccine research accounts for less than 2% of the world's total investment in the field of HIV, including patient care.9 In 2016, 1.17 billion dollars was invested in preventive research. The breakdown of the various providers of funds is as follows: US public sector (75%), Bill & Melinda Gates Foundation (12%), other public sectors (6%), private investors (5%), and other charity organizations (1.5%).10 The pharmaceutical industry has taken a step back for some time from anti-HIV vaccine research. Recently, some industrial partners have resumed this work, particularly the Janssen laboratory. This laboratory, like others, is developing new vaccine platforms based on the use of viral vectors in particular, with the idea that HIV will open up new vaccine paradigms. To give you an example, whatever will be used for HIV is used for Ebola, and may be used in the future for the Zika virus or tuberculosis. Entities in the industry are therefore once again interested in pursuing HIV research, although for a very long time they had completely given up.
Is there anything particular about France when it comes to research on a preventive HIV vaccine?
Yes and no. Things are of course different in other countries. The low incidence of HIV infection in France means that it is not feasible to conduct phase-2B or phase-3 vaccine trials, or they would have to be conducted in very high-risk populations such as men who have sexual intercourse with other men. Many of these trials are conducted under the aegis and with the support of the ANRS. Finally, it is important to keep in mind that we are in a country where vaccination is a sensitive topic; we are the country where it raises the most problems, so necessarily, whether we like it or not, this interferes with the performance of clinical trials. Even if we ultimately only recruit a very small number of volunteers, it is obvious that this is made more difficult for us because of this perception. Furthermore, unlike what has been done in many other countries for a very long time, we did not compensate the volunteers, and we continue not to compensate them. We reimburse their expenses more than we compensate them for their participation.
This work specifically concerns the recruitment of volunteers. What are the legal and ethical matters involved in the recruitment of healthy volunteers?
In 2017, it is possible to recruit healthy volunteers for trials anywhere in France. However, it should be noted that the centers that want to conduct trials of preventive vaccines on healthy volunteers must have a specific permit, that is, a permit to operate a biomedical research site (Autorisation de lieu de recherche biomédicale). Just because we often conduct clinical trials among patients does not mean that we can conduct clinical trials among healthy volunteers. This permit, which we have to obtain from the Regional Health Agency (Agence régionale de la santé, ARS), is very specific and has precise requirements that must be complied with. Then, when we submit a draft clinical trial to the ANSM (French national agency for the safety of drugs and medical products) and the CPP (Committee for the Protection of People), certain points will be verified. Obviously, because these trials are aimed at healthy volunteers and currently solely concern the study of the biological efficacy of immunogenicity, the balance between risk and benefit must be very much tipped toward the benefit. The risk must be minimal and everything must be done to ensure this.
What are the benefits?
The benefits are very complex in this case because there is no specific medical benefit in receiving a vaccine in phase 1 or 2 of a trial. The benefit can be social: feeling like a part of research, taking part in research on a pathology for people who would not be able to afford it financially and who want to be involved, in the same way that they donate their bone marrow.
When we interview volunteers, some of them make this comparison spontaneously. And for someone in good health, participating in a clinical trial is one of a number of other engagements such as blood donation. However, engagement in a trial is much longer and much more costly in terms of availability, compliance, etc. It is something entirely different to take part in a vaccine trial for 8 or 10 months. PreP raises other questions. So is it really comparable?
The relevance of the comparison is necessarily limited. The profile of people who are recruited during a clinical trial has varied a little over time. If we take trials that were conducted several years ago, there was really this very strong idea of the commitment of the participants. The people participating were clearly personally affected. They included family and friends of people suffering from the disease or who had died from it. It was very clear that the volunteers wanted to take part in these trials because of their relationship with someone who had been ill, as is very often the case with donations for cancer. We had volunteers who had already been involved elsewhere in various kinds of donations of their body (blood donation, various associations, or other), as well as somewhat older people. We changed the way we recruit volunteers. We now use a strategy that aims to recruit younger volunteers and involves, in particular, less drastic exclusion criteria regarding sexual behaviors. Thus, the exclusion criteria concerning sexual activity, which is obviously correlated with the risk of acquiring the HIV infection, were initially very strict because these criteria had been defined at a time when no antiretroviral treatment yet existed. The people who conducted these trials always bore in mind the risk that volunteers would think that they were in a trial for a vaccine which was going to be truly effective, that they were going to be protected, and that there was a guarantee they would not be infected. It was therefore necessary to recruit volunteers whose sexual life was in perfect order, that is, with more or less one partner in their entire lives. This approach was changed radically and a decision was made to align with what was being done in other countries, that is, people were recruited whose sex life corresponded with their age. By this, I mean that the number of partners during the year will obviously be very different at the age of 20 compared with at the age of 50. We modified these criteria and therefore somewhat modified the sociology of the trial participants.
You mentioned the fact that the way AIDS is perceived has changed due to the appearance and availability of antiretroviral treatments. HIV resembles a chronic disease although socially it is not comparable with cancer, which is seen as potentially affecting everyone. The question of engagement has also changed. HIV is no longer a cause or an issue that mobilizes people to organize and take action. Have these changes in the social aspects of the disease changed how you recruit?
The way in which we recruit has not affected the perception of the virus among the general population. However, judging by the responses of volunteers when asked, this perception is completely different from what it used to be a few years ago. To put it simply, we now see much less of an impact by HIV itself in engagement compared with the past. This means that volunteers take part in preventive vaccine trials for a whole range of reasons. The fact that the trial is for Ebola or HIV seems to be a less obvious and decisive factor than it used to be a few years ago.
But there are works nevertheless which show that there is still discrimination
Absolutely. However, it is less obvious now than in the past when we recruit volunteers and talk to them.
In this context, what role can anti-HIV associations play in the recruitment of healthy volunteers for vaccine or PreP trials?
Associations necessarily have an important role to play in the recruitment of subjects, regardless of whether this is for the purpose of preventive trials. However, at present, associations are essentially patient associations or associations of people who are very close to patients or very involved in HIV pathology. It is therefore much easier to recruit for PreP-type trials than for prophylactic vaccine trials because in PreP-type trials, you look for people who are at risk of HIV infection. This therefore involves a type of volunteer who has been clearly identified by the people whose work is typically related to HIV. For prophylactic vaccine trials, the general population is targeted more, which has very different expectations and demands. This is why it is sometimes difficult to talk to HIV associations because they do not necessarily have this view of 2 quite different things in terms of recruitment.
Are the methods and problems of recruiting healthy volunteers for preventive HIV trials a topic of interest in the scientific community? Would you say that this is a concern of the scientific community? In the study on the recruitment for the ANRS-VRI 01 trial, we emphasized that the recruitment was much less difficult than the design and implementation of the trial
It is the poor cousin of the process of implementing a trial. For now, we will be sticking to the following approach: we will cast a net and look at what we catch rather than, to continue the fishing analogy, taking a fishing rod and using a very specific bait to get the right fish. Due to the very limited efficacy of vaccine strategies at the moment, we are still dealing with something which is reserved for the specialists of the specialists in HIV infection. And these specialists are much more focused on the question of immunology and vaccinology rather than the question of recruitment in trials. It is true that there is a real job to be done to understand how best to recruit these volunteers, so as not to waste money, so as not to waste time, and then to have people who are themselves proactive and will be able to lobby for further trials. For the moment, social science data for volunteer recruitment are very few, just a few publications. These publications very often contain sociodemographic data comparing the recruitment of volunteers in Africa, Europe, or the United States. Few question the process, barriers, and expectations of volunteers, although of course such studies do exist.11
In the social sciences, the requirement of reproducibility is very problematic, although this does not mean that it does not exist. Judging from the results of the work, it is very difficult to identify avenues that we can be sure will be effective for recruitment
The most relevant studies would involve a real comparison with the same tools, for example, as we mentioned earlier, people who are recruited for an HIV trial, people who are recruited for an anti-Ebola trial, an anti-tuberculosis trial, to understand why people are interested but do not go through with it. Unfortunately, the way we did this was far from perfect.
Our question concerned what was being said in the investigator community. You are talking about the social sciences. It is interesting and may potentially contribute to providing work for researchers. What about the idea of involving other professions such as communications consulting, which knows how to implement systems to collect donations and mobilize people for a cause?
For the time being, there is probably a reluctance among academics who are developing the vaccine because we seem to be in an exploratory phase for a significant number of strategies. The recent history of other vaccines in the field of HIV, for example, therapeutic vaccines, makes us fear to do too much publicity around something which is still being explored. In our discussion with the communications companies who helped us to carry out our recruitment, we could clearly see that they found it difficult not to oversell our trials. They always wanted to emphasize that the vaccine or trial was extremely innovative and that it would definitely change something. But when we are still in an exploratory stage, we do not know if it will change anything. The design of a trial can be interesting and new; otherwise, the trial would not be done. But we are very afraid of overselling. Obviously, if you talk to academics, it is different because they understand that. But when we work with people who are in the private sector, who are used to selling things, we have great difficulty making them understand that we do not want to sell our product but simply to recruit people. That is a real problem.
Would it be accurate to say that because there are few benefits, no promises can be made to future volunteers?
We are trying to find something but it is not strictly necessary. It is in an exploration stage. There are no promises, but we can say that even negative results contribute to scientific progress.
So these communications experts find it difficult to highlight the disinterest
Absolutely. Nonacademic communications experts provide a service for other organizations as well, in other fields, such as political marketing. But the problems involved in engaging people are specific to each field. Engaging in a trial is not the same as engaging in a political party, and the concept of disinterest is sometimes strange to them.
We would now like to talk about how society sees researchers as well as scientists and their activities in general. HIV is characterized by the importance of the role of associations because the pathology is at the origin of the development and participation of associations of patients and their friends and family. Is your work receiving more attention these days from the media and the rest of society?
That is a difficult question to answer. Among the general public, we can see that over time, HIV infection has become more ordinary. Nevertheless, every year, we still manage to raise about the same amount of donations through Sidaction. We have managed to maintain the visibility of the disease. We do this for several reasons. Perhaps, one important reason is the role that France has had in the history of the infection because of the Nobel Prize of Françoise Barré-Sinoussi, the ANRS, and the high visibility of French research in this field. The scientific community has always been able to show society the extent to which it was present on an international level. There is a still a view that France is highly involved in HIV, that is, the disease in general. It should be understood that the infection itself is now well under control, there are more and more treatments, which are becoming increasingly simple and are tolerated better. So, there is a resurgence in interest regarding anything that still continues to pose a problem, that is, the prevention and eradication of this infection. And in this context, there is a resurgence in interest in vaccination on the part of clinicians, patients, and associations. There is a lot of talk about the prophylactic vaccine but it is very much associated with the therapeutic vaccine. And even if in the end the 2 targets are different, research in these 2 fields is very similar. So, the topic of vaccination is gaining importance within the HIV community, at least much more so than a few years ago when the priority was to have effective and well-tolerated treatment. The vaccine seems to be the new way forward. The treatment has not resolved everything, but the treatment has resolved many things and the problem now is more to do with spreading the treatment, that is, treatment for all and 90-90-90 strategies. We have achieved a lot of progress in terms of treatment. Now we have to make the treatment available for everyone. It is a political and economic problem of public health. In terms of the more fundamental scientific aspects, immunology issues, and in particular the vaccine, are the most important.
There have been very premature and problematic announcements about advances in vaccine research from laboratories that are partly funded by pharmaceutical companies. Is this because the competition is so high?
The therapeutic aspect of the vaccine is a major competitive issue for patients. Also, through important advances in vaccine research, the prospect of developing vaccines which could work for everyone, even if it is not in the short term, we are making breakthrough after breakthrough. There are new strategies. We might soon have a vaccine which can provide up to 50% protection, and with such a vaccine, we would totally change the perception of the epidemic. The main problem for us would then be how to achieve acceptance of large-scale vaccinations with a vaccine which only works 50% of the time.
In addition, if we consider future phase 2B-3 vaccine trials, the main problem will be the use of PreP, because when we do a trial with a new vaccine, such as the one recently developed in South Africa, the efficacy of the vaccine is compared with that of the placebo. Therefore, in future, it will no longer be ethical to do a preventive trial for a placebo and we will have to include a PreP arm because this is able to induce protection in at least 90% of cases. This is going to be a major problem for subsequent preventive vaccine trials which require that a marker be found which is truly associated with protection. We do not have one currently.
We mentioned it before, but there is a mistrust of vaccines and certain trials in French society. This may be connected in part with the media, which has given a lot of attention to accidents during trials, for example, although these are rare. Is this something which is noted by the scientific community that you are a member of? Is it something you think about?
Of course it is something we think about. And every time something happens to a healthy volunteer in any vaccine trial, we feel directly involved, even if only because it will have a negative impact on research overall. However, scientific journalists, that is, not journalists who want to write a paper about something new or which they do not necessarily understand, are generally very well informed and they can distinguish between the different types of trials. Even if there is a general mistrust in the vaccine, we do not perceive it very much at our level, especially when we do trials that will affect no more than a 100 people, or slightly more, at most. We do not really feel the impact of mistrust in the vaccine. And the feedback from journalists is very favorable because people have the impression that research is progressing in France. The story might be different when there is a vaccine and it has to be offered to the entire population. But we are not there yet.