HIV preventive vaccines: myth and reality
AIDS has reached a mythical dimension, often escaping our modern paradigms of time and evidence. It has become a thriller of human proportions affecting every great theme of our existence: life and death, love and hatred, sex and blood, maternity and birth, morals and notions of retribution, judgements about what is right and wrong. It affects many of the most vulnerable, stigmatised and marginalised in society but, almost paradoxically, also some of the most glamorous and privileged. Beyond its impact on individuals and families, AIDS has a vast societal impact with the potential for social unrest, a growing economic burden and a threat to the progress we have made on fundamental health issues, such as the survival of mothers and the welfare of children.
Because AIDS is, for many, as much a question of human rights and values as it is of illness, it generates emotions that we associate with few other diseases. As a scientist, I cannot deny these human aspects of the epidemic but I urge people to treat the science of AIDS as science, not myth. We must drop our elevated expectations, our exaggerated fears and our primeval, instinctual responses so that we can deal with the situation as it is. In my area of expertise, HIV vaccines, this is the situation: a vaccine is clearly possible and we will probably find one that ‘works’ within the next decade. We have to think about the enormous commitment required to pursue the research and the efforts we must make now if any resulting vaccine is to reach those who need it most. And we have to be clear what we mean by a vaccine that ‘works’.
The magnitude of the scientific challenge presented by the development of an HIV vaccine was initially vastly underestimated. American (and a few European) prophets and apostles of wishful thinking, among them well-known scientists, were keen to throw to the public and media a good dose of false hope (‘the vaccine will be available in three to five years’, some scientists predicted in the mid-1980s). It was sometimes the pleasure of showing off; sometimes, the desire to show that science really could meet all of humanity’s expectations.
By way of a backlash, others went to the opposite extreme, threatening the world that this endeavour was impossible and even dangerous. Tabloids and unscrupulous media have filled their columns with scurrilous rubbish about the judgement of God not being thwarted or mutant viruses rampaging loose. Amidst all of these wild promises and silly scares in the West, few talked about the growing epidemic in the developing world and those who did argued that there was, in any case, no market or infrastructure. So why bother?
Developing country researchers and health authorities were caught between these two extreme attitudes and sometimes were wise enough to follow a middle path along with scientists and public health field researchers. India is a prime example of a country that got it right. A visionary scientist, the late Professor Ramalingaswami, convinced the government that vaccines should be a priority, that a vaccine could eventually be found, that sound scientific safeguards could assure ethical research. Equally, that there was no shortcut or quick fix.
The government committed itself to harnessing India’s strengths – its manufacturing prowess and its world-class research infrastructure – whilst collaborating with foreign groups which could deliver resources not immediately available at home, such as new biotech vaccine constructs and learnings from the conduct of early trials in the USA, Thailand and Africa. This pragmatic approach led to the emergence of the collaboration of IAVI and its partners and the strengthening of the research capacities at the National AIDS Research Institute (NARI) in Pune and at other ICMR institutions.
HIV vaccines (and treatment) definitely belong to the ‘high tech’ world, a world with very limited access for developing countries without India’s science or manufacturing base. Most of the researchers in these countries lack the training or equipment to follow the pace of US and European research agencies, especially in the absence of collaboration with international partners. Many felt they were passive observers, brought into the general discussion just to show political correctness at fancy conferences. Ideas were thrown about and decisions made about developing country assessment without consulting them. Industrialised world arrogance was compounded by developing country denial of the epidemic and the post-colonial syndrome. Things are getting better. HIV/AIDS research has spurred an unprecedented wave of international, north/south and south/south, collaboration. IAVI alone is working in five of the worst affected countries in collaboration with governments and national institutions.
All of us, as stake holders in this appalling epidemic, seem to have a growing awareness that we are on the same dreadful wreck, looking across an ocean of scientific ignorance. Maybe we are beginning to realise that we need the same lifeboat and the same navigation charts. But it is too early to say that relationships between developed and developing countries are as good as they could be.
First, HIV/AIDS vaccine research in the industrialised world is driven by both the public and the private sectors. Both tend to have strict research and development agendas (albeit of different provenance), tight budget constraints and timelines that do not necessarily fit the context of research in most developing countries, where adaptation, more time and more money are needed. In a regrettable lost opportunity, Chiron Vaccines decided to discontinue their HIV vaccine clinical research in Thailand because they could not make it fit their business model.
Second, there are fewer researchers in most developing countries than in the industrialised world. The former are often caught in multiple research and management activities working in difficult financial and logistical conditions, solicited by several groups and agencies. The latter have probably more luxury to narrowly focus on their research and to pursue sometimes abstract academic concerns. Both are entangled with their political environment and with considerations of national policy and pride, but often the industrialised world researchers consider their work uniquely valid and worthy of consideration. This permanent imbalance between both generates useless tensions detrimental to the common goal of one day making an HIV vaccine available for those in need.
Finally, researchers in the worst affected countries can develop a sense of hopelessness. The process of trials is long and complex: in the most optimistic scenario, six years separate the earliest human trials and the results which will permit use of a vaccine in the general population. And even then, history suggests that it might be another 20 or so years before there is any real access in the developing world.
Science has often delivered vaccines which have been far too expensive (at on-patent, industrialised country rates) for use anywhere outside the OECD. The rich nations have been unwilling to provide the assistance needed to develop the infrastructure necessary to deliver these vaccines even when they do finally become affordable. If we want to motivate the scientific elite of the developing world, we have to convince them that things will be different this time. Politics, nationalism and commercial advantage will not cripple or hinder vital trials. Innovative IP agreements – like that between IAVI, its commercial partners and the Government of India – will assure that immediate, affordable access is guaranteed before communities and hard-pressed researchers are asked to support clinical trials.
However motivated and driven by the new paradigm, anyone working on an HIV vaccine will soon encounter difficulties of daunting magnitude. The virus is genetically hypervariable – it changes and mutates all the time. Over time this has led to the development of six distinct subtypes of HIV in different parts of the world. Today, these subtypes are ‘crossbreeding’ – of course, viruses do not ‘breed’ but genetic recombinations between viruses from different subtypes are now emerging around the world, including in India. We cannot predict whether a vaccine which protects against one virus subtype will protect against another subtype (though some recent scientific research seems to indicate that this ‘cross-protection’ may be possible). We may end up needing a multi-subtype vaccine (as we do in some other diseases) which means that we will have to develop a vaccine against each subtype and then produce a protective cocktail.
An even bigger problem is that we do not know for sure how the body can best protect itself against AIDS. The holy grail is an antibody which will neutralise the virus before it can take hold by disabling one of its life-support systems. In the world of ideal forms, that vaccine would protect against all possible routes of transmission: intravenous (blood transfusions, needle sticks and the like) or mucosal (transmission through sexual contact or from mother to child). That may not be possible in the near-term and we may have to settle for a cell-mediated immune response: empowering the body to better identify HIV-infected cells and to kill them, avoiding the dissemination of the virus. This would decrease the amount of virus circulating and might mean that the body could keep HIV in check completely, thus avoiding progression to disease: you would still be HIV-infected but you might never go on to develop AIDS.
One day, we will have both: a vaccine to stop initial infection and a fallback vaccine to boost the body’s ability to contain any virus that slipped through the first set of defences. However, the first generation of vaccines will, we hope, develop these cell-mediated responses although they will not be able to prevent initial infection. As well as saving individual lives, these vaccines will hopefully have a vital societal benefit: by decreasing the viral load in those who received the vaccine (but still became HIV-infected), the vaccine would make it much less likely that those HIV-positive people would pass on the disease to others.
Testing vaccine approaches is not easy. Animal models are of limited value in developing human defences as no animal gets ill from HIV, and since the immune systems of even monkeys are quite different to ours. Animal models can give us valuable information, guidance and reassurance about safety but they cannot ever replace human testing, especially for demonstration of efficacy. We will not actually know whether animal models predict efficacy until we find something that has been proved to work in humans and then look back to see whether animal models accurately predicted its success.
Clinical trials are long and costly and must follow strict pathways and procedures. They require years of hard, detail-driven and often tedious work. It is tempting to say, let the industrialised world run the trials and let the benefits come to the developing world. In HIV this is not possible. Trials in developing countries are important for several reasons. First, 90% of HIV infections occur in these countries, where an effective vaccine would eventually be used and be most beneficial. Second, to produce valid and timely results, the big trials need to be conducted in populations with high incidences of HIV infection. Third, HIV may necessitate testing different candidate vaccines in different areas of the world because HIV varies in different regions. Finally, it may be necessary to evaluate how different routes and co-factors (such as other infections) for HIV transmission influence vaccine protection.
Several developing countries – including Brazil, China, Cuba, Haiti, Kenya, Thailand, Trinidad and Tobago, Botswana and Uganda – are now actively engaged in HIV vaccine clinical trials. Other countries are preparing for clinical trials including India, Côte d’Ivoire and South Africa. Their pioneering efforts must be acknowledged. Thailand, a newly industrialised country, continues to play a major role in South East Asia not only of leadership but also in HIV prevention, care and HIV vaccine development with the imminent initiation of a second efficacy trial.
With the exception of the trials in Thailand, all clinical trials in developing countries so far are in their early stages. These small, ‘phase I and II’ trials ensure that a vaccine is safe in human beings, that it induces an immune response in the body and that it has no unanticipated effects. Some of these trials are also looking at the best doses and at how often vaccines have to be given before they offer protection. The real challenge will come in ‘phase III’ or efficacy trials: those designed to test whether a vaccine actually protects people from AIDS. These trials need up to 20,000 people. If many of those fail to stick with the trial for its full course, the results may be invalid and the trials useless. Regulatory agencies – the Drugs Controller General in India, the European Agency for the Evaluation of Medicinal Products (confusingly known by the acronym, EMEA) and, the Food and Drugs Administration in the USA – require extraordinarily careful and detailed record keeping if they are to use these results as the basis for permitting the use of a vaccine in their territory.
Paradoxically, the success of prevention programmes could pose a challenge for HIV vaccine efficacy trials. The decrease in HIV incidence amongst different populations will require larger sample sizes to conduct these trials. Indeed, this illustrates how difficult it is for the vaccine developer to catch the moving target of the epidemic when prevention methods succeed. Similarly, the finding of an efficacious first generation HIV vaccine could render the implementation of other efficacy trials very difficult. For ethical reasons, the first generation vaccine would have to be used instead of a placebo for comparison purposes with the new vaccine. Clearly, the sample size needed for such a comparison would have to be extremely large. In areas where HIV incidence is low, such a trial may well become impossible.
One absolute condition to conduct clinical trials is that they operate within a strict ethical framework. International ethical standards and WHO-UNAIDS guidelines for HIV vaccine trials should be followed including the respect of good clinical practices, an informed consent process made understandable to volunteers, the respect of confidentiality and individual freedom, the prevention of stigmatisation and social harm. The gap in ethical and legal framework has spurred ethicists and scientists to work closely together to issue guidelines.
Much work has taken place on the format and content of the informed consent. How to explain science and the trial process, and related subtleties to subjects with limited education? Sometimes informed consents are as thick as a phone book and one wonders whether they are designed to protect the individual or the sponsor’s and pharmaceutical industry’s liability. We will have to be simpler, fairer and more intelligible in AIDS vaccine trials.
Critical issues will need to be tackled during these trials, including the level of care and treatment that should be offered to volunteers who become infected during the course of the trial, and how to make vaccines available to the population once their efficacy has been demonstrated. Teenagers below the legal age of adulthood are among the most at risk for HIV infection but for sociocultural and legal reasons, they may not enrol in most trials. We need to think about whether this is the right way to protect the next generation whilst safeguarding the rights and health of those alive now.
Potential difficulties and obstacles inherent to the specific Indian sociocultural context lie ahead of researchers involved in HIV vaccine clinical development. Beyond the technical difficulties, the recruitment of volunteers for HIV vaccine trials in India may pose a real challenge. Some past history of vaccine research in India has darkened and generated distrust about human biomedical research and acceptance of vaccination. Stigmatisation of HIV-infected people, especially women, may generate suspicion amongst volunteers who would like to participate in the trial.
Complete participation by the communities is essential to ensure adequate recruitment. Transparency between political authorities, researchers, community workers and communities is a key factor in building confidence and trust. Efforts should be made to word simply the trial goals and development process to ensure a good understanding of the trial goals and vaccine development process.
Medical research needs calm and peace to operate in good conditions (one cannot play good music when surrounded by too much noise). On a visit, the principal investigator of the first HIV vaccine trial in Paris at the Institut Pasteur said to me, ‘How do you think I can work quietly?’ The door of his office was covered with post-its from journalists for both the volunteers and the medical team. Rumours and misunderstandings that would jeopardise the effort must be avoided at any cost. All advocates of HIV vaccines have to play a critical role in this regard, including the media and various partners in research.
AIDS vaccine trials are good for reinforcing overall prevention. In Thailand, those participating in trials are much less likely than the general population to become HIV infected whether they have received the placebo or the active vaccine, because the pressure of counselling may be stronger during a vaccine trial. Other HIV prevention efforts need to be good within and outside trials: it will be a very long time before a vaccine can completely replace other HIV preventive interventions, especially if the first generation of vaccines have only modest protective efficacy. These vaccines would need to be delivered as part of comprehensive HIV prevention packages, including other health promotion and behavioural interventions, which may be redesigned around future vaccine delivery programmes, with strong community participation.
All prevention strategies against HIV infection/transmission must be reinforced, strengthened and encouraged, especially where antiviral drugs are not affordable or impractical. A terrible misconception would be to think that once available, HIV vaccines would stem the tide of the HIV epidemic from one day to another. No vaccine is hundred per cent efficient. Individuals who are infected, vaccinated or not, may still transmit HIV (albeit less frequently amongst those in whom vaccination has reduced the amount of circulating virus). Therefore, to be vaccinated would not necessarily mean to be protected against HIV infection.
In addition, because of the long period of latency before developing AIDS, the impact of HIV vaccines on the disease burden will take some time before it brings tangible benefits to the community. The disease and economic burden of HIV-infected and AIDS people will coexist for years with the effort to deploy HIV vaccines, once available.
One thing is certain: long term commitments as well as a global and concerted effort are needed from all key players. It will not be easy, nor will it be fast, and it will require intense international collaboration, coordination, partnership and leadership. If our common goal is to succeed we must also share the risk of a possible failure.
Are these paradoxes and the tensions generated obstacles to HIV vaccine research and development? I would say quite the contrary. Tensions and breaking of paradigms are the necessary ferments allowing the emergence of new ideas and original solutions. Possibly one of the greatest and invaluable benefits of the HIV epidemic and the related research, given the unique mythical dimension mentioned earlier, may be to bridge the differences, singularities and chasms between cultures in a way that the rational arguments of science never could.