1 March 2008, 07:45
A war of words over AIDS vaccines can determine whether you are an optimist or a pessimist.
At the America Association for the Advancement of Science meeting on 14 February 2008, the new AAAS President and Nobellist David Baltimore shocked AIDS vaccine researchers by emphasising the enormous challenges that had to be faced in creating such a vaccine. A few days later, the International AIDS Vaccine Initiative IAVI, headed by Seth Berkely, issued a rebuttal and reaffirmation of hope and commitment the following day.
Are you a vaccine optimist or a pessimist? You might judge through your response to the views expressed. Here are extracts the Baltimore and IAVI texts, placing IIAVI’s response first.
IAVI: “At the annual conference of the AAAS, the organization’s president, eminent scientist and Nobel laureate David Baltimore, commented on 14 February in Boston on the current state of AIDS vaccine research. Professor Baltimore expressed concern at the field’s lack of success so far in developing an effective AIDS vaccine but emphasized that researchers must continue to move ahead given how crucial it is to develop such a vaccine…
“…IAVI agrees with Professor Baltimore that the search for a vaccine is vital. Since HIV was identified as the virus responsible for AIDS 25 years ago, researchers have made considerable progress understanding the virus and human responses to it. In response to these news reports, IAVI issued the following statement to provide an overview of the broad spectrum of scientific evidence from human studies of HIV infection and animal models to support the belief that an AIDS vaccine is possible. The evidence includes:
“The experience of elite controllers. An important fact is that almost everyone who becomes infected with HIV manages to control the virus for many years without the need for antiretroviral drugs. At the extreme, there are clearly documented cases of individuals who have been infected for 25 years or more and have shown no ill effects. Called elite controllers or long-term non-progressors, at least some of these individuals control their HIV infection by means of their immune system. If scientists can work out the type of immune responses that afford the elite controllers protection, then the hope is that researchers can replicate those with a vaccine.
“The experience of highly exposed uninfected individuals. There are also documented cases of individuals who have been repeatedly exposed to HIV but have not become infected. These individuals, known as the highly exposed uninfected, were first described among commercial sex workers in Nairobi, Kenya. These women remained free of HIV infection despite repeated exposure to HIV from infected partners, suggesting they have immunity to HIV. Again, if scientists can define precisely how these individuals manage to be resistant to HIV infection, it might provide vital clues about how to create a vaccine.
“The success of live-attenuated vaccines in non-human primates. Research on non-human primates (NHPs) provides further evidence that a preventive HIV vaccine is possible. Some NHPs injected with a vaccine made from live-attenuated SIV, the simian equivalent of HIV, and then challenged with SIV do not become infected. They are protected by the vaccine. The overwhelming majority of non-human primates immunized with live-attenuated SIV significantly suppress the replication of the virus, thus slowing or blocking progression to disease. It is not considered safe to make vaccines for humans using the same approach, that is, using live-attenuated HIV. But by studying how this model works in non-human primates, our closest relatives, the AIDS vaccine field can gain clues about how to make a safe vaccine for humans. IAVI’s Live Attenuated Consortium, which brings together world-class scientists from a variety of institutions, is devoted to this issue.
“The promise of broadly neutralizing antibodies. AIDS vaccine experts also know that some individuals who are HIV infected produce broadly neutralizing antibodies. These are antibodies that will destroy the vast majority of types of HIV circulating in the world today. In animal experiments, scientists have injected high doses of these human antibodies into non-human primates and found that this injection prevents infection from a challenge. So if researchers can figure out how to design a vaccine that would teach the body to make broadly neutralizing antibodies, there is hope we can design an effective AIDS vaccine for humans. IAVI’s Neutralizing Antibody Consortium is focused on this subject.
“Through these consortia and through other efforts, AIDS vaccine researchers today are aggressively working to develop a new generation of vaccine candidates with capabilities that go beyond those currently in testing. Experts are trying to develop candidates that elicit different immune responses from those currently in clinical trials. This includes research on new vectors that replicate in the gut and those that stimulate immune responses at blood and mucosal surfaces where HIV enters the body.
“Innovation is a must. To that end, IAVI, with support from the Bill and Melinda Gates Foundation, last year launched a program to identify and evaluate pioneering ideas from outside the AIDS vaccine field that could deliver the breakthroughs that are necessary to move the field forward.
“Scientists don’t know how long it will take to develop an AIDS vaccine. We do know from history that a vaccine is the only way to end a major viral epidemic and that perseverance and long-term investment are necessary to develop a vaccine. A robust AIDS vaccine effort has only been underway for the last decade and only two vaccine candidates have been advanced all the way through to efficacy testing.
“The world can’t afford not to develop a vaccine. The costs of providing life-prolonging treatment will continue to escalate. UNAIDS projected in September that the pricetag of universal access to AIDS prevention, treatment and care would be roughly US$42 billion a year by 2010. Since then UNAIDS has revised its epidemiological figures downwards, but even with a 20% cost reduction, spending on AIDS would have to go from a tenth to a quarter of all overseas development assistance to meet the goal of universal access, crowding out other priorities like basic health care, clean water and education.
“It is certainly true that developing an AIDS vaccine has proven more difficult than researchers imagined when they first set out on the mission decades ago. But nobody entered this field thinking this was easy work. On the other hand, every researcher involved knew it was vital, and it remains more so today than anyone could have imagined 25 years ago.”
David Baltimore said: “…I want to comment on how we can ever expect to reverse the spread of this scourge. There is no AIDS vaccine; no hopeful candidate AIDS vaccine; HIV has evolved to be virtually impossible to attack by antibody, and without antibody sensitivity it’s pretty well uncontrollable by the immune system.
“This is a huge challenge; because to control HIV immunologically the scientific community has to beat out nature – has to do something that nature, with its advantage of four billion years of natural evolution, has not been able to do.
“Our lack of success may be understandable but it’s not acceptable. Thus calling an AIDS vaccine a ‘Grand Challenge’ is not hyperbole.
“You might ask: Why is HIV different than most other viruses? Why can vaccines control so many viruses but not HIV? The answer is buried in the evolution of the virus. HIV managed to evolve to be immunologically protected. Its code is structurally refractive to antibody inactivation, and host cellular immune system responses don’t produce durable control.
“Virtually no other virus has combined these two modes of immune avoidance. If one virus can do it, why not others? Why aren’t all the viruses out there like HIV?
“The answer I think is that HIV has chosen a lifestyle different than that of all other viruses. Most viruses don’t avoid immune attack, and they don’t really need to; they carry out the generation of their lives, and then they get passed on to a new host, within the week that occurs between the encounter of the immune system with a new virus and the establishment of an immune reaction to that virus.
“But HIV, by avoiding immune attack, can establish a chronic infection that the body is unable to eliminate.
“Interestingly, HIV evolved in chimpanzees – and for unknown reasons it does not cause disease in chimps. Thus this lifestyle based on immune avoidance is not much of a liability in its natural host. But when HIV jumped to humans, it found a host where it caused a serious degenerative disease.
“Thus we are the victims of a diabolical circumstance: HIV, a benign virus of chimpanzees, came into our lives and produced a disaster.
“Against that background, the vaccine community has tried its best. It initially made an attempt to control the virus through antibodies – but found that the virus was quite solidly protected against that mode of attack.
“Then [the vaccine community] switched, trying the other arm of immune protection, the cellular immune system. That’s never actually been mobilized to protect against a virus, and sure enough, a full-scale clinical trial of the first such candidate vaccine gave no protection.
“The community is still trying this route of attack, because it is one of the few natural hopes we have. Some are still trying the antibody route, because it has been so successful against a host of other viruses.
“But the community is depressed – because we see no hopeful route to success.
“I should add that this depression is not halting development activity. Knowing how crucial it is to get a vaccine, the community of vaccine developers are moving ahead even recognizing the long odds against success.
“I would point out that none of this work could have been done but in the most technologically advance countries. It involves the most sophisticated concepts and techniques of modern science – and even so it hasn’t worked.
“Our only hope may lie in finding new ways of providing antiviral protection. And under the aegis of the Bill and Melinda Gates Foundation, we are attempting that. I don’t want to get too technical – but we are trying to combine gene therapy, immunologic therapy, and stem cell therapy, to stimulate an immunologic attack on HIV through new routes. This is truly a grand challenge, and we hope that we can make some progress. At least we’ll give it a try.
“So dealing with the most difficult challenges is not something that the less developed countries can solve on their own. An AIDS vaccine, a TB vaccine, a malaria vaccine are all grand challenges, and we need the very best laboratories to undertake them. We need visionary funders like the Gates Foundation to make this possible. And of course, if there’s even a glimmer of hope, the materials need to be tested in a partnership between the countries that suffer from the diseases and those that developed the candidate vaccine. And we must be certain – as recipients of Gates grants must promise – that the developed materials are affordable by those that most need them.”
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