Important note: Information in this article was accurate in September/ November 2000. The state of the art may have changed since the publication date. IAVI Report - September / November 2000
Marc Girard has been in the AIDS vaccine research field since the mid-1980s, working first on chimpanzees and then on macaques as model systems for vaccine testing. Girard headed the French research agency's HIV Vaccine Task Force from 1988-1998 and recently finished a three-year stint on IAVI's Scientific Advisory Committee. In 1999, he left Paris' Pasteur Institute after 22 years to direct the European Research Center for Virology and Immunology (CERVI) in Lyon. Here Girard describes EUROVAC, a newly-launched European AIDS vaccine project he chairs, and discusses his views on primate models in AIDS vaccine development.
It started from scratch, when a few European AIDS researchers met in a cafe during the 1998 Geneva AIDS conference to discuss what we Europeans can do on vaccines.
After much discussion, we decided on some key points. First, that our aim was Phase I trials in humans. Mac-aques might be useful for some challenge experiments, but our ultimate goal had to be human testing. This meant that we would need to prepare vaccines according to Good Manufacturing Practices (GMP), which takes an industrial partner. We then talked to Pasteur Mérieux [now Aventis Pasteur] and several smaller pharmaceutical companies in Europe, and they were willing to join us.
Next, we decided on a prime-boost combination of a pox virus and a glycoprotein. We will evaluate vaccines based on two attenuated pox viruses, MVA and NYVAC. That directly interested Aventis Pasteur, because NYVAC was their product.
Our choice of clades C and B came only after a lot of heated discussion between the immunologists and the industry people. The immunologists said, why work on clade C virus? We don't have the reagents we need - antibodies, peptides. For clade B we have everything. Industry people said, we want to make a vaccine for developing countries, and clade C causes the most disease globally. The immunologists responded that we're not making a vaccine, we're doing a prime-boost experiment to see what works. In the end we decided to compare clades B and C head-to-head, in CTL responses and cross-clade CTLs. Each of them will be boosted with a clade C gp140.
I went to discuss the broad outline of the project in Brussels. They said that it sounded very interesting but they would not pay for clinical vaccine batches. I then told them there would be no project, because we need GMP products to do human testing. Then they said that industry should pay for it. But I did not expect that industry would pay for this - they have their projects, and this work is outside of them.
We finally ended up winning EU support. Our project got the highest marks, and it's the biggest grant [8.8 million Euros] that the EU has ever given for this type of work.
Altogether there are 20 groups in 8 countries. [Editor's note: click here for a complete list.] From the industry side, besides Aventis Pasteur, IDT in Germany will make the MVA and the gp140 will come from an English company called Lonza.
Since we will use standardized assays and centralized labs to analyze the immune responses of the volunteers, we designed three networks - for T-cell analysis, chemokine analysis and antibodies. And we decided to incorporate parallel macaque studies, for two reasons: first, to see whether there is any difference between NYVAC and MVA in their ability to protect, and, second, to support some preclinical studies of other types of vaccines. Most of the animal work will be done by Jonathan Heeney in The Netherlands, plus some in England and Germany.
We have milestones for each of the steps, leading to human trials by early 2002. Beyond that, we are also thinking about Phase I/II in developing countries, since we will have the clinical vaccine batches available. There has been a working meeting in China, but it is premature for us to commit ourselves to any site. And we're applying for additional funds to move other candidates forward, such as DNA, Semliki Forest virus or Salmonella vaccine.
I don't want to sound un-European. But you should realize two things. First of all, it is very difficult to work as a unit in Europe. A united Europe is a nice image, but nations and governments have their own scientific programs. So it's not surprising that most of the support from Brussels so far has been for small research grants. EUROVAC is the first time that a grant of this size has gone to product-oriented research. It's all new for the EU, and the rules do not exist - they are being invented along the way.
Second, there is very little expertise in public health, vaccines, medicine at the European Commission level. There are meetings of the ministers for research, commerce, defense, whatever, from the member countries, but not of health ministers.
So to go beyond research and into vaccine development and clinical trials, we have to rely on the will, dynamism and energy of individuals. The director of research at the European level has a hard time. If he pushes vaccines too far, somebody is going to remind him about the problems in agriculture, or with the big radio telescope. There are many political difficulties and priorities in defining major themes. That's where I think IAVI has a beautiful role to play - as a catalyst and a leader in the field.
EUROVAC has good expertise, good scientists. The products we're developing are not that new. But I think the way we're working - as a group of coordinated networks - is a reasonable way to do this type of research. IAVI, on the other hand, can help with testing the vaccines in developing countries.
I work with non-human primates, mostly rhesus macaques, testing a variety of HIV antigens and DNA vaccines and doing SHIV protection experiments. We have a new SHIV, a CCR-5-dependent virus that has kept the native envelope of the primary isolate it was derived from. It should be interesting to use for challenging the macaques. We are now trying to make it pathogenic by passaging in monkeys.
We are also testing whether vaccines with the rev and tat genes can protect macaques. There have been contradictory results about this - some people claim full protection using these antigens; others claim a partial effect on reducing viral load. So we are testing this using a Semliki Forest virus recombinant vaccine followed by an MVA recombinant, both made in our lab from primary isolates. We should have some results by the end of this year.
Partly it comes from how the animals are challenged. In our case we use only intrarectal challenges, which test mucosal transmission. Some labs use intravenous challenges. There is also is a wide variety of SHIVs available for challenging. For example, SHIV-MN is a very wimpy virus - it grows only to very low levels, so it's relatively easy for a vaccine to protect against this challenge. At the other extreme, Norman Letvin's SHIV-89.6P is much more pathogenic, and I don't know anyone who can claim that they've protected more than 50% of the animals in a direct challenge.
Another difficulty is how you define protection. I define it to mean that no virus is found by co-cultivation and that viral load is only transient and usually less than, say, 6,000 RNA copies per milliliter. Also, that there are no visible immunological signs, such as a drop in CD4 cell count. But it is obviously not sterilizing protection, which is perhaps not achievable.
Absolutely right.
So how do you decide rationally what strain to use for challenge?
The classical way to develop vaccines has been to set up animal model assays, making clear that these do not necessarily reflect what actually happens in human. This approach goes back to the beginning of the century, with the development of the first bacterial vaccines.
For example, the model for testing pertussis or rabies vaccines is awful. You inject the challenge material intracerebrally into mice. These models have nothing to do with what you want to protect against. But they are still useful for standardizing vaccines, even though they're only a correlate of protection - they say nothing about how the vaccines work.
With HIV there's a tendency to ask a lot from animal protection experiments, to give us a huge margin of security in humans. So people tend to challenge animals with hot viruses.
That is a key point. To be honest, we have been talking about this for several years, but there is still no real standardization. Actually, the trend is that new SHIV strains are being made, and we hear that so-and-so has protected some animals against these viruses whose properties nobody knows. So it's very difficult to assess and compare results. How useful are monkey data in deciding whether to move a candidate vaccine into human testing? No single criterion can tell us whether a vaccine should go into human testing. Different factors and priorities will play a role, and the monkey model is one of them. But I don't see primate models as a compulsory route to Phase I.
Still, we would obviously like to see good protection in monkeys. I would feel much more confident if a vaccine protected 80% of my macaques, especially against a strong challenge like 89.6P. But at this point we have no example of human and monkey data on the same vaccine from which to build a model that could guide these decisions. So for now I think it's reasonable to test humans and monkeys in parallel.
Macaque data are very important for going past Phase I, even though we cannot extrapolate directly to humans. After all, how else can we see what sort of efficacy is possible, short of doing a Phase IIB or Phase III trial? You would feel much more confident launching such a trial in human volunteers if the same type of vaccine protects macaques against SIV or SHIV.
Another thing is that there are now SHIVs of clade E, clade A, clade C and of course, a lot with clade B. So you can start asking whether your vaccine provides some broad protection across clades.
To me this is a very important question. I'm a bit anxious seeing that some countries think they must use an isolate from their own country to make a vaccine. This has never happened before for any classical vaccine. To my knowledge, there is no evidence at this point that a vaccine derived from clade A could not work against viruses of other clades.
It can slow down the field. It may also hamper some vaccine development if you have to remake your vaccine each time you change country. Let's not even think of the commercial problems, which could be very difficult.
Perhaps we will find that there are something like HIV 'super-types' that depend on a variety of virus properties, including neutralization type and serotype. But there is no evidence for this now.
I don't subscribe to that fear. We're getting our monkeys from China rather than from India, because India does not export macaques any more. Indian monkeys now come from U.S. breeding centers, which imported animals a long time ago. With the possible exception of the Dutch primate center, Europe has no such centers.
Our Chinese rhesus macaques are outbred animals captured from the wild and are less susceptible than Indian macaques to SIV disease. They tend to behave more like long-term non-progressors - they can stay infected for more than two years and nothing happens. No clinical signs. But you can measure viral load, and the CD4 cell counts stay very low. Clinically, animals usually survive for at least two years; many don't die at all, even after a strong challenge like SHIV89.6P that kills Indian macaques in 6 to 9 months.
It's very expensive, although not nearly as much as working with chimpanzees, as we used to do.
But the cost of these experiments is not only the cost of the monkeys. Some of the reagents - for example, for measuring cytokines - are tremendously expensive.
One of the biggest limitations is space for housing the monkeys. At the Pasteur Institute, we have one facility that is now almost national, because it's subsidized by the ANRS. Anyone who wants to do HIV or SHIV experiments in France goes there. But we have only 150 cages, so it fills up fast. The Dutch Primate Research Center has a huge breeding center, but they are also limited by their facilities for housing animals. It's a logistical problem that could be solved with enough dollars, but nobody has made that investment.
Yes, by having a task force of experienced people in the field who agree to standardize and validate their assays, share their reagents and perhaps exchange samples. In Europe, this has been done in part by Gerhard Hunsmann, for example, in the early tests of whole killed SIV vaccines. Different groups used the same batch of virus for challenge, but one group challenged the animals vaginally, another intramuscularly, and a third intravenously. So each group had a piece of the pie. It was a smart way of sharing resources and providing more facilities than anyone could have had alone.
So there are ways out. But it can take a lot of negotiation and discussion. And if you have an idea and would like to do a quick test, this approach doesn't work.
It's the perpetual question of the optimist or the pessimist - whether the glass is half full or half empty. If you're an optimist, like many Americans, then you say, gee, we've come such a long way, it's beautiful, we have many things in the pipeline. If you are pessimist - and perhaps we are more pessimistic in Europe - you say, yes, we've come a long way, but we still don't know how to induce neutralizing antibodies to primary isolates, and we've induced only transient CTL responses - with the possible exception of AAV, which is not yet made into a vaccine. Everything else tried so far, including DNA, does not give great long-term responses.
To get around this we combine different vaccines, and indeed this gives better immune responses. But then imagine the situation in the field. How can you go into a remote country and tell people that they need two shots with DNA, then two shots with MVA, then perhaps two more with gp120? That's just not going to work; it's not a practical vaccine.
It is certainly fantastic progress, but I would remain cautious and say that we have to work much, much harder before we will have a vaccine.
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©2000. The IAVI Report.
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