Important note: Information in this article was accurate in December 2000. The state of the art may have changed since the publication date. IAVI Report - December 2000 / January 2001
Jaap Goudsmit has worked in the AIDS field since the epidemic's early days, when he and several colleagues began studying progression to full-blown AIDS in cohorts of gay men and intravenous drug users — now the longest-standing HIV cohorts in the world. His virological studies of HIV led him to an interest in vaccines, where he has helped mobilize several international vaccine efforts, including IAVI. Goudsmit now chairs IAVI's Scientific Advisory Committee and serves on its Board of Directors, and last year became co-chair of the European Union–sponsored EuroVac project. He has an M.D. and Ph.D. from the University of Amsterdam and is Professor of Virology at its Academic Medical Center.
IAVI now has four projects. Let's assume that we picked the best ones, initially. What is always going to happen is that, while a vaccine candidate is being developed, other candidates come along that look even more promising. But what you learn from industry is that you cannot go back. You have to move the vaccines into people and see what they do.
We have to look closely at the individual products resulting from these projects and begin testing them in different combinations. In other words, how can we best work with these individual components?
Exactly. Take DNA vaccines, for example. The scientific problem is clear: their expression levels vary in different cell types, depending on which construct you're using. So IAVI will need to compare three or four DNAs head-to-head, say in monkey models. You have to figure out which antigens to include, what is the best DNA expressing system, what is the best way to administer the vaccine. Then you combine your best product with your best delivery system.
The next step is to get lots of vaccine into vials on the shelf. You need enough of each to do several Phase I trials, plus parallel monkey studies.
My point is, you may or may not have the ideal constructs, but by mixing and matching, you can use them optimally.
The go/no-go decisions depend totally on whether there are other products available which are better.
Say that one criterion is T-cell immunity as measured by a particular assay. Your vaccine gives 30% CTL at one or more time points during the trial. That is not especially high. What do you do? I would say, since this is about the highest you see with canarypox, my product should do a little better. Say 40%. I'd consider 30% too low for moving into a Phase IIB trial.
On the other hand, I don't think we should throw this product out. We should ask whether it can be improved, whether it is useful in any combination. I would pretty much exhaust my product in monkeys, and only give up when there is not a single good idea on how to make it more useful.
I expect we will get vaccines that do two things. They should delay disease as long as possible — just like a therapy. On top of that, they should lower transmission rates.
Of course we want to get sterilizing immunity. But that will take much longer.
In the T-cell field, things are moving now that we have testing systems. Again, compare this to therapy. The initial breakthrough was not a therapy. It was identifying viral load as a predictive marker for disease, and measuring it accurately. It was learning that the more virus people have, the worse off they are. So we knew that we had to bring down load.
Yes. In a similar way, my feeling is that we're close to figuring out in monkeys how much viral load reduction you get from what T-cell response levels or affinities. I think we will also find this out for humans.
So I'm optimistic that there will be good approaches within a short time frame — especially in the DNA field, because you can make new DNA vaccines so fast. There will be good T-cell immunity–based, partially protective vaccines out there, which work by reducing viral load.
There is one caveat, though — CTL escape. We have data showing that nearly everyone with low viral load at setpoint — less than 1000 copies per ml — loses control of viremia after ten years or more. This tells me that we need longer follow-up in monkey challenge studies with load-reducing vaccines.
Antibodies are much harder. No one has a way to induce humoral immunity effectively. Even in a natural infection it isn't easy to get neutralizing antibodies — they appear only very late. My bias is that this will be difficult without long-term expression of the viral envelope, using persistently expressing vectors and perhaps also modulating the envelope structure.
That's a terrible question to have to answer. Of course, we don't really know.
First of all, we shouldn't restrict ourselves to clades in thinking about HIV diversity and vaccines. To me, the overriding issue is the biological properties of the isolate. So it might be a lot more important when you take your isolate and how you culture it than which clade or exactly what genotype it is.
What properties do I mean? It's easiest to grow an aggressive bulk culture of HIV. If you biologically clone it, you see that it is a mixture of slow- and fast-replicating strains. Depending on its origin, it might also be a mixture in terms of receptor use — CCR-5 only, or mixed CCR-5 and CXCR-4. Early cultures tend to be fairly homogeneous in their genotype and their replication properties, while later cultures are more mixed. We don't know if immunogenicity is affected by long versus short culture, or by culture in different types of cells.
Beyond the culture history, we should also pay more attention to the clinical history — when an isolate was taken relative to seroconversion. This is usually poorly documented, even in our own programs. I don't know which of these is the best starting point for a vaccine.
Yes. People spend very little time on this. They mix all these strains into one bag, although we don't know if any of these differences matter. I think this is an undervalued issue, and an important one.
Maybe a good starting point is an early strain from a long-term non-progressor with high levels of broadly reactive neutralizing antibodies and CTLs. I hope that IAVI can help promote standardization and compatibility.
One way would be to characterize immune responses in people infected with each of the different subtypes — say, people one year after infection who still have intact immune systems. You could simply ask exactly what parts of HIV — which epitopes — they recognize. Then you look at whether these epitopes are the same or different among the clades.
A nicer experiment would be to make a peptide set of overlapping 15-mers for a whole viral genome from each clade. Then you would look at the T-cells of, say, clade A–infected individuals one year after seroconversion and see which peptides they recognize. If someone with subtype A recognizes certain T-cell epitopes from B, C, D and E, then you have hard information about whether you need a multivalent vaccine. With antibodies, cross-clade neutralization — even including HIV-2 — is well-documented in sera of infected people.
I'm doing a study on CTL escape and natural history of infections. We do it exactly this way. We make overlapping peptides from people with a given HLA type and look for escape in certain anchor residues. Bruce Walker is also doing this type of study. He sees that, although certain HLA types recognize slightly different epitopes, overall they are reasonably conserved. So you can easily map this for infection. Of course we don't know if it would be the same for protection.
The point is that we need to build a data set to counteract the political arguments, which go farther than ever these days. It's even beyond clades — some people are saying, we need a national vaccine. They don't accept the same clade from another country.
It is clearly gathering momentum. We started with EuroVac, which was launched last year on EU funds (see IAVI Report, Sept.–Nov. 2000, p.9). The idea was to create a structure so that European scientists can work together on vaccines. EuroVac is basically a collaborative system made up of units — T-cell people, mucosal immunity people, neutralization people. The scientific goal is to develop poxvirus candidates and get them through Phase I testing in combination with gp120 vaccines. The program was awarded €8.8 million ($8.1 million), which is the biggest grant the EU ever gave for such a collaboration.
We're now waiting to hear about a second EuroVac grant, to develop vaccines based on naked DNA and on SFV (Semliki Forest Virus). That project is pure product development, without the basic science that the first grant has. I'm keeping my fingers crossed that it will get this type of EU research funding.
But what is very positive is that the EU's science directorate, DG Research, is now totally aware of the need to create new funding mechanisms, and there is real movement. Marc Girard and I went to the leadership and said, "What if our Phase I project is successful? Will there be money to take it further?" At the moment there is no mechanism to pay for Phase II or III trials. The EU recognizes this, and the sense is growing that we should do something about it.
Yes, there is a plan on the table. We call it the EU action plan for HIV vaccine development, and it's being discussed at the level of the European Commission and the commissioner for science. It calls for a minimum of €150 million ($138 million).
The plan is aimed at moving several preventive HIV vaccine candidates, chosen from national and institutional research programs within Europe, into Phase II and III trials. The selection will be handled in a technical steering committee, which has to establish the criteria for moving products forward. My hope is that this can be done in conjunction with IAVI.
So the plan involves selecting candidates, building a network for clinical trials, producing clinical lots and performing the trials. It's not for building capacity. Somebody else should do that.
Criteria will be of two kinds. Eligible candidates will have proven their safety and immunogenicity in Phase I studies. They will also have to show feasibility of production within a few years into a product suitable for large-scale use.
We have done an inventory of European products currently in the pipeline. There are the EuroVac vaccines — DNAs, the NYVAC poxvirus and hopefully SFV. The first of these should be through Phase I in 2003. The ANRS (French government research funding agency) and Aventis Pasteur in France have the ALVAC canarypox products and a lipopeptide vaccine. Then there are the Oxford MVA and DNA candidates that IAVI is supporting now in Phase I studies, which should be finished next year. We don't know exactly what SmithKline will do, but it will probably involve protein plus an adjuvant. And there is the tat-based vaccine from Ensoli's group in Italy, and presumably DNA vaccines from Britta Wahren and her group in Sweden.
This will build on existing bilateral collaborations between European and developing countries. For example, in Holland we work with scientists in Ethiopia. The French have funding for several countries, including Vietnam and Senegal, the Italians work in Uganda, the U.K. in Gambia, Uganda and South Africa, and the Swedes in Tanzania. It might take some extra money to get these sites fully ready for vaccine trials, but the basic structure is there. So are mechanisms to train people from these institutes.
We are also exploring the possibility of building cohorts of IDUs and homosexual men in Europe. Our Public Health Service in Amsterdam is thinking about organizing Phase III trials in Europe with these types of cohorts, alongside the womens' cohorts.
Besides Amsterdam, there are possibilities in France, Spain and Italy. The incidence in these groups is above 2%, which is enough. We would need 5,000 to 10,000 people. The logistics might be a challenge, but not a bigger one than for Phase III situations in the developing world. The VaxGen Phase III study in North America, Canada and Amsterdam shows us that it is feasible.
In the end we are aiming for national vaccine trial centers linked in a network we're calling the EVTP — European Vaccine Trial Platform — with sites in each participating country.
Yes, absolutely. And not only from scientists — there is also a broader context. Europeans want to see their efforts as enhancing development. That's why national governments in Europe are incorporating AIDS vaccines into their development programs. It's also the reason some EU countries are giving money to IAVI — as a way to invest in this problem, to get focused money out there. All the European money to IAVI has come from developmental funds.
So there is broad support for national and EU-level activity on AIDS vaccines. The UK's MRC supports this idea. The ANRS supports it. In the Netherlands our situation is different — we don't have an MRC or ANRS structure for linking our efforts to the medical area. So I'm working for an alliance with the malaria and TB people and entering from the development angle, trying to set up a Netherlands Center for poverty-related diseases. It would also involve universities, NGOs and the EU.
The EU action plan would have to be implemented in 2003 so that vaccine candidates now in the pipeline can keep moving.
The plan was developed by a group of scientists under the auspices of DG Research. It was produced with the help of DG Research staff, who are very supportive and willing to help until 2003. That's exactly the starting point for the EU's next funding program, the 6th Framework, which is not yet written. So we scientists are now trying to influence that process, to integrate vaccine action plans — for AIDS, malaria and TB — into the 6th Framework. In the meantime we will hopefully also have some money from DG Development for capacity building.
We're also discussing the plan with the European Parliament, because that's where the allocation and appropriation process takes place. If they decide they want to allocate a billion euros to an EU action plan, they can do it. Then the EU directorates have to figure out how to distribute the money.
I see a sort of natural growth in the field now, where the different players are finding their niche.
The US invests heavily in basic research, which fuels the ideas. Now they're adding the Vaccine Research Center (VRC) under Gary Nabel, to focus on early vaccine studies. I'm sure good ideas will come out. NIH is also beefing up investment in product development and clinical trials. The ANRS in France is investing in similar areas, on a smaller scale.
IAVI is an organization that can make a product on the fast track and push it into humans. Over time, more money will go towards trials, probably including Phase III studies, and to access issues.
Now we see the EU planning to focus on Phase II and III, and also on access. And downstream there's UNAIDS, working on the political and far back end — licensure issues, how to deliver vaccines to the world.
The only people we have to stimulate to do more is industry. And I think that's starting to happen. At least they're more enthusiastic — there's buy-in from Merck, Aventis Pasteur, which was always involved, is getting more active. GlaxoSmithKline are slowly but surely getting into the game.
So the whole global picture is not so bad. It is a long way from where we were five or ten years ago — even two years ago.
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©2000. The IAVI Report.
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