The Waterford Project

https://web.archive.org/web/20040815035319/http://www.waterfordproject.org/participants/sab.html


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Scientific Advisory Board

Chairman:

Warner C. Greene, M.D., Ph.D.

Director, Gladstone Institute of Virology and Immunology

Professor of Medicine and Microbiology and Immunology

University of California, San Francisco

Co-director, UCSF-GIVI Center for AIDS Research

Thomas J. Coates, Ph.D.

Executive Director

UCSF AIDS Research Institute

Professor of Medicine and Epidemiology

University of California, San Francisco

Vice-Chair:

Max Essex, D.V.M., Ph.D.

Chairman

Harvard AIDS Institute

Harvard School of Public Health

Anthony L. DeVico, Ph.D.

Institute of Human Virology

University of Maryland

Biotechnology Institute

Vice-Chair:

Robert C. Gallo, M.D.

Professor and Director

Institute of Human Virology

University of Maryland

Biotechnology Institute

James O. Kahn, M.D.

Associate Professor of Medicine

Associate Director, UCSF-GIVI Center for AIDS Research

University of California, San Francisco

Joseph M. McCune, M.D., Ph.D.

Senior Investigator

Gladstone Institute of Virology and Immunology

Professor of Medicine and of Microbiology and Immunology

University of California, San Francisco

George Lewis, Ph.D.

Director, Vaccine Research

Institute of Human Virology

University of Maryland

Biotechnology Institute

Bruce D. Walker, M.D.

Professor and Director

Partners AIDS Research Center

Massachusetts General Hospital

Harvard Medical School

Robert Redfield, M.D.

Director, Clinical Research

Institute of Human Virology

University of Maryland

Biotechnology Institute

Dr. Tun-Hou Lee, D.Sc.

Professor, Department of Immunology and Infectious Diseases

Harvard School of Public Health

David Scadden, M.D.

Partners AIDS Research Center

Massachusetts General Hospital

Harvard Medical School




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Board of Directors

Thomas J. Coates, Ph.D.

Executive Director

UCSF AIDS Research Institute

University of California, San Francisco

Warner C.Greene, M.D., Ph.D.

Director, Gladstone Institute of Virology and Immunology

Professor of Medicine and Microbiology and Immunology

University of California, San Francisco

Co-director, UCSF-GIVI Center for AIDS Research

Max Essex, D.V.M., Ph.D.

Chairman

Harvard AIDS Institute

Harvard School of Public Health

Gary M. Olson, Ph.D.

Professor and Associate Dean

School of Information

University of Michigan

John D. Evans

Chairman, CEO

Evans Telecommunications

Douglas Van Houweling, Ph.D.

President and CEO

Internet2 / University Consortium for Advanced Internet Development

Robert C. Gallo, M.D.

Professor and Director

Institute of Human Virology

University of Maryland

Biotechnology Institute

Marc Nathanson

Chairman

Mapleton Investments, Inc.

Michael Goldrich

Chief Operating Officer

Institute of Human Virology

University of Maryland

Biotechnology Institute

Bruce D. Walker, M.D.

Professor and Director

Partners AIDS Research Center

Massachusetts General Hospital

Harvard Medical School

 

Stephen R.Effros

President & CEO

The Waterford Project



https://web.archive.org/web/20040814211111/http://www.waterfordproject.org/plan/

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Critical HIV expertise seamlessly interfaced
into a collaboration whose collective
output exceeds the sum of its parts.

The paradigm offered by the Waterford Project is one in which critical HIV expertise in basic and clinical research, from across the country, and eventually from around the world, is seamlessly interfaced into a collaboration whose collective output exceeds the sum of its parts. It will initially be privately funded, allowing the science collaborators themselves to establish their own flexible funding priorities guided by a singular focus of developing an HIV/AIDS vaccine. It is held together, in real-time, by the "glue" of advanced IT systems design, and enabled by the leading-edge technology of Internet2. This type of IT organizational structure has been termed a "collaboratory."

The Waterford Project collaboratory paradigm is a blueprint for the core of a "virtual Manhattan Project"-an intense, collaborative, multi-disciplinary effort toward a single, common goal within a short timeframe-without the need to relocate participants to a single lab site. Some of the benefits, such as additional flexibility, cost-savings from use of pre-existing facilities and their resources, and fostering of simultaneous interactions between all participants, have tremendous implications for advancing the pace of HIV vaccine development, and ultimately the design for medical research of any kind.


AIDScience Vol. 1, No. 6, July 2001

Gallo on HIV vaccines

Robert Gallo has been involved with HIV/AIDS research since the beginning of the epidemic. Together

with other groups, he now seeks to start the Waterford Project, a 'Manhattan Project' for HIV vaccine

research and development. He is currently the director of the Institute of Human Virology (where he

also heads the Division of Basic Science), University of Maryland Biotechnology Institute in Baltimore,

Maryland. Roberto Fernandez-Larsson interviewed him for AIDScience on July 19, 2001.

[AIDScience] As an introduction and in general terms, could you give us a sense of the mission

and research focus of the Institute of Human Virology, which you lead?

[Robert Gallo] In terms of research we do not work only with AIDS there is some cancer and multiple

sclerosis research, and some research on viruses other than HIV. However, it is recognized and will be

recognized primarily as and HIV/AIDS institute. The Institute has five divisions: Clinical, Animal

Model, Vaccine, Epidemiology-Prevention and Basic Science. I am the head of Basic Science. There

are two general scientific goals in HIV/AIDS research:

First, to develop more biological approaches to therapy, which we hope and plan to make more feasible

to the Third World that was the inspiration for the formation of the Institute. Not just the Third World,

but to make therapy more palatable for the entire world, including our own country. What do I mean by

biological approaches to therapy? Well, therapies that include naturally existing molecules involved in

HIV infection such as cytokines, chemokines, other natural blockers of HIV, therapeutic vaccines

coming out of rational research that you target to certain HIV proteins, modulation of over-produced

cytokines, and augmenting some other cytokines. There are all kinds of new venues for additional HIV

therapies. You could say that our chemokine discoveries of 1995, published in December of that year in

Science [PubMed], that block HIV infection, were a major catalyst for the discovery of CCR5 and

CXCR4. These have opened up new therapies that involve chemokines blocking HIV infection.

The second general objective is, of course, to develop a preventive HIV vaccine. The philosophy of our

Institute is that the current consensus in the scientific community is a mistake, specifically the

development of vaccines that limit infection but allow infection and then declare victory. I think that

we cannot trust that those vaccines will work well; the virus may return full-blast. We have to go for

the jugular first and do our best to develop [a vaccine that imparts] sterilizing immunity. We have not

given up on that we think it is doable. The major part of our vaccine program is to prevent HIV. A

preventive vaccine, in my view, is the philosophy of our Institute and is a little different from the

consensus of the field today. The consensus is that we can allow infection as long as we contain the

virus. I worry about that because if your vaccine succeeds allowing infection but containing the virus

and not allowing disease, then 10 years from now the virus could take off. In other words, to us the

goal of a preventive vaccine is sterilizing immunity complete block of infection. They say it is raising

the bar it is the highest bar. We think it is doable and we think we are on a pathway to achieve it.

It is something that has worked for many viral diseases in the past.

Right, that is my view.

Besides grants to individuals by the government and others, how is the Institute funded?

The predominant funding is of course by sponsored research; NIH [U.S. National Institutes of Health]

grants, a bit of funding from the pharmaceutical industry, foundations, charity, and philanthropy.

Maryland State funding, which started the Institute, is now coming down like any part of the University

of Maryland there is some basal funding, but it is becoming a smaller percent of the total. At one time,

when we came from the NIH, of course we had no money so we were totally dependent on the state.

We have now something like $23 million of sponsored research funding.

Going back to HIV vaccine research, could you give us a couple of good reasons why we do not

have an HIV vaccine more than a decade and a half after the discovery of the virus?

Of course, this is a loaded question (laugh). At the very beginning, there were scientific issues that had

to be settled. Okay, when were those scientific issues adequately settled? You will get different

answers from different people regarding this. Some will say they are not settled yet. I could say that,

roughly, five to eight years ago there was enough science and a crash program was in order. So, I think

we could have gone faster. I do not mean this as an attack on any one person, persons or organizations.

That is just what I think, and I tried, for example, with Project Inform leader Martin Delaney to have a

crash program in 1988, but it never got off the ground. People did not believe the science was right, so

the money was not there, or really the interest. Maybe I did not try hard enough, I do not know. In any

case, I believe that one reason [we do not have an HIV vaccine] is we did not try as early as we should

have for a crash program. I tried twice, at the beginning of the field and then when I thought the science

was ready, about eight years ago. There were also scientific reasons that impaired rapid progress,

including the variation of the virus and the fact that the virus integrates into DNA upon infection, it

being a retrovirus. This means that the immune response has to be ready and quick if you are going to

have a sterilizing immunity, to take the virus down and help to destroy a minimal number of infected

cells. This entails a difficulty greater than with some other viruses.

The third and maybe underestimated difficulty is the lack of a small animal model. In fact, to the

surprise of some of my scientific colleagues, I often list this as the number one problem. Think about it,

if we had a small animal model. We can stick virus and vaccines into mice and rats and we can

measure the immune response, but we cannot measure protection these animals do not get infected, as

you know. Think about the limitations [we have] when we have to go to monkeys. How many scientists

have access and money for monkeys, and how many scientists know how to work with monkeys, even

if they had access to them. Also, how much longer does it take with a monkey model than it would if

we had a rodent model? This is a serious handicap.

Another problem has been a general lack of total cooperation between nations, activists and scientists

in the first half of the history of the field. That is now infinitely better, fostered by the informed media,

and has improved things a lot. Also, [non-governmental organizations] like the Gates Foundation and

the credibility that has been given to the IAVI [International AIDS Vaccine Initiative] these have

catalyzed things moving forward in a more serious way.

There was never enough money for vaccines it costs so much. Also, when you have advancement

sometimes you do not know how to take it to the next level. Scientists and the NIH are not equipped for

practical advances; they are equipped for hypothesis-driven basic questions. When you get to the more

practical [advances], it was very hard for the NIH to find the mechanism to fund someone. That is why

IAVI was so important, and I think they helped catalyze the NIH moving more in that direction. We

still do not have all the practical issues solved. It still takes a lot of effort to get GMP [Good

Manufacturing Practice] production and the problem of how to get the monkeys IAVI does not solve

that problem. Then we have the problem of selecting which candidate [vaccine] goes forward. There

are so many complications at many levels, but I think it is 10 times better than it was 5 years ago.

You are joining an AIDS vaccine effort called the Waterford Project, which will link your

institution to leading researchers at Harvard and the University of California, San Francisco

(UCSF).

That is correct, and also with the University of Michigan in terms of the technological issues.

Is this already a reality?

It is a reality in this sense: John Evans, who heads the Waterford Project administratively, has put up

his own seed money between $1 and $2 million already. It is also a reality in that we meet and have

met several times and have worked out the intellectual property rights, the fears of collaborating with

another group we are not used to collaborating with, and we are sharing things pretty much equally. All

those things have been worked out. What has not happened yet is the generation of the funding that

John Evans and his staff are trying to raise. They are going to try hard, and it is not like they have been

wasting their time; they just did not have our business plan. Now the scientists have done that and they

have had it in their hands for a few months, and they are off and running.

Maybe if it had been around for a while.

Yes, if you saw somebody else take it!

I recall the early Salk experience; there were vaccine failures.

That is exactly the point. Therefore, needless to say, the argument was intelligent people will never

accept it at the FDA [U.S. Food and Drug Administration]. The experiments that were done were not

many, and in more than one lab were not impressive.

What about the attenuated virus vaccines there are not too many folks that buy that?

You are asking the wrong person, because I was the most rigorous against it, from the moment that Ron

[Desrosiers] talked about it. So I cannot change history. I already took a very strong standing since the

very first set of experiments. I believe it was something worth supporting scientifically, but not to get

serious anymore, even though I know some prominent scientists were pushing it, like Robin Weiss and

[David] Baltimore for a while, but they had not thought it through.

Last year, you demonstrated in a Proceedings of the National Academy of Sciences paper [Full

text article] that chemically inactivated Tat toxoid could immunize rhesus monkeys and, while

not protecting them from infection, it attenuated disease effects after challenge. What are you

doing with this project now, and could it become a main player in the list of vaccine alternatives

in the future?

I believe so, and the answers to both your questions are yes and yes. I would never accept it as a

vaccine alone. I disagree with using native Tat. We find that inactivated Tat is better than the native

form, and secondly, the native form reduces the immune response to gp120. You are targeting Tat

because you believe it to be immunosuppressive, and indeed it is, so why would you want to use native

if you can use inactivated. We have never seen complete protection with native or inactivated Tat. We

believe what we reported, we believe it could be a component of a vaccine, and in our case it will be,

but that is not going to be our first major component.

Which is the main biological approach to therapy that you are interested in?

I would say the whole area: naturally occurring inhibitors of HIV. We have defined four chemokines so

far, then we discovered two more, which do not work by blocking entry.

If the Waterford Project funding becomes a reality, perhaps for the next 3 years research

funding will not be a consideration for you. Assuming that will happen, what else would you want

to see happening in the next 3-5 years, that is not happening now?

We will still get funding from NIH, for more basic science more likely. But clinical trials cost a

fortune, as you know. If the Waterford Project raises $140 million, which is what we hope, for a period

of 5 years, that is about $30 million a year. Now divide that by 3.5, and now you are talking about $8

million [for the Institute]. Is $8 million enough to do the monkey experiments, getting through the FDA

and the clinical trials? Of course, it is not. We would have to go to IAVI, the Gates Foundation, the

NIH, everyone you can go to to get funded. We hope that it does not backfire, if people think we do not

need money.

Lastly, when you look at other groups, what do you see as the top prospect for an HIV vaccine?

I work on what I work on because I think it is the top. Obviously, if we did not think so, we would go

elsewhere. So, we made our choice, and by the way, both approaches are original and both are

innovative. Some of the other approaches are interesting, when properly combined. I collaborated with

Pasteur-Merieux for many years on ALVAC. It is not enough. The thing that has impressed me is

alphavirus [vaccine vectors], delivering HIV genes I think it is [Robert] Johnston. I think it is kind of

interesting; it may be exciting.

Harriet Robinson demonstrated as much as possible that a good cell-mediated immune response can

hold virus titers down, at least in the primate system with MVA [modified vaccinia Ankara] and

multiple antigens [PubMed]. Osterhaus, in Rotterdam, has argued that Tat as an early antigen is a better

target than some of the structural proteins which are later antigens, and I think he has demonstrated this

very elegantly in recent scientific experiments. This is an idea unlike ours, where we attack Tat because

we believe it to be extracellularly suppressing the immune system of uninfected cells.

I think the proper use of cytokines with the proper adjuvants will be very important for anybody's

vaccine. I do believe that, like us, some people will return to humoral immunity and demonstrate that it

is possible to have broadly neutralizing antibodies. Some people are already targeting in that direction,

or they were already in that direction but had not achieved what they wanted yet. For example, an

excellent scientist that just came to the NCI [U.S. National Cancer Institute], John Mascola, has been

after the antibody approach for some time.

Finally, the reason it takes so much time is that it takes time.

Copyright Information

Science's AIDS Prevention and Vaccine Research Site

http://aidscience.com/Articles/aidscience006.htm (8 of 8) [7/24/2001 6:13:12 PM]

2001 (Sep 17) - Forbes : "Outsmarting AIDS"

Robert Langreth   /   Sep 17, 2001,12:00am EDT

https://www.forbes.com/forbes/2001/0917/160.html?sh=5813e68c5289

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Robert Gallo, the man who codiscovered the HIV virus, hopes a bold new approach may finally produce a vaccine to halt his killer.

Twenty years after the global outbreak of AIDS, no one has developed an effective vaccine against the HIV virus, a far more cunning foe than polio, smallpox or measles. Though at least 30 different candidate vaccines have been tested in humans, only one has advanced to the final stages, and most scientists are skeptical that this one will work.

Now comes Robert Gallo, codiscoverer of the HIV virus and director of the Institute of Human Virology in Baltimore, with a glimmer of hope. Researchers at his institute have devised a prototype vaccine that targets a vulnerable spot obscured by the surface of the virus. The vaccine appears to sidestep HIV's bedeviling ability to mutate and evade capture by the human immune system, a trait that has stymied efforts to concoct an effective inoculation. In tests on macaque monkeys, the vaccine produces potent antibodies that disable a variety of HIV strains from around the world, something previous vaccines have generally failed to do.

"This is like nothing we've seen before. It has neutralized almost all the strains we have tested, and we have tested a lot," Gallo says. Adds David Montefiori, a veteran AIDS researcher at Duke University Medical Center who has been evaluating how AIDS vaccines produce antibodies: "I've tested just about everything anybody has tried, and this is the best I've seen."

Now comes the hard part of translating this preliminary result into a vaccine suitable for large-scale human trials. In the past promising prototypes have often languished in the lab, partly because private-sector support for an AIDS vaccine has been limited. After all, selling one-shot vaccines to developing nations isn't as profitable as selling once-daily drugs to richer markets. But Gallo hopes to speed the vaccine forward with an innovative new collaboration called the Waterford Project, spearheaded by his entrepreneur friend John Evans, cofounder of C-SPAN.

The Waterford plan is to use broadband technology to link Gallo's lab with researchers at Harvard and the University of California at San Francisco and bring the new vaccine into human trials in as little as 18 months. Using Internet 2, an advanced version of today's network operating at up to 2.4 gigabits per second, the researchers will share early data as it is being developed, breaking down walls between otherwise competing labs.

The new vaccine was dreamed up almost a decade ago by Anthony DeVico, now a 44-year-old biochemist at Gallo's institute. Back then AIDS vaccine research was focused on stimulating the immune system to produce antibodies against the virus, a standard strategy that worked for polio and other diseases. But HIV is a master of disguise. The protein on the surface of the virus, called gp120, constantly mutates to escape detection by antibodies. The early results were so discouraging that some researchers concluded it would be impossible to devise a vaccine that fully blocked the infection.

In the early 1990s DeVico figured he might get around the mutation problem by targeting the crucial portion of gp120 that is normally obscured by HIV's surface. This portion doesn't mutate much; the virus uses it to hijack human blood cells and reproduce itself. But gp120's innards are exposed for 30 minutes or so while the protein is hooked to its human receptor, called CD4, in preparation to invade a cell. DeVico's idea was to build a vaccine consisting of gp120 permanently fused to its CD4 receptor. He figured shots of this fused vaccine would prompt the immune system to create an army of antibodies motivated to sniff out and disable the virus in its exposed position during that crucial 30-minute period.

The concept was so far off the beaten track, hardly anyone paid attention at first, but his recent tests of the vaccine in monkeys are generating excitement among the few researchers who have seen the data. In the tests DeVico and his colleagues inoculated several monkeys with the gp120-CD4 vaccine, then tested their blood against HIV in a test tube. Sure enough, the blood contained antibodies that disabled a spectrum of strains from Africa, North America and elsewhere. DeVico won't discuss details of his study pending publication.

In the meantime Gallo and Evans had already formed the Waterford Project, which arose from Gallo's frustration with the pace of vaccine research and his desire to bring scattered researchers together. Evans suggested that high-speed data links could help far-flung labs share results.

In 1999 Evans brought together Gallo and a handful of scientists and Internet experts at his Virginia farm, Waterford House, to discuss the idea. Initially the scientists were uneasy. "In research you plant a flag and defend your turf. We were not natural collaborators," explains Warner Greene, who directs San Francisco's Gladstone Institute of Virology & Immunology. But over time the egos faded, and the scientists realized how much faster they could progress by cooperating. The possibility of making history for producing the vaccine that wiped out AIDS didn't hurt either. "It has been the most exciting single enterprise I have been involved with," says Greene. When Gallo showed the DeVico data in person to his Waterford collaborators less than a year ago, they quickly agreed to make it a top priority. "The more I looked at the data, the more excited I became," says Greene. As a first step Waterford is now installing videoconferencing equipment.

Much remains to be done to confirm the finding and turn it into a practical vaccine. The researchers need to perform a more realistic test to see if the vaccine indeed protects monkeys exposed to an AIDS-like virus. They must tinker with the vaccine to boost the quantity of antibodies it makes, figure out a reliable production process and prove it is safe to use in millions of patients. Stimulating the production of antibodies--only one arm of the immune system--may not be enough. Ultimately, researchers will likely want to combine it with one of the vaccines being developed to stimulate production of killer T cells.

Despite all the promise, the group is still short on money. The original Waterford plan, conceived at the height of the bull market, was to raise money from telecom firms using Evans' connections. But with the market slump, those money sources have dried up. Evans has donated $1.5 million of his own, but that is a fraction of the planned $14 million annual budget. Gallo's lab has government funds to continue its vaccine work, but it will go faster with several labs working together.

For Waterford collaborator [Dr. Myron Elmer "Max" Essex (born 1939)] of the Harvard School of Public Health, a vaccine can't come soon enough. Essex, advance man for human trials, is spending this fall in Botswana, where 38% of adults are already infected. "It's unbelievably urgent," he says. "What do you do if you want to have kids and get married?" A vaccine won't cure the 36 million already infected, but every day HIV claims 15,000 more.


http://aidscience.org/articles/aidscience024.asp

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Broadly cross-reactive anti-HIV neutralizing antibodies:

A conversation with Robert Gallo

Robert Gallo is director of the Institute of Human Virology, University of Maryland Biotechnology Institute. Recent data published by his group showed that covalently cross-linked complexes of the HIV-1 surface envelope glycoprotein and CD4 elicited antibodies in rhesus macaques that were able to neutralize a wide range of primary HIV isolates, regardless of their subtype or coreceptor use. Roberto Fernandez-Larsson interviewed him for AIDScience during the 2002 International Meeting of the Institute of Human Virology held in Baltimore, September 9-13, 2002.




[AIDScience] What are the most relevant things that have happened in your lab in the last 12 months?

[Robert Gallo] We have taken the gp120-CD4 complex [PubMed] [PubMed] to another stage of development for a preventive vaccine. We have a complex that is able to induce broad, neutralizing antibodies. We are able to get a very good, long-lasting titer. Eventually that titer is going to go down. However, you want a response — right away — when the virus enters the body.

The project is now at the level of a biotech company, and we are collaborating with the International AIDS Vaccine Initiative (IAVI). We will probably make a deal with IAVI to help carry this project to the next level as fast as we can.

Last year you told us about the Waterford Project (WP). Is the WP involved?

It is not. John Evans, who started the WP and donated half a million dollars of his own money, was never able to raise the big money, like IAVI. Evans has gracefully bowed out and is trying to do things to help IAVI.

Who came up with the CD4-gp120 complex project?

Anthony DeVico [PubMed] started it and independently by John Gershoni [PubMed], who was in my lab in 1988. Tim Fouts [PubMed] did the bulk of the work. Franco Celada [PubMed] was the first that was dealing with a structure like this, but for purposes other than a vaccine.


Dr. Robert Gallo, director, Institute of Human Virology, University of Maryland Biotechnology Institute.

Do you think virus escape mutants are still possible with a vaccine like this?

Anything is possible, but if you are protecting against the first step of the infection you have to fight against total prevention. It is theoretically possible — let's say we have variants that combine with another receptor that is not included in the region of gp120 — but we hope that the incidence will be very low.

Are there two camps in the HIV vaccine research community, those who favor a vaccine that promotes cell-mediated immunity and therapeutic vaccines, and those that favor a preventive vaccine that promotes neutralizing antibodies?

I would not look at it like that. Anybody with a brain bigger than a bird would agree that if you can get broadly reactive neutralizing antibodies that block entry completely you would be an idiot not to agree.

They may agree with the concept, however, they are working on something else.

The reason is because anything is possible. I also was involved in trying to get broadly reactive antibodies with HIV envelope: it does not work. That happened in the late 1980s; the field went into a depression. Then in the early 1990s, they thought maybe they could do this with cytotoxic T lymphocytes (CTL) and cell-mediated immunity (CMI), and ended up with good monkey data. We decided to stay with viral entry block — not many people did. Now, the CTL-CMI people are worried because it looks bad. Suddenly, monkeys are breaking through.

How is the gp120-CD4 complex vaccine going to be delivered?

There are multiple possibilities and needs to be experimented: directly with protein, the DNA form, or our Salmonella DNA vaccine vector [PubMed] that can be delivered orally. First, we will probably go for direct protein or intramuscular DNA delivery.

... https://pubmed.ncbi.nlm.nih.gov/11672930/ .. .

Mucosal and systemic HIV-1 Env-specific CD8(+) T-cells develop after intragastric vaccination with a Salmonella Env DNA vaccine vector

M T Shata 1, M S Reitz Jr, A L DeVico, G K Lewis, D M Hone 


What is the time frame for this vaccine?

I think the project will go to trials in about 20 months. It all depends on money — I think we are going to get it.

Last year when we talked, your Tat vaccine [PubMed] was more in the forefront than this project...

Last year this project was in the planning and the in vitro stage. The results on Tat that we have been publishing recently are confirming a lot of the in vitro data, and we also have a little bit of monkey data. Aventis is already doing small therapeutic clinical trials in Europe. Our Institute has started therapeutic Tat vaccine trials in the U.S.

Can you foresee the Tat vaccine improving vaccines developed by other investigators?

Yes. Not everybody can explain this to you because it is complicated. Our view is that it is a very sensible therapeutic vaccine that needs large testing. It also makes sense to add it to a preventive vaccine. Let us say, for example, that our gp120-CD4 complex is a success, protecting experimental monkeys for a while. My prediction is that in humans the following would happen: vaccinated with the gp120-CD4 complex, the subjects become protected against infection, and therefore do not need any Tat vaccine. However, three years later, some of the vaccinated people have low titers. What is needed to boost these titers? Normally, to boost you would need exposure to the virus, but HIV rapidly down-modulates the CTL response through Tat. This is what we believe — our hypothesis — based on data, and we want to convince the Aventis group that they should also include it in their preventive vaccine strategy.

In the discussion that followed one of the presentations I heard you make a comment about highly active antiretroviral therapy (HAART) versus vaccines in Africa...

There are ethicists, and economists have joined them, that say that it is unethical if you do not use HAART in Africa. This inhibits new experimental developments that could be more practical for Africa. I cannot believe — I do not care who tells me otherwise — they are not going to have an immense problem. I think you should use HAART wherever it is possible, but for the bulk of Africa I do not believe you can follow people [in treatment] when you need an infrastructure that will cost you three times the cost of the drugs. I also think you will make massive drug-resistant strains. So, I would say, go ahead with drug treatments but do not stop people from initiating experimental approaches that could prove to be more practical. If Tat were helpful, why would you stop it? I also believe — as do others — that interferon alpha, which overproduces quickly after infection and especially in late HIV stages, is immunosuppressive. It would be easy, simple, and safe to vaccinate to reduce that overproduced level. We could give three injections per year — something that anybody in the village can do.

If it worked, it would certainly be better than having millions of people take several pills a day...

Right, and it is nontoxic. Why should we do in Africa what we are doing in the U.S. or in Europe? It is ridiculous. I am not saying that one should not work hard if one can, for example in some of the major cities in Africa, but nobody is going to tell me that you are going to treat 70 million people — or 50 or 60 million — and follow them every day to make sure they are in compliance and do the viral analyses for mutants.