Frank Volovovitz (born 1948) ( founder )
Plans for the first human trials in this country of an experimental AIDS vaccine were announced today by Federal officials and a Connecticut company that developed the substance. But the officials warned that an effective vaccine for widespread use was still years away at best.
In formally announcing the decision, which was disclosed in news reports Monday, Federal health officials expressed hope and optimism about the new vaccine but said there was nothing about its development that suggested an imminent breakthrough in preventing the deadly disease, which cripples the immune system.
[Dr Anthony Stephen Fauci (born 1940)], director of the National Institute for Allergy and Infectious Diseases, said there was ''really no change in the timetable'' previously issued by health experts that a useful vaccine would probably ''not be widely available'' until ''well into the 1990's.''
He spoke at a news conference this morning at which MicroGeneSys Inc., a tiny biopharmaceutical firm in West Haven, Conn., and the Federal Government jointly confirmed widespread reports that the company had received the first approval from the Food and Drug Administration to conduct a small-scale clinical trial in humans. The first tests are expected to begin by the end of this year.
Small-scale human tests of other AIDS vaccines have already started in Zaire and France, but the new study, to be conducted with 81 volunteers who will be treated at the Clinical Center of the National Institutes of Health, in Bethesda, Md., is the first authorized in the United States.
The study will investigate only the safety of the vaccine and the degree to which it stimulates protective antibodies in the recipients. It will not try at this point to determine whether the vaccine is truly effective in preventing AIDS. That would require a much bigger and more complicated study that could not be started for at least another 18 months, even if initial tests are promising, officials say.
Federal health experts said the MicroGeneSys vaccine was only the first of several candidate vaccines to reach readiness for first-phase trials. A spokesman for the F.D.A. said two other vaccine developers, Oncogen, a Seattle-based subsidiary of Bristol-Myers, and a team that includes the Institute for Immunologic Disorders in Houston, had also sought approval to test AIDS vaccines. Other companies are also working on potential vaccines, as are scores if not hundreds of researchers at institutions around the world.
Officials said the MicroGeneSys vaccine was the first to gain approval for human testing in part because the company completed the preliminary requirements first, and in part because its vaccine looked highly promising in stimulating the production of neutralizing antibodies in animal tests. Such antibodies are the part of the immune system that is expected to fight off the AIDS virus.
The vaccine was tested in hundreds of mice, guinea pigs and rabbits, as well as 12 Rhesus monkeys and 2 chimpanzees. It was particularly effective in raising antibody levels in guinea pigs. But the company has not yet performed tests to see if the vaccine can protect chimpanzees from infection with the AIDS virus, and none of the other animals are subject to such infection.
The human tests will be conducted by researchers from the infectious disease institute who are already recruiting volunteers from the Washington area. The initial test, called a Phase One study, will take about six months to complete. The scientists will administer various doses of the vaccine to 60 healthy homosexual men who have no trace of the AIDS virus or AIDS antibodies in their blood and whose sexual behavior puts them at ''low risk'' of infection. Their antibody levels will be compared with those of a second group consisting of 15 homosexual men who will be inoculated with an alternative material and 6 heterosexuals who will receive either the vaccine or the alternative inoculation.
The study will focus on homosexual men because they are the group at greatest risk in this country and are the most likely target for an effective vaccine. Moreover, homosexual men typically suffer from a different range of infections than the general public and thus might respond differently to a vaccine.
The company said it hoped to test the vaccine in a heterosexual group in Canada as well.
If the study looks promising in the first phase, it will enter second phase trials involving 100 to 200 more volunteers and lasting a year, to determine the best dosages. Only after that, if the vaccine still looks promising, would a large-scale ''phase three'' test, involving thousands of volunteers, be undertaken to determine whether the vaccine can actually prevent acquired immune deficiency syndrome. Experts have not yet worked out the difficult problem of how to test the vaccine's effectiveness; virtually all experts believe it would be unethical to expose the vaccinated people deliberately to the lethal AIDS virus.
Company officials said they would retain patent rights to any vaccine that might emerge but would pay royalties to the Government for its technical assistance.
Although most medical experts expected that some company would receive approval this year from the Food and Drug Administration for human clinical trials of an AIDS vaccine, the list of possible candidates never included Microgenesys Inc. Indeed, until this week few analysts who follow the biotechnology industry had heard of the tiny company, which is based in West Haven, Conn., and has now become the first company to get that F.D.A. approval.
Founded in May 1983 by an immunobiologist named [Frank Volovovitz (born 1948)], Microgenesys (pronounced mi-CRO-gen-esis) is privately held and has not been financed with venture capital. Mr. Volvovitz, who is 38 years old, formed the company to explore the use of an insect virus as an agent for the production of pharmaceutical proteins using recombinant DNA technology. The company has fewer than 30 employees and has yet to market a product.
Mr. Volvovitz, who received a B.S. degree in biology and did graduate work in immunology and virology at New York University, founded a company, Biotechnologies Inc., in 1979 to produce interferon by natural rather than genetically engineered means. That company folded after a year and a half, and Mr. Volvovitz began recruiting scientists for Microgenesys. Among those he signed up are Mark A. Cochran from the National Institutes of Health and Gale A. Smith from Texas A & M University, the two researchers who jointly developed the possible AIDS vaccine.
Although the approval from the F.D.A. puts the spotlight on Microgenesys, analysts said it does not mean the company has a serious lead on others developing AIDS vaccines. These include the [Chiron Corporation], in collaboration with the Ciba-Geigy Corporation; the Repligen Corporation working with Merck & Company, and the Oncogen subsidiary of the Bristol-Myers Company.
In a telephone interview, Mr. Volvovitz emphasized that the AIDS vaccine is in a very early trial stage using animals. He said Microgenesys was working on vaccines for seven other viruses, and that it was ''quite possible'' that one of them would become the company's first marketable vaccine. The company is also using AIDS antigens to develop a diagnostic test for AIDS antibodies, which could be its first marketable product, possibly in late 1988.
Working with the National Institute of Allergy and Infectious Diseases in Bethesda, Md., Microgenesys has done trials of the AIDS vaccine on mice, rabbits, guinea pigs, rhesus monkeys and chimpanzees. In addition to looking for side effects, the tests have sought evidence that the vaccine is immunogenic: Does it cause antibodies to form, what are their nature and what other cellular immune responses occur?
Of the animals tested, only chimpanzees can be infected by AIDS, and none of the animals have been exposed to the AIDS virus. ''What we have seen in the animals is that antibodies are produced, and that sera from the animals would protect human cells in a laboratory,'' Mr. Volvovitz said. ''That is a great distance from determinining whether the vaccine would prevent infection by the virus.''
Viren Mehta, a biotechnology analyst with Wood, Mackenzie & Company Inc. in New York, said, ''If they have not challenged chimps, that would put them seriously behind'' other companies working on AIDS vaccines.
''It is curious that the F.D.A. would let them go ahead,'' Mr. Mehta said.
Jim McCamant, editor of the Medical Technology Stock Letter, said he still thinks that Chiron has the most advanced effort under way on an AIDS vaccine, although the company has been publicity-shy about its work. Microgenesys is ''obviously only one of the players'' in AIDS vaccine research, he said. ''There are two or three others I expect will get approval by the end of the year.''
The human trials, which will not expose subjects to the virus, will use 81 volunteers from the Washington, D.C., area, of whom 75 will be male homosexuals.
''This is predominantly a study on the male homosexual population because that is one of the groups most likely to use such a vaccine,'' said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases. The volunteers will be screened for the absence of AIDS, and to make the trial valid must not engage in activities that would put them at risk of contracting AIDS, he said.
The AIDS vaccines likely to enter trials this year all use recombinant DNA to produce proteins that mimic the outer envelope of the virus. But, Dr. Fauci said, the Microgenesys vaccine has one possible advantage. Because it is produced in animal cells rather than in bacteria, the vaccine has sugar molecules on its surface, so it ''mimics the virus more closely,'' he said.
While most genetically engineered hormones and proteins are produced using bacteria or yeast cells, Microgenesys uses a virus found in insects called a ''baculovirus,'' which can be commandeered to produce substances such as the AIDS virus envelope.
IT is a small company on a quiet street in an industrial section of West Haven. It has fewer than 30 employees and no sign on its door, and it shares the building with an office furniture warehouse and helicopter parts supplier.
From such modest circumstances has come what researchers hope will be a major step in the fight against AIDS - the clinical testing on human beings of a possible vaccine to protect against the disease.
The company, Microgenesys Inc., is the first to receive Federal permission to conduct such tests. The attention has been enormous, and, according to the company's 38-year-old chairman and president, a little disconcerting.
''Let's say we're quiet,'' said the company president, Franklin Volovitz. ''We're not trying to make ourselves visible.''
Whether it is trying or not, the company has become very visible, and the office bulletin board was filled last week with newspaper clippings about the company from around the world and written in Japanese, Spanish and English. There were more to be clipped and posted, and a copy of Business Week magazine with an article about the company sat on Mr. Volvovitz's desk.
The company is now ''trying to go back to work as usual,'' he said.
''It's not only the first AIDS vaccine trial which makes it exciting, but in addition to that, it's our first product going into clinical trial,'' he said. His company won the honor over several large and well-known competitors that have also been working on AIDS vaccines.
Under the arrangement between the Federal Food and Drug Administration and Microgenesys (pronounced ''mi kro GEN ess iss''), 60 homosexual men from a group of 81 volunteers are to be inoculated with the vaccine under the supervision of the National Institutes of Health in Bethesda, Md. The first phase of the testing is to last six months starting in October.
Mr. Volvovitz emphasized that the trials did not mean a cure for acquired immune deficiency syndrome had been found or that there was a vaccine ready for use. ''We're at least two years away from asking the question in clinical science of whether the vaccine can be used in AIDS protection,'' he said.
Mr. Volvovitz refused to specify the amount of money his company had spent on developing the AIDS vaccine, only saying that it was millions of dollars. The company is privately financed.
The only exception was $200,000 from the Connecticut Product Development Corporation, a financing arm of the State Department of Economic Development. It was for development of an insecticide that the company is testing to control the apple worm, an orchard pest.
In addition to the AIDS vaccine, the company's 20 scientists are developing seven other vaccines, including one for malaria, Mr. Volvovitz said. He said he expected one of the others ''to reach the market before the AIDS one, because the testing for it is more straightforward.''
The firm is also developing an AIDS diagnostic test, which has been tested in Canada.
After the announcement by the F.D.A. about the trial of the AIDS vaccine, business investors in companies doing AIDS-related research expressed surprise about the choice of Microgenesys, with some saying they never heard of the company.
''We've been very visible to those who follow technical developments,'' Mr. Volvovitz said. ''We may not have been visible to others. I don't know why.''
He pointed out that scientists from his company made four major presentations in the last year at important scientific meetings. They were the Cold Spring Harbor Symposium on Long Island, the Third International Conference on AIDS, the Seventh International Congress on Virology in Edmonton, Alberta, and an international scientific meeting run by the Food and Drug Administration in Bethesda.
Mr. Volvovitz grew up in West Hartford. His interest in science goes back to his childhood. ''People that even knew me in grammar school generally identified me with science,'' he recalled.
After attending public schools in West Hartford, he received a bachelor of arts degree in biology at New York University, where he has also done graduate work in virology and immunology. He worked as an immunobiologist at St. Vincent's Hospital in Manhattan.
In 1980, he founded his first company, Biotechnologies Inc., which developed, manufactured and marketed human and animal interferon for laboratory and clinical research purposes. A year later, it went out of business after his investors decided to liquidate.
Mr. Volvovitz wanted to start a new company. He did market research to find a biotechnological area with ''potential for commercial development,'' he said. ''I concluded that what was an obscure area, baculovirus, an insect virus, could serve as the technical foundation of the company.''
He looked at the possibility of developing biological insecticides and pharmaceutical products for new drugs based on genetic engineering. The apple worm insecticide was the first product his new company developed. It has been tested in South American and is now being tested in California and Washington State.
He said that although he planned to double the size of his staff in the next year, he still would not be looking for a prominent image.
''We might have a small sign out front,'' he said. ''We're not about to put out a big billboard.''
''We really don't want to be distracted at this point,'' he said. ''Progress of significant worldwide importance could be slowed down.''
A second experimental vaccine that researchers hope could prevent infection with the AIDS virus was approved today for human testing by the Food and Drug Administration.
The experimental vaccine was developed by the Bristol-Myers Company and is produced through genetic engineering techniques.
It is made from vaccinia virus, the virus from which smallpox vaccine has been manufactured. Genes from the surface, or protein envelope, of the AIDS virus are injected into the vaccinia virus. using the techniques of recombinant DNA.
While the proteins themselves will not cause disease, researchers believe they may stimulate the body to produce antibodies that may be effective against AIDS infection.
Studies will be carried out at the Pacific Medical Center under the direction of [Dr. Lawrence A. Corey (born 1947)], director of the virology division of the University of Washington School of Medicine.
The vaccine will be tested in 30 to 60 healthy homosexual volunteers who are not infected with the AIDS virus. A control group will receive smallpox vaccine.
The initial tests will be designed to determine the vaccine's safety and the particular subtypes of antibodies it provokes the body to produce.
In announcing the approval, the F.D.A. Commissioner, Frank E. Young, called the experimental vaccine ''a major step in recombinant vaccine development'' but emphasized that it is in the earliest phase of clinical testing.
''Even the most optimistic experts predict that an AIDS vaccine will not be in general use until well into the 1990's,'' Dr. Young cautioned. ''But I remain hopeful for the future because of the highly sophisticated research techniques, especially recombinant technology, and the vast resources being applied by both government and private sector organizations toward the search for a successful vaccine,'' Dr. Young said.
While scientists are following several different approaches to the design of possible AIDS vaccines, they are not sure that any will work.
The first potential AIDS vaccine approved for human testing in the United States was developed by Microgenesys Inc., of West Haven, Conn. Approved for testing on Aug. 18, it is cultured from an insect cell. Other potential vaccines are being tested in chimpanzees as a prelude to possible human studies.
In Africa, scientists from France and Zaire have begun trials of another vaccine candidate.
Bleak results from recent experiments indicate that the quest for a vaccine against AIDS will be even more difficult than many experts had imagined. The results also raise the possibility that current lines of vaccine research may be fruitless.
A year ago, the search for a vaccine seemed off to a good start as a French scientist injected himself with an experimental vaccine and also began testing the vaccine on volunteers in Africa. Shortly afterward, the Food and Drug Administration approved the first human tests in this country of vaccine candidates that had shown some promise in animal tests.
But the effort has suffered major setbacks in recent weeks, scientists say, as two important animal studies indicated that the main current approach to a vaccine might not work. Chimpanzees given doses of a type of antibody that blocks the AIDS virus in laboratory dishes were not protected against AIDS infections. And monkeys, immunized with an inactivated virus that causes a disease similar to AIDS, had an excellent antibody response but were completely unprotected against the monkey version of AIDS.
A successful vaccine would protect a person from becoming infected with the AIDS virus by bolstering the body's defenses. Scientists are also working to develop drugs that defeat the virus once a person is infected, or reduce the severity of the disease it causes.
While no one has abandoned hope, recent findings have sorely disappointed the large cadre of scientists searching for a vaccine that could curb the global epidemic of the fatal disease. ''They are real setbacks and they raise serious concerns about the viability of the vaccine program,'' said Dr. Jerome Groopman of New England Deaconess Hospital in Boston.
Dr. Malcolm Martin, a molecular biologist at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., said, ''I think the field has come around in general to have a much more pessimistic outlook on vaccines.'' Dr. Martin played a major role in developing an experimental vaccine that is now being tested in volunteers.
''There are no easy fixes,'' Dr. Martin added. ''I'm not saying we will ever have a vaccine.''
The theory, or at least the hope, behind current efforts is to find a vaccine that will stimulate the body's immune system to ward off invasion by the AIDS virus. Researchers are seeking an agent that elicits production of ''neutralizing antibodies,'' a type that defeats the virus in the laboratory, and also provokes ''cell-mediated immunity,'' in which ''killer'' cells of the body's defensive system attack cells infected with the virus.
From the beginning scientists have been unsure whether a vaccine for acquired immune deficiency syndrome would be possible. Both neutralizing antibodies and killer cell responses occur in people who are infected with the AIDS virus, but they do not halt the virus's deadly progress. The hope, though, is that the virus might be stopped if the immune defenses had already been in place when the virus first enters the body.
But the new animal results have caused experts to ask whether their basic assumptions hold true. The AIDS virus seems to be breaking the normal rules of immunization.
''I don't know of anything like this,'' said [Dr. Maurice Ralph Hilleman (born 1919)], a vaccine researcher with 45 years of experience who is director of the Merck Institute of Therapeutics in West Point, Pa. ''This is the first time in vaccine development that neutralizing antibodies don't seem to amount to much.''
Discouraged scientists note that their slow progress is a far cry from the ebullient statement made in 1984 by the Secretary of Health and Human Services, Margaret Heckler, who announced that the AIDS virus had been isolated and proudly proclaimed that a vaccine would be available within two years.
Still, scientists say that it is too soon to judge whether the new results are temporary setbacks or foreshadowings of failure.
''Is a vaccine possible?'' said Dr. Robert Gallo of the National Cancer Institute. ''Anyone who gives you an answer to that is talking preposterously. There is still too much uncertainty.''
Dr. Malcolm Gefter, an immunologist at the Massachusetts Institute of Technology in Cambridge, Mass. agreed. ''I wouldn't say the outlook is gloomy,'' he said. ''It's just that it hasn't been bright.'' The recent studies have simply shown that the ''quick and dirty'' approach in which scientists ''clone a viral protein, inject it and get protection against the AIDS virus'' will not work, Dr. Gefter said. He added that these first attempts were only the beginning. ''There are all sorts of things that could be tried and haven't been tried yet,'' Dr. Gefter said.
Vaccine studies are proceeding in several directions. Daniel Zagury of the Pierre-et-Marie Curie University in Paris has injected himself and volunteers in Zaire with a vaccine consisting of a synthetically made protein from the AIDS virus, GP-160, that is delivered by the vaccinia virus, the virus used to inoculate against smallpox.
In the United States, the Federal Government and six medical research institutions are recruiting volunteers for vaccine studies that also use synthetic GP-160, in this case injected directly rather than delivered in a virus. The vaccine is made by MicroGeneSys Inc. of West Haven, Conn. In addition, Oncogen, a biotechnology company in Seattle that is a subsidiary of Bristol-Myers, is recruiting volunteers to test a vaccine consisting of a different AIDS protein, GP-120, attached to a vaccinia virus.
At the same time, scientists are testing a variety of other potential vaccines in small laboratory animals such as guinea pigs and in chimpanzees and macaques. Although the chimpanzee is closest to humans and is the only animal that can be chronically infected with the AIDS virus, antibody responses can be stimulated in other species.
Both GP-160 and GP-120 are proteins from the viral envelope, which forms the surface of the AIDS virus. Scientists reasoned that the surface proteins are what the immune system encounters when a person is first infected with the virus. ''Classically, with envelope viruses, envelope proteins provide immunity,'' said Dr. Anthony Fauci, who as director of the National Institute of Allergy and Infectious Diseases is in charge of Federal vaccine research.
But investigators also want to try vaccinating with proteins from the core of the AIDS virus. Researchers have noticed that people infected with the AIDS virus make antibodies to the interior core proteins and speculate that these proteins might induce a protective immune response. ''Probably, in the near future, there will be a vaccine candidate made up of a core protein,'' Dr. Fauci said. ''That hasn't been done yet, but since this is an unprecedented infection causing an unprecedented disease, we have to cover all bases.''
Another idea is to try a killed virus vaccine, a proposal championed by Dr. Jonas Salk who used this approach in his polio vaccine. He reasons that killed AIDS viruses would help induce cell-mediated immunity and also might induce a better antibody response. But some experts wonder whether they can be certain that injecting even a killed AIDS virus will be safe.
Fundamental stumbling blocks stand in the way of all these vaccine ideas, experts say. One problem is that the human AIDS virus does not make any animal, including chimpanzees, ill with AIDS, making the relevance to humans of any animal experiment uncertain.
''We are limited and bottlenecked by the lack of an animal model,'' Dr. Gallo said. ''We have to do our tests in man. But how do you know which vaccine is the better candidate? You really don't.''
In addition, scientists still do not know why the body's normal immune response to an AIDS virus infection is unable to defeat it.
Dr. Bernard Moss of the National Institute of Allergy and Infectious Diseases has found that all patients infected with the AIDS virus do produce killer cells that attack other body cells infected with the AIDS virus. But, Dr. Moss says, ''since these people go on to develop AIDS, these cells obviously are not eradicating the virus.''
Likewise, people infected with AIDS make large amounts of several kinds of antibodies. But nearly all the antibodies they make have no effect against the AIDS virus. Neutralizing antibodies, the type that should deter the virus, are usually mysteriously missing early in infection and when they do appear a year or two later, they do not seem to affect the course of the disease.
Vaccine experts are puzzled. In infections with other viruses, anyone who makes neutralizing antibodies is protected against the disease. In AIDS infections, the role of neutralizing antibodies is unclear.
''There is no correlation between neutralizing antibodies and whether a person is healthy or sick,'' Dr. Martin said. ''I don't know what neutralizing antibodies mean.''
Dr. Hilleman said that the way researchers ordinarily go about developing vaccines is to inoculate people with viruses or virus particles that induce them to make neutralizing antibodies. Anyone who makes these antibodies is protected against the disease. ''For ordinary viral infections, that's it,'' Dr. Hilleman said. ''That's the name of the game.''
Despite their uncertainties, scientists felt they had no time to lose in starting to test vaccines. ''Since this is an unprecedented infection causing an unprecedented disease, we felt we had to cover all bases,'' Dr. Fauci said. Last August, Federal scientists began preliminary tests of a vaccine candidate consisting of GP-160. Since then, the Food and Drug Administration has approved the expansion of this test and also the testing another vaccine, made of viral coat protein GP-120 attached to a vaccinia virus.
The GP-160 protein was chosen because it easily elicited neutralizing antibodies in guinea pigs, rabbits and chimpanzees, according to Dr. Fauci.
At the National Institutes of Health, homosexual men who are not infected with AIDS are being recruited to test the GP-160 vaccine. A total of 81 volunteers are needed, but only about 35 have been enrolled so far. This study ''started off slow, for a variety of reasons,'' Dr. Fauci said. He added that it has been difficult to recruit volunteers, in part because the volunteers are afraid of the ''stigma'' of having antibodies to AIDS, even though they will not have the disease.
The Federal study is a test only of the vaccine's side effects and its ability to elicit neutralizing antibodies. The investigators are not planning to determine if the volunteers are protected against AIDS and they counsel the volunteers to assume that they are not protected.
The 35 volunteers who have participated in the study so far received one of two relatively low doses of the vaccine. They failed to make any neutralizing antibodies to the vaccine, Dr. Fauci reports. ''They had no antibody response,'' he said. There are no data yet on whether cell-mediated immune responses occurred. Dr. Fauci said he was not surprised by the lack of neutralizing antibodies because the vaccine doses were so low. Higher doses are to be tried.
Dr. Gefter cautioned that the negative initial result was not definitive because it sometimes took fairly large doses or several booster shots before people made neutralizing antibodies to vaccines. The hepatitis B vaccine, he said, elicits neutralizing antibodies only after six months and three vaccine shots.
The GP-160 vaccine study is continuing at the National Institutes of Health, where volunteers are sought for two higher vaccine doses and it is also being expanded to include women and heterosexuals, Dr. Fauci said. The expanded study will be conducted at six medical research centers.
The study of GP-120 attached to vaccinia viruses is now at the stage of recruiting volunteers, who are to be homosexual men not infected with the AIDS virus. Dr. Lawrence Corey of the University of Washington in Seattle, who is directing this study, said 60 volunteers were needed and that ''things are going O.K.'' He added that ''we're busting our rear ends to do this as quickly as possible.''
Dr. Zagury in Paris has reported that the GP-160 vaccine that he is testing on himself and some Africans elicited both neutralizing antibodies and cell-mediated immunity but he has not reported any evidence that the vaccine protects people against the virus.
All the human vaccine studies have their critics who point out that none of the vaccine candidates have protected chimpanzees against AIDS virus infections. Although chimpanzees do not become ill with AIDS, the virus multiplies in their cells.
''To my knowledge, no one has shown that they can protect one chimp from infection,'' Dr. Gallo said. ''That's our problem.'' Others have argued that if chimpanzees had a large enough amount of neutralizing antibodies in their blood before they were infected with the AIDS virus, the antibodies might block the AIDS infection in its tracks. The recent studies are leading experts to question even that assumption, however.
Dr. Alfred Prince of the New York Blood Center devised a test to see whether neutralizing antibodies would make a difference in chimpanzees. He decided to give the animals antibody injections to insure that they had plenty of neutralizing antibodies before they were injected with the AIDS virus.
Dr. Prince pooled antibody-containing blood serum from patients who made relatively large amounts of neutralizing antibodies, and his colleague, Dr. Jorg Eichberg of the Southwest Research Foundation in San Antonio, Tex., injected the serum directly into chimpanzees.
In the first experiment, Dr. Eichberg gave the chimpanzees a standard dose of neutralizing antibodies. It was a dose that, were it any other disease than AIDS, would have easily protected the animals, Dr. Prince said. The antibodies did nothing. 'We Were Really Shocked'
Then Dr. Eichberg gave the chimpanzees 10 times as many neutralizing antibodies. ''It was a really huge dose,'' Dr. Prince said. But, he added: ''Once again, there was no protection whatsoever. We were really shocked.''
Dr. Prince said he is ''now trying to figure out what this means.'' It could be that the dose of AIDS virus he used to test the chimpanzees was so high that it overwhelmed the ability of the antibodies to protect, he said. But over all, the finding has disturbed experts.
In the second recent study, Dr. Ronald Desrosiers of the New England Regional Primate Research Center in Southborough, Mass., tried to immunize macaques against a monkey virus, called SIV for Simian Immunodeficiency Virus, that causes a disease closely related to human AIDS.
He tested both killed viruses and viruses that he had taken apart and reassembled with a substance called Quill A that is derived from from a South American bush. This sort of reconstitution has been shown by others to greatly enhance the effectiveness of viral vaccines. ''It's state-of-the-art,'' Dr. Desrosiers said.
Both vaccines appeared at first to be effective. The macaques made plenty of antibodies to the monkey virus, Dr. Desrosiers said, including neutralizing antibodies. But then, when Dr. Desrosiers inoculated the vaccinated monkeys with live SIV, ''they all became persistently infected,'' he said. ''The vaccinated animals did no better clinically than those that were not vaccinated,'' Dr. Desrosiers said.
''We learned a lot,'' Dr. Desrosiers added. He and his colleagues are now reasoning that the AIDS virus may be evading the vaccines and neutralizing antibodies because it can persist for a long time in the body, hiding in the genetic material of cells and giving no sign to the immune system that it is there. That means, Dr. Desrosiers said, that if any AIDS virus slips thorugh the barrier of neutralizing antibodies, a person could become infected. ''Most vaccines don't protect absolutely,'' he said. ''But once the AIDS virus gets its foot in the door, it's there for life.''
Dr. Prince also asks whether the AIDS virus might escape neutralizing antibodies by constantly changing the makeup of its outer coating. ''The virus might be so variable that there are always a few that escape,'' he said. If so, a vaccine may be impossible.
For now, however, scientists say they are having to regroup and consider again how to defeat the AIDS virus with a vaccine.
''We're early in the game,'' Dr. Prince said. ''The AIDS virus is obviously a harder nut to crack than most.'' In fact, he added, ''it is the most difficult virus I ever saw to immunize against.''
''As of now, it looks like finding an AIDS vaccine is going to be a very long and very difficult problem,'' Dr. Hilleman said. ''But those of us who have been working with vaccines for many years are never optimistic about any vaccine,'' he added. ''You are never optimistic until you have your license to market the vaccine in your hand.''
An experimental AIDS vaccine made with a genetically altered version of the virus used in smallpox vaccinations will soon be tested on volunteers at six university medical centers, the National Institute of Allergy and Infectious Diseases has announced.
Each of the medical centers will recruit nine volunteers to first determine the vaccine's safety and its ability to produce an immune response.
There is no chance of contracting AIDS from the vaccine, since it contains no live or killed human immunodeficiency virus that causes the deadly disease, the institute said Wednesday.
The volunteers must be healthy men or women who pass a blood test showing they are not infected with the virus that causes AIDS and ''who are not engaged in behavior that would place them at high risk of contracting HIV,'' the institute said.
The vaccine, manufactured by the Bristol-Myers Company, is the second to enter human trials in the United States. It consists of live vaccinia virus that has been genetically altered to produce a surface protein from the AIDS virus.
Human studies began earlier this year of another potential vaccine, manufactured by Microgenesys Inc. of West Haven, Conn. That vaccine consists of a different AIDS virus protein, manufactured by a genetically altered insect cell. Still other potential vaccines are being tried in Europe and Africa.
Scientists hope that inside the body, the AIDS virus proteins will provoke defensive reactions that would ward off any future invasion by the AIDS virus. But no one is sure whether an effective vaccine will prove feasible.
''We are quite a distance away from getting a vaccine that would be approved for general use,'' said Elaine Baldwin, spokeswoman for the Federal institute. ''
The vaccinia virus, used in the Bristol-Myers vaccine, has served for years as a smallpox vaccination. That disease has now been wiped out worldwide.
At each of the six centers, six volunteers will receive the AIDS vaccine and three will receive vaccinia vaccine alone, as a control. Neither the volunteers nor the physicians conducting the test will know which vaccine each person is receiving until data are analyzed.
The medical centers that will conduct the studies are the University of Maryland, Baltimore; Johns Hopkins University, Baltimore; Vanderbilt University, Nashville; the University of Rochester; Baylor College of Medicine, Houston, and Marshall University, Huntington, W.Va.
After investing billions of dollars and dreaming for years about creating pharmaceutical products that would change daily life, the biotechnology industry is running out of cash.
Industry experts say that investors, who once seemed to have limitless pockets, have stopped putting up money at a critical time when many biotechnology companies are seeking badly needed cash to push research forward and bring long-awaited products to market.
The experts blame the stock market crash of a year ago, when biotechnology stocks plummeted. Scaled-back sales projections of a widely publicized new drug have further soured the investment community on the industry.
In fact, in the last year only two new biotechnology stock offerings were made, and both were not eagerly received. In years past, some offerings met such enthusiasm that the founders of fledgling companies became enormously rich overnight.
As a result of the cash shortage, many biotech companies are cutting costs, abandoning research projects and focusing on products with the best chance of getting to market soon.
To obtain cash, more biotech companies are forming partnerships with large pharmaceutical or chemical companies, a sign that the young concerns will not supplant traditional drug manufacturers, as many industry experts had thought. Instead, they will play a supporting role.
The fund shortage is also likely to create a wave of mergers among the biotech companies themselves and spur acquisitions by large companies and foreign interests.
Biotechnology is ''entering a very critical period with the capital markets closed, a period when the industry is going to have severe cash needs,'' said Peter Drake, vice president of Vector Securities in Chicago. He foresees near-term cutbacks in research and development to preserve cash, which will mean a long-term loss of competitiveness worldwide.
''The industry as we know it is going to change dramatically over the next two years, and not for the positive,'' he said.
No one is ready to write the nascent industry's obituary, but some analysts believe the belt-tightening and the short-term focus of investors could cede industry leadership to foreign countries.
In Japan, the Ministry of Trade has identified biotechnology as a major area of concentration for the 1990's. The Government fosters the industry by offering tax incentives and seed capital, and permitting consortiums.
Prompted in part by the Japanese efforts, Senator Lawton Chiles, Democrat of Florida, introduced the ''biotechnology competitiveness bill,'' which would have created a national biotechnology policy board and an information center similar to the National Library of Medicine, as well as other advisory functions. The measure passed the Senate but stalled in committee in the House.
The American industry's woes were highlighted in recent weeks when the premier biotechnology company, Genentech, reported lower sales than expected for its most promising drug, Activase, which dissolves blood clots and can stop a heart attack in midstream. A year ago, as the drug was about to become available, analysts predicted 1988 sales as high as $500 million. Earlier this fall, the company scaled back projections to $180 million.
Although sales of $180 million for a new drug in the first year are robust by most standards, the lower-than-expected sales for Activase sent tremors through the industry. Stock prices, already depressed from the market crash, dropped further. This, in turn, has made investors even more wary of the industry.
To be sure, these developments come as no surprise to some industry experts. These analysts point out that the bull market of the last several years allowed companies with no earnings to issue stock at high prices. Those prices are now being corrected, and the current shakeout of companies is typical of any new industry, they add.
In this longer-term view, the biotechnology industry is merely entering a period of commercial Darwinism and those companies that survive the tough times will emerge stronger for the experience.
''There is a cash squeeze, but because of the long-term attractiveness of the technology, and the existence of large pools of capital that want into it, the net result is not going to be worthy companies and products going down the drain,'' said Jeffrey Casdin, publisher of Biotech Investor.
But Mr. Casdin added that some companies were abandoning projects earlier than they might have if cash were not a problem. ''They are de-emphasizing products that haven't panned out,'' he said. Large-scale layoffs have not been common but restructurings and personnel freezes are.
''In these tough times it becomes very important to get your priorities right, very important to tighten your belt,'' said Robert Fildes, president and chief executive of the Cetus Corporation. With access to $150 million in cash, Cetus is well positioned, despite the battering of its share price, but the company has frozen personnel levels and is focusing efforts on projects with near-term market potential.
Cetus is fortunate, Mr. Fildes said. Of 300 to 400 companies pursuing biotechnology in the United States, ''very few have the cash resources in place to see them through this period,'' he said.
Revenues that have fallen short of expectations are prompting belt-tightening at Genentech, too. While research and development spending at the company is still $120 million a year, it will not increase. ''We're watching our pennies,'' said Robert Swanson, Genentech's chief executive. ''It's a matter of postponing things you'd like to do to keep things under control.''
Some smaller companies have made even more dramatic changes. Liposome Technology Inc. of Menlo Park, Calif., started the year with eight projects, and is now actively pursuing only three. Two others are in research with no major financial commitment, and ''we threw the rest away,'' said Nick Arvanitidis, chairman and chief executive. ''This is a reaction to the realization that there are no markets now and there won't be any until mid-1990 or early 1991,'' he said. ''If you spend your money on the wrong projects right now, you're finished. There is no tomorrow.''
Two years ago, the Repligen Corporation of Cambridge, Mass., pursued health care and personal care, as well as industrial and agricultural products, with such diverse projects as AIDS diagnosis, hair coloring and insecticides. Now it is focusing solely on health care, emphasizing virology and immunology.
The shortage of public funds for companies like Repligen ''is a very serious problem, a tragedy,'' said Mr. Fildes of Cetus. ''The U.S. has a lead and should try to keep it. If we lose some of these second-generation companies, we will lose those opportunities.''
Since the stock market crash there have been only two public offerings by biotech companies: an inital offering by Neorx of Seattle and a tertiary offering by the Cambridge Bioscience Corporation. Microgenesys Inc., a small West Haven, Conn., company that received the first approval by the Food and Drug Administration for human trials of an AIDS vaccine, recently announced plans for an initial offering of about $31 million.
''It would be almost impossible to do any sizable public offering today,'' said G. Steven Burrill, chairman of the high-technology group of Arthur Young & Company.
For companies that have consumed one or more rounds of venture capital and might have expected to have an initial public offering, partnerships with large pharmaceutical companies may be the only alternative to being absorbed.
Such partnerships have been a fixture of the industry since its inception, and terms are much more favorable for biotechnology companies at which the research has matured and products are closer to market. But corporate partnerships remain controversial, and some in the biotech industry deride them as licensing away a company's future.
''The current market may mean that big companies with deep pockets will find these struggling biotech companies inclined to cut deals,'' said Richard H. Holton, a professor of business administration at the University of California at Berkeley.
Mr. Burrill added that some companies were now spending at a higher rate, shortening the time they can survive without more cash. ''We will see consolidation; we will see a tremendous amount of strategic linkage,'' he said. Large pharmaceutical companies that were late to get involved in biotech ''can now acquire their way in,'' he said, adding, ''without the crash, that would not have been true.''
In the wake of their disappointment with Genentech's Activase, analysts are now reassessing other drugs about to emerge from biotech laboratories. The most important is erythropoeitin, or epo, a hormone used to treat anemia. Amgen Inc. recently received approval for epo in France and Switzerland and is expected to get Food and Drug Administration approval soon.
George Rathmann, Amgen's chairman, is reluctant to predict the size of the market for epo or its projected price in the United States. Since the drug will initially be used only for kidney dialysis patients, he said, Genentech's experience with Activase would not be relevant to epo's marketing situation.
But if Amgen has been careful not to inflate expectations for epo, there has been no shortage of voices on Wall Street ready to pronounce it the next ''billion dollar drug.'' The optimism comes despite significant challenges facing Amgen, including a protracted patent dispute with Genetics Institute Inc. and some doubt that Medicare will provide 100 percent reimbursement for epo for kidney dialysis patients.
Most major drugs of biotech companies are not as ready as epo for marketing, but analysts' estimates and actual sales could continue to ride a seesaw for some time. Because one successful drug can build a company to an extent that no single product can in other industries, the perceived successes or failures of the biotech drugs can have a huge effect on the valuation of companies.
''It is a big risk that investors' expectations are set so high that just doing a nice solid business won't interest them,'' said Edward E. Penhoet, president and chief executive of the Chiron Corporation. ''You shouldn't expect these companies to become Merck overnight.''
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An experimental AIDS vaccine given to eight human volunteers started the production of immune cells able to seek out and destroy AIDS-infected cells in blood samples from three of them, researchers said today.
But the researchers cautioned that a proven vaccine remained years away.
Dr. Robert Siliciano, of the Johns Hopkins School of Medicine, who led the study, said that although the findings showed the vaccine's potential to halt the spread of the AIDS virus through the human immune system, ''we're still far away from knowing whether vaccinated individuals would be protected if exposed'' to the virus.
The study, being published Friday in the journal Science, used the drug VaxSyn HIV-1a, made by Microgenesys Inc. of West Haven. The vaccine, based on a synthetic version of a protein found on the surface of the HIV virus, which causes AIDS, was the first to be approved by the Food and Drug Administration for human testing in this country.
In a telephone interview, Dr. Siliciano said the research was exciting because the killer cells had been produced using only a portion of the virus's outer coat. Normally these type of cells are triggered only with a vaccine that includes a live virus, he said. Many scientists avoid human experiments using live viruses, even if weakened or genetically altered, because of the danger of accidentally causing disease.
The researchers injected eight healthy male volunteers with the vaccine over 18 months. Samples of their blood were then drawn and the white blood cells were separated out and mixed in the lab with AIDS-infected cells. White cells able to seek out and kill infected cells were found in blood from three of the volunteers.
By Philip J. Hilts, Special To the New York Times / June 24, 1990 / Source : [HN01VI][GDrive]
Mentioned : MicroGeneSys, Incorporated / Dr. Jay A. Levy (born 1938) / Dr. Wayne C. Koff (born 1952) / Dr. Jay Arthur Berzofsky (born 1946) /
Optimistic after a string of laboratory successes, researchers are assembling potential vaccines against AIDS and may start preliminary testing within a year, scientists at the Sixth International Conference on AIDS said today.
In sessions so crowded that some people were turned away, researchers on Friday reviewed their most hopeful work, steps they have taken toward creating a vaccine that could prevent spread of the human immunodeficiency virus.
''In the past year, we've cracked open the door in our optimism about a vaccine,'' said [Dr. Wayne C. Koff (born 1952)], chief of vaccine research at the National Institute of Allergies and Infectious Diseases. ''And I think in the next two or three years we will knock it down.''
Some of the experiments came after dozens of failed experiments in animals since 1986, failures that produced a deep pessimism about whether a vaccine would ever be possible.
Reports given at the meeting demonstrated that monkeys, chimpanzees, cats and cells in an artificial human immune system can be protected against infection. These early experiments will continue, Dr. Koff said at a news conference after the Friday session, but it is also urgent to begin tests as soon as possible.
He said that within a year, researchers may begin experiments in which a vaccine will be used to treat pregnant women already infected with the virus. The researchers hope the vaccine may retard the development of disease in the women and may prevent them from passing the infection to their babies, Dr. Koff said. About one-third of the babies born to infected women acquire the disease in the womb.
Tests of the more conventional use of a vaccine, to protect the population against infection, are not likely to begin for two to four years. Researchers said how long it would take to create a working vaccine depended on success at each step along the way, though there is now hope that one may be on the market in 10 years.
Vaccine research was the topic of several sessions at the conference over three days ending today. [Dr. Jay Arthur Berzofsky (born 1946)], chief of immunogenetics and vaccine research at the National Cancer Institute, outlined the progress and difficulties to those at the conference Friday and elaborated on those points in an interview today.
The recent successes demonstrate that a vaccine in humans is at least feasible, Dr. Berzofsky said.
Results from three successful chimpanzee experiments and three successful monkey experiments were reported at the meeting, but Dr. Berzofsky said the success was limited. In each experiment, the animals were given a vaccine, then given doses of the live virus, and the researchers found that the animals were protected against infection by the virus.
Dr. Berzofsky said that the doses of live virus given to the animals were low and that the virus was given in shots, whereas actual human infection occurs through the skin of the genitals or elsewhere.
Also, he said, only the virus itself was given to the animals, while humans are infected by such free virus as well as virus hidden inside infected cells in the blood or sperm. The body has different means of responding to each type of infection.
It is not known if the animal tests would be successful if they were given both free virus and cell-carried virus, Dr. Berzofsky said.
[Dr. Jay A. Levy (born 1938)], a virologist at the University of California at San Francisco, said, ''That will be one of the most important experiments to do now. When animals are protected from cell-associated virus, that will be a real breakthrough,'' he said.
One series of experiments reported here explored the difference between the failed experiments of previous years and the successful ones of the past year.
Researchers from Genentech, a California biotechnology company, reported that in 1986 they had taken a portion of the outer shell of the virus and injected it to make the chimpanzees' immune system produce antibodies and killer cells as if a viral attack was under way.
But after the vaccination, when live virus was given to the chimp, the protection failed and the animal quickly became infected.
Beginning in 1989, the group changed its approach. Researchers around the country began to report that a crucial segment of the viral shell, called the Third Variable region, or V3 loop, is the most powerful in creating defenses against the virus.
The Genentech group found that in its earlier experiments that region had been snipped in half by enzyme, and was disabled. In the new experiments they made sure the V3 loop was intact. The experiments succeeded, and two chimpanzees were protected by the new vaccine.
Researchers at a competing company, [MicroGeneSys, Incorporated] of Boston, say there are other important active sites. In addition, each different strain of the virus has slightly different versions of these active sites, so that it will probably be necessary to assemble a vaccine that includes bits of active sites from five or six different strains.
The Genentech team also noted a potential danger in the vaccine work in general: When the immune system makes antibodies to protect itself, some antibodies, ''enhancing antibodies,'' actually do the opposite and may dramatically speed up the progession of disease.
In a chimpanzee experiment that failed to protect the animals, Genentech researchers saw that the animals became infected twice as fast as might normally be expected.
In order to overcome the problem, the researchers say, a vaccine must not include bits of the shell that will elicit ''enhancing antibodies.''
There are now about 30 vaccine candidates being tested in laboratories around the world, and about $180 million is being expended on the work, Dr. Koff said, including $150 million for research and $30 million for preliminary safety tests being done in humans.
At the meeting, two groups, one led by Dr. Jonas Salk, creator of the Salk polio vaccine, and Dr. Alexandra Levine of the University of Southern California, and the other led by Dr. Robert Redfield of the Walter Reed Army Medical Center, reported that giving vaccines to humans produces a substantial immune response without significant side effects.
In the work presented by Dr. Levine, 82 patients already infected with the virus were given a vaccine created from a live but disabled AIDS virus. Among the 82, given the vaccine at various times over the past two years, only one has developed an infection characteristic of AIDS, and five have developed Kaposi's sarcoma, the cancer associated with AIDS.
The experiment had no comparison group, so no conclusions may be drawn, but it appears that rate of progression to disease is about a fifth of the rate found in other experimental groups.
A leading AIDS researcher is under investigation by Federal officials after allegations that he may have overstated the therapeutic effects of an experimental vaccine against the deadly disease.
The investigator is [Dr. Robert Ray Redfield Jr. (born 1951)] of the Walter Reed Army Institute of Research. Central to the inquiry are statements made by Dr. Redfield earlier this year that use of the vaccine, a protein known as gp-160, might reduce blood levels of H.I.V., the virus that causes AIDS, in those already infected, said Major Rick Thomas, a spokesman for the Defense Department which is conducting the investigation.
The vaccine, the first approved by the Federal Government for testing in people, has been more widely tested than any other candidate vaccine against HIV. Unlike typical vaccines, which prevent a virus from establishing itself in the body, gp-160 is designed to help the immune system fight an established infection.
"The validity of Dr. Redfield's data is not in question," said Major Thomas. "The question is whether that data has been interpreted and presented properly."
Dr. Redfield is perhaps the scientific community's leading proponent of gp-160 as a treatment for those already infected by H.I.V.. Major Thomas said the allegations against Dr. Redfield were bought by fellow researchers.
Dr. Redfield, who is chief of the department of retroviral research at Walter Reed, did not respond to several telephone calls to his laboratory this week. However, he has apparently backed away from his earlier comments in recent months.
Major Thomas said that the military's inquiry will review all research performed by the Army on gp-160. Initial tests have shown it to be safe and indicated that it might stablize the conditions of those infected by H.I.V. The Defense Department is the lead Federal agency working on gp-160 which is currently being administered to about 500 patients at 17 test sites around the country.
"We are awfully proud of what we have done," said Major Thomas. "But we want to make sure that everything that we have done is accepted by the scientific community. This may be just a difference in interpretation of the data."
The disclosure of the investigation comes on the heels of another controversy involving gp-160. Last month, Congress approved spending $20 million on expanded tests of the vaccine in humans. But several top Government scientists denounced the move because lobbyists representing MicroGeneSys Inc., the company that pioneered development of gp-160, engineered the appropriation by directly lobbying Congress without the knowledge of Federal researchers.
A blue ribbon panel of AIDS researchers convoked by Dr. Bernadine Healy, the director of the National Institutes of Health, is scheduled to meet today to review whether the expanded gp-160 tests should go forward. The top officials of N.I.H., the Defense Department and the Food & Drug Administration have five months to make a decision on the issue. Should they decide to delay or forego the tests, Congress has directed that the $20 million will still go to AIDS research.
The tests at issue in the military inquiry were preliminary and lacked some of the controls being used in the gp-160 trials now underway.
Major Thomas said the inquiry, which was disclosed to Army researchers about two weeks ago, is expected to take about 60 days.
The dispute over Dr. Redfield's interpretation of gp-160 test data apparently started soon after an international meeting of leading AIDS researchers in Amsterdam. It was there that Dr. Redfield reported lowered H.I.V. levels in a small number of patients treated with gp-160.
But in August, researchers associated with Dr. Redfield reviewed that same data and saw no reduction in viral blood levels, according to a memo written at the time by Dr. William McCarthy, the director of the department of biostatistics at the Henry M. Jackson Foundation for the Advancement of Military Medicine in Rockville, Md. The organization supports Government research and at times shares laboratories with military scientists like Dr. Redfield.
Dr. McCarthy said that he had not brought the accusations against Dr. Redfield. Dr. Vahey could not be reached for comment.
The existence of Dr. McCarthy's memo was first disclosed in the October 24 issue of New Scientist, a British science periodical. The magazine also reported that in September, soon after Dr. McCarthy's memo was written, Dr. Redfield gave a presentation in which he backed away from his early claim and said that gp-160's effects on viral blood levels were unclear.
Addressing a gathering of Hollywood elite in a home in the hills overlooking Santa Monica Bay, Franklin Volvovitz looked as if he'd been hit with a left hook.
It was suddenly clear his audience regarded him as something sinister -- a symbol of big business poised to make obscene profits off victims of a terrible epidemic.
In his mind, Volvovitz had every reason to expect these celebrities to be excited. He'd flown out to Southern California from Connecticut to persuade them to buy stock in his little company, MicroGeneSys Inc., which had developed the first experimental AIDS vaccine approved for human tests in the United States.
MicroGeneSys (pronounced micro-gen-e-sis) was far from a corporate giant. It had never made a profit and was betting its existence on the vaccine -- its only product.
Four dozen stars, agents and power brokers had convened to hear Volvovitz at the sprawling house owned by Michael Roth, well-known as Elizabeth Taylor's doctor. Actor Richard Gere and his wife, supermodel Cindy Crawford, dressed casually like the others, had helped arrange the catered affair on a Sunday afternoon last September.
Very formal in a dark business suit, Volvovitz narrated a highly technical slide show in Roth's sumptuous living room, which overlooked an outdoor pool and the surf beyond.
His supporting cast, two East Coast doctors who had run trials of his vaccine, described the scientific results. Before the doctors finished, some people in the audience wandered out to the poolside bar.
AIDS was eating into the Hollywood community. A few of Roth's guests were infected themselves and were being treated with the MicroGeneSys vaccine. They and others were deeply frustrated that promising treatments were bogged down in the government's scientific bureaucracy.
Volvovitz hoped to raise $20 million. But nobody wanted to invest. They were receptive to the idea of donating money to expand tests of the product in more people. Yet, many were offended that they were being asked to buy a piece of a company that could profit from AIDS and turn Volvovitz into a multimillionaire.
"It got very heated," said Gary Blick of Greenwich, one of the two doctors who had gone with Volvovitz. "People were pointing at Frank Volvovitz and saying, `You're the problem.' "
Volvovitz admits the reaction took him by surprise. "It turned out to be a total misread," he recalled. "You would have thought that I was basically like some guy from outer space. ... They said: `We don't want to make any money off of AIDS. And we're surprised you do.' "
Volvovitz, a 44-year-old microbiologist turned entrepreneur, arouses strong feelings.
His allies call him a lone wolf and a visionary, devoted to doing something to stop a public health disaster. They applaud his tenacity, his willingness to break with convention to get wider recognition of a vaccine that could be the prize AIDS scientists have been seeking for 12 years.
Others consider him a money-hungry megalomaniac who has no friends -- an ingrate, ready to exploit anyone or any situation to promote himself, his company and its product.
"Volvovitz is simply an opportunist," said Malcolm Martin, a top government research scientist at the National Institutes of Health. "We think we've helped him out a lot, and we think he's very ungrateful, and we feel that we've been used."
There is widespread skepticism in the scientific community about him, his product and his radical idea of using a vaccine to treat, as well as prevent, disease.
Yet the MicroGeneSys vaccine has emerged as a prime contender in the race to find a way to stop or slow the insidious AIDS virus. Probably no other AIDS vaccine has been tested in as many people or has produced as much tantalizing evidence that it can boost the body's immune defenses.
It has been five years since the MicroGeneSys product was first approved for human trials, and -- if it proves effective -- Volvovitz is still at least two years from the finish line.
The controversy over the product has been heightened by Volvovitz himself, who has steered his company on an untraditional course. His style has so enraged the nation's science establishment that many people wonder how it will affect the future of MicroGeneSys and its vaccine.
However, Volvovitz has not budged from the conviction that he is right, and that his Meriden company deserves millions of dollars in financial support from state and federal governments.
Lately he has been pressuring Connecticut officials to take a huge risk, to help him finance the construction of a manufacturing plant at an estimated cost of $30 million to $100 million -- a factory that could produce nothing but cobwebs if the vaccine fails to win federal approval.
"We operate most of our lives on the basis of doing things that have probable odds of success," said Austin "Chip" Broadhurst Jr. "Frank doesn't. His sense of the odds is very different."
Broadhurst, a managing director at Russell Reynolds Associates in New York, knows Volvovitz through his work recruiting executives in the biotechnology field.
"Frank Volvovitz can't be assessed according to conventional terms," Broadhurst said. "You've got to look at him in terms of the grails that he is seeking, and [an AIDS cure] is one of the most significant grails anyone could undertake to seek in our lifetimes."
To understand Volvovitz, consider one of his most unconventional moves. In 1979, within months of getting a doctorate from the New York University School of Medicine, he walked away, driven by a craving to become a pioneer in the emerging biotechnology industry. Independence and a knack for enterprise seem to be in the family genes.
In the 1920s, Volvovitz's grandmother, Fannie Fruchtman, moved to Hartford with her two children after her husband was killed in a robbery at the family's store in Brooklyn, N.Y. For 50 years, until she was 89, she ran her own delicatessen on Albany Avenue, serving up sandwiches and soda to a loyal following in the Jewish community and the political world.
Volvovitz's father, Harry, is an independent electrician, owner of the Voltz Electric Co. in Bloomfield.
His brother is an independent insurance agent.
As a child, Volvovitz tinkered with small electrical projects, once building a shortwave radio. But he soon developed a passion for biology. While a student at Conard High School, he turned the basement of his family's West Hartford home into his laboratory. He filled it with glass fish tanks and became one of the first people in Connecticut to breed discus fish, an obscure tropical species.
"Back then," he recalled, "it was considered a major feat."
Meanwhile, his chief distinction at the local high school, as recorded in the yearbook, was serving as vice president of the chess club.
Volvovitz went on to New York University, where he earned an undergraduate degree in biology and entered a doctoral program in microbiology. In 1974 he began working with interferon, a protein made in small amounts by cells after they are invaded by a virus.
He explored the role interferon plays in boosting the body's immune defenses, and, as he tells it, his research was met with skepticism because "it was not embraced in terms of being within conventional wisdom."
Volvovitz called his research "leading-edge," and his doctoral adviser, Jan Vilcek, doesn't quarrel with that description.
By 1979, Volvovitz had virtually completed writing his dissertation.
Expecting that he would follow the usual path of continuing his education in a government or university laboratory, Vilcek helped line up a postdoctoral position for Volvovitz at the government's National Institutes of Health in Bethesda, Md., the world's largest medical-research complex.
But Volvovitz turned down the job, then turned his back on the degree. He already had plans to start his own company.
At that time the biotechnology industry was in its infancy. It started with the 1976 birth of Genentech Inc., a South San Francisco-based firm that set out to derive a new generation of drugs from the body's immune system using an approach called recombinant-DNA technology, commonly known as gene-splicing.
Volvovitz had read about Genentech, recognized the potential of biotechnology and wanted to be a part of it. "I thought science and business could work together," he said, "and produce very good progress."
But he said his ambition did not sit well with some of the NYU faculty: "Some friends of mine came up to me and said, `Frank, let's face it, you may get the Nobel Prize, but you're not going to get your degree at this point.' I was caught in a situation. I was about to start a company. The funding for the company was coming together. The people most responsible for my degree were intensely opposed to that. The writing was on the wall."
Vilcek doesn't remember it that way.
"This sounds like perhaps a way for him to justify a decision that I believe was not a very wise decision," he said. "I am absolutely certain he would have received his Ph.D. if he so desired."
In 1979, Volvovitz's first company, BioTechnologies Inc., was incorporated in Connecticut, and he left NYU. By Vilcek's estimate, he had just one to two months of work left to complete his dissertation and get his doctorate.
Volvovitz said he didn't need the piece of paper. "What I need is in my head," he said. "I know what I've done. I know what I can do."
BioTechnologies Inc., in East Hartford, was created as an extension of Volvovitz's work with interferon. It survived only a year.
While still at NYU, Volvovitz turned to family connections to get financing for his first company -- an old friend who had worked part time in his grandmother's delicatessen. The friend, now a successful businessman, got in touch with others who were willing to invest, and asked Hartford lawyer Joseph D. Hurwitz to help with the legal work.
"There were 10 or a dozen investors who put in money," Hurwitz recalled. "There was concern about whether Frank could make it. It was all outgo and virtually no income."
Having recognized interferon's potential as a student, Volvovitz set up the company to produce interferon as an experimental cancer drug for studies being conducted at the Yale School of Medicine.
Using a technique developed in Finland, he planned to harvest interferon from white blood cells, and arranged to pay the Red Cross for separating white cells from donated blood.
He worked 18-hour days, including weekends. A second infusion of money was needed to keep the company alive, and the investors grew disillusioned.
"Ultimately the cash on hand began to run out," Hurwitz said. "While Frank wanted to go on, the investors felt they had put in all they wanted to put in, and they arranged for an orderly liquidation."
Volvovitz has vivid memories of the day the company was shut down. It was his 33rd birthday.
"The board met and decided to suspend operations," he recalled. "They said, `Please take your things.' They basically then locked the place up. I turned in my keys, they changed the locks, and that was the end of it." Hurwitz remembered that Volvovitz made his unhappiness known. "I think he was not as appreciative of his original investors as he should have been," Hurwitz said. "They lost a lot of money trying to get something started for him and with him."
Most of the investors, successful businessmen, had no experience in high technology.
"The enormous lead time and enormous need for infusions of capital were beyond them," Hurwitz said. "They also thought they were headed down the wrong road. Interferon didn't turn out to be the miracle drug."
Volvovitz blamed press reports, in part, for the decision to liquidate. "Unfortunately, the demise of interferon as reported by the popular press around 1981 was certainly premature," he said. "With that went the enthusiasm."
Today, he said, sales of interferon as a cancer treatment top $500 million annually.
As the doors to his first company were locked behind him, Volvovitz drove back across the Connecticut River to his parents' West Hartford home, where he was living. That night he went downstairs to the familiar basement and started working on his next company.
"I cleared off half of a pingpong table, which wasn't being used very much," he said. "Then I called the phone company and ordered a phone."
He was determined that only he would have the power to pull the plug on his next venture.
"When I set up [MicroGeneSys], it was not going to be a company where some guy with a large bankroll, either a venture capitalist or somebody else, was going to control the company," he said. "You have to have a strong foundation and a degree of independence. You cannot do that if you have to rely on the vagaries of what other people think."
He got on the phone to bankers and potential investors. He called scientists. He drew up a checklist of the strengths and weaknesses of his first company. When he wasn't on the phone, he was in the library, reading scientific literature, deciding what he wanted to target.
He settled on a relatively obscure area of science involving baculoviruses, a variety of insect viruses that primarily infect butterflies and moths.
His vision was to use insect viruses and gene-splicing techniques as a means of manufacturing pest-control agents and natural proteins that play key roles in preventing and treating human diseases.
In the fall of 1982, Volvovitz went to Ithaca, N.Y., to talk to scientists at a professional conference at Cornell University. He wanted to convince them that their work could have commercial applications.
"A lot of them said I was the first person who ever said, `You guys are doing something good, that's exciting, that can have an impact on medicine,' " he recalled.
Volvovitz, a trim, dark-haired man who wears glasses, is stiff in a social situation. He can be cold and abrupt. He shakes hands as though it is a chore. But while talking business and science at the Cornell conference, he impressed two leading researchers whom he later would hire -- Gale Smith from Texas A&M; University and Mark Cochran from the National Institutes of Health, both working with baculoviruses.
Cochran was enthusiastic. "To actually commercialize this kind of biology I thought was tremendous," he recalled. "Here's this weird-looking guy, totally out of place at this meeting where a bunch of entomologists were. He was the most serious person I met. ... I thought this guy might pull it off."
Volvovitz created MicroGeneSys Inc. in May 1983.
After lining up enough financing, he hired Cochran away from the government as his first scientist in 1984. During his first few weeks on the job, Cochran scraped floors, painted, banged nails and lined up used equipment for the laboratory taking shape in a West Haven warehouse. Volvovitz's father did the electrical work.
The company's initial goal was to produce a pesticide as a way to demonstrate that the company could take a relatively modest project from start to finish.
MicroGeneSys did produce a pest-control product that accounted for just $56,000 in sales during a two-year period. But the company evolved quickly toward vaccines, and the pesticide faded into the background.
Volvovitz saw vaccine development as a wide-open field at the time, full of opportunity. "The pharmaceutical industry had significantly moved away from vaccines," he said.
MicroGeneSys started working on hepatitis B. Then malaria. Soon, the scientists were looking in a new direction.
AIDS was identified as a disease in 1981, but the government did not announce its cause officially until April 1984, when Margaret Heckler, secretary of Health and Human Services, said scientists had isolated the villain, a variant of a human cancer virus that came to be known as the human immunodeficiency virus, HIV.
At that time optimistic federal officials proclaimed that the discovery should lead to development of a vaccine that would be ready for testing within two years.
A little more than a year after Heckler's announcement, MicroGeneSys joined the hunt.
"The initial decision was an easy one," Volvovitz said. "We were the only ones with the baculovirus technology. ... When we decided to go into the AIDS area, we did it as a matter of public responsibility, for lack of a better word."
The first step in developing an AIDS vaccine was to obtain a molecular clone of HIV -- not an easy task. Volvovitz worked his connections, but it was Cochran who unexpectedly was offered the clone while talking with a friend at the National Institutes of Health who already had given Cochran a gene for his work on hepatitis.
"He said, since I did so well with hepatitis B, I could have another gene if I could guess what it was," Cochran recalled. "I said I hate these games. I guessed herpes. Then it dawned on me. He was talking about HIV." MicroGeneSys got the clone through a collaborative research agreement with NIH.
The clone contained the genetic blueprint for the protein that makes up the outer covering of the HIV virus. Volvovitz and Cochran planned to extract a gene from the clone to manufacture their vaccine -- a harmless copy of the virus' outer covering that might be able to teach the human body to develop an immune defense to AIDS before the disease struck.
Along with Cochran, one of the few pioneers in baculovirus research was Smith at Texas A&M;, which had patented his techniques. Volvovitz obtained a license from the university to use Smith's research as the basis for producing vaccines, then he hired Smith, who brought two Texas colleagues with him.
At the end of 1985, Cochran and Smith began working as a team on an AIDS vaccine at the West Haven warehouse.
MicroGeneSys was the only company then trying to develop vaccines using insect cells. "I had some experts on the outside who told me I was wasting my time," Volvovitz said.
At that time few people in the world of science had given Frank Volvovitz and his company much thought. Soon, that would change
In an effort to resolve a bitter dispute over how to test an experimental AIDS vaccine, top Government researchers have tentatively agreed to shift the task of testing the vaccine from the Army to the National Institutes of Health.
The move, which still faces legal hurdles, would be a rebuke to Army officials who decided to proceed with a $20 million trial of the vaccine, GP-160, despite concern by scientists over the testing method.
The Army planned to test only GP-160. Scientists from the institutes and the Food and Drug Administration argued that GP-160 should be tested against other vaccines.
Johanna Schneider, a spokeswoman for the National Institutes of Health, said the tentative agreement was reached yesterday during a meeting at the Pentagon that included Dr. Bernadine Healy, director of the N.I.H., [], the Commissioner of Food and Drugs, and top military research officials.
Sources familiar with talks said that legal hurdles remained because Congress had appropriated the research money to the Army and that it was unclear if it could be transferred without Congressional approval.
Susan Hansen, a Defense Department spokeswoman, declined to comment pending an announcement.
The action comes at a time when Federal officials are moving to consolidate AIDS research under the N.I.H. But Army researchers, who have spearheaded the testing of GP-160, would probably participate in any comparative trials of it conducted by the N.I.H., the sources said.
The GP-160 vaccine was developed by MicroGeneSys Inc., a small biotechnology company in West Haven, Conn. The controversy over the testing erupted last fall after former Senator Russell B. Long of Louisiana led a lobbying effort on behalf of MicroGeneSys that resulted in Congress appropriating $20 million for the Army to test the vaccine.
Researchers expressed dismay that politicians, rather than scientists, were setting the country's AIDS research agenda. The dispute prompted Congress to add an amendment to the appropriation requiring unanimous agreement among the N.I.H., the F.D.A, and the Defense Department if the trial were to be stopped.
The agencies were given six months to resolve the issue among themselves but in late March, just before the deadline expired, the Army indicated that it planned to proceed with the GP-160 test, setting the groundwork for a replay of the earlier dispute.
Although only one of several AIDS vaccines in development, GP-160 has been tested on far more human subjects than the other vaccines.
The vaccine was developed by MicroGeneSys (pronounced micro-gen-EE-sis) in the mid-1980's from a protein on the surface of H.I.V., the virus that causes AIDS. In 1987, the company became the first to get permission from the Federal Government to test an AIDS vaccine.
Franklin Volvovitz, the chairman of MicroGeneSys, said he was dismayed that other Government scientists had interfered with the Army's research program because the Army had led the effort to develop a vaccine that could save thousands of lives.
'If this is true, it will take many more years now to develop an AIDS vaccine than if our test had gone forward," Mr. Volvovitz said today.
The dispute over the Army's decision to continue sole testing of GP-160 began to heat up last week when Dr. Healy and Dr. Kessler wrote letters to the House Appropriations Committee repeating their positions that the vaccine should be tested with other vaccines under development.
Last Friday, Health and Human Services Secretary [Donna Edna Shalala (born 1941)] wrote to Defense Secretary Les Aspin stating a similar argument.
The White House was also pulled into the issue when officials of Genentech, which makes a competing vaccine, visited Bob Hattoy, a White House aide, according to a source familiar with the meeting. Mr. Hattoy did not return a telephone call seeking comment. At a news conference about the health department's budget today, Ms. Shalala said she expected to announce a "resolution" of the testing dispute within 24 hours. She did not indicate what the resolution would be.
Several sources familiar with the discussions about the tests said that significant hurdles could remain. For one, Government lawyers were arguing yesterday about whether it was legal for one agency to transfer funds to another agency.
One White House source said a possible resolution would be legislation that would authorize additional AIDS vaccine testing to which GP-160 funds could be contributed.
Along with Genentech, other companies whose vaccines might be part of the tests include Chiron-Biocine, ImmunoAG and Immunization Products Ltd.
A preliminary study sponsored by the Federal Government has found that a genetically engineered flu vaccine is as effective as the one now in use.
The potential advantage offered by the experimental vaccine, made by MicroGeneSys Inc. of Meriden, Conn., is that it could be produced faster, permitting health officials to respond more effectively to the unexpected emergence of new strains of influenza.
"Everyone agrees that the vaccine we have now works," said Dr. John J. Treanor of the University of Rochester School of Medicine, an author of the study published in the June issue of the Journal of Infectious Diseases. "But there are a lot of things which you'd like to improve."
The vaccines currently in use are harvested from fertilized chicken eggs. The process takes six to nine months, depending on the dosage, said Dr. Nancy Cox, the head of the influenza branch of the Centers for Disease Control and Prevention in Atlanta. This means that manufacturers must try to determine almost a year in advance which strains of flu are likely to turn up in the United States.
The new vaccine uses moth cells as factories to produce hemagglutinin, a protein found on the outer membranes of the two types of influenza viruses that cause serious illness. The hemagglutinin then induces the body to produce antibodies against influenza. Once manufacturing got under way, the new vaccine could be made in just two to three months, said Dr. Gale Smith, chief scientific officer of MicroGeneSys.
The study, sponsored by the National Institute of Allergy and Infectious Diseases in Bethesda, Md., involved 127 adults. Some were given regular doses of either the current vaccine or the new vaccine. Others got a placebo. Still others got the new vaccine in a dose four times as large as the regular one. Compared with the conventional vaccine-manufacturing method, genetic engineering makes it easier to produce vaccines in high doses. But researchers wanted to know if a high dose would be more effective and just as safe as the regular one.
The results were expressed in terms of how many antibodies to hemagglutinin were produced. The regular doses of both the new vaccine and the current vaccine produced about the same amount of antibodies. The higher dose of the new vaccine produced one and a half to four times as many antibodies without any increase in side effects.
Dr. Treanor said at least several more years of study were needed before the vaccine would be available to the public.
Dr. Cox said the Centers for Disease Control was pleased with the development of the new vaccine. "The real advantage would come in a situation where we would have a new strain emerging unexpectedly and we would have a need to produce a lot of vaccine in a short period of time," she said. "If we were to be surprised by a new pandemic strain or a new epidemic strain, we could be caught short."
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FOunded by Franklin Volvovitz
By Gina Kolata / April 19, 1996 / Source : [HN01RL][GDrive]
The end came today for a highly touted AIDS vaccine in a carefully worded announcement by the small company that produced it saying a study of the vaccine "did not demonstrate statistically significant clinical benefit."
The vaccine was meant to stimulate the immune systems of people who were already infected with the human immunodeficiency virus, which causes AIDS. It consists of a protein, Gp-160, that is found on the fatty membrane that envelopes H.I.V.
But the study, directed by researchers at the Walter Reed Army Institute of Research in collaboration with the National Institute of Allergy and Infectious Diseases, failed to find any evidence that people who received the vaccine benefited. Half of the 608 people in the study received the vaccine and the others received a placebo.
Robert Scherrer, the president of [MicroGeneSys, Incorporated] of Meriden, Conn., which makes the Gp-160 vaccine, said that the company was conducting other studies but that "this one was pivotal." He declined to comment on whether the company would drop Gp-160, its major product.
The Gp-160 vaccine was the subject of a rancorous debate several years ago when Microgenesys tried to get Federal financing for a large study, without waiting for the results of the study, which was just completed.
In 1992, the company hired former Senator Russell B. Long, a Louisiana Democrat, to lobby Congress, which included a $20 million appropriation in the Defense Department budget to test Gp-160 in a large study.
Dr. Bernadine Healy, who was director of the National Institutes of Health, said she was outraged by the appropriation because she saw no evidence that the Gp-160 vaccine was promising enough to be tested on such a scale. Some advocates for people with AIDS argued that it was better to take the $20 million and spend it on the vaccine than to lose it altogether. But, Dr. Healy said, "this was a total subversion of the process of doing research."
Eventually, Dr. Healy and other angry scientists obtained a compromise. The money was shifted from the Defense Department to the National Institutes of Health to pay for vaccine research in general rather than a Gp-160 study in particular.
With today's announcement that the smaller Gp-160 study had failed, some AIDS vaccine researchers said they felt vindicated.
Dr. Dani Bolognesi, an AIDS vaccine expert at Duke University School of Medicine, said he was not surprised that the vaccine was ineffective because there was virtually no preliminary evidence that such an approach might work. "It was difficult to see conceptually how this might happen," he said.
Dr. John Moore, an AIDS researcher at the Aaron Diamond AIDS Research Center in New York was among the most vociferous critics of the $20 million appropriation for a Gp-160 study. He said the results should give companies pause when they try to push ahead too fast. "I hope it will be a humbling experience," Dr. Moore said.
And, Dr. Moore added, he anticipated more such arguments to come as companies push to have vaccines tested that they hope might prevent H.I.V. infections.