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Hilary Koprowski - The Originator of Aids
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Tom Curtis
: http://www.whale.to/vaccines/curtis.htm
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13-04-2005 07:55
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As it happens, equatorial Africa was the site of the world's first mass trials of an oral polio vaccine -- a vaccine cultured in monkey kidneys but different in at least one important respect from the Sabin vaccine ultimately adopted worldwide. This footnote in medical history took place from 1957 to 1960 right in the middle of what was then the Belgian Congo, Rwanda and Burundi -- the epicenter of the future African AIDS epidemic. It was developed by a naturalized American polio researcher named Hilary Koprowski
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Born and educated in Poland, where he studied to be a concert pianist while going to medical school, Koprowski began work for Lederle Laboratories in 1946. Like Salk and Sabin he took up the cause of saving the world from polio. He tested weakened strains of the virus in monkeys and chimps and in March 1951 surprised a meeting of polio researchers sponsored by the March of Dimes in Hershey, Pennsylvania. There he revealed that he had become the first physician in history to administer a polio vaccine to humans. The "volunteer" research subjects for Koprowski's live, weakened polio vaccine included twenty children he later described as "mentally deficient" who lived in Letchworth Village, a facility operated by the New York State Department of Mental Health. Later he vaccinated other groups of children, among them the newborn babies of institutionalized women in New Jersey. But a larger test of the vaccine, planned for children of Belfast, Northern Ireland, in 1956, was scrapped amid reports that some of his tamed oral vaccine had reverted to its wild, paralytic form. While no one was paralyzed and Koprowski insists that one one ever would have been, authorities in Belfast feared that such a "reversion to neurovirulence," to use the medical jargon, might spark a new polio epidemic.
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After the Belfast debacle, Koprowski, who was racing Sabin for the distinction of producing the oral polio vaccine of choice, left Lederle Laboratories to direct Philadelphia's Wistar Institute, then a modest research organization best known for developing a unique laboratory rat. But he held tightly to his goal of producing the winning polio vaccine.
Almost immediately, Koprowski arranged to have his weakened polio viruses tested in a colony of 150 chimpanzees in Camp Lindi at Stanleyville, in the Belgian Congo (now Kisangu, Zaire). To protect the animals' caretakers, these humans, too, were fed the weakened virus. The successful immunization of the keepers then became the justification for the mass vaccination trials in the Congo itself --the first mass trials in the history of an oral polio vaccine.
Called by drums, rural Africans traveled to village assembly points. There they lined up and had a liquid vaccine squirted into their mouths. Using this spray method, nearly a quarter million Africans were innoculated in six weeks. Later another 75,000 or so children in Leopoldville, now Kinshasa, got the vaccine, too --though European children living there apparently received their vaccine in capsure form, possibly a significant variation.
From the beginning, Koprowski's campaign was marked by controversy. _Trial by Fury_, Aaron Klein's 1972 account of the development of the polio vaccines, reports that Koprowski apparently claimed he had the backing of the World Health Organization, but the
WHO denied sanctioning the claim. Koprowski says today that although he was challenged by WHO, he needed only the approval of the Belgian authorities -- and there's no doubt he had that. Other preparations of Koprowski's polio vaccines were later used in Poland, Yugoslavia and Switzerland, among other places.
Herald Cox, Koprowski's superior at Lederle, had begun growing the polio virus in developing embryos in chicken eggs. Early on, Koprowski also used the brains of cotton rats to select his weakened strains and nurture the virus. But by 1956 and 1957, when he was readying his vaccine for use in the Congo, Koprowski had long since switched to minced-up monkey kidneys.
Monkey kidneys contained innumerable monkey viruses. Might the one that causes AIDS be one of them? And if it were, would Koprowski's method of delivery -- shooting liquid into people's mouths -- be capable of transferring the virus from monkeys to humans?
"You can't hang Koprowski with that," Albert Sabin growls at me. He's sitting at the desk in his study; the walls are covered with testimonial plaques, certificates of commendation and achievement, photos of him with several presidents. Sabin insists that the AIDS virus won't survive swallowing. He's certain of it. But whether it does or doesn't survive is really not so clear-cut, Dr. Robert Gallo and other retrovirus researchers acknowledged to me; no one knows for sure. Moreover, Gallo's colleague, Dr. William Haseltine of Harvard and also of the Dana-Farber Cancer Institute, in Boston, and others have reported that the AIDS virus infects mucous cells -- which of course occur in the mouth as well as the genetalia.
And Dr. Robert Bohannon of Baylor College of Medicine, in Houston -- who in November 1991 reported finding a monkey retrovirus in the tumor of an AIDS patient with no known contact with monkeys -- pointed out to me that the process of squirting the polio vaccine in people's mouths would tend to send tiny drops into the air. It might go directly to the lungs or nose and thence to the blood cells it is known to infect.
Later I pose the same question -- Could squirting an HIV-laden polio vaccine into people's minds cause AIDS? -- to Dr. Tom Folks, the chief retrovirologist at the Centers for Disease Control in Atlanta. "Sure it could," he says. "Any time a person has a lesion in his mouth, then there could be transmission if you put enough" of the virus in.
Monkey AIDS
But was there anything to transmit? The answer to that question hinges on the kind of monkeys used to make Koprowski's vaccine.
In 1957, when the Congo trials began, most researchers were using rhesus macaques from India. It would be another four years before scientists fully appreciated the danger that macaques, the natural hosts for SV40, were passing along the virus to humans. Once that troubling discovery was made, in 1961, vaccine producers shifted to kidneys from African green monkeys, which in the wild were free of SV40.
Unfortunately, green monkeys were infected with something else. More than two decades later, in 1982 and 1983, veterinarians at the California Primate Research Center and at Harvard's New England Primate Center observed that large numbers of their macaques were dying periodically of AIDS-like illnesses. These disorders had been killing animals since 1969, but suddenly, the researchers were struck by the similarity to the new disease afflicting American homosexual men. The monkeys' illnesses, the researchers discovered, were triggered by a previously unrecognized retrovirus called simian immunodeficiency virus (SIV).
Among the natural hosts for this virus were none other than African green monkeys, but in that species, typically, SIV didn't cause serious disease. SIV turned out to be related to HIV, though it was only about forty percent similar in genetic structure to the chief AIDS-causing human retrovirus, known as HIV-1. Robert Gallo says some versions of this monkey virus are virtually indistinguishable from some human variants of HIV-2, the second virus that causes AIDS in human beings and mainly afflicts western Africa.
No one who was involved with Koprowski's Congo project and is alive today remembers what kind of monkey kidneys were used in 1957-60. Koprowski is still vigorous and remains at the Wistar Institute, in Philadelphia -- now as an institute professor and until 1991 as the director of the facility, which is housed in a stolid Victorian structure on the campus of the university of Pennsylvania.
Koprowski insists that his associates used kidneys from African green monkeys to make the Congo vaccines. When I express surprise and mention that Salk and Sabin were using rhesus monkeys at that point, he agrees to check. When we speak next, he admits he can't find a single paper describing which species was used to make his vaccine. "But I have a suspicion the virus was grown in the rhesus monkey at the original beginning," he tells me in his thick Polish accent. "Now when we switched to green monkeys, I have no idea." Thomas Norton, his associate who grew the virus for the vaccine, is now dead, Koprowski says -- as are those who worked with Norton to prepare the vaccine. Significantly, the large lots of the vaccine used in the Congo apparently were prepared at the laboratories of the Wistar Institute, he says. Wyeth Laboratories made subsequent preparations, including those used in Poland.
Contamination
The question of which monkeys were used to make the Congo vaccine may not be crucial. The virus that causes monkey AIDS occurs in several species, though the original hosts -- African greens and others --remain healthy even when infected. Monkeys frequently were gang-caged in those days, facilitating the spread of the viruses. If a green monkey turned out to have a virus quite similar to HIV-1, it could have infected the other monkeys.
Although most American researchers in this period apparently did use rhesus macaque monkeys from Asia, for a while around the time Koprowski was working with his vaccine, the monkey supply was interrupted. The Indian government -- responding to popular alarm among its people about the widespread slaughter of Indian macaques for vaccine production and other research -- barred export of rhesus monkeys to the U.S. For a time at least, that ban must have made suppliers scramble to find different markets and alternate monkey species, probably including African monkeys. Moreover, Koprowski says the kidneys used at Wistar were bought already removed from their hosts, meaning that researchers might not have been sure what kind of monkeys they came from, much less what viruses came with them.
According to no less an authority than Albert Sabin himself, at least one other virus did contaminate Koprowski's vaccine used in the Congo. In 1959, Sabin reported in the _British Medical Journal_that a special test he had devised revealed the presence of an "unidentified" cell-killing virus in "Koprowski's Type 1 'Chat' vaccine used in the Belgian Congo trials." More than three decades later, Sabin says he never figured out exactly what the virus was.
Koprowski insists -- as he did at the time in the _British Medical Journal_ -- that two other labs examined his vaccine and found nothing except the weakened polio virus. But one eminent polio researcher, Dr. Joseph Melnick, former chairman of the Department of Virology at Baylor College of Medicine in Houston, who himself developed an oral polio vaccine while working at Yale Medical School, says Sabin probably was right. "Sabin was a very careful worker in the laboratory," says Melnick, a tall, formal, distinguished-looking man. "And I have not known him ever to say that he has found a virus in some preparation that did not exist in that preparation."
In any even, Melnick says, "Monkeys have a very high prevalence of lentiviruses," one of the subfamilies of retroviruses. "You can isolate it from their tissues, particularly from their kidneys. That is one reason why we stopped using monkeys from the wild and just used home-grown monkeys." Melnick pauses. "It's of interest," he says, "that HIV is a lentivirus." So are simian immunodeficiency virus and the so-called foamy virus, both of which widely infect monkeys, Melnick says. "In the early days of the vaccines, we didn't know much about monkey viruses." As for Koprowski's contention that others looked and didn't find the virus in his Congo vaccine that Sabin had noted, Melnick has a simple explanation, "It may not be in one batch and may be in another batch."
A Tale of Two Maps
Writing in the _British Medical Journal_ on July 26th, 1958, Koprowski and his colleagues offered a preliminary report on their mass vaccination campaign. They included in the paper a detailed map showing where nearly a quarter million inoculations had taken place in the northeastern part of the Belgian Congo. The area outlined corresponds roughly to another map in a report published thirty years later in the _Reviews of Infectious Diseases_ -- this one identifying the regions of highest HIV infection in equatorial Africa.
Still another paper that appeared in the _British Medical Journal_ in 1985 reviewed HIV infection in the Kivu District, a remote, rural population in eastern Zaire. There, somewhat puzzlingly, the researchers discovered "a high prevalence of antibodies" to the AIDS virus without symptoms of the disease. The Kivu District happens to be where Koprowski's colleagues vaccinated the lion's share of their reported sample --215,504 children and adults. And there may have been many more vaccinations than initially reported. "Could have been 200,000 more, I really don't know," Koprowski says, because the subsequent mass trials were interrupted by tribal chaos and the civil war the followed independence. No one really knows how those individuals fared over time. No long-term follow-up was possible, Koprowski says.
The researchers who studied the Kivu District in 1985 offered several possible explanations for why the people they found with antibodies for the AIDS virus might not have the disease. The fact that there were more children than adults with antibodies to the virus suggested that the adults could have been exposed in childhood, and some of them might have died or departed from the area. Perhaps, the researchers ventured, if members of a rural population that was biologically adapted to the virus moved into an urban area, exposing a pool of more susceptible adults, this would create "new opportunities for the virus to cause illness in urban adults and the epidemic appearance of the disease in Africa." Moreover, the researchers pointed out that they were looking at a region of "high mortality in childhood, particularly from infectious diseases." Cases of AIDS in children a generation ago simply might have gone unrecognized.
Of course, many of the viruses contaminating the monkey kidneys went unrecognized in the Fifties and early Sixties. Koprowski and his colleagues in the mass-vaccine campaigns found some monkey viruses and eliminated them from their preparations. But many others weren't known, and no test to identify their presence had been developed. "That's the problem," Koprowski says. "The viruses which you know, there's a test -- there's no problem; the viruses which lurk, for which there is no test, obviously you can't do anything about."
So, might Koprowski's Congo vaccine have been the vector that unwittingly first unleashed the AIDS virus among people in Africa? I ask the question and Koprowski dismisses the idea with a deep laugh: "Ho, ho, ho, ho, ho."
I'm asking the question, I say. He laughs again, this time longer and deeper. "By then you would have had plenty of opportunity to see AIDS in the vaccine," Koprowski says. "You have started in 1960; now it's thirty years. The latency period of AIDS is nine years."
But according to Dr. Gallo, I point out, some retroviruses may take up to forty years to express themselves.
"There is no indication from any part of the world that any other virus occurring there [in the various polio vaccines] causes any problem," Koprowski says.
There are reasons, however, why AIDS in the former Belgian Congo may have been invisible to medical science. In remote, rural eastern Zaire, where most of Koprowski's vaccine was administered, or even in Kinshasa, the disease simply may have passed unnoticed or may not have been identified. "In the tropics, the wealth of lethal infectious pathology is matched by the poverty of diagnostic facilities, rendering undetectable sporadic appearances of AIDS," notes Dr. Mirko D. Grmek, a medical historian, in his recent book_History of AIDS_. "It is entirely possible that localized or even moderately large epidemics have passed unnoticed."
On the other hand, AIDS may have been slow to express itself when it was confined to rural areas where people had fewer sexual partners. A laboratory experiment with monkeys also showed how AIDS may have taken a bit longer to emerge as an epidemic in its present nasty form. When a researcher took a simian AIDS virus from a healthy mangabey, a monkey species in which it typically causes no symptoms, and injected it into a group of macaques, the disease became progressively more virulent each time it passed through the body of another macaque. Finally, this isolated virus even sickened a mangabey, although that species has natural resistance to the original virus. A similar process may have made African AIDS in humans increasingly deadly over time: It's easy to envision a progression in which an original carrier infected by, let's say, a Congo vaccine would have to infect several others before the disease became virulent. Such a process would take time and might explain the lull before the African epidemic appeared (just about the same time the epidemic surfaced in the United States and in western Europe).
The Zaire Connection
In 1987, Belgian researchers writing for a Scandinavian medical journal identified seven AIDS cases originating in Zaire and in nearby Burundi between 1962 and 1976 -- well before the African epidemic exploded. Three of these were retrospectively identified as AIDS; the other four were cases in which patients had antibodies for the AIDS virus. Taken together, the authors said, the evidence indicated "that AIDS had already occurred in Central Africa several years prior to its emergence in the United States."
There is yet another curious Zaire connection: its relation to the secondary AIDS hot spot, Haiti. No one knows for sure whether AIDS migrated from Africa to Haiti or from the U.S. to Haiti. But according to Grmek, in the early Sixties, after independence came to the former Belgian Congo, many Haitians worked in Zaire, especially in Kinshasa. The Haitians -- who were French speaking, black and had no ties to Belgium -- filled the void previously occupied by Belgian colonialists. Their arrival, of course, came only a couple of years after Koprowski's vaccine had been tested in Kinshasa and in remote eastern Zaire.
As for the idea that the Congo vaccine started the African epidemic, Koprowski is skeptical. "Why do you choose Africa?" he asks. "Why don't you compare the enormous number of other countries where exactly the same [vaccine] material was used? Why didn't it start an HIV epidemic there?"
This answer seems to beg the question. Specific lots of a particular vaccine -- not all polio vaccines everywhere -- might have unintentionally spawned AIDS. For instance, specific batches of Salk's killed-poliovirus vaccine prepared by Cutter Laboratories turned out to be insufficiently inactivated by formaldehyde, and those batches paralyzed 150 of the people who received them and killed 11. Later, specific lots of Salk's and Sabin's vaccines were found to have been contaminated by the monkey virus SV40, with as-yet undetermined long-term consequences in people. Why is it unreasonable to ask whether a specific batch of Koprowski's preparation -- say, the unique lots prepared at the Wistar Institute solely for use in the Congo mass trials -- likewise might have been made from monkey kidneys unknowingly contaminated, in this case by a retrovirus that causes AIDS? "You're beating a dead horse," Koprowski says. "My opinion is that this is a highly theoretical situation, which ... does not make sense."
Testing Seed Stock?
Koprowski told me that he maintains the seed stocks -- samples of the original vaccines -- from the Congo mass trials in freezers at the Wistar Institute. I venture that it would be easy enough to answer the question just by testing those stocks.
"Yes," Koprowski begins uncertainly. "But I don't really know how much HIV is really present in monkey kidney .... I have great doubt it would find its way to epithelial cells such as kidney. You are postulating that in the highly processed monkey kidney, you'll get these viruses. I doubt that they are present there."
Later, Koprowski describes for me how the kidneys used in tissue culture were minced up using "scissors or something like that." He is quite correct that HIV and its monkey counterpart, SIV, do not appear to grown in kidney cells. Instead, as he points out, these viruses are known to grow in lymphocytes and macrophages-- cell froms found in the blood. But this doesn't mean that under the right conditions a polio vaccine grown in monkey kidney cultures might not harbor an AIDS virus.
I raise this issue with Tom Folks, chief of the retrovirus laboratory at the Centers for Disease Control in Atlanta. "You see, the problem with the kidney," says Folks, is that "there's blood and there are lymphocytes that would be contaminating the tissue. So, no matter how hard you try to mince it up -- and I've made monkey kidney tissue cultures many a time -- you haven't gotten rid of contaminating lymphocytes. So, if the monkey that it's derived from has a pretty fulminant SIV infection, and then they were placing polio [virus] on top of the monkey kidney, but there were contaminated lymphocytes, that is going to be part of the stock. Yeah, it would be there.
"That wouldn't be surprising at all," Folks continues. "And the fact that it's a live vaccine would indicate that they had not gone through any inactivation procedures to denature the AIDS virus, because it would probably denature the polio virus. So, the polio virus is kept alive, and the SIV virus would just travel with it. The theory, the possibility is real. And I don't think anyone would deny it."
The ultimate way to test the idea, Folks agrees, would be to return to the original seed stocks of the vaccine and actually isolate the retrovirus, if any, from the polio vaccine.
Does Folks think there is value in figuring out where AIDS came from? "I think any time we can learn more about natural history, it helps us understand the pathogenesis [how the disease process works], and it helps us understand the transmission." Nonetheless, he says: "It's a delicate issue. You're going to put some people
on the spot -- the person who has the stocks."
Some others in the AIDS establishment -- like Dr. David Heymann, who heads the office of research for the World Health Organization's Global Programme on AIDS, and Harvard pathology professor William Haseltine -- are so hostile to the possibility that a vaccine could have introduced AIDS that they refuse to discuss it. "The origin of the AIDS virus is of no importance to science today," Heymann says in a phone interview from Geneva. "Any speculation on how it arose is of no importance."
Haseltine is even more adamant. "It's distracting, it's nonproductive, it's confusing to the public, and I think it's grossly misleading in terms of getting to the solution of the problem," he says. "It's over, it's done with, it's very, very, very unlikely it happened that way, and it's another nonsense article. It's the worst kind of reporting as far as I'm concerned."
But you haven't even heard anything about it, I say. "I know what the theory is," Haseltine snaps. You don't think the origin of AIDS is a significant question? "It's not relevant," Haseltine insists. "Who cares what the origin was? Who really cares? If you want to do something good, write about problems people experience. Who cares where it came from? It's an unanswerable question."
It may or may not be unanswerable, I say. "I'm not interested in discussing it," he says again, and we end the conversation.
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