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 that 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, this 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 STOCKS?
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 seed 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 grow in the kidney cells. Instead, as he points out, these viruses are known to grow in lymphocytes and macrophages – cell forms 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 anybody 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 the 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 that 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.
MONKEY VIRUS = HUMAN VIRUS
In AIDS research, and in any inquiry about it, all roads lead to Dr. Robert Gallo, the federal government’s preeminent AIDS researcher. Gallo, the embattled chief of the National Cancer Institute’s Laboratory of Tumor Cell Biology, in Bethesda Maryland, was more open-minded than Haseltine and Heymann.
Among the reasons Gallo cites supporting what he considers the settled question of the origin of AIDS in Africa was “the greater divergence in people of the virus.” “The more divergent a microbe is in a population, the more time it’s had to diverge, all things being equal,” Gallo says. “The divergence in Zaire is far greater than the divergence in the United States or Europe or anywhere else.”
But how did the virus come to infect Africans? Thanks to recent research by Gallo’s protégé, Beatrice Hahn of the University of Alabama, Gallo notes, we now know that there are genetic sequences of SIV that are extremely similar to HIV-2, the second identified AIDS virus that afflicts people and is found mostly in western Africa. “In other words,” Gallo explains, “the monkey virus is the human virus – there are monkey viruses as close to isolates of HIV-2 as HIV-2 isolates are to each other.”
The same is true, Gallo says, of HTLV-1, the human T-cell leukemia virus, a retrovirus he discovered that causes a form of leukemia in people. Genoveffa Franchini in Gallo’s lab has found some monkey viruses, specifically simian T-cell leukemia viruses known as STLV-1, which are, Gallo says, as close to most of the human HTLV-1 viruses isolated from the Caribbean islands, southern United States, southern Japan and equatorial Africa as some STLV-ls are to one another.
What does this mean? Logically, it seems to suggest that there may well be a monkey with a virus that exactly matches the one that causes AIDS in humans. So far, however, nobody’s found it. The closest counterpart – the so-called missing link – has been found in two chimps from Gabon. But Gallo says that it is nowhere near as close as the two other monkey viruses he described are to HIV-2 and HTLV-1. “Close enough to argue that it might have been a source of entry some decades ago,” he says. “But it’s not close enough to be called equivalent.”
I ask if Gallo thinks a monkey with a virus resembling HIV-1 will ever be found. “I wouldn’t be shocked if there was another species where [the virus] was even closer [to HIV than the variant found in the two chimps],” he says. “Nobody would be shocked. It would be interesting and in a sense exciting, but you wouldn’t say, I can’t believe it.”
So I raise the question of whether Koprowski’s polio vaccine, if contaminated with a simian AIDS virus, could have passed it on to man.
At first Gallo dismisses the idea. “Chimps have a virus like ours,” he says. “The African green monkey doesn’t. So, start with the basics, okay? You make an assumption that it’s got to leapfrog and change dramatically. Well, that’s ridiculous…. SIV from African green monkeys is not real close to HIV-1. So, stop right there. It ends your theory. Period.”
But, I ask, if we know some monkeys have a virtual twin of HIV-2, and if some monkeys have a virtual twin of the human T-cell leukemia virus, why wouldn’t some group of monkeys somewhere have a twin for HIV-1? Might this monkey virus exist somewhere?
“Your point is well taken,” Gallo says. “In support of your contention is the fact that HTLV-1 is a far more ancient virus in man. A very ancient virus in man. You can say that conclusively. There are Melanesians who were never exposed in Europeans until the last fifty years who are widely infected with HTLV-1…. Yet … yet, there are HTLV-ls that are virtually identical to some monkey STLV-ls, even though it’s had much longer to evolve [in man]. Similarly, HIV-2 is probably an older infection in man than HIV-1. Yet there are HIV-2s and SIVs that are almost identical – that are as identical as many HIV-2s are to each other.”
“Therefore, you would suppose that in a newer infection of man you would be far more likely to find an identical virus in a species of monkeys,” says Gallo. “That’s the support of your notion. Very much so. Against it is that a great number of species have been looked at without finding anything.”
“Maybe I’ll just say I would have expected somebody would have found it by now,” Gallo says. “But maybe we just haven’t looked at anywhere near enough monkeys. Because I guess you could argue that even a monkey species where we think we know the virus [exists], that it could have a second virus [equivalent to HIV]. And that not all monkeys are infected with that second virus and that we haven’t hit the monkey that is.”
After pausing for thought, Gallo adds, “I don’t think that we can easily come upon that data, though, because there’s not a lot of experiments being done on monkeys in the wild in Africa.”
A THEORETICAL POSSIBILITY
But even assuming that a monkey version of human immunodeficiency virus exists, Gallo, like Koprowski, initially questions whether it would grow in monkey kidney cells and whether enough virus would be in the preparation to infect people – perhaps through lesions in their mouths, through mucous membranes in the mouths or since the vaccine was sprayed into people’s mouths and some of it may have become airborne, through the lungs into the blood system. After hearing how the polio vaccines were prepared and delivered in the Fifties, Gallo concedes that in some fashion this way of transmitting AIDS is “a theoretical possibility.” One important issue is whether the virus can be absorbed through mucous membranes. Gallo has his doubts, but Haseltine and others think it can.
Earlier in our talk, before I broached the polio-vaccine theory, Gallo discussed the case of a Norwegian seaman who visited an east African coastal city in the mid-Sixties, became sick with an AIDS-like illness in 1966 and died in 1976 at age thirty after infecting his wife and a daughter, who died shortly thereafter. The family’s blood-serum specimens were tested in the mid-Eighties and were positive for HIV.
Gallo reminds me of the Norwegian sailor’s case. “That sort of goes against” the theory, he says, noting that the sailor was only known to have been in east Africa, some 700 miles away from Kivu.
The virus “sure traveled,” says Gallo sarcastically. He pauses, considering the large numbers of people inoculated with the oral polio vaccine. “It might travel,” he says, “but if those are rural people, I wouldn’t expect it to travel to east African prostitutes that fast.”
“IT COULD HAPPEN”
But the vaccine wasn’t administered only in rural areas. It was given to at least 75,000 people in Leopoldville, a port city on the Congo River that was on a major trade route and that was visited at the time by around a million people a year, according to a paper by Koprowski and his colleagues.
After hearing these facts, Gallo pauses and then says: “It could happen.”
Well, I ask, based on the circumstantial case alone, wouldn’t it be wise to check Koprowski’s seed stocks ?
“Sure, why not ?” Gallo says “Certainly it’s not a hard thing to do. How can I argue against checking the seed stocks ? I think clearly that would be interesting. You have to say what they [Koprowski and his colleagues] were doing was a good thing, trying to help people.”
Absolutely, I agreed. If this happened, it would be as unintended an effect as –
Gallo cuts me off.
“It happens, sometimes, in medicine”
EPILOGUE: AVOIDING FUTURE CATASTROPHES
At my suggestion, Dr. Robert Bohannon of Baylor College of Medicine has already written to Koprowski in Philadelphia requesting samples of his Congo vaccine so that the material can be tested for the presence of extraneous viruses including HIV. Koprowski hasn’t yet responded, but the pressure on him to do so may be building. The original source for this story, Blaine Elswood, has submitted a paper to a European medical journal, which has sent Elswood’s paper to Koprowski for comment.
Bohannon has also written to the U.S. Food and Drug Administration requesting access to early seed stocks of the Salk and Sabin vaccines. The FDA has agreed to supply seed stocks dating from 1976 on. But Bohannon won’t be getting any earlier samples – there isn’t enough of this material left. Dr. Gerald Quinnan, acting director of the agency’s Center for Biologics Evaluation and Research, tells me that Sabin’s original seed stocks from the early Sixties were not tested even by the World Health Organization in the middle Eighties when concern about simian AIDS was high. That was because there are “only a small number of vials” of the preparation, Quinnan says, and tests “might use it all up.”
In his 1991 book Virus Hunting, Robert Gallo suggests that probing for the origins of AIDS and especially seeking to find out whether a monkey carries the virus that causes AIDS in people is an important quest. “We may never know for certain the answers to these questions,” he writes, “but they are of more than academic interest because answering them may help avoid future zoonotic catastrophes – that is, transmission of disease from lower animals to humans.”
Current methods of growing the Sabin poliovirus vaccine “eliminate most of the blood and lymphocytes” known to be susceptible to the AIDS viruses, Quinnan tells me. Preparations are monitored, and that “provides assurance that there is freedom from most agents,” he says. As for being sure the stuff is free from all agents, like some new retrovirus we don’t yet know about, Quinnan says: “No, you can never prove something absolutely. However, as far as we know, the system we use doesn’t result in any extraneous viruses.”
Like Salk and Sabin, Koprowski had the best intentions: He wanted to eradicate a debilitating and deadly scourge. But with what we know now, it’s clear there was a certain hubris involved in the rough-and-ready campaigns to conquer polio. There is evidence that all three pioneers used vaccines inadvertently contaminated with viruses from a species dangerously close to our own. If the Congo vaccine turns out not to be the way AIDS got started in people, it will be because medicine was lucky, not because it was infallible.
[sidebar] MAN, MONKEYS AND DISEASE
1932: Young Albert B. Sabin identifies and isolates a monkey virus that has killed a polio researcher at Bellevue Hospital, in New York. It is later named monkey B virus.
1946: Hilary Koprowski and his superior at Lederle Laboratories, in Pearl River, New York, begin work on live polio-virus vaccine.
1950: Koprowski tests first polio vaccine on human beings – a live oral vaccine. The virus is grown in chicken eggs and passed through rat brains.
1954: Jonas Salk introduces his killed polio vaccine, made from virus grown in monkey kidneys.
1955: India, reacting to the widespread slaughter of monkeys to make vaccines, restricts exports of rhesus macaques.
1956: Sabin begins testing a live polio vaccine on humans.
1957: Koprowski’s vaccine, now grown in as monkey kidneys, becomes the first oral polio vaccine to be tested on a large population – in the Belgian Congo. More than 240,000 are vaccinated in the first six weeks, most in the remote eastern part of the country.
1957: Sabin begins field trials of his vaccine in the Soviet Union. Later, upward of 70 million get it there.
1958: A three-year campaign to vaccinate African children in Leopoldville (now Kinshasa, Zaire) begins. Some 75,000 children receive Koprowski’s vaccine.
1959: Nationalist riots erupt in Leopoldville.
1959: The first detection of HIV in Leopoldville, according to two standard blot tests of stored blood conducted in 1986.
1959: Sabin reports that an unidentified monkey virus contaminated Koprowski’s Congo vaccine.
1960: Independence and civil war come to the Congo; Belgian workers depart. At least 325,000 Congolese, maybe many more, have been inoculated. No long-term follow-up is done.
1960: First case of HIV, according to a rough estimate based on genetic-sequencing calculations by Gerald Myers of Los Alamos National Laboratory, New Mexico.
1961: Batches of Salk and Sabin vaccine given to millions worldwide are reported to have been contaminated with SV40, a monkey virus that causes cancer in hamsters.
1961: French-speaking Haitians stream into the former Belgian Congo to take over jobs previously held by Belgian colonialists.
1961-62: Sabin vaccine is licensed in the U.S. and becomes vaccine of choice. Koprowski’s is frozen out.
1962: Several more AIDS cases originate in Zaire in this year and later, according to subsequent testing. Some scientists believe that AIDS radiates outward in Africa from Zaire.
1967: Marburg monkey virus kills polio researchers in Germany and Yugoslavia.
1980: A new, fatal disease – later identified as AIDS – begins to appear among American homosexual men.
1982: An AIDS-like disease is identified as killing monkeys at California and Massachusetts primate centers; a virus is later isolated as the culprit. The contagions, it turns out, have been wiping out captive monkeys since 1969.
1983: AIDS virus isolated by Luc Montagnier in Paris.
1985: Researchers report finding HIV among remote villagers in the Kivu District, in eastern Zaire.
1987: “Missing link” chimps found with closest thing yet to the human AIDS virus.
1991: Some strains of simian immunodeficiency virus (SIV) are found to be almost identical to HIV-2, the form of AIDS plaguing West Africa. This boosts speculation that a monkey with a virus quite dose to HIV-1 eventually will be found.
1991 (December): Researcher Robert C. Bohannon requests samples of Koprowski’s, Salk’s and Sabin’s seed stocks to check for contaminating monkey viruses. No response to date from Koprowski; limited success with the Food and Drug Administration. – T. C.
RELATED LINKS: Brian Martin (2001) “The Politics of a Scientific Meeting: the Origin-of-AIDS Debate at the Royal Socity” in Politics & the Life Sciences, pp. 119-130 online