How do pandemics begin?

From a chimpanzee research centre in the Congo to a laboratory in China, pandemics have tangled origin stories that science struggles to unravel.

Corporation workers and medical staff in Chennai during the nationwide lockdown imposed in the wake of the COVID-19 pandemic, on April 27, 2020. | Photo Credit: K. PICHUMANI

In 1999, a British journalist named Edward Hooper published The River a painstakingly researched, carefully written book on the emergence of HIV/AIDS, in which he argued that HIV did not arise naturally but was a man-made disaster caused by trials of an oral polio vaccine in Central Africa in the 1950s.

Hooper was struck by the fact that areas in the then Belgian Congo became ground zero for the HIV pandemic four decades after a polio vaccine developed by Hilary Koprowski was tested on nearly five lakh children and adults there. Hooper suggested that the polio vaccine had been contaminated with simian immunodeficiency virus (SIV), the ancestral virus for HIV.

The parallels with the controversy around the origins of SARS-Cov-2, the virus that causes COVID-19, are striking. A determined group of Hooper-like insurgents who believe that the scientific establishment is covering up evidence that points to a man-made virus cooked up in a laboratory in Wuhan is pitted against more mainstream scientists who are convinced the virus evolved naturally. Are there lessons in the way the debate over the origins of HIV/AIDS unfolded that could provide a way forward in the SARS-Cov-2 debate?

Hooper’s suggestion in his book that HIV arose through human error outraged those involved in the vaccine trials. Few scientists wanted to consider that the vaccines might have been contaminated, and most dismissed his hypothesis as irresponsible because it reduced public confidence in vaccines, particularly polio vaccines. But there was little danger that the debate would affect the polio programme: Koprowski’s vaccine was not used outside clinical trials in Africa and Europe between 1957 and 1960. Albert Sabin’s rival oral polio vaccine was judged to be safer and became the workhorse of the polio eradication campaign. Koprowski’s vaccine, despite being the first oral polio vaccine, languished as a footnote in history until Hooper’s book resurrected it as an unlikely villain in the story of the HIV/AIDS pandemic.

Not the first to suggest a link with polio vaccine

Hooper was not the first to suggest a link between early polio vaccine trials and HIV/AIDS. In an article published in Rolling Stone magazine in 1992, an American journalist, Tom Curtis, asked whether the monkey kidney cells in which the polio virus was grown might have been contaminated with SIV. Could this have been the route through which SIV infected humans and later evolved to become HIV?

The suggestion was not outlandish. We now know that the monkey kidney cells used in the 1950s and early 1960s to manufacture polio vaccines harboured a variety of viruses. Batches of the Salk polio vaccine manufactured from 1955 until the early 1960s were discovered to have been contaminated with the simian virus SV40. SV40 was only identified in the 1960s and could not have been detected earlier. As a result, several million children across the world were infected with it after being given vaccines with SV40.

Despite decades of study, there is no clear evidence to indicate the harm the virus caused. In animals, SV40 is known to cause brain, bone, mesothalmic, and lymphatic cancers. In humans, SV40 has been detected in tumours, but it is not clear whether the virus caused these tumours or whether they were just found in tumour cells. Also, there is not enough data to find out whether the prevalence of tumours and the presence of SV40 are greater in those who received polio vaccines in the late 1950s and 1960s.

After SV40 was discovered, Asian rhesus monkeys, which harbour the virus, were no longer used for vaccine production, and African green monkeys, which do not host SV40, were used instead. Curtis asked what if these African green monkey kidneys were contaminated with SIV viruses, which were also undiscovered in the 1950s and 1960s? SIVs are endemic to different species of African monkeys and great apes and could well have entered the vaccine-manufacturing process, he argued.

Dr Hilary Koprowski. | Photo Credit: AP

Scientists dismissed Curtis’ article perhaps because it was written by a journalist and appeared in Rolling Stone. Its impact was also dampened in the US after Koprowski sued Rolling Stone for defamation and was awarded a token $1 in damages. But the story did not go away. Instead, Hooper took Curtis’ argument forward and suggested a mechanism through which the polio vaccine might have been contaminated with SIV.

He argued that chimpanzee kidney cells harvested from a research station in the rainforest near Stanleyville, present-day Kisangani in the Democratic Republic of Congo, had been used to grow the polio virus and develop the vaccines that were used in clinical trials in 1958 and 1959. Chimpanzees harbour SIV-1, the closest animal precursor to HIV-1, the strain of HIV that caused the pandemic. Hooper marshalled large amounts of data from interviews with those who had worked in the chimpanzee research station and from laboratory records to suggest that this was a more plausible way for the pandemic to have begun than the mainstream scientific explanation that bloody encounters between bush meat hunters and the chimpanzees they caught had led to SIV passing to humans and evolving into HIV.

Hooper’s case was well argued, and though scientific journals dismissed his book, it was well reviewed in the news media, including The New York Times, whose medical correspondent Lawrence Altman said: “It offered tantalising clues to revive and expand the polio vaccine hypothesis.” Hooper’s evidence was circumstantial, but it did suggest a possible alternative origin story for HIV. William Hamilton, a respected sociobiologist and geneticist at Oxford University, was intrigued enough to partner with Hooper to find evidence for or against the hypothesis.

The pair travelled to the Congo, where Hamilton collected samples to understand how prevalent SIV was in the local chimpanzee population. Hooper visited a camp that in the late 1950s housed the chimps that were used to test the safety of polio vaccines and interviewed employees to see whether chimp kidneys had been used in the manufacture of polio vaccines.

Highlights

• When the British journalist Edward Hooper hypothesised, in his book The River (1999), that HIV did not arise naturally but was a man-made disaster caused by trials of an oral polio vaccine in Central Africa in the 1950s, those involved in the trials were outraged.
• In September 2000, the Royal Society in London conducted a two-day scientific conference where evidence was presented for both an insurgent hypothesis suggested by a non-scientist and for a mainstream hypothesis from scientists.
• The conference was not able to definitely refute Hooper’s hypothesis, but it did show how tenuous our knowledge of the origins of a pandemic virus is and how limited is our understanding of the mechanisms by which zoonotic viruses emerge, evolve, and spread in human populations.

Royal Society conference

The effort to re-examine the standard “cut-hunter” theory of the origin of HIV culminated in a two-day scientific conference at the Royal Society in London in September 2000, a rare instance when evidence for both an insurgent hypothesis suggested by a non-scientist and for a mainstream hypothesis from scientists was presented at the same forum.

Hamilton himself tragically passed away before the meeting following an illness contracted during his trip to the Congo, but Koprowski, Stanley Plotkin (who helped run the Congo trials as Koprowski’s postdoctoral researcher before becoming a distinguished immunologist and vaccinologist), and Hooper presented evidence.

In The River, the author Edward Hooper argues that HIV did not arise naturally but was a man-made disaster caused by trials of an oral polio vaccine in Central Africa in the 1950s.

In his introductory remarks, Aaron Klug, president of the Royal Society, spoke of the “emotion and dissension” aroused by the suggestion that polio vaccine trials had caused the HIV/AIDS pandemic. Koprowski, Plotkin, and other scientists were incensed by the accusations, and a sense of their injured innocence comes through when one reads the proceedings of the conference even two decades later.

Plotkin’s paper was called “Untruths and Consequences: the false hypothesis linking Chat type 1 polo vaccination to the origin of human immunodeficiency virus”, a title far from the bland neutrality that scientific journals profess. Plotkin admitted it was “the strangest paper he had given, belonging more to literary exegesis than science”, but said it was important to set out the true history of the vaccine trials and correct Hooper’s misrepresentations.

Koprowski called his paper “Hypothesis and facts” and complained that he had been painted as the creator of a vaccine that gave the world HIV/AIDS and killed millions of people. He maintained that the real facts excluded “any link between oral polio vaccine and human immunodeficiency virus”.<EP>Hooper’s paper said he had new evidence to support his hypothesis, but he complained that the conference did not provide a forum for free and fair debate on the origins of HIV/AIDS and spoke darkly of behind-the-scenes manoeuvrings to discredit his theory.

Some evidence produced at the conference was more appropriate to a court of law than a scientific forum. Plotkin produced sworn statements from his associates denying that chimpanzee kidneys had been used to manufacture polio vaccine. Hooper produced interviews from people who had worked in research centres in the Congo at the time stating they were sure that kidneys were harvested from chimpanzees and that tissue had been cultured in which the vaccine could have been manufactured. None of this was scientifically acceptable evidence.

However, enough solid evidence was presented to weaken Hooper’s hypothesis and there was not enough to back it. Hooper needed to have demonstrated that chimpanzee kidneys were indeed used to manufacture the polio virus and that these kidneys were contaminated with SIV that survived the purifying and filtering processes used to manufacture the oral polio vaccine. None of this could be demonstrated except by hearsay evidence.

On the other hand, molecular genetic modelling presented at the conference suggested that the earliest introduction of HIV in the human population happened around 1930, if not earlier, at least two decades before the vaccine trials, reducing the probability that polio vaccine seeded the pandemic.

A year after the conference, a more definitive test blew a hole in the oral polio vaccine hypothesis. Samples of the original vaccine lot used in the Congo were retrieved from a laboratory where they had been stored and when tested revealed no trace of either SIV or evidence that chimpanzee tissue had been used as the culture. This effectively ended the oral-polio-vaccine-as-the-cause-for-HIV hypothesis.

What the Royal Society conference did was to turn the spotlight on the tenuous knowledge of the origins of a pandemic virus and the limited understanding of the mechanisms by which zoonotic viruses emerge, evolve, and spread in human populations. After the first cases of AIDS were identified in the US in the early 1980s, it took three or four years to identify the virus that caused the disease, followed by decades of work to trace the virus back to West Africa. But the exact paths by which viruses from chimpanzees and sooty mangabey monkeys travelled to human beings and then evolved to become HIV-1 and HIV-2 respectively are still unknown.

The Royal Society meeting produced evidence that made the natural origins hypothesis the most likely explanation for the origin and spread of HIV. But it left many questions unanswered. If SIV had passed to humans through hunting, a practice that must have been going on for centuries, why did the HIV virus emerge relatively recently and spread in pandemic form even more recently? A number of routes have been suggested, including the growth of large urban centres in West and Central Africa in the 20th century that allowed a virus confined to remote rural areas more opportunities to spread, improved transportation that allowed both humans and viruses to travel to new areas, social upheavals that led to changing sexual mores and new opportunities for the virus to spread, contaminated blood transfusions, and vaccination with unsterile syringes. But, at the end of the day, these remain hypothetical mechanisms. Robin Weiss, a molecular biologist at University College London, summing up the conference proceedings, said: “Exactly how, when, and where the first human(s) became infected… is likely to remain a matter of conjecture.”

If SARS-Cov-2, the virus that causes COVID-19, is the result of a laboratory experiment gone bad at the Wuhan institute, then this needs to be backed by evidence. | Photo Credit: Getty Images

What relevance does all of this have on the origins of SARS-Cov-2? There are two battling hypotheses to explain its emergence. One says the virus passed naturally from bat to man via intermediary animals and that the Huanan market in Wuhan was possibly where it multiplied and began to infect humans. This is similar to how the first severe acute respiratory syndrome (SARS) epidemic broke out in late 1999-2000 in the animal markets of Guangzhou province in China.

The alternative laboratory origin hypothesis rests substantially on location: the pandemic broke out in Wuhan, also the location of the Wuhan Institute of Virology, one of the world’s leading centres for bat coronavirus research, and therefore an experimental virus could have leaked from a laboratory in the institute.

Would a Royal Society-like conference in which both sides produce evidence help resolve this dispute? It would be useful for supporters of both hypotheses to present their evidence in the relatively tranquil atmosphere of a scientific gathering rather than through the supercharged environment of social media.

A sample of blood being taken from a test tube at a laboratory where pharmaceutical research is going on in the search for drugs that work against COVID-19. | Photo Credit: Dragos Condrea

It could be an occasion for the causal chain of events for both hypotheses to be laid out, allowing gaps in information to be identified. For example, if SARS-Cov-2 is the result of a laboratory experiment gone bad at the Wuhan institute, then this needs to be backed by evidence such as samples of precursor viruses cultured in the laboratory and records on the work that was being done on these viruses that might have led to SARS-Cov-2. If SARS-Cov-2 escaped from a laboratory, there ought to be evidence of infections among laboratory workers.

Similarly, the hypothesis that SARS-Cov-2 emerged at one, or perhaps two, animal markets in Wuhan is largely based on precedent: as we know similar diseases such as SARS emerged out of contacts between animals and humans in markets. The close proximity of different kinds of animals and humans can allow viruses to travel between hosts and acquire characteristics that make it easier for them to transmit to and between humans. Once again, there is a paucity of evidence even on what kinds of animals were sold in the markets. Farms where these animals are bred needed to have been tested for precursor viruses. Extensive sampling and testing of animals along the supply chains to the market in Wuhan are needed. Since animal markets are common across China, the question of why SARS-Cov-2 broke out in Wuhan and not elsewhere needs to be determined.

Can these holes be filled? It seems unlikely at present. The biggest obstacle is the Chinese government, which has dismissed the laboratory leak hypothesis and will not allow any further investigation. What is less well known is the glacial Chinese silence on any attempts to find evidence for the evolution of SARS-Cov-2 amongst the market livestock. The Chinese focus is to try and establish that the virus did not originate in China but elsewhere. One hypothesis China has floated is that the virus came through imported frozen meat, pointing to traces of viral material found on packets of frozen meat in a SARS-Cov-2 outbreak in Qingdao in northern China. Another suggestion is that the foreign competitors at the world military athletics championship held in Wuhan in 2019 might have seeded the virus. The possibility that animals smuggled illegally from South-East Asia might have brought in the virus is another hypothesis (and one well within the realm of possibility, unlike the other two).

China’s position on the search for the origins of SARS-Cov-2 can be described as ABC: Anywhere But China. Until this changes, it is hard to see greater clarity emerge on the origin of SARS-Cov-2. The natural origins hypothesis favoured by most scientists has huge gaps in data. The insurgent laboratory origin theory has, if anything, greater gaps. But until China’s position changes, the battle between hypotheses will continue.

Thomas Abraham is the author of Twentieth Century Plague: The Story of SARS and Polio: The Odyssey of Eradication