Following the Science

"On reading," by Simon Wain-Hobson, is a weekly discussion of scientific papers and news articles around gain of function research in virology.

Since January 2024, Dr. Wain-Hobson has written weekly essays for Biosafety Now discussing risky research in virology. You can read his entire series here.

Golden bow, late afternoon, winter, Stockholm

On reading three flu papers from the NIH.

• Influenza: The Once and Future Pandemic by Jeffery Taubenberger & David Morens, Public Health Rep 2010; 125 Suppl 3:16-26.

• Pandemic influenza: certain uncertainties by David Morens & Jeffery Taubenberger, Rev Med Virol. 2011; 21:262–284

• Pandemic influenza viruses - Hoping for the road not taken by David Morens, Jeffery Taubenberger & Antony Fauci. N Engl J Med 2013; 368:2345-234

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Following the science was the mantra used endlessly by public health officials and onwards to politicians during the COVID pandemic. Let’s see how it holds up in the context of GOF bird flu virus controversy. Just before, a little context.

First, the above three papers were published in 2010, 2011 and 2013 and came on the back of the 2009 flu pandemic that saw a swine H1N1 flu virus pass to humans somewhere in NW Mexico. From the fall of 2011 onwards the GOF H5N1 flu controversy engulfed virology with the Fouchier and Kawaoka papers being published in 2012. 2013 saw a novel bird flu virus H7N9 spilling over to humans in China. Fortunately, they were dead end infections, and the virus didn’t spread between humans. However, the number of cases quickly outnumbered those for the H5N1 virus, so it was a shock.

Second, the authors are Dr. Taubenberger, an established US flu researcher at the NIH and perhaps best known for resurrecting the 1918 Spanish flu virus. Dr. Morens is an epidemiologist who has studied past flu pandemics and has worked for Dr Fauci. Dr. Fauci needs no introduction. Old hands like On reading know him for his steadfast handling of HIV/AIDS. It was scary back then – a remorseless infection where HIV would kill over 98% of those infected. Fortunately, game changing triple therapy arrived in 1995.

From the first paper, under the section The next pandemic, we learn that No one predicted the emergence of the 2009 H1N1swine-origin pandemic virus; with current knowledge, we doubt that anyone will be able to accurately predict any future pandemic either, including when or where it will occur, what subtype it will be, and what morbidity/mortality impact it will have. Emphasis added in bold here and elsewhere. Despite this we know that the promise claimed for the GOF H5N1 work by its proponents was to predict the next pandemic strain.

Clearly H5N1 was in everybody’s mind for the following sentence is While concern over the emergence of an H5N1 pandemic is clearly warranted, if for no other reason than its current high case fatality rate, many other possibilities for future pandemic emergence must also be anticipated and planned for. Enough said. A good teacher repeats important things at least twice.

The paper finishes thus: The unpredictable nature of influenza presents a challenge for both research and pandemic preparedness planning. Our ability to anticipate pandemic events is poor and our anti-pandemic armamentarium weak. In an ever-shifting landscape of influenza evolution, we must be far-sighted and forceful in optimizing pandemic response capacity. The last sentence is mere prose to round off a grim statement of fact. We get that, although it is unfortunate as logically, how can you optimize anything when you don’t know how severe the pandemic will be?

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The second paper is clear from the get-go. Its title Pandemic influenza: certain uncertainties is quickly backed up by the last sentence of the abstract: These uncertainties make it difficult to predict influenza pandemics and, therefore, to adequately plan to prevent them.

There follows an erudite and fascinating history of flu pandemics which is worth reading. Figure 5 succinctly shows how the pandemic flu strains of 1918, 1957, 1968, 1977 and 2009 are genetically related.

It closes with some tough observations: the historical evidence suggests that pandemics are instead a heterogeneous collection of viral adaptational events, the determinants of which are probably highly complex and remain obscure. Such uncertainties make it difficult to predict the occurrence of, and the severity of, pandemics and therefore to adequately prevent and control them. Planning for the worst while hoping for the best, health authorities risk creating public confusion and the perception of “crying wolf.” Ongoing and emergency planning is essential to pandemic containment, yet in recent decades, public health authorities have been repeatedly criticized for over-reacting to pandemics that either failed to materialize or were less severe than was predicted. For public health decision-makers, the dilemma remains constant because the determinants of influenza pandemics remain hidden. With human influenza, the only certain thing seems to be uncertainty.

We saw in the essay UK COVID response report that The UK prepared for the wrong pandemic. The significant risk of an influenza pandemic had long been considered, written about and planned for. However, that preparedness was inadequate for a global pandemic of the kind that struck. Agreed, everybody felt the pain. Yet as Morens and Taubenberger noted in their paper, many other possibilities for future pandemic emergence must also be anticipated and planned for. Nobody should have been surprised.

This is the hard reality behind pandemic preparedness. It is indeed a dilemma for public health decision-makers.

With COVID in mind one epidemiologist remarked that if we had waited to understand scientifically the emerging pandemic before acting, it would have been too late to contain the virus. In these situations, we can only act on experience. However, as the evidence evolves, adapting prior decisions based on new data is probably the key to public health responses.

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Soon after this June 2011 paper by Morens and Taubenberger was posted online, Dr. Fouchier spoke to the 4^th European scientific working group on influenza in Malta on September 13 where he presented his work adapting bird flu virus H5N1 to transmission between ferrets by the aerosol route. They had “mutated the hell out of H5N1”.

This was followed by a December 30, 2011 Op Ed in the Washington Post by Dr. Fauci and the head of the NIH supporting what was soon to become known as Gain of Function virology. We have covered the difficulties they had in arguing their case and the inappropriateness of this Op Ed (Chilled virology).

Predicting the next pandemic strain was the cornerstone to Fouchier and Kawaoka’s justification of their work. Why did they talk up their work when the corpus of flu virology reviewed by Morens and Taubenberger said otherwise?

Surprisingly Morens and Taubenberger came out clearly in favor of the H5N1 flu GOF research in a commentary in Nature - in the same issue that saw Dr. Kawaoka’s work published. Apparently, they can ignore their own scientific papers when it pleases them. But why? Both Drs. Morens and Taubenberger worked in Dr. Fauci’s institute at the NIH with the former being part of the Office of the Director. Indeed, Morens and Fauci have authored 36 scientific papers together while Taubenberger & Fauci have 14 together. Guild mentality/corporate spirit? Whatever, they simply couldn’t care.

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The reservoir for the H7N9 influenza virus is in ducks and birds like the vast majority of influenza A viruses. The first known case of H7N9 influenza infecting humans was reported in March 2013, in China. Cases continued to be recorded in poultry and humans in China over the course of the next 5 years. Between February 2013 and February 2019 there were 1,568 confirmed human cases and 616 deaths associated with the outbreak in China.

This brings us to the third paper of the trio which dates from June 2013 so everything H7N9 related was still very new. We read that: …whether pandemic viruses are rare entities whose complex gene constellations cannot easily be configured except by rare and still-obscure mechanisms.

But given influenza viruses’ unpredictability, the implications of this historical behavior for H7N9’s likelihood of evolving into a human pandemic virus remains unclear.

Like every human influenza pandemic and major outbreak in more than a century, H7N9 has left us surprised and puzzled.

The paper finishes with H7N9’s journey has just begun. We can only hope that the road to a pandemic is the road not taken.

These remarks are consistent with the first two papers which makes sense as Morens and Taubenberger are authors. Yet as we saw they did a U-turn over H5N1 bird flu so can we be sure? In the face of a new bird flu virus spilling over to humans, yet not being transmitted between humans, their take home message is We can only hope… That may sound non-scientific, but it is a blunt reminder of the unknowns associated with novel viruses.

The story could have ended there but, as you guessed, flu contradictions keep cropping up again and again. The flu research community immediately proposed performing GOF research on the new H7N9 bird flu virus. However, in view of the controversy surrounding the H5N1 studies, the call was published in Nature (August 2013) and signed by 22 prominent flu researchers lead by Fouchier and Kawaoka, mainly from the US. Safety in numbers under the cover of the top scientific journal Nature?

A couple of excerpts: to fully assess the potential risk associated with these novel viruses, there is a need for further research, including experiments that may be classified as 'gain of function' (GOF).

Since the H5 transmission papers were published, follow-up scientific studies have contributed to our understanding of host adaptation by influenza viruses, the development of vaccines and therapeutics, and improved surveillance.

The flu virologists couldn’t make a good case for performing H5N1 bird flu GOF work back in 2012. None came to the fore during the next decade. This call is more of the same false logic and jars with the third paper from Morens, Taubenberger and Fauci in the top medical journal, The New England Journal of Medicine.

Note the second quote - the juxtaposition of the H5 transmission studies of Fouchier and Kawaoka that brought the house down with follow-up studies that generated vaccines… The two parts are totally unlinked, the former did not beget the latter in any way. This slight of keyboard recurs time and time again.

The schizophrenia/attempts to control the narrative are highlighted in a roundup in the top journal Science. A few takes are given as bullet points below.

• "There are strong arguments to do the science," but it has to be done properly or not at all. … "It's not a rubber stamp," Fauci said.

Despite the reserves expressed in his June 2013 paper, Dr. Fauci backs the call to do GOF research on the novel H7N9 virus. No doubt there are parallel flu worlds.

• “Unfortunately, the tone of the letter doesn't invite debate, says Michael Imperiale, a virologist at the University of Michigan. "They're hoping this is going to make the work appear more transparent," he says, but beyond influenza researchers, he says, the scientific community has not engaged in adequate discussions about whether such experiments should be done in the first place.

And Imperiale raises another concern shared by many in the public but largely dismissed by infectious disease researchers: the fear that a lab-created pandemic virus could escape containment. "If this type of work proliferates, eventually there is going to be a lab accident," he says. "It becomes a matter of statistics. I'm not saying these guys aren't being incredibly careful. We know from past experience that lab accidents happen."

"The authors state that the H5N1 studies have 'contributed to...the development of vaccines and therapeutics, and improved surveillance'. I would like to see the evidence that supports this claim."

While On reading has disagreed with Imperiale a few times (Deconstructing the picture, Flights from Reason, Perilous posturing), here he was precise and to the point. Thanks Mike.

• Michael Osterholm, director of the University of Minnesota's Center for Infectious Disease Research and Policy, is part of the NIAID-funded network of influenza centers that employ those who signed the letter. "I continue to support gain-of-function work from a basic research standpoint. But ... I sit in the middle here where I think there still are major questions about the risks-benefits of this work that need to be addressed," he said.

"I support doing them for basic research purposes, and I have always maintained that Yoshi [Kawaoka] and Ron [Fouchier] could do this work safely," he said. "But my concern is that publishing their data would allow labs around the world, which won't adhere to the same safety requirements, to do the same."

So, he supports this work knowing full well that there still are major questions about the risks-benefits of this work. Why even do the work before solving the risk-benefit equation? This is the essence of the Dual Use debate. Osterholm says nothing for the issue is simply unresolved by anyone in the life sciences (Virus research of concern).

• Even the journal Nature chipped in by way of an editorial: The long-term benefits of such work are clear - as long as it is done to the highest biosafety standards. It will shed light on, for example, the mechanisms of virus transmissibility and pathogenicity. But the immediate benefits to public health and our short-term ability to counter the threat of H7N9 are less clear-cut. Scientists cannot predict pandemics…

No, the purported benefits of the H5N1 work were never substantiated and the same is true of the proposed H7N9 experiments. They will generate qualitative results tainted by observer bias and of no use to public health. As Scientists cannot predict pandemics, you don’t do this work. Period. Plus, remember what Mike Imperiale said about risk.

The thing to do is to admit the difficulties and dilemmas when planning for the next pandemic (inevitable) initiated by a flu virus (always a good bet), perhaps another coronavirus (visible now although we need far more work on bat coronaviruses in the wild) or some other microbe.

It’s tough for the scientists, harder for public health officials, exasperating for politicians who ‘want answers’ (understandable but please shun yes people) and exhausting for a post-COVID public who want to say, ‘never again’.

The only meaningful advice is to follow the science when there is a consensus built upon data, not sayings, opinions or polls. When there isn’t, wait. That scientists follow competing hypotheses is different for its part of their job. That’s not ‘the science’. That is science in the making, not yet at consensus level.

Whatever, check and discuss, check and discuss and check and discuss again. People’s lives depend on it.

Conclusion

Papers by these authors on flu should be flagged up as inconsistent and unreliable.

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Aside 1

Although hardly an aside, why ignore the corpus of existing knowledge? It will waste time and money. Talk of overturning dogma may sound fun, but most of science is incremental. Why was the NIH top brass fooled by the claims of GOF flu virology when they were writing about certain uncertainties? That is the question.

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Aside 2

A fascinating paper came out in 2022 on the H7N9 virus in humans funded in part by the US National Institute of Allergy and Infectious Disease (NIAID). We conclude that human-adapted H7N9 viruses are unlikely to emerge during typical spillover infections. Our findings are instead consistent with a model in which the emergence of a human-transmissible virus would be a rare and unpredictable, though highly consequential, “jackpot” event. Unpredictability again - what a surprise! Dr. Kawaoka was one of the senior authors on this paper - the very same who signed the call for GOF research on H7N9. ALSO, the astute lay science observer, spotted that parallel flu world.

Can the same be said of H5N1 bird flu, or cow-adapted H5N1? We don’t know just as we can’t predict its trajectory. So far Dr. Kawaoka or colleagues have not yet called for GOF studies on this cow virus. Others have. Mid-winter madness.

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Aside 3

The H7N9 flu outbreak in China has been partially contained by a program of poultry vaccination that started 2017.

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Simon Wain-Hobson is an emeritus professor at the Institute Pasteur, Paris, from which he retired in 2021. He and his colleagues were the first to sequence the genome of HIV, and Wain-Hobson has published more than 230 papers on virology and cancer.