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The consequences of a lab escape of a potential pandemic pathogen
by Lynn C. Klotz, The Center for Arms Control and Non-Proliferation, Washington, DC, USA; and Edward J. Sylvester, Science and Medical Journalism, Walter Cronkite School of Journalism and Mass Communication, Arizona State University, Phoenix, AZ, USA
Frontiers in Public Health
August 11, 2014

In letters to the journals Science and Nature (1, 2), 22 virologists notified the research community of their interest in expanding research to develop strains of the already deadly H7N9 Asian influenza virus that would be transmissible via aerosols among mammals, thus creating potential pandemic pathogens. PPPs are defined as pathogens that are potentially highly contagious, potentially highly deadly, and not currently present in the human population. Mammalian contagious avian flu, the 1918 pandemic flu, and SARS are examples. The letter writers cite their scientific reasons for the need for such research, much the same reasons as given by those working on similar projects for the H5N1 avian flu virus (3, 4). This new proposed research signals wider interest in making dangerous influenza viruses (5, 6) contagious in mammals via respiratory aerosols. At present, there are no international regulations or guidelines in place to decide whether such a research project should proceed.

Now is the time to address the next critical question: what is the likelihood that one of these viruses will escape from a lab and seed the very pandemic the researchers claim they are trying to prevent? As we shall estimate, that probability could be as high as 27%, a risk too dangerous to live with.

First, from the calculations in two in-depth pandemic risk analyses (7–9), there is a substantial probability that a pandemic with over a 100-million fatalities could be seeded from an undetected lab-acquired infection (LAI), if a single infected lab worker spreads infection as he moves about in the community. From the Klotz (2014) analysis, there is about a 1–30% probability, depending on assumptions, that, once infected, the lab worker will seed a pandemic. This large probability spread arises from varying the average number of people infected by an infected person between 1.4 and 3.0 (R0, in standard epidemiology notation), varying the details of commutes to and from work on public transportation, and whether infected acquaintances are quarantined before spreading infection. The Merler (2013) study, based on a computer-generated population grid of size and varying density of the Netherlands, supports our concern over a lab escape not being detected until it is too late: “there is a non-negligible probability (5–15%), strongly dependent on reproduction number and probability of developing clinical symptoms, that the escape event is not detected at all.”

Different methodologies were used in the Klotz (2014) and Merler (2013) risk analyses. Additional analyses are needed using other methodologies, such as the mathematical model employed for SARS (10), which hopefully will lead to some consensus on risk. The Klotz and Merler studies, however, are the first to raise these concerns and point to valid issues about the potential risks from a single LAI.

Given such a dire predicted outcome by the existing studies, the critical question is: what is the probability that a worker acquires an undetected infection in the lab in the first place? To answer this question, we reproduce here one part of the Klotz (2014) analysis: the probability of an escape through an LAI from at least one of the many labs expected to be involved in this research enterprise.

A 2013 Centers for Disease Control report is a significant source of recent data on LAIs (11). The report documents four undetected or unreported LAIs in registered US Select Agent, high-containment BSL-3 labs between 2004 and 2010. An undetected or unreported LAI implies an escape when the infected person leaves the lab. The report identifies an average of 292 registered Select Agent BSL-2, BSL-3, and BSL-4 labs operating over those 7 years, for a total of 292 × 7 = 2,044 lab years. Unfortunately, the study does not break down numbers into BSL-2, BSL-3, and BSL-4 labs or lab years.

Thus, the probability of escape for a single year, p1, can only be calculated as 4 LAIs/2,044 lab years = 0.002 or 0.2% per lab per year. This is clearly an underestimate since BSL-2 and BSL-4 labs contribute to the denominator. (The denominator used here, 2,004, equals the number of BSL-2 plus number of BSL-3 plus number of BSL-4 labs. But the denominator in our calculation should be just the number of BSL-3 labs, so the denominator is overestimated and the percent escape is then underestimated. Although requested, the CDC has not supplied us with the number of BSL-3 labs for us to do the exact calculation.) This basic probability is consistent with that for SARS escapes in Asia through LAIs (12) and with all known escapes from BSL-4 labs in the Soviet Union from LAIs and Great Britain from a mechanical failure (13).

To illustrate potential risk, the probability of no escape from a single lab in a single year is (1 − p1), so

pno=(1− p1)N × Y (1)


is the probability of no escape from N labs in Y years. And

pat least one= 1−(1− p1)N×Y (2)


is the probability of at least one escape from N labs in Y years.

Given the Science and Nature articles listed above (1, 2), it is reasonable to assume that at least 10 labs will undertake this research and that this work would continue for 10 years, so

pat least one= 1−(1−0.002)10×10= 0.18 (3)


or an 18% likelihood of at least one escape from at least one lab for the whole research enterprise, almost 100-times greater than the likelihood for a single lab in a single year.

We noted above that the probability p1 = 0.2% is conservative, estimated from the CDC data alone. The first Department of Homeland Security risk assessment for the planned National Bio- and Agro-Defense Facility in Manhattan, Kansas estimated a significantly higher escape risk, over 70% likelihood for the 50-year life of the facility (14), which works out to be a basic probability of escape, p1 = 2.4% per year. The National Research Council (14) overseeing the risk assessment remarked “The … estimates indicate that the probability of an infection resulting from a laboratory release of FMDv from the NBAF in Manhattan, Kansas approaches 70% over 50 years (see Figure 3-1) with an economic impact of $9–50 billion. The committee finds that the risks and costs could well be significantly higher than that…” While the DHS subsequently lowered the escape risk to 0.11% for the 50-year lifetime (14), the NRC committee (14) was highly critical of the new calculations: “The committee finds that the extremely low probabilities of release are based on overly optimistic and unsupported estimates of human error rates, underestimates of infectious material available for release, and inappropriate treatment of dependencies, uncertainties, and sensitivities in calculating release probabilities.” We have more trust in the NRC committee conclusions, as they have no skin in the game.

With this higher number, which we take as a worst-case scenario, the likelihood of at least one escape from 10 labs in 10 years becomes 91%, almost a certainty.
It follows that, if the likelihood of one LAI leading to a pandemic is 30% in the worst-case scenario, the likelihood of an LAI-caused pandemic resulting from this whole research enterprise could be as high as 30 × 91% = 27%, a likelihood that is too dangerous to live with, as we noted. While this represents a worst-case scenario, it is not improbable.

Recent self-reported mistakes at the CDC (15), involving a particularly deadly strain of anthrax removed from BSL-3 containment and H5N1 Asian bird flu released from the CDC laboratories altogether, lend support to our concern that the probability of escape may be much greater than the 0.2% per lab per year from just LAIs. The CDC report spawned a congressional inquiry (16) and led to dozens of newspaper articles with concerns about lack of safety in high-containment laboratories.

Our concern is shared by many virologists and epidemiologists. A recent letter to the President of the European Commission (17) co-signed by 56 scientists from more than a dozen countries warned, “The probabilities of a lab accident that leads to a global spread of an escaped mutated virus are small but finite, while the impact of global spread could be catastrophic.”
The European Centre for Disease Prevention and Control (18) weighed-in with its concerns as well, as did the Cambridge Working Group (19). It must be noted that some of the signers of the European Commission letter and the Cambridge Working Group’s consensus statement are the same.

The risk of a man-made pandemic from a lab escape is not hypothetical. Lab escapes of high-consequence pathogens resulting in transmission beyond lab personnel have occurred (20, 21). The historical record reveals lab-originated outbreaks and deaths due to the causative agents of the 1977 pandemic flu, smallpox escapes in Great Britain, Venezuelan equine encephalitis in 1995, SARS outbreaks after the SARS epidemic, and foot and mouth disease in the UK in 2007. Ironically, these labs were working with pathogens to prevent the very outbreaks that they ultimately caused.

Do benefits outweigh risks? Those who support PPP experiments either believe the probability of PPP escape is infinitesimal or the benefits in preventing a pandemic are great enough to justify the risk. In making decisions for what lines of research will lead to new knowledge, experts must rely on intuition honed by years of research in a particular field. In the case of this PPP research, in our opinion it would take extraordinary benefits and significant reduction of risk via extraordinary biosafety measures to correct such a massive overbalance of highly uncertain benefits to too-likely risks (Wain-Hobson, 2013).

Whatever number we are gambling with, it is clearly far too high a risk to human lives. This Asian bird flu virus research to develop strains transmissible via aerosols among mammals, and perhaps some other PPP research as well, should for the present be banned. We must emphasize that we have been considering only a very small subset of pathogen research. Most pathogen research should proceed unimpeded by unnecessary regulations.

Special precautions in BSL-4 laboratories for work with PPPs should be adopted (22). These would include:

• Training a full-time technical staff for work with PPPs. Experiments could be directed by scientists outside the laboratory using modern audio-video technology.

• Requiring the staff to follow up extended work shifts with periods of quarantine before they leave the containment area to assure that no PPP escapes from the containment area through an LAI.

• Restricting these PPP laboratories to remote locations, where an aerosol escape or other containment failure would pose the least risk of infecting an outside community.

We label BSL-4 laboratories with the special precautions, BSL-4+. While PPP experiments would be carried out primarily under BSL-4+ containment, BSL-3 containment with the special precautions might suffice for some work.

Given the global threat, the international community should insist on discussions leading to an international agreement that would require the strictest oversight to conduct this particular research anywhere. To place responsibility with the international community where it belongs and to provide maximum transparency, policy makers should require that international inspectors have access to facilities at any time on short notice.

As it stands, there is no proactive oversight nor regulations for this PPP research, so any and all of the world’s nations can carry out this dangerous work without regard to consequences. But consequences would be shared by all of us. In the meantime, insurance companies who routinely provide insurance for biological research should consider excluding such risky research from coverage.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Fouchier RA, Kawaoka Y, Cardona C, Compans RW, García-Sastre A, Govorkova EA, et al. Gain-of-function experiments on H7N9. Science (2013) 341:612–3. doi: 10.1126/science.1243325

2. Fouchier RA, Kawaoka Y, Cardona C, Compans RW, Fouchier RA, García-Sastre A, et al. Avian flu: gain-of-function experiments on H7N9. Nature (2013) 500:150–1. doi:10.1038/500150a

3. Herfst S, Schrauwen EJ, Linster M, Chutinimitkul S, de Wit E, Munster VJ, et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science (2012) 336:1534–41. doi:10.1126/science.1213362

4. Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K, et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature (2012) 486:420–8. doi:10.1038/nature10831

5. Zhang Y, Zhang Q, Kong H, Jiang Y, Gao Y, Deng G, et al. H5N1 hybrid viruses bearing 2009/H1N1 virus genes transmit in guinea pigs by respiratory droplet. Science (2013) 340:1459–63. doi:10.1126/science.1229455

6. Sutton TC, Finch C, Shao H, Angel M, Chen H, Capua I, et al. Airborne transmission of highly pathogenic H7N1 influenza in ferrets. J Virol (2014) 88:6623–35. doi:10.1128/JVI.02765-13

7. Klotz LC. The Human Fatality and Economic Burden of a Man-made Influenza Pandemic: A Risk Assessment. The Center for Arms Control & Non-Proliferation (2014). Available from: http://armscontrolcenter.org/The_Human_ ... 1-5-14.pdf or http://bio-security.org/wp-content/uplo ... 1-5-14.pdf

8. Klotz L, Sylvester S. Opinion: The Fatality Burden. (2013). Available from: http://www.the-scientist.com/?articles. ... ty-Burden/

9. Merler S, Ajelli M, Fumanelli L, Vespignani A. Containing the accidental lab escape of potential pandemic influenza viruses. BMC Med (2013) 11:252. doi:10.1186/1741-7015-11-252

10. Lipsitch M, Cohen T, Cooper B, Robins JM, Ma S, James L, et al. Transmission dynamics and control of severe acute respiratory syndrome. Science (2003) 300:1966–70. doi:10.1126/science.1086616

11. Henkel RD, Miller T, Weyant RS. Monitoring select agent theft, loss and release reports in the United States 2004-2010. Appl Biosafety (2012) 17:171–80. Available from: http://www.absa.org/abj/abj/121704FAHenkel.pdf

12. Specific Incidences of Lab-Acquired SARS-CoV Infections. Centers for Disease Control and Prevention (2005). Available from: http://www.cdc.gov/sars/lab/biosafety.html

13. Klotz LC. Sharpening Our Intuition on Man-made Pandemics. Breeding BioSecurity Blog (2012). Available from: http://bio-security.org/wp-content/uplo ... on0515.pdf

14. Evaluation of the Updated Site-Specific Risk Assessment for the National Bio- and Agro-Defense Facility in Manhattan, Kansas. The National Academies Press (2012). Available from: http://www.nap.edu/catalog.php?record_id=13418

15. Report on the Potential Exposure to Anthrax. Centers for Disease Control and Prevention (2014). Available from: http://www.cdc.gov/od/science/integrity ... Report.pdf

16. Review of CDC Anthrax Lab Incident. Energy & Commerce Committee, United States House of Representatives. (2014). Available from: http://energycommerce.house.gov/hearing ... dent#video

17. Wain-Hobson S. Response to Letter by the European Society for Virology on “Gain-of-Function” Influenza Research. The Foundation for Vaccine Research (2013). Available from: http://www.nature.com/polopoly_fs/7.145 ... letter.pdf

KNAW has invited two scientists who contributed to the debate on gain-of-function by writing a letter to the president of the EU-Commission, Mr Barroso. In his capacity as chairman of the European Society for Virology, professor Giorgio Palù, asked attention for the potential benefits of this kind of research. Professor Simon Wain-Hobson, chairman of the Foundation for Vaccine Research, responded with a letter undersigned by 56 other scientists -- that challenged the arguments in favour. In their opening statements both Dr Palù and Dr Wain Hobson will explain and elaborate their main arguments.

Following their presentations both speakers will –- for the first time -– have a debate with each other. Of course there will be attention for the more scientific aspects of gain-of-function research. However, the political and societal debate was not only –- and probably not even in the first place – on science, but even more on the security aspects. One of the reasons for the debate is the risk of bioterrorism: the creation of a pandemic by terrorists having the knowledge and the biological agents. Since the attack with anthrax letters in the USA life scientists know -– or should know -– that this is a real issue of concern. How to deal with it, as science and as society?...

PRESENTATION SIMON WAIN-HOBSON

His main thesis for this debate is as follows: gain-of-function avian influenza research is frighteningly out of touch. The flu that worries us is that among humans. Influenza viruses are characterized by two kinds of proteins called H (hemagglutinin) and N (neuraminidase) at the surface of the virus that allow it to get into and out of cells. Human pandemics have been provoked by H1N1 (Spanish flu 1918, 1977 and 2009), H2N2 (Asian flu, 1957) and H3N2 viruses (Hong Kong flu, 1968). By contrast the greatest reservoir of influenza viruses is among ducks, birds and chickens and they rarely cross over to humans. Occasionally an epidemic of avian flu spills over to humans and can give rise to hundreds of H7N9 infections in man in a matter of months. Fortunately, these viruses are almost never transmitted from human to human. This is the same as with the rabies virus. Such dead end infections are not new in virology. The question is could these viruses become transmittable between humans and if so how? In modern virological parlance, what mutations are necessary to convert such a virus into a highly transmissible virus between ferrets, the animal of choice in influenza biology. This is the basis of the H5N1 projects of Fouchier and Kawaoka. As is now well known, they succeeded in doing this for the H5N1 virus and it involved a handful of mutations.

It should be emphasized that the conditions in a laboratory differ enormously from those in nature. Influenza virus evolution takes years, while in a laboratory there is a massive acceleration thanks to the selection of mutants by the virologist.
To illustrate this, suffice to say that for some reason nature has not yet succeeded in morphing any influenza virus into a major human pathogen other than H1N1, H2N2 and H3N2 in 100 years. Even the resurrection of the Spanish flu HIN1 virus did not help us to predict or prepare for the H1N1 flu pandemic of 2009.

This is one of the major scientific weaknesses in the so-called gain-of-function influenza research. We do not know if the experiments reflect what happens in nature. As an HIV expert he can say this because the lab is not a good template for what happens in the clinic. There are hundreds of possible trajectories and only a few can be tested in laboratory. One can never know which are the “right ones” – that can only be appreciated as being “right” once the pandemic has struck. As for obvious ethical reasons these experiments cannot be done in humans, an important objection to this work is that it is not falsifiable. This constitutes a real issue as science tries to solve problems, not to create them.

He gave two examples of quantum jumps in recent gain-of-function influenza research. An ostrich H7N1 virus was selected to become droplet transmissible between ferrets. It did not lose lethality -- three out of five animals died (Sutton et al., J Virology 88, 6623 (2014)). A 60% lethality rate is much greater than the 2% that characterized Spanish flu. We must realize that until now no case of H7N1 in humans has been reported, so it is no threat to humans. The world is becoming a more dangerous place by making the virus aerosol transmittable. The second example is an unpublished experiment from Dr Kawaoka. He engineered the human 2009 pandemic H1N1 virus to escape neutralization by convalescent sera. By doing this the virus escaped vaccine coverage. It needs no explanation that if there ever were a lab accident the consequences could be enormous because this virus is unquestionably transmissible between humans.

The benefits of this kind of research: Scientists are used to work with the probability of benefits versus risks, just as they are used to handling dangerous agents. One of the arguments in favour of this gain-of-function research is developing vaccines and drugs. GOF research has nothing to offer for making vaccines. Development of vaccines is a very time-consuming and expensive effort. Moreover, each strain of influenza virus would need its own vaccine. And as mentioned above there is a great number of possible strains. And as it cannot be predicted which strain will cause an epidemic, this kind of research does not have much utility. Developing and stockpiling these vaccines would cost an enormous amount of money. As for drugs the choice is binary: we must hope that the next pandemic strain is sensitive to available drugs and use them accordingly. If the strain is resistant, it will take too long for the new drugs to be tested -– by then the pandemic will be over.

Now the risks of gain-of-function research: There is always the risk of an accident. For a virus that the human system has never seen this could lead to millions of deaths. Wain-Hobson does not call this risk, but catastrophic risk. But there are also less catastrophic outcomes, e.g. the equivalent of a seasonal flu outbreak where mortality is less than a million. The economic burden of seasonal flu costs a lot of money (say $71-167 bn/year to US economy alone). What would be special in the event of release of a lab engineered virus is that it is genetically ‘barcoded’. It would be trivial to trace the origin. Massive liability claims would be sought for the unwarranted deaths and economic damage. Liability experts (e.g. from RAND corporation) say that this really could lead to claims of 100 billion dollars and more, an amount that no insurance company would be willing, or able, to pay. Liability of this magnitude would jeopardize the existence of private universities and institutions such as the Institut Pasteur or even Harvard.

Some scientists argue that there is not much guidance on these biosafety issues. Of course there is the Fink report of 2004 (NRC -- National Research Council (2004), Biotechnology Research in an Age of Terrorism. Washington DC: National Academies of Science). And there is the InterAcademy Panel 2007 Statement on Biosecurity. This statement has been signed by 76 Academies of Sciences, such as KNAW, Royal Society, Leopoldina and the US NAS. Basically this statement says that scientists have an obligation to do no harm (the Hippocratic oath). It also says that individual good conscience of scientists does not imply that one can ignore the possibility of misuse. However, many scientists do so. Scientists are responsible for the knowledge they produce and publish. The statement also refers to the necessity of oversight over the research. This certainly is relevant for funders but also journal editors should adhere to these principles in making their decisions on the publication of dual use research. Amazingly hardly anyone knows about this document. It is good to have such a statement, but it is important that people know about it! So, maybe there is not so much a lack of guidance, but a lack of good communication of that guidance. For the moment scientists effectively transfer their biosafety and biosecurity problems to journal editors who have to handle them at “5 minutes before midnight”.

From his point of view we should freeze on gain-of-function research, because not doing so means waiting for an accident. With this breathing space virologists can look for more coordination and cooperation in taking safety and security measures, because they are very divergent now. Very important –- and Giorgio Palù and Simon Wain-Hobson agree on this -– is having more debates with more stakeholders getting in; lawyers, defence experts, insurance companies, etc. We need more risk–benefit analysis, although with the disagreement among virologists, it seems hard to get an agreement on the benefits. For the moment learned societies, governments and funders do little to advance this field. They fund and support this research without taking care of risk or liability.

Wain-Hobson finishes with this statement: On 22 March 2012, Russian president-elect Vladimir Poutin [Putin] promised to develop new weapons based on advanced technologies, including genetics (Raymond Zilinskas, The Soviet biological warfare program and its uncertain legacy, Microbe v9, p151, 2014). Although the Soviet Union was one of the initiators and first signatories and depository state of the Biological and Toxin Weapons Convention, there are clear signals that they went on with research and development of biological weapons until 1990. It has never been verified, because that was not possible for political reasons. So, how do we understand this recent statement from Poutin [Putin]? Bluff or a serious warning?

Virology is hopelessly misguided in pursuing gain-of-function research. It will not lead help us predict or prevent influenza. Although virology has made great advances, it is a dream that is still years away. Indeed flu viruses may always be one step ahead of us precisely because they evolve to escape immunity to them. As long as that is the case debate is needed, among virologists, but also with experts from other fields.

-- Gain-Of-Function Research: Report of a Debate between Prof. Giorgio Palù and Prof. Simon Wain-Hobson, 25 June 2014, Trippenhuis, Amsterdam, by Koos van der Bruggen


18. Circulating Avian Influenza Viruses Closely Related to the 1918 Virus Have Pandemic Potential. European Centre for Disease Prevention and Control. (2014). Available from: http://ecdc.europa.eu/en/activities/sci ... d72&ID=765

Circulating Avian Influenza viruses closely related to the 1918 virus Have pandemic potential
by European Centre for Disease Prevention and Control
July 16, 2014

A recent article by Watanabe et al. in the Cell Host & Microbe journal describes an attempt to assess the risk of emergence of pandemic influenza viruses closely related to the 1918 influenza virus.

Reverse genetics methods were used to generate an avian influenza virus closely related to the 1918 influenza virus, based on sequence information reported from various avian influenza viruses. Further experiments were done to demonstrate what mutations are required for this virus to become easily transmissible between mammals. Effectiveness of the current influenza vaccine and the antiviral drug oseltamivir against the 1918-like influenza virus was also assessed.

It was experimentally demonstrated that a 1918-like avian influenza virus with a limited number of additional mutations exhibits relatively high pathogenicity in mammals, although lower than the original 1918 influenza virus strain that was also recreated with reverse genetics technology in the laboratory. In the transmissibility studies, only some constellations of the virus genes allowed transmissibility between ferrets, suggesting roles for RNA replication complex, HA and NA in virus transmission.

To further assess the risk of the emergence of such avian influenza viruses that could infect humans, the team examined the prevalence of avian influenza viruses that are similar to the 1918 influenza virus, and looked for avian influenza viruses possessing human-type amino acid residues.

The study thus demonstrated the continued circulation of such avian influenza viruses that possess 1918 virus-like proteins and viruses that may acquire 1918 virus-like properties. This would suggest that a potential exists for a 1918-like pandemic virus to emerge from the avian virus gene pool.

ECDC comment

The study by Watanabe et al. is the latest in a series of genetic engineering experiments where research groups have created influenza viruses of pandemic potential. The new study discussed here further confirms the power of recombinant technology to create pathogenic viruses that are not currently circulating in nature. From the public health perspective, this poses a risk both for the laboratory personnel working with these viruses, even in very secure biosafety conditions, and to the general public in case of a laboratory escape. Recent incidents remind us that laboratory accidents and laboratory escapes can happen with dangerous pathogens, even if the highest security standards are applied [1,2,3]. The developments in technology should not and cannot be stopped and research laboratories should have the freedom to apply the latest technologies for science purposes as long as this is done with full adherence to good ethical and biosafety practices. However, the decision to fund this type of gain of pathogenic function studies in influenza viruses and other human pathogens has stirred scientific controversy about the mechanisms currently in place to ensure sound assessment of risk and benefits by independent reviewers [4].

The public health perspective to the critical review of funding such dual-use research of concern including studies aiming at the creation of potential pandemic pathogens has been so far limited. Very often the research groups justify their research agenda with pandemic preparedness and better understanding of the avian influenza viruses without further specifying how exactly the results may improve the preparedness plans. It is important to ask what this type of result adds to the field of pandemic influenza preparedness and how the prediction of efficacy of influenza vaccines or antivirals against influenza viruses is improved based on these results. Furthermore, it is pertinent to ask for justification of the methods, and if any of those could be replaced by safer experiments. It is of utmost importance that the biosafety practices and controls in the laboratories undertaking such research are kept to a high standard. A forum for public health discussion around dual-use research of concern topics is not yet available at European level. ECDC advocates for open discussion about studies where potential pandemic threats are created. The research community should in all their work apply the medical ethical principle of “first do no harm”.


19. Cambridge Working Group Consensus Statement on the Creation of Potential Pandemic Pathogens (PPPs). Available from: http://www.cambridgeworkinggroup.org/

Cambridge Working Group Consensus Statement on the Creation of Potential Pandemic Pathogens (PPPs)
by cambridgeworkinggroup.org
July 14, 2014

Recent incidents involving smallpox, anthrax and bird flu in some of the top US laboratories remind us of the fallibility of even the most secure laboratories, reinforcing the urgent need for a thorough reassessment of biosafety. Such incidents have been accelerating and have been occurring on average over twice a week with regulated pathogens in academic and government labs across the country. An accidental infection with any pathogen is concerning. But accident risks with newly created “potential pandemic pathogens” raise grave new concerns. Laboratory creation of highly transmissible, novel strains of dangerous viruses, especially but not limited to influenza, poses substantially increased risks. An accidental infection in such a setting could trigger outbreaks that would be difficult or impossible to control. Historically, new strains of influenza, once they establish transmission in the human population, have infected a quarter or more of the world’s population within two years.

For any experiment, the expected net benefits should outweigh the risks. Experiments involving the creation of potential pandemic pathogens should be curtailed until there has been a quantitative, objective and credible assessment of the risks, potential benefits, and opportunities for risk mitigation, as well as comparison against safer experimental approaches.
A modern version of the Asilomar process, which engaged scientists in proposing rules to manage research on recombinant DNA, could be a starting point to identify the best approaches to achieve the global public health goals of defeating pandemic disease and assuring the highest level of safety. Whenever possible, safer approaches should be pursued in preference to any approach that risks an accidental pandemic.

Original Signatories & Founding Members:
(Founding Members met in Cambridge on July 14 and crafted the statement)

Amir Attaran, University of Ottawa
Barry Bloom, Harvard School of Public Health
Arturo Casadevall, Albert Einstein College of Medicine
Richard Ebright, Rutgers University
Nicholas G. Evans, University of Pennsylvania
David Fisman, University of Toronto Dalla Lana School of Public Health
Alison Galvani, Yale School of Public Health
Peter Hale, Foundation for Vaccine Research
Edward Hammond, Third World Network
Michael Imperiale, University of Michigan
Thomas Inglesby, UPMC Center for Health Security
Marc Lipsitch, Harvard School of Public Health
Michael Osterholm, University of Minnesota/CIDRAP
David Relman, Stanford University
Richard Roberts (Nobel Laureate '93), New England Biolabs
Marcel Salathé, Pennsylvania State University
Lone Simonsen, George Washington University
Silja Vöneky, University of Freiburg Institute of Public Law, Deutscher Ethikrat

Charter Members:
(Charter Members of the Cambridge Working Group endorse the statement)

Porter W. Anderson Jr (Lasker laureate '96), Harvard Medical School & University of Rochester
Roy Anderson, Imperial College London, UK
Rustom Antia, Emory University
Ann Arvin, Stanford University School of Medicine
Birgitta Åsjö, University of Bergen, Norway
John Bartlett, Johns Hopkins University School of Medicine
Patrick Berche, Necker-Enfants Malades Medical School, Paris, France
Paul Berg (Nobel laureate '80), Stanford University
Pamela Björkman, California Institute of Technology, Pasadena
Steven Black, Center for Global Health, Cincinnati Children's Hospital
Jesse D. Bloom, Fred Hutchinson Cancer Research Center
Sebastian Bonhoeffer, ETH Zürich, Switzerland
Michel Brahic, Department of Genetics, Stanford University School of Medicine
Christian Bréchot, Institut Pasteur, Paris
Sydney Brenner (Nobel laureate '02)
Roger Brent, Fred Hutchinson Cancer Research Center
John S. Brownstein, Harvard Medical School
Donald S. Burke, University of Pittsburgh
Dennis Burton , Scripps Research Institute, La Jolla
Donald Coen, Harvard Medical School
Vittorio Colizzi, University of Rome Tor Vergata, Italy
Larry Corey, Fred Hutchinson Cancer Research Center
Roel Coutinho, University Medical Center Utrecht, The Netherlands
Pascale Cossart, Institut Pasteur, France
Clyde S. Crumpacker, Beth Israel Deaconess Medical Center
Malcolm Dando, University of Bradford, UK
Norman Daniels, Harvard School of Public Health
Patrice Debré, Hôpital Pitié Salpetrière, Paris
Jonathan A. Eisen, University of California, Davis
Santiago Elena, CSIC, Spain
Max Essex (Lasker laureate '86), Harvard School of Public Health
Stanley Falkow (Lasker laureate '08), Stanford University School of Medicine
Michael Farzan, Scripps Research Institute, Miami
Marcus W. Feldman, Stanford University
Neil M. Ferguson, Imperial College, UK
Adam Finn, University of Bristol, UK
Christophe Fraser, Imperial College, UK
Julio Frenk, Harvard School of Public Health
José Gatell, Hospital Clínic, University of Barcelona, Spain
Gabriela Gomes, Instituto Gulbenkian de Ciencia, Portugal
Eric P. Goosby, University of California San Francisco
Nathalie Grandvaux, Université de Montréal, Canada
Warner C. Greene, Gladstone Institute of Virology and Immunology, University of California San Francisco
Jeanne Guillemin, MIT
Willem Hanekom, Bill & Melinda Gates Foundation, and University of Cape Town, South Africa
Elisa D. Harris, Center for International and Security Studies at Maryland
Eric Harvill, Pennsylvania State University
Daniel L. Hartl, Harvard University
Donald A. Henderson (Presidential Medal of Freedom '02), University of Pittsburgh
Martin S. Hirsch, Harvard Medical School
Richard Jackson, University of Cambridge
Laura H. Kahn, Princeton University
Phyllis Kanki, Harvard School of Public Health
Lynn Klotz, Center for Arms Control & Non-Proliferation
Keith Klugman, Bill & Melinda Gates Foundation
Roberto Kolter, Harvard Medical School
Mathilde Krim, Founding Chairman, amfAR, The Foundation for AIDS Research
Leonid Kruglyak, UCLA
Richard E. Lenski, Michigan State University
Matti Lehtinen, University of Tampere, Finland
Bruce R. Levin, Emory University
Gunnar Lindahl, Lund University, Sweden
W. Ian Lipkin, Columbia University
Ian M. Mackay, University of Queensland, Australia
Adel A. Mahmoud, Princeton University
Rick Malley, Boston Children's Hospital
Howard Markel, University of Michigan
Robert M. May (former president Royal Society), University of Oxford, UK
Mike McCune, University of California, San Francisco
Kenneth McIntosh, Boston Children’s Hospital
Andrew McMichael, University of Oxford
Andreas Meyerhans, ICREA & Universitat Pompeu Fabra, Barcelona, Spain
Julio S. G. Montaner, University of British Columbia
Jonathan D. Moreno, University of Pennsylvania
Richard Moxon, Oxford University, UK
Neal Nathanson, Microbiology, University of Pennsylvania
Kathryn Nixdorff, Darmstadt University of Technology, Germany
Kate O'Brien, Johns Hopkins Bloomberg School of Public Health
Paul Offit, The Children's Hospital of Philadelphia
Gérard Orth, Institut Pasteur, France
Eli Perencevich, University of Iowa
Joshua B. Plotkin, University of Pennsylvania
Stanley Plotkin, University of Pennsylvania
Peter Piot, London School of Hygiene & Tropical Medicine, UK
Mark Poznansky, Harvard Medical School, Massachusetts General Hospital
Andrew Rambaut, University of Edinburgh, UK
Johannes Rath, University of Vienna, Austria
Andrew Read, Pennsylvania State University
Gili Regev-Yochay, Sheba Medical Center, Israel
Félix Rey, Institut Pasteur, Paris, France
Douglas D. Richman, University of California San Diego
Steven L. Salzberg, Johns Hopkins School of Medicine
Philippe Sansonetti, Institut Pasteur, Paris
Mathuram Santosham, Johns Hopkins University
Mauro Schechter, Projeto Praca Onze, Universidade Federal do Rio de Janeiro, Brazil
Olivier Schwartz, Institut Pasteur, Paris, France
Jeffrey Shaman, Columbia University
Kai Simons, Max Planck Institute of Molecular Cell Biology & Genetics, Dresden, Germany
Stephen C. Stearns, Yale University
Tomoko Steen, Georgetown University Medical School
John Steinbruner, University of Maryland
Bruce Stillman, Cold Spring Harbor Laboratory
Klaus Stöhr, Novartis Vaccines and Diagnostics
Amalio Telenti, University of Lausanne, Switzerland
Paul Turner, Yale University
Robert D. Truog, Harvard Medical School
Ross Upshur, University of Toronto, Canada
Paul Volberding, AIDS Research Institute, University of California San Francisco
Mark Wainberg, McGill University, Montreal, Canada
Simon Wain-Hobson, Institut Pasteur, France
James D. Watson (Nobel laureate '62)
David Weiner, University of Pennsylvania
Robin Weiss, University College London, UK
Hans Wigzell, Karolinska Institutet, Stockholm, Sweden
Daniel Wikler, Harvard University
Claus O. Wilke, The University of Texas at Austin
Rüdiger Wolfrum, Max Planck Institute, Germany
Priscilla Yang, Harvard Medical School
Moshe Yaniv, Institut Pasteur, France
Patrick Yeni, Hôpital Bichat and University of Paris 7 Paris, France
Jerome A. Zack, David Geffen School of Medicine, University of California Los Angeles

Charter Members who signed the statement online:

Andrew Noymer, University of California, Irvine
Maimuna S. Majumder, MIT
Christopher McCabe, University of Alberta, Canada
Mike McCormick, Labwatch
Nicole E Basta, Princeton University
Steven Riley, Imperial College London
Ben Ashby, University of Exeter
Gautam I Menon, The Institute of Mathematical Sciences, Chennai, INDIA
Ted Cohen, Harvard School of Public Health
Toby Ord, Oxford University
Sean O hEigeartaigh, University of Oxford
Daniel Dewey, University of Oxford
Joann Mead, @JoannJMead
Christian Althaus, Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland
Marius Gilbert, Université Libre de Bruxelles
Joshua S. Weitz, Georgia Institute of Technology
Charles N Haas, Drexel University
R. Taylor Raborn, Indiana University
Amy Greer, University of Guelph
Brett Edwards, University of Bath
Antoni Trilla, Hospital Clinic - Univ. of Barcelona
David S. Fedson, Sergy Haut, France
Hortense Gerardo, Lasell College
Joseph Baglieri, Barrister & Solicitor
Dawn Kubly, Fort Healthcare
Charles R. Stack, University of Illinois at Chicago School of Public Health
Lisa Murillo, Los Alamos National Laboratory
Anders Sandberg, Oxford University
Evan Skowronski, TMG Biosciences
Kathleen Gilbert, California Institute of Technology
Mukilan D Suresh, SRM University, School of Bioengineering (student)
Roberto Anitori, Clark College, WA, USA
Andrew Leifer, Princeton University
Pankaj Mehta, Boston University
Megan Murray, Harvard Medical School
Eric S. Starbuck, Department of Health & Nutrition, Save the Children USA
Carl T. Bergstrom, Department of Biology, University of Washington
Nicola Low, University of Bern, Switzerland
Sünje J. Pamp, Technical University of Denmark
Andrew Snyder-Beattie, University of Oxford
Viktor Müller, Eötvös Loránd University and the Hungarian Academy of Sciences, Budapest
Tami Lieberman, Harvard Medical School
Alan Barbour, University of California Irvine
Sven Bergstrom, Umea University, Sweden
Sophia Roosth, Assistant Professor of the History of Science, Harvard University
Sibel Ascioglu, Hacettpe University, Dept. of Infectious Diseases, Turkey
Janet D. Stemwedel, San José State University
Fernando Baquero, Department of Microbiology, Ramón y Cajal Institute for Health Research (IRYCIS) Madrid, Spain
Carlos S. Moreno, Emory University
Sarah Otto, University of British Columbia
Richard Levins, Harvard School of Public Health
Andrew Tatem, University of Southampton
Benjamin Kerr, University of Washington
A. David Paltiel, Yale School of Public Health / Yale School of Management
Rochelle Walensky, Massachusetts General Hospital
John W. Jackson, Brigham and Women's Hospital
Julie Parsonnet, Infectious Diseases, Stanford University School of Medicine
John McGowan, Emory University Rollins School of Public Health
John Quackenbush, Dana-Farber Cancer Institute and Harvard School of Public Health
Rafael Canton, Servicio de Microbiologia. Hospital Universitario Ramón y Cajal. Madrid. Spain
Jane Kim, Harvard School of Public Health
Thomas F O'Brien, Brigham and Women's Hospital, Boston, MA
Simon Levin, Princeton University
James Lloyd-Smith, UCLA
Andrew Yates, University of Glasgow
Richard C. Larson, Massachusetts Institute of Technology
Victor DeGruttola, Harvard University
Melinda M. Pettigrew, Yale School of Public Health
Marc D. Natter, Harvard Medical School
Ramanan Laxminarayan, Center for Disease Dynamics, Economics & Policy, New Delhi
Cynthia Schuck-Paim, Origem Scientifica
Emma McBryde, University of Melbourne & Victorian Infectious Diseases Service, Doherty Institute
Robin Bush, University of California, Irvine
Pieter Trapman, Stockholm University
Lumi Viljakainen, University of Oulu
Isabelle Magnoli, Université catholique de Louvain
Jeremy Van Cleve, Duke University
Francisco Dionisio, University of Lisbon
Daniel Wilson, University of Oxford
Amy Hurford, Memorial University of Newfoundland
Sergios-Orestis Kolokotronis, Fordham University
Pedro Silva, University of Lisbon, Portugal
Oscar E. Gaggiotti, University of St Andrews, UK
Richard Edwards, University of New South Wales
Emilia Vynnycky, London School of Hygiene & Tropical Medicine, UK
Martin Kulldorff, Harvard Medical School
Erik F. Y. Hom, University of Mississippi
John Mekalanos, Harvard Medical School
Stephen W. Schaeffer, Pennsylvania State University
Christina Davy, Trent University, Peterborough, Ontario, Canada
Clark Freifeld, Boston Children's Hospital
David A Harmin, Harvard Medical School
Anne D. Yoder, Duke University
Nicholas G Reich, University of Massachusetts - Amherst
Gerald Learn, University of Pennsylvania
Pleuni Pennings, San Francisco State University
Zachary A Szpiech, University of California, San Francisco
Stan Finkelstein, MIT/Harvard Medical School
Paul Avillach, Harvard Medical School
Alain-jacques Valleron, Inserm. Paris, France
Ellen L. Simms, University of California, Berkeley
Anahi Espindola, University of Idaho
Claudio Jose Struchiner, Oswaldo Cruz Foundation, Brazil
Jan Medlock, Oregon State University
Maarten Vonhof, Western Michigan University
Heather Douglas, University of Waterloo
Michael Höhle, Department of Mathematics, Stockholm University
Joy Scaria, Cornell University
Preben Aavitsland, Epidemi, Kristiansand
Fernando Gonzalez-Candelas, University of Valencia, Spain
Dr. Sameeh Ghazal, King Fahad Medical City
William J. Etges, University of Arkansas
Sadia Shakoor, Aga Khan University
Angela Hancock, Max F. Perutz Labs, University of Vienna
Michael Merson, Duke University
Donald R. Olson, New York City Department of Health and Mental Hygiene
Robert Gordon White, Carleton University
Paul Schmid-Hempel, ETH Zurich
Matt Keeling, University of Warwick
Victoria Shaffer, Infection Preventionist; CHWC, Bryan, Ohio
Matthew J. Brown, University of Texas at Dallas
Joel L. Sachs, University of California - Riverside
Jacques Dubochet, University of Lausanne (retired)
François-Xavier Weill, Institut Pasteur, Paris, France
Rodrigo Angerami, State University of Campinas/UNICAMP
Omar Cornejo, Washington State University
Wladimir J. Alonso, Origem Scientific Consultancy
Jacob-S. Seeler, Institut Pasteur, Paris
Sarah Cobey, University of Chicago
Joshua Metlay, Massachusetts General Hospital/Harvard Medical School
Barbara E. Giles, Umea University, Sweden
Brigitte Autran, University Pierre et Marie Curie, Paris
Nicholas S Kelley, University of Minnesota
Jean-Michel Guillon, University of Paris Sud, France
Jon Zelner, Princeton University, Dept. of Ecology and Evolutionary Biology
William C. Miller, UNC - Chapel Hill
Katia Koelle, Duke University
Thomas W. Jeffries, University of Wisconsin - Madison
Harry Greenberg, Stanford University
Romain Gallet, INRA - Montpellier (France)
Allan Hance, INSERM, Paris, France
Simon Fellous, INRA - CBGP, France
Tatyana Novossiolova, University of Bradford
Patricia Baldacci, Institut Pasteur
Godwin Wilson, Hamad Medical Corporation, Qatar
Ralf Koebnik, Institut de Recherche pour le Développement
Elaine Nsoesie, Boston Children's Hospital, Harvard Medical School
Nicolas Voirin, Hospices Civils de Lyon
Mariet Feltkamp, Leiden University Medical Center
Conor Browne, Queen's University Belfast
Quentin Sattentau, University of Oxford
Michael Costa, Abt Associates
Jonathan A. Cooper, Fred Hutchinson Cancer Resarch Center
Andrew Lakoff, University of Southern California
Peter V. Markov, Institut Pasteur
Doug Cyr
bracha rager, faculty of health sciences, ben gurion univ. Israel
Mark Eisler, University of Bristol
Miles Davenport, UNSW Australia
David Bofinger, Grand Canyon Univerity - Graduate Student -Psychology
Daniel Leifer, UC Davis School of Medicine
Benjamin de Bivort, Harvard University
James Lyons-Weiler, PhD, Ebola Rapid Assay Development Consortium
Camillo Di Cicco, University of Rome
Roberto Bruzzone, HKU-Pasteur Research Pole
Anders Huitfeldt, Harvard T.H. Chan School of Public Health
Viktoriya Krakovna, Harvard University PhD student, Future of Life Institute cofounder
sally, uLVxnqHkrg
Emma Kowal, Harvard University
Ales Flidr, Harvard College
Max Kesin, Professional
Dr. Roman V. Yampolskiy, University of Louisville
Robert J. Taylor, Sage Analytica, Bethesda Maryland
Niel Bowerman, Future of Humanity Institute, University of Oxford
Nancy Connell, Rutgers New Jersey Medical School
Kathleen Burns, Sciencecorps
Louis Kang, Harvard University/MIT
Thomas Choate, Air
Aaron Supple, Beth Israel Deaconess Medical Center
Dominic Hall, Cambridge University, Stem Cell Institute
Niran Adeyanju, Obafemi Awolowo University, Nigeria.
Joseph (Jo) Walker, US CDC (signing in personal capacity)
Jeremy Ferranti, Researcher
Bonnie Page
NICOULAUD GHISLAINE
Alexandra Richter, DPFA-Regenbogen-Schulen
David Hartsuch, MD MS CPA, Emergency Resource
Jimmy Joseph Moise, Le P'ti Club inc.


20. Furmanski M. Lab Escapes and “Self-fulfilling prophecy” Epidemics. Center for Arms Control and Nonproliferation (2014). Available from: http://armscontrolcenter.org/Escaped_Vi ... -17-14.pdf

21. Furmanski M. Threatened pandemics and lab escapes: self-fulfilling prophecies. Bull Atom Sci (2014). Available from: http://thebulletin.org/threatened-pande ... hecies7016

22. Klotz LC, Sylvester EJ. The unacceptable risks of a man-made pandemic. Bull Atom Sci (2012). Available from: http://thebulletin.org/unacceptable-ris ... e-pandemic
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Re: U.S. government gave $3.7 million grant to Wuhan lab at

Postby admin » Mon Aug 03, 2020 4:19 am

Letter to The NSABB Board [U.S. National Science Advisory Board for Biosecurity]
by Lynn C. Klotz, Ph.D., Senior Science Fellow and member of the Scientist Working Group on Biological and Chemical Weapons Center for Arms Control and Non-proliferation, Washington, DC, USA
September 2015

To: The NSABB Board (in advance of the September 28, 2015 meeting)
From: Lynn C. Klotz, PhD, Senior Science Fellow and member of the Scientist Working Group on Biological and Chemical Weapons Center for Arms Control and Non-proliferation, Washington, DC, USA
Home contact Information: 5 Duley Street, Gloucester MA 01930, 978-281-6015, lynnklotz@live.com

The following document is a first draft of a literature-research project that started in the summer of 2015. The project is in an early stage, but has gone far enough to make its point: There is an urgent need for international proactive oversight of influenza research that might increase the pathogenicity of influenza viruses. Some of this gain-of-function research may create lab-made potential pandemic influenza viruses.

Even if the probability is small for an escape from a lab in a single year for such a virus, the fact that there are a large number of research projects underway throughout the world, projects that will be conducted for many years, the overall probability of escape from at least one lab is uncomfortably high.


The Potential Pandemic Influenza Research Enterprise

In a recent Letter to the Editor titled Danger of Potential-Pandemic-Pathogen Research Enterprises (http://intl-mbio.asm.org/content/6/3/e00815-15.full), I argued that there are likely many labs throughout the world, many not funded by the NIH, that are developing mammal-contagious influenza viruses. Research that makes avian, mammalian, or human influenza viruses more virulent, increases their transmissibility, alters their host range, or evades countermeasures is potentially dangerous and may create potential pandemic pathogens.

Influenza viruses are more likely to fuel an uncontrollable outbreak because of their long history of doing just that. This kind of research got considerable attention in 2011 when Professor Ron Fouchier announced that his laboratory had made the H5N1 highly pathogenic avian influenza virus (HPAI) airborne transmissible by respiratory aerosols from ferret to ferret.


In the context of this analysis of recent publications reported in Pub Med (references (1) through (35)), the larger category of Experiments of Concern (EoC) is used as a guide to look for potentially dangerous research. In 2004, the National Academy of Sciences published a report Biotechnology Research in an Age of Terrorism (http://www.nap.edu/catalog/10827.html). The so-called Fink Committee that produced the report was asked to “consider ways to minimize threats from biological warfare and bioterrorism without hindering the progress of biotechnology, which is essential for the health of the nation.” The committee recommended that the “Department of Health and Human Services…create a review system for seven classes of experiments (the Experiments of Concern) involving microbial agents that raise concerns about their potential for misuse.” Specifically, the EoC are:

“1. Would demonstrate how to render a vaccine ineffective. This would apply to both human and animal vaccines…

2. Would confer resistance to therapeutically useful antibiotics or antiviral agents. This would apply to therapeutic agents that are used to control disease agents in humans, animals or crops…

3. Would enhance the virulence of a pathogen or render a non-pathogen virulent. This would apply to plant, animal, and human pathogens…

4. Would increase transmissibility of a pathogen. This would include enhancing transmission within or between species. Altering vector competence to enhance disease transmission would also fall into this class.

5. Would alter the host range of a pathogen. This would include making non zoonotics into zoonotic agents. Altering the tropism of viruses would fit into this class.

6. Would enable the evasion of diagnostic/detection modalities. This could include microencapsulation to avoid antibody-based detection and/or the alteration of gene sequences to avoid detection by established molecular methods.

7. Would enable the weaponization of a biological agent or toxin. This would include the environmental stabilization of pathogens.”


These seven classes of experiments “will require review and discussion by informed members of the scientific and medical community before they are undertaken [proactive oversight] or, if carried out, before they are published in full detail.” For experiments making deadly avian influenza viruses airborne transmissible, many scientists think they should not be carried out at all.

An excellent system for reviewing potentially dangerous experiments, Controlling Dangerous Pathogens: A Prototype Protective Oversight System, was developed in 2007 by The Center for International and Security Studies at Maryland (http://drum.lib.umd.edu/bitstream/1903/ ... ograph.pdf). It recommends a tiered review, from most to least dangerous research. Paraphrased from the Maryland paper:


International Oversight: Activities of Extreme Concern –- An international body would be charged with approving and monitoring all research projects of extreme concern. That authority would be narrowly focused only on those ... that could put an appreciable fraction of the human species at risk, such as research with potential pandemic pathogens.

National Oversight: Activities of Moderate Concern -– National oversight bodies would be responsible for research activity of moderate concern, such as work with anthrax and other agents already identified as having biological weapons potential.

Local Oversight: Activities of Potential Concern—This “encompasses those activities that may increase the destructive potential of biological agents that otherwise would not be considered a threat.

No oversight: All other research


In my opinion, there should be two levels of local oversight. The first level is the currently employed Institutional Biosafety Committee (IBC), and the second is an outside committee. There is concern that IBCs will simply rubber-stamp research proposals from labs in their own institution, so I suggest proactive oversight by a committee outside the institution (perhaps at the state level in the US) for experiments of concern on influenza viruses that do not carry an immediate threat of an outbreak from an escape from the laboratory (e.g., vaccine viruses and other attenuated and inactivated viruses).

Because of the potential for some strains of lab-made influenza viruses to cause international outbreaks, research mutagenizing these viruses that could result in increased pathogenicity (gain of function) should be subject to external oversight. At present, there is little national and no international proactive oversight with any authority to guide or ban experiments. See for instance: Gronvall GK, Rozo M. Synopsis of Biological Safety and Security Arrangements. UPMC Center for Health Security.July 2015. Available at http://www.upmchealthsecurity.org/ourwo ... rangements.

The literature analysis

To date, only one general Pub Med search term, “avian influenza virus mutagenesis,” has been used here to identify potentially dangerous research that might fall under the Experiments of Concern (EoC). To focus on the most recent research, only research over the last two years (September 1, 2013 through August 29, 2015) published Pub Med abstracts were read. Thirty-five potential EoC were identified in 136 abstracts for this single search term. Many of the 136 abstracts (136-35=101) described research that did not constitute EoC; for the most part, they did not employ live viruses.

For each of the 35 abstracts that seemed to describe EoC, parts of the full research papers were read to confirm their EoC status. Since I have only a modest grasp of molecular virology, I may have labeled a few that are not EoC, and I may have missed a few that are EoC.

The actual number of EoC research being carried out today is likely much greater than 35 because of the following:

• Only a single avian influenza search term was used; other influenza search terms would yield additional EoC. In particular, viruses that have already caused pandemics such at the 2009 H1N1 virus.
• Expanding the search back to 2012, and even before that, would yield more EoC.
• There are surely some EoC that are not yet published.
• Search terms involving other pathogens such as SARS, MERS and Ebola would yield more EoC.


A summary of the 35 EoC found from the search is provided in Table 1. Titles and citations for the reference numbers are in the reference list at the end.

Reference No. / Countries of Authors / Viruses / Biosafety Level / EOC Category

1 / USA, Korea / H1N1 vaccine strain / ? / 2
2 / China / Avian, human H6N1 / BSL3 / 5
3 / China / H5N1 HPAI / not reported / 1, 3
4 / USA, Egypt / H5N1 HPAI / ? / 1, 3
5 China / H9N2 avian / BSL3 / 3, 5
6 / Japan, USA / H5N1 HPAI / BSL3 / 3, 5
7 / Netherlands, UK / H1N1 2009 / BSL2 / 1, 3
8 / China / H5N1 HPAI / Not reported / 3
9 / China / H7N1 avian / BSL3 / 3, 5
10 / China H9N2, H1N1 2009, H5N1 HPAI / BSL3, BSL3+ / 3
11 / USA, Japan / H5N1 HPAI / BSL3 / 3
12 / China / H6N1 avian / ?? / 3, 5
13 / Japan, Thailand / H5N1 HPAI / BSL3 / 3
14 / China / H9N2 duck / ABSL3+ / 3, 5
15 / France / avian H1N1 / BSL3+ / 3, 5
16 / USA / A/WSN/1933 H1N1 / likely BSL2 / 5
17 / Netherlands / airborne trans H5N1 HPAI animal / BSL3+ / 3, 4
18 / China / H7N9 HPAI / ABSL3 / 3
19 / Japan / H7N9 HPAI / BSL3+ / 3
20 / China / H1N1 2009 pandemic / not reported, BSL2? / 3
21 / China / H1N1 2009 pandemic / not reported, BSL2? / 2
22 / Spain, UK / influenza A vaccine strains / assume BSL2 / 3
23 / Netherl., Germany / HPAI H5N1 / BSL3+ / 1
24 / USA ; H1N1 vaccine strain / assume BSL2 / 1
25 / USA / H3N2 / BSL2? / 2
26 / Germany / HPAI H5N1 / BSL3+ / 1
27 / China, USA / HPAI H5N1 / BSL3, ABSL3 / 2
28 / Russia / nonpath H5N2, HPAI H5N1 / not reported, BSL2? / 1
29 / Germany / 1968 pandemic H3N2 / not reported, BSL2? / 3?
30 / USA / H1N1 vaccine strain / not reported, BSL2? / 1
31 / USA / HPAI H5N1 / BSL3 / 3, 5
32 / UK HPAI H5N1 / BSL3 / 3, 5
33 / USA / H3N2, H1N1 / not reported, BSL2? / 3?
34 / USA / HPAI H5N1 / ABSL3+ / 3, 4
35 / USA / human H3N2, HPAI H5N1 / ABSL3+ / 1

Table 1: The 35 EoC. The boldface in the Countries of Authors column indicates the country where the BSL2, BSL3 research was performed. Much of that research is being carried out in Asia, particularly China.


The 35 published research listed in the Table are described briefly below. The descriptions are a combination of quotes from the Pub Med abstracts and full papers, often paraphrased to make them readily understandable with regard to EoC. The numbers, 1 through 35, at the beginning of each entry below correspond to the numbered reference citations at the end of this document. The bold-face [italicized] highlighted descriptions are the greatest concern in my opinion because the mutated viruses are often more pathogenic than the wild-type strains and are potentially airborne transmissible from human to human.

1. Recombinant influenza viruses were made that have single or double substitutions in neuraminidase N3, N7 and N9 subtypes in a background of an H1N1 vaccine strain. N3, N7 and N9 subtypes have caused human infections. The research discovered resistance to neuraminidase inhibitors in some strains. [Comment: Mutagenesis of vaccine strains are not of the highest concern, unless there is reason to believe that the mutagenesis could make the strain virulent.]

2. Avian H6N1 virus was adapted to human receptor-binding. Receptor-binding was analyzed using isolated H6 proteins. Binding was confirmed using two avian and one human-derived H6N1 recombinant viruses. The research found two HA substitutions important to acquire the human receptor-binding. [Comment: Only one case of human H6N1 infection has been reported to date. Could increasing receptor binding in humans lead to more human cases?]

3. Site-directed mutagenesis was used to generate different patterns of stem glycans on the HA protein of an HPAI H5N1. The results indicated that some glycans were dispensable for the generation of replication-competent influenza viruses. Some combinations of glycans led to a significant decrease of the growth rates of the mutant viruses in animal cells in comparison to wild type virus. Furthermore, most of the mutant viruses were more sensitive to neutralizing antibodies than the WT virus. [Comment: Could researchers predict results in advance? These are experiments that should be proactively reviewed, as some mutations could have increased virulence or avoided existing vaccines. The outcome is, however, reassuring]

4. Variant H5N1 viruses with five mutations in the HA gene were made. The research indicated that targeted mutation in the HA may be effectively used as a tool to develop broadly reactive influenza vaccines to cope with the continuous antigenic evolution of viruses. [Comment: Could researchers predict results in advance? These are experiments that should be proactively reviewed, as some mutations could have increased virulence or avoid existing vaccines. As viral mutant population sizes are huge, the probability of finding an adaptive mutation is pretty large for RNA viruses.]

5. The research found three mutations in HA, N and PB2 proteins that after four passages conferred high virulence to H9N2 virus in mice. Adaption in mice enhanced the viral polymerase activity and receptorbinding ability, which resulted in a virulent phenotype in mice but not a transmissible phenotype to guinea pigs. [Comment: This additional guinea pig experiment was useful to reduce concern or fear over increased host range.]

6. Mutations made in the PA protein enhanced HPAI H5N1 virus growth capability in human lung cells and increased pathogenicity in mice, suggesting that they contribute to adaptation to mammalian hosts.

7. Mutants made with substitutions in the hemagglutinin of a strain of 2009 H1N1 pandemic influenza virus revealed that single substitutions affecting the loop adjacent to the receptor binding site caused escape from ferret and human antibodies elicited after the 2009 H1N1 pandemic influenza virus infection. The majority of these substitutions resulted in similar or increased replication efficiency in vitro compared to that of the virus carrying the wild-type hemagglutinin. However, none of the substitutions was sufficient for escape from the antibodies in sera from individuals that experienced both seasonal and pandemic H1N1 virus infections. [Comment: This is the virus that infected 25% of the world population world-wide in 2009 and killed thousands of people. Any experiment that increases replication efficiency or escapes antibodies should not be carried out in BSL2.]

8. Mutant HPAI H5N1 viruses made with loss of two HA protein glycosylation sites showed increased pathogenicity, systemic spread and pulmonary inflammation in mice compared to the wild-type H5N1 virus.

9. Two mouse-adapted variants of wild-type avian H7N9 made by independent serial passages in mice confer enhanced virulence in mammals. [Comment: This virus has infected and caused fatalities in humans from direct contact with poultry. It would have been informative if the researchers had carried out a single ferret to ferret transmission experiment to see if this mouse-passaged virus has increased host range and virulence in a species (ferrets) that is perhaps a model for humans.]

10. Mouse-adapted PB2 gene reassortants with a phenylalanine-to-leucine mutation contributes to enhanced polymerase activity, enhanced replication, pathogenicity of H9N2 in mice, increased virulence of H5N1 and 2009 pandemic H1N1. [Comment: Could increasing virulence in the 2009 pandemic flu cause a new outbreak among humans?]

11. The introduction of an arginine residue into PA of HPAI H5N1 significantly increased the viral polymerase activity in mammalian cells and its virulence and pathogenicity in mice.

12. A substitution in the PB2 protein and a substitution in the PA protein enhance virulence and expand the tropism of H6N1 virus in mice. [Comment: Only one case of human H6N1 infection has been reported to date. Could increasing virulence and tropism in humans lead to more human cases?]

13. Introduction of a single substitution into PB1 polymerase of an HPAI H5N1 increased both polymerase activity in chicken cells and the pathogenicity of the recombinant viruses in chickens. [Comment: This translates to humans.]

14. A nonpathogenic duck-origin H9N2 virus was serial-passaged in mouse lungs. Increased virulence was detectable after five passages, and a highly pathogenic mouse-adapted strain was obtained after 18 passages. There were eight amino-acid substitutions in six viral proteins. [Comment: Since serial passage was in lungs, this kind of research could lead to airborne transmission. A single ferret to ferret passage experiment should have been carried out to see if airborne transmission was achieved.]

15. A deletion in the NS segment of a duck-origin avian H1N1 virus showed both increased replication potential and an increased pathogenicity in chicken embryonated eggs and in a chicken lung epithelial cell line.

16. Mutants created in the PB2 subunit identified critical residues required for general polymerase function and specific residues preferentially required in human but not avian cells. [Comment: It is unclear what virus was used in the study. It may have been PB2 mutants reassorted into A/WSN/1933 H1N1 virus. A/WSN/1933 is a derivative of 1918 flu virus and is not around today. This is a mouse brain adapted virus so not a threat.]

17. Five substitutions proved to be sufficient to retain the airborne-transmissible phenotype of HPAI H5N1. [Comment: A large number of substitution experiments on an airborne transmissible, deadly virus were carried out in this study, and a large number of nose and throat swabs and blood samples were taken, all increasing significantly the likelihood of an LAI. This is follow-up research from the Fouchier lab.]

18. An H7N9 virus from a fatal case was used as the recombination background to study the contribution of the E627K mutation in PB2 and of other mutations to the pathogenicity of H7N9 virus infection in mammals. All the mutant viruses generated were likely to be loss-of-function mutants with regard to pathogenicity, compared to the wild-type H7N9. [Comment: The research appears to yield less pathogenic H7N9. Nonetheless, it is not possible to predict pathogenicity at the outset of the experiments. Since the background virus is a fatal case; proactively, the generated viruses could have been more virulent humans. It would have been informative if the researchers had carried out a single ferret to ferret transmission experiment to see if this virus was more virulent in ferrets, the model for human lung.]

19. Potentially mammalian adapting amino acids were converted individually and in combination to their avian virus-type counterparts in a H7N9 virus. Several mutants were slightly more virulent in mice than the wild-type A(H7N9) virus and exhibited increased polymerase activity in human cells.

20. A single “consensus” PB2 mutation common to swine and the 2009 H1N1 pandemic virus increased pathogenicity. Mutant virus prepared by recombination of a 2009 H1N1 pandemic virus with a segment containing the single PB2 mutation significantly enhanced polymerase activity in mammalian cells. Also, the virus exhibited increased growth properties and induced significant weight loss in a mouse model compared to the wild type. [Comments: This more pathogenic virus could win the battle with the immune system, so cause significant illness.]

21. Reduced sensitivities to oseltamivir were observed in three mutant H1N1 2009 pandemic viruses. A double mutant showed a large increase of IC-50 for the drug Oseltamivir from 0.7 nM for WT to 4,000 nM for the double mutant, a 5,700-fold difference [Comment: Such a large increase in IC-50 would almost certainly make the drug unusable in humans.]


[22-27 MISSING]

28. A non-pathogenic avian H5N2 was adapted to mice by lung-to-lung passage. Also, the reverse genetics-derived influenza virus containing the HA and NA genes of an HPAI H5N1 in the genetic background of a high-growth H1N1 vaccine strain was obtained. Antibody escape mutants using these two viruses were obtained. Monitoring of effects of HA mutations found in H5 segment escape mutants is essential for accurate prediction of mutants with pandemic potential. [Comment: While H5N2 does not appear to have caused any human infections, adapting it to mice by lung to lung passage could have made it virulent in humans and even airborne transmissible.]

29. Influenza A viruses circulating in humans from ∼1950 to ∼1987 featured a nonstructural (NS1) protein with a C-terminal amino acid extension present in the H3N2 1968 pandemic flu virus. This research deleted the NS1 extension in the H3N2 in order to compare the wild type H3N2 with the virus with the NS1 deletion. The replication kinetics of the wild-type H3N2 and the deletion mutant were indistinguishable in most experimental systems. However, wild-type virus out-competed the mutant during mixed infections, suggesting that the NS1 extension conferred minor growth advantages. [Comment: The resurrection/rescue of an historical pandemic virus is potentially as dangerous as a lab-made PPP if it escapes from the laboratory, provided that the virus employed is identical to or very close to the 1968 pandemic strain.]


[30 MISSING]

31. A particular point mutation in the PB2 protein of HPAI H5N1 virus, PB2 627K, has been identified as a virulence and host range determinant for infection of mammals, and is present in strains capable of airborne transmission. This mutation in the PB2 gene appeared from day 4 and 5 along the respiratory tracts of mice inoculated intranasally and was complete by day 6 post-inoculation. The mutation correlated with efficient replication of the virus in mice. [Comment: This kind of experiment may be on a path to an airborne transmissible strain.]

32. This research focused on the particular PB2 point mutation in Reference 31, just above. Viruses constructed by reverse genetics were made to contain converse PB2 627K/E mutations in a Eurasian HPAI H5N1 virus and, for comparison, a historical pre-Asian HPAI H5N1 virus that naturally bears PB2 627E. Effects on viral fitness were observed in in vitro or in vivo experiments. Results suggest that the PB2 627K mutation supports viral fitness in Eurasian-lineage viruses; in contrast, the mutation carries a significant fitness cost in a historical pre-Asian virus.

[33 MISSING]

34. Influenza virus entry is mediated by the acidic-pH-induced activation of HA protein. This research investigated how a decrease in the HA activation pH influences the properties of highly pathogenic H5N1 influenza virus in mammalian hosts. Viruses containing either wild-type HA or an acid-stabilizing point mutation were prepared. Wild-type and viruses with the mutation promoted similar levels of morbidity and mortality in mice and ferrets. The mutation was found to enhance the growth of an H5N1 influenza virus in the mammalian upper respiratory tract, and yet it was insufficient to enable contact transmission in ferrets. Neither virus transmitted efficiently to naive contact cage-mate ferrets. [Comment: It is fortunate that contact transmission was not found.]

35. The research focused on an antigenic cluster associated with a natural single hemagglutinin (HA) substitution that occurred between 1992 and 1995 in the H3N2 virus. Reverse-genetics experiments demonstrated that the HA mutation increases viral receptor binding avidity. The mutation does not prevent antibody binding; rather, viruses possessing this mutation escape antisera simply because the virus attaches to cells more efficiently. [Comment: The H3N2 virus has caused human infections when transmitted from swine. In a 2012 small outbreak, there was no evidence of community transmission. Nonetheless, the virus is an immune escape strain.]

While the search term was not designed to pick up the 2009 human pandemic H1N1 virus, it did pick up a few experiments involving mutagenesis of that strain. While some of this research is carried out at BSL2, it could be classified as research of great concern because that virus is airborne transmissible.

For research involving mutagenesis of vaccine strains, biosafety level was generally not reported. It is assumed that it is BSL2, as vaccine strains are attenuated or inactivated viruses. One concern is that some mutagenesis research could make a vaccine strain virulent. Researchers should be prepared to argue for the safety of their particular proposed vaccine-strain mutagenesis research to defend the lower BSL2 containment.

Several of the EoC (references 7, 10, 14, 17, 20, 21, 28, 29) are lab-made potentially dangerous influenza viruses that could spread from human to human by the airborne route.

Proactive review at the local, national, or international level that considers risk and value (benefits) should be considered before allowing any mutagenesis and related research that might result in Experiments of Concern to go forward, and under what conditions.

Conclusion

Research that employs, makes, or could make airborne transmissible strains is of the greatest concern. All this research should be subject to proactive international review and oversight. There is an urgent need for a binding international process. While the NSABB mandate is likely restricted to NIH-funded research or perhaps any research in the United States, it behooves the NSABB to urge the State Department to seek a binding international agreement for proactive review and oversight of potential pandemic research.

I would like to thank Simon Wain-Hobson for comments and insights.

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Re: U.S. government gave $3.7 million grant to Wuhan lab at

Postby admin » Mon Aug 03, 2020 4:37 am

Danger of Potential-Pandemic-Pathogen Research Enterprises
by Lynn C. Klotz
American Society for Microbiology
DOI: 10.1128/mBio.00815-15
Copyright © 2015 Klotz

LETTER

The research goal in a number of laboratories is to make highly pathogenic avian influenza (HPAI) viruses contagious to humans via respiratory aerosols. For instance, the H5N1 influenza virus has been made contagious to ferrets (1), the animal model often used as a proxy for humans. Concern over escape from a laboratory of a deadly human-contagious virus (e.g., influenza, severe acute respiratory syndrome [SARS], and Middle East respiratory syndrome [MERS] viruses) prompted the U.S. Government to hold back funding for this research “until a robust and broad deliberative process (2) is completed that results in the adoption of a new USG gain-of-function research policy.” This discussion is now under way in the United States and is to be completed in 2016.

In relation to this discussion, mBio published three letters to the editor in a debate between Dr. Ron Fouchier and me. Defending the safety of his work in the first letter (3), Dr. Fouchier calculated that it would likely take more than a million years for an escape from his lab through a laboratory-acquired infection (LAI). Intuitively, this million-year claim seems dubious. I questioned the equation used in the Fouchier calculation and the extremely low probability of escape that he employed in the calculation, and I outlined an alternative approach (4). Fouchier's response to my comments was then published in mBio (5). It is clear that he did not understand my methodology.

In calculations of the probability of a community LAI (“E”), Dr. Klotz further assumes that transmission studies in the Erasmus MC facility will be performed for a period (“y”) of 1 million years. I am hopeful that our research enterprise will have reached solid conclusions on determinants of airborne transmission a bit sooner.


Rhetorical quip aside, neither his million-year result nor my questioning of it implies or assumes in any way that research must be performed for a given number of years. My questioning and my alternative approach were simply a comment on his approach. Elsewhere in my comments (4), I assumed that the research enterprise will be concluded in 10 years, as does he.

In order to respond to Fouchier's misunderstanding and to expand on the general usefulness of my approach, I provide here two simple equations for estimating both the likelihood of escape and the elapsed time to an escape. The equations may be employed for a single lab and for a “research enterprise” of many labs. The conclusion is that the likelihood of an escape may be uncomfortably high and that the elapsed time to an escape may be uncomfortably short.

Dr. Fouchier uses the simplistic formula y = 1/P1 to calculate the likely number of years elapsed, y, before an escape occurs, where P1 is the probability of escape from his lab in 1 year. His 1-million-year calculation (3) is misleading, as it does not account for the fact that research will proceed for more than 1 year, and it was not expanded to calculate the number of years that elapse before an escape occurs for the many labs in the research enterprise.


My approach, embodied in equation 1, may be used to calculate the probability, E, that at least one escape will occur for an n-lab research enterprise conducting research for y years (at least one is likely exactly one, as the probability that two or more escapes will occur is extremely small, and if an escape does occur, the whole n-lab research enterprise would almost certainly be shut down), and equation 2 may be used to calculate the number of years that elapse, y, before an escape.

E=1−(1−P1)yn [1]

Solving equation 1 for y gives

y=(1/n)×log(1−E)/log(1−P1) [2]

Derivations of equations 1 and 2 may be found in the Appendix.

In equation 2, probability E may be viewed as how much escape risk we are willing to tolerate, that is, the value of E that is too high a risk for an n-lab y-year research enterprise. Is an E of 0.1%, 1%, or 10% too high? The level of risk that we are willing to tolerate is subjective. Since a lab escape may result in an uncontrollable disease outbreak with thousands to millions of deaths, even a 1% chance, E = 0.01, seems much too high.

Following Fouchier's focus on elapsed years as a measure of biosafety, only elapsed years will be calculated here. The results, presented in Table 1, are for a 15-lab research enterprise; 15 is the number of NIH-funded labs that have been identified as subject to the research pause. (Originally 18 labs were identified for the funding pause. That number was subsequently reduced to 15.) While some of these labs do not focus on developing mammal-contagious influenza viruses, there are likely many labs throughout the world not funded by the NIH that are, so the number 15 seems a reasonable guess for the size of the research enterprise.

TABLE 1. Calculation of numbers of years that elapse before an escape for 15 labs

P1 / y with an E ofa: 0.001 / y with an E ofa: 0.01 / y with an E ofa: 0.5 / Comment


0.002 / 0.033 / 0.33 / 23 / From CDC data
0.0001 / 0.67 / 6.7 / 462 / Klotz estimate
1.00E−06 / 66.7 / 670.0 / 46,210 / Fouchier estimate

a The data of the table, calculated from equation 2, are the expected numbers of years that elapse before a lab escape (y) from one of the labs in a research enterprise of 15 laboratories for three different risk tolerances (E) and three different probabilities (P1) of escape from a single lab in a single year.


Presented in Table 2 are the same calculations but for a single lab (n = 1), such as Fouchier's lab.

TABLE 2. Calculation of numbers of years that elapse before an escape for a single lab

P1 / y with an E ofa: 0.001 / y with an E ofa: 0.01 / y with an E ofa: 0.5 / Comment


0.002 / 0.50 / 5.02 / 346 / From CDC data
0.0001 / 10.0 / 100 / 6931 / Klotz estimate
1.00E−06 / 1000 / 10,050 / 693,147 / Fouchier estimate

a The data of the table, calculated from equation 2, are the expected numbers of years that elapse before a lab escape (y) from a single lab.


Three quite different probabilities for escape, P1, are employed in the calculations in the tables. The highest probability (P1 = 0.002) is a minimum estimate calculated (6) from CDC statistics (7) for undetected or unreported LAIs in biosafety level 3 (BSL3) labs. This probability is likely higher than that for LAIs in BSL3 labs that have extra biosafety precautions in place (called BSL3+), such as Fouchier claims for his lab. The probability (P1 = 0.0001) is 20 times lower and is an estimate for differences between BSL3 and BSL3+ labs. The final probability (P1 = 1 × 10−6) is Fouchier's estimate (3). To make his estimate, Fouchier itemizes the various safety measures in his lab and generously reduces the probability for each safety measure but admits that it is a guess: “the magnitude of this increase in safety is not known.” Finally, the discussion here of probabilities has been restricted to LAIs, but there are other routes of escape, such as mechanical failure and removal of live virus from BSL3+ containment accidentally or for hostile purposes.

From Table 1, it is clear that the research enterprise is unsafe when an intermediate small P1 equal to 0.0001 and a risk tolerance (E) of 1% are employed. The number of years that we would need to wait to exceed the 1% chance of an escape is only 6.7 years, well within the estimated 10 years for the research to be completed. If P1 is equal to 0.002, as calculated from the CDC statistics, there would be a 1% chance of an escape in less than a year (y = 0.33 year).

If P1 is really as low as Fouchier suggests, we would need to wait 670 years to reach a 1% chance of escape, an elapsed time that would appear to make the research enterprise safe in some researchers’ thinking, but risk equals likelihood times consequences, and consequences such as fatalities could be very high for a human-contagious influenza virus with a high case fatality rate. This would lead to an intolerable number of fatalities even using Fouchier's low P1 estimate. Potential fatalities for the enterprise and the fatality burden for each lab in the enterprise were quantified for his very low P1 of 1 × 10–6 in my published criticism (4) of Fouchier's million-year calculation. The conclusion there was that each lab in the enterprise would carry the potential burden of over 14 fatalities per year. “To put this fatality burden number in perspective, no Institutional Review Board tasked with assessing human subject research would approve a proposed research project with 14 potential fatalities per year.”

Turning to the number of years that elapse before an escape occurs for a single lab in Table 2, for a 1% chance of escape with the intermediate P1, it would take 100 years of research to exceed the 1% risk tolerance. For Fouchier's low P1, it would take 10,050 years to reach a 1% chance of an escape, making the research seem quite safe.

I suspect that most researchers in the enterprise use this reasoning to justify the safety of their own lab, but this kind of thinking is flawed, as argued over 200 years ago by the philosopher Immanuel Kant for his “categorical imperative,” which is the cornerstone of his moral reasoning: “Act only according to that maxim whereby you can at the same time will that it should become a universal law without contradiction.” The “it” in the quote is labs in the research enterprise. (Immanuel Kant's categorical imperative and the examples used here were called to my attention by my colleague, the late Edward Sylvester, a science journalist with a strong background in philosophy.)

At the risk of trivializing Kant's complicated moral reasoning, a few examples should make the categorical imperative argument clearer. Is it really acceptable for a manufacturing company to dump mercury in the ocean, because that one factory's output would not be enough to pose any danger to us when we consume fish? Is there nothing wrong if I buy a gas guzzler that gets 10 miles per gallon and has faulty emissions control, since my car's individual contribution to climate destruction is minimal?
“What if everyone researched live smallpox?” has been implicitly answered according to Kant's categorical imperative by everyone agreeing to limit research to two places.

Clearly, the magnitude of the basic probability (P1) is critically important in assessing the risk of the research enterprise, and its magnitude is a point of contention. Finding a good estimate of this basic probability should be a major focus in Gryphon Scientific's risk-benefit assessment.

Fouchier has other criticisms of my comments that I feel should be addressed. His response is problematic in several ways. In addressing the problems, I will quote frequently from my comments and from his response to make sure that it is clear what was said.

The biggest problem is that Dr. Fouchier does not once address my calculation of potential fatalities and fatality burden that employs his low probability of an undetected or unreported LAI escaping from his laboratory. Instead, he chooses to argue against my peripheral comments that his probability is likely much too low. His focus unfortunately draws attention away from my calculation that finds intolerable numbers of potential fatalities and the fatality burden.

I number specific comments below to keep each point separate.

1. Dr. Fouchier writes (5)

Dr. Klotz suggests that incidents at the U.S. CDC laboratories and the long history of escape of LAI agents and other escapes from laboratories show that my estimates of the likelihood of LAIs occurring at the Erasmus MC facility are too low.


The CDC's shipping of an H5N1 virus-contaminated sample to the USDA and similar incidents show the importance of not underestimating human error, especially if one considers the influenza lab at the CDC to be one of the top federal labs in the country. Although biosecurity measures have improved greatly over the years, human nature has not. Laboratory accidents will happen, and laboratory workers will get infected, not realize it or not admit it, and so take the infection home. The Achilles’ heel in Fouchier's argument is that no number of safety procedures can provide for human error.

While the history of escapes should make us worry that the probability may be very high, here the difference between Fouchier and me is moot since I employ his low probability in my calculations.

2. Dr. Fouchier writes (5)

Dr. Klotz proposes to multiply the low likelihood of LAIs by 300, based on an estimated 30 laboratories involved in the “whole research enterprise” for 10 years, and assumes that part of this research enterprise may lack the rigorous safety practices in place at Erasmus MC. Both assumptions are wrong, to the best of my knowledge; just over a handful of laboratories have worked on airborne transmission of avian influenza viruses, each of which has rigorous safety practices in place.


Our disagreement here is because we define “research enterprise” differently. I defined it as research on potential pandemic pathogens with NIH funding (influenza and SARS category pathogens) and labs otherwise funded. He defines it as only influenza virus research. I implied that the whole research enterprise includes the other pathogens by picking the number 30, doubling the NIH's 15 projects subject to the pause. Perhaps I should have been explicit by listing the pathogen categories as I have just done. In addition, some of the laboratories throughout the world conducting this research that are not funded by the NIH may have lax safety standards.

Thus, both of my assumptions were likely correct. In this article, however, I meet Fouchier half way by considering only avian influenza virus research.

3. Dr. Fouchier writes (5)

Another key aspect is that Dr. Klotz estimates the likelihood of onward transmission from a case of LAI as 0.1 (10%), in contrast to my justification for an adjusted likelihood of <1 × 10–5, based on the specific conditions under which the research is performed, without providing a rationale for that important deviation.


I certainly do provide a rationale for the 10% likelihood of LAI (4) through references 8 and 9 (risk assessment studies).

Summarizing the literature, Lipsitch and Inglesby estimate the probability that a community LAI leads to a global spread (pandemic) to be 5 to 60%. This range is consistent with the 5 to 15% range found by Merler and coworkers (8) and with the 1 to 30% range found in a focused risk assessment (9) for infection spread beginning on crowded public transportation.


Furthermore, there is a rather arcane subject in probability, branching theory, which allows prediction of the likelihood of uncontrolled spread of any pathogen based on its observed reproductive number (Ro) value and the variance to mean of the Ro. A large variance to mean could occur due to superspreaders, for instance, some people infected with SARS virus. For a wide range of Ro values, Lipsitch and coworkers have calculated the probability of uncontrolled spread (see Fig. 4a in their study [9]). For a single infected individual with an Ro of 2, the probability of an uncontrolled outbreak ranges from 10% (spread of Ros) to 80% (uniform Ro).

Thus, the pandemic likelihood from a single infected individual is potentially large. I suspect that future risk assessments will confirm that once a highly contagious potentially pandemic pathogen escapes, the probability of an uncontrolled outbreak is significant, leading again to a focus on the probability of a laboratory escape as the important factor.

Fouchier mentions vaccination and antivirals (5) as factors that reduce onward transmission. Antivirals would not be prescribed for undetected LAIs. Vaccines may reduce viral replication in the index case, but active virus may still be present when the infected person leaves the laboratory, potentially infecting unvaccinated persons. The annual flu vaccine is sometimes less than 50% effective, so it is unclear if vaccinated laboratory workers are protected by the laboratory vaccine strain.

I would classify vaccination and antivirals, effective or not, as inside laboratory measures. But if an LAI escapes, clearly these measures were not effective in preventing the undetected or unreported LAI. Again, we come back to the probability of escape from a laboratory as a key challenge in this debate.

Once an undetected or unreported LAI from a highly contagious pathogen escapes, it is out of Fouchier's control. Its global spread will depend on the reproductive number, Ro, and other factors external to Fouchier's laboratory.


Fouchier claims (3) that “the viruses are ferret adapted rather than human adapted,” which could lead to a lower Ro in humans. Among the different mutated viruses presumably under development in his laboratory, some could be highly transmissible and deadly in humans. We will never know, for testing them on humans is, fortunately, unethical. Of course if one escaped….

The argument of being ferret adapted and not human adapted is misleading. First, it cannot be proved. Second, Fouchier's own work may have already brought an avian H5N1 virus far closer to successful replication in humans. If such a virus escaped from his laboratory, it may well adapt within the individuals in the early transmission chain and then take off in a big way. Dr. Fouchier and the field do not have the knowledge to know just how short of a successful virus they have engineered. That is why they are doing this work.

4. Dr. Fouchier concludes (5) the following.

Finally, Dr. Klotz describes the (apocalyptic) scenario of an influenza pandemic with 140 million fatalities based on a 10% case-fatality rate in 20% of the world's population. These numbers not only ignore the scientifically justifiable counterarguments raised before (2) but also are at odds with the documented influenza pandemics of the past. In my view, the “gain-of-function” debate has suffered from the apocalyptic scenarios that are provided as factual whereas they provide estimates that are far beyond the observed worst cases (8).


It is estimated that the 2009 pandemic influenza virus infected 20% of the world's population. The 1918 H1N1 “Spanish” flu killed perhaps 2% of its victims. The H5N1 avian influenza virus, the subject of Fouchier's research, kills about 50% of those who are infected through direct contact with poultry. The scenario I use as an example represents a combination of these three real events. While this scenario has not yet and may never occur in nature, it is a possible scenario perhaps more likely from a laboratory escape.

Since the consequences of most scenarios, even one on a par with seasonal influenza—several hundred thousand deaths—would be catastrophic and unacceptable, it behooves us to be exceedingly careful in deciding which potential pandemic pathogen research should be allowed. For much of this research, the potential risk far outweighs the potential benefits.

APPENDIX


Derivation of equations for determining numbers of years to a lab escape.

Let P1 be the yearly probability of escape of a pathogen from a single lab. The first question to be asked is “what is the probability of at least one escape from one of the n labs conducting research on the pathogen for y years?” The probability of no escapes in y years for a single lab is (1 − P1)y. For y years and n labs, the probability of no escapes is (1 − P1)yn.

The probability of at least one escape in y years from one of the n labs (E) is

1−(1−P1)yn [3]

Solving equation 3 for y will allow this question to be answered.

log(1−E)=log(1−P1)yxn=y×n×log(1−P1), [4]

where

y=(1/n)×[log(1−E)/log(1−P1)]

Checking the limit for equation 4, if there is no likelihood of escape, P1 is equal to 0, log(1) is equal to 0, and as expected, y is equal to ∞.

Another observation about equation 4 is that the number of years of research, y, which must elapse before we reach our risk tolerance is inversely proportional to the number of labs, n.

ACKNOWLEDGMENT

I thank Simon Wain-Hobson for comments and contributions to the text.

Copyright © 2015 Klotz.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

REFERENCES

1. Herfst S, Fouchier RA, Schrauwen EJ, Linster M, Chutinimitkul S, de Wit E, Munster VJ, Sorrell EM, Bestebroer TM, Burke DF, Smith DJ, Rimmelzwaan GF, Osterhaus AD, Fouchier RA. 2012. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336:1534–1541. doi:10.1126/science.1213362.Abstract/FREE Full TextGoogle Scholar
2. U.S. Department of Health and Human Services. 2014. U.S. Government gain-of-function deliberative process and research funding pause on selected gain-of-function research involving influenza, MERS, and SARS viruses. U.S. Department of Health and Human Services, Washington, DC. http://www.phe.gov/s3/dualuse/documents ... pdf.Google Scholar
3. Fouchier RA. 2015. Studies on influenza virus transmission between ferrets: the public health risks revisited. mBio 6(1):e02560-14. doi:10.1128/mBio.02560-14.FREE Full TextGoogle Scholar
4. Klotz LC. 2015. Comments on Fouchier's calculation of risk and elapsed time for escape of a laboratory-acquired infection from his laboratory. mBio 6(2):e00268-15. doi:10.1128/mBio.00268-15.FREE Full TextGoogle Scholar
5. Fouchier RA. 2015. Reply to “Comments on Fouchier's calculation of risk and elapsed time for escape of a laboratory-acquired infection from his laboratory.” mBio 6(2):e00407-15. doi:10.1128/mBio.00407-15.FREE Full TextGoogle Scholar
6. Klotz LC, Sylvester EJ. 2014. The consequences of a lab escape of a potential pandemic pathogen. Front Public Health 2:116. doi:10.3389/fpubh.2014.00116.CrossRefPubMedGoogle Scholar
7. Henkel RD, Miller T, Weyant RS. 2012. Monitoring select agent theft, loss and release reports in the United States—2004–2010. Appl Biosaf 18:171–180. http://www.absa.org/abj/abj/121704FAHenkel.pdf.Google Scholar
8. Wikipedia contributors. Accessed 8 June 2015. Categorical imperative, on Wikipedia, The Free Encyclopedia. http://en.wikipedia.org/wiki/Categorica ... ive.Google Scholar
9. Lipsitch M, Cohen T, Cooper B, Robins JM, Ma S, James L, Gopalakrishna G, Chew SK, Tan CC, Samore MH, Fisman D, Murray M. 2003. Transmission dynamics and control of severe acute respiratory syndrome. Science 300:1966–1970. doi:10.1126/science.1086616.Abstract/FREE Full TextGoogle Scholar
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Re: U.S. government gave $3.7 million grant to Wuhan lab at

Postby admin » Wed Aug 26, 2020 12:00 am

I'm finally taking the time to do a full write up on COVID-19 because the ignorance and lack of critical thinking by the majority of people on this site is really pissing me off. And because this sub is one of the few left that is not manipulated by corrupt mods.
byu/MaximilianKohler
Reddit.com
8/16/20

I'm finally taking the time to do a full write up on COVID-19 because the ignorance and lack of critical thinking by the majority of people on this site is really pissing me off. And because this sub is one of the few left that is not manipulated by corrupt mods.

Preface:

I shouldn't have to preface with this, but I probably do: I agree "Trump bad". He's a senile, low functioning, sociopathic narcissist. He handled this crisis as ineptly as he's handled virtually everything else. That is not reason to politicize a crisis to this extent, while rejecting all critical thinking and remaining wilfully ignorant.

The way this crisis has been politicized and polarized has been massively detrimental to both the welfare of the population, and to the already abysmal level of critical thinking, objectivism, rationality, nuance, etc..

I am actually going to move most of the preface from the beginning to the end. Because of how polarized, political, and faction-based the discussion has become, I think that a majority of people who read the preface would simply downvote and remain wilfully ignorant about the rest. So I'm going to start with the facts and evidence, and hope there are enough redditors left who care about those.

Here are some of the things you're not seeing due to the manipulation of content (in large part by moderators, but also by votes) all over reddit:

Who is at risk from this virus?

Primarily people who are both old and unhealthy. And to a much lesser degree, people who are unhealthy but not elderly.

Yet again, I should not have to preface with this, but I am in the high-risk category. I have been chronically ill for many years (despite full-time, years of tremendous efforts). I am not making this argument from a privileged position.

More young people have it, but only the elderly get symptoms. Screenshot from covid.is. Dutch citation.

Mostly effects the elderly and people with underlying health conditions: https://www.cdc.gov/mmwr/volumes/69/wr/mm6924e2.htm - https://www.cdc.gov/mmwr/volumes/69/wr/mm6928e1.htm

Nearly half of hospitalized COVID-19 patients without a prior diabetes diagnosis have hyperglycemia, and the latter is an independent predictor of mortality at 28 days https://old.reddit.com/r/ScientificNutr ... _patients/

In Italy only 0.2% of all deaths were people under age 40, 59.9% had 3 or more serious comorbidities, only 3% of all deaths had no comorbidities and median death age is 81 (May 2020) https://www.epicentro.iss.it/en/coronav ... y_2020.pdf

CDC Director: Threat Of Suicide, Drugs, Flu To Youth ‘Far Greater’ Than Covid (Jul 2020) https://archive.vn/wip/bXM7U

Doctors from Stanford and UCLA: It’s time to end the state of emergency over COVID-19 (Jun 2020) https://archive.vn/4x2pQ “These infection fatality rates are remarkably low and are similar to the fatality rate for the seasonal flu.” “The virus is 10 times less fatal than we first thought.”

42% of all COVID-19 deaths are taking place in facilities that house 0.62% of the U.S. population (nursing homes and assisted living facilities) https://www.forbes.com/sites/theapothec ... f3213674cd

Official death rates per the CDC vary from month to month. Estimated overall fatality rate of those infected with the virus – with and without symptoms – would be 0.26% (Jun 2020) https://www.usatoday.com/story/news/fac ... 269331002/

Various websites quote wildly varying death rates, to as much as 5.2% of infected people. There is clearly bias all over the place. But only 1% of the US population has been infected.

Dutch CDC: 98% of infections go without barely any symptoms https://viruswaarheid.nl/medisch/van-di ... de-mensen/

WHO Says Studies Put Coronavirus Mortality Rate at 0.6% https://www.bloomberg.com/news/videos/2 ... -0-6-video

The COVID Panic Is a Lesson in Using Statistics to Get Your Way in Politics (Jul 2020) https://mises.org/wire/covid-panic-less ... y-politics

COVID-19: There have been approximately 760,213 deaths reported worldwide. Flu: The World Health Organization estimates that 290,000 to 650,000 people die of flu-related causes every year worldwide. https://www.hopkinsmedicine.org/health/ ... vs-the-flu

People citing the number of people who have died are frequently being misleading. The human population has almost quadrupled over the past 100 years: http://thedatadreamer.com/wp-content/up ... -Chart.png. So of course vastly more people are going to be impacted by anything. Even rates are going to go up due to increased population density. But rates are still the most accurate statistic.

Consequences of acting vs not acting, and economics:
It is idiotic and unethical to not fully inform ourselves and then weigh the consequences of our actions. The fact that there are so many adults who do not understand this is extremely alarming.

Millions of people die every year around the globe. We cannot currently prevent all deaths, and we don't even attempt to, in large part due to the costs/consequences of the interventions being too large.

Democracy Now covers economic, social, and health consequences of using quarantines/stay-at-home orders to combat COVID-19:

The content goes far beyond the quoted headlines.

U.N. Warns of Lockdown's “Potentially Catastrophic” Economic Toll on Children - reduced household income, school meal programs, maternal and newborn care: https://www.democracynow.org/2020/4/17/headlines

Nearly 1 in 5 U.S. Children Going Hungry as Unemployment Surges to Great Depression Levels. EU Warns Pandemic Economic Recession Will Be Worst in History https://www.democracynow.org/2020/5/7/headlines

“Diarrhea, Dehydration, Hunger, Exhaustion”: India’s Rural Poor Suffer Most Under Lockdown https://www.democracynow.org/2020/5/22/ ... neoliberal

Bolivian Protesters Demand End to Coronavirus Lockdown as Hunger Mounts https://www.democracynow.org/2020/5/20/headlines

Oxfam Warns COVID-19 Pandemic Could Push 122 Million to Brink of Starvation https://www.democracynow.org/2020/7/9/headlines

Study Warns 1.1 Million Children Could Die From Secondary Impacts as Pandemic Interrupts Access to Food & Medical Care (May 2020) https://www.democracynow.org/2020/5/21/ ... lity_rates

PBS covers food chain and economic problems: https://www.youtube.com/watch?v=vjfLXrke66I

Beyond the public health crisis, there's a massive economic and humanitarian crisis that is emerging because of this lockdown. People who are not monthly wage workers don't have any savings, so, they're practically facing severe starvation. https://www.pbs.org/newshour/show/dense ... -challenge

Watch through to Sen Pat Toomey's interview: https://www.youtube.com/watch?v=BoPelzsFjYk&t=365

State reopening plans force trade-offs between health and economy https://www.pbs.org/newshour/show/state ... nd-economy

Dr. Anthony Fauci says staying closed for too long could cause 'irreparable damage' (May 2020) https://www.cnbc.com/amp/2020/05/22/dr- ... amage.html

Doctors on front line of worst-hit city in world say it’s time to end shutdown (May 2020) https://www.telegraph.co.uk/news/2020/0 ... -shutdown/

CDC director: Keeping schools closed poses greater health threat to children than reopening (Jul 2020) https://thehill.com/policy/healthcare/5 ... o-children

The risks of keeping schools closed far outweigh the benefits (Jul 2020) https://www.economist.com/leaders/2020/ ... e-benefits

The Results Are In for Remote Learning: It Didn’t Work. The pandemic forced schools into a crash course in online education. Problems piled up quickly. (WSJ, Jun 2020) https://archive.fo/cm9I5

‘The Biggest Monster’ Is Spreading. And It’s Not the Coronavirus. - Tuberculosis kills 1.5 million people each year. Lockdowns and supply-chain disruptions threaten progress against the disease as well as H.I.V. and malaria. https://www.nytimes.com/2020/08/03/heal ... laria.html

COVID-related hunger could kill more people than the virus https://unglobalcompact.org/take-action ... -the-virus

UNICEF analysis predicts 6000 child deaths PER DAY due to COVID response https://www.unicef.ie/stories/impact-covid-19-children/

Lockdown 'killed two people for every three who died of coronavirus' at peak of outbreak. Estimates show 16,000 people died through missed medical care by May 1, while virus killed 25,000 in same period (Aug 2020) https://www.telegraph.co.uk/news/2020/0 ... ronavirus/

One example of many: 31yo mother dies from cancer after treatment is delayed due to coronavirus. https://archive.vn/wip/WAPyL

CDC: 11% of US adults seriously considered suicide in June https://www.businessinsider.com.au/cdc- ... une-2020-8

CDC: One quarter of young adults contemplated suicide during pandemic (Aug 2020) https://www.politico.com/news/2020/08/1 ... mic-394832

Coronavirus pandemic may lead to 75,000 "deaths of despair" from suicide, drug and alcohol abuse, study says (May 2020) https://www.cbsnews.com/news/coronaviru ... mic-75000/

It is ‘inhumane and heartless’ not to recognise the human costs of lockdowns (Jul 2020) https://www.skynews.com.au/details/_6176537337001

Ever since the UK entered “lockdown”, those pushing for it to end have been labelled “callous” or “selfish” or accused of putting profits before people. Meanwhile millions are unemployed and a global famine is on the horizon. The lockdown will kill more people than the virus, and needs to be ended. (May 2020) https://off-guardian.org/2020/05/12/opp ... ore-people

More Than Half of U.S. Business Closures Permanent (Jul 2020) https://www.bloomberg.com/news/articles ... -yelp-says

Study between Finland and Sweden indicates school closings had no measurable impact on number of cases in children. https://www.folkhalsomyndigheten.se/con ... ildren.pdf

Reopening schools in Denmark did not worsen outbreak https://www.reuters.com/article/us-heal ... SKBN2341N7

New US Centers for Disease Control and Prevention guidelines on education and child care come down hard in favor of opening schools, saying children don't suffer much from coronavirus, are less likely than adults to spread it and suffer from being out of school. (Jul 2020) https://www.cnn.com/2020/07/23/health/c ... index.html

Three large Southern states that moved aggressively to reopen amid the coronavirus crisis have seen new cases and deaths largely hold steady since then https://nypost.com/2020/05/22/no-corona ... s-re-open/

As Wisconsin completely reopened last month, they have not seen the dire consequences that were predicted for them. https://www.wbay.com/content/news/Wisco ... 08001.html

The first-to-reopen state maintains a Covid-19 death rate well below those of northeastern states—though you’d never know it from the media coverage. https://www.city-journal.org/covid-19-georgia-reopening

The number of cases in Arizona is quickly decreasing, despite open restaurants, barber shops and churches https://archive.vn/V5vZ1

There is already a major problem with overexpenditures on end of life care https://archive.vn/UbC0K#selection-223.18-223.19 - this is not "saving lives", this is slightly postponing deaths.

When I first heard India was shutting down I was shocked and horrified. One has to be tremendously out of touch to not know that huge swaths of developing country's populations live day to day and will literally starve to death if you prevent them from going to work. And developing countries do not have the same economic means to provide monetary and food welfare to their populations. After seeing the coverage of it on Democracy Now it seemed clear to me that it was a privileged minority shutting down the whole country to protect themselves with complete disregard for the millions of poor people who would suffer severely.

And even beyond developing countries' inability to provide welfare to their citizens, there are global consequences to even just developed countries shutting down. It puts millions of people in developing countries out of work, causing them severe hardship.

This is made worse by the fact that:

"57% of Mumbai slumdwellers have Covid antibodies. Experts believe herd immunity can be achieved when around 60% of the population has been exposed to the virus. Estimated fatality rate of 0.05-0.10%" [1]. And other Indian cities have similarly low infection fatality rates (IFR) of 0.02% and 0.08%. And an IFR of 0.1% for India.

There's a popular and prevalent notion on reddit that the economy is some abstract thing that doesn't matter. As you can see above, it's not "lives vs economics", it's "lives vs other lives that will be harmed by shutting down the economy".

It's been appalling to see virtually 100% of the left-wing in the US supporting the shutdowns with the myopic mindset of "we're doing a good thing by protecting the vulnerable". And seemingly entirely ignorant and unable to think for themselves about the consequences. It's been very interesting to see this issue split down political lines in the US, with the right-wing advocating against the shutdowns and the left-wing supporting them. This mantra that I've seen before seems applicable here – "the right is evil, the left is incompetent". I'm sure other variations of that mantra may be more appropriate.

Incompetence and misinformation:
Both of these things are widespread. Including among "professionals". Assuming that every degree holder is well informed, competent, intelligent, and in agreement, is naive. Given that the reddit demographic is young, it's not surprising how common this notion is on reddit. There are major problems among professionals of all kinds: https://archive.fo/ofBvs#selection-809.0-809.1

Yes, I realize how problematic and dystopian this is. If you can't trust professionals/degree holders, it's total chaos. However, it's the reality. That reality is incredibly disturbing to me. Which is why I've spent years writing about it and trying to get people to do something to fix it. Ignoring that reality is not a fix.

Analysis: England's COVID-19 death toll is wrong. "You could have been tested positive in February, have no symptoms, then be hit by a bus in July and you’d be recorded as a Covid death.” https://archive.vn/wip/6SXR4

Article title: "Perfectly Healthy 16-Year-Old Died Suddenly from COVID-19". Article Content: Kid was diabetic and obese. https://archive.vn/wip/i6aV2

Twitter: @Sciencing_Bi - fake professor account, claims to have died of COVID-19, blaming the university where @Sciencing_Bi supposedly worked for making people teach on campus during the pandemic https://heavy.com/news/2020/08/sciencin ... ghlin-asu/ - https://gizmodo.com/science-twitter-got ... 1844591277

(@NateSilver538): I've seen a few too many mainstream media stories of "unusual" COVID cases where the most likely explanation is a false positive or a false negative test and the article doesn't really even explore the possibility at all. https://archive.vn/jJ4hA

New York Times retracts cover story on a 26 year old ER doctor in NY said to have died of COVID-19: https://web.archive.org/web/20200528053 ... 5335043072 - https://archive.vn/NpreZ#selection-3251.0-3255.12

Highly upvoted r/science thread with a misleading title claiming that children are spreaders of the virus. Commenters point out the misleading title and link to other studies that show children do not spread the virus, and asymptomatic spread is rare: https://archive.vn/wip/HsBIm

How the media has us thinking all wrong about the coronavirus, by Emily Oster, professor of economics https://www.washingtonpost.com/opinions ... ronavirus/

Censorship:

There are degree holders who moderate many major reddit subs, and have been corruptly, unethically, and unscientifically manipulating content. Here's one example: https://archive.vn/iQtIq

Here are other examples of moderators manipulating content on reddit in regards to COVID-19:

r/economics censored discussions https://archive.vn/UbC0K#selection-223.18-223.19 - https://archive.vn/wip/DDwDh

Banned from r/covid19 for pasting a link to a news article about increase in poverty due to lockdowns: https://archive.vn/Oo2yr#selection-823.0-823.1

r/california_politics censored discussion: https://archive.vn/Dc5VT#selection-1709.9-1709.10

Then muted for 28 days after mod demonstrates complete apathy for facts, evidence, and science: https://www.scribd.com/document/4721652 ... nd-science

That is exactly what is occurring all over reddit, and has been for years.

Coronavirus Censorship Crisis, by Matt Taibbi https://taibbi.substack.com/p/temporary ... censorship - covers experts getting things wrong, expert & media bias and conflicting messaging, attacking questions instead of behaving scientifically, and censorship on social media.

The result of all that misinformation, censorship, and thus ignorance:

Poll:

Jul 2020 https://www.kekstcnc.com/media/2793/kek ... wave-4.pdf

- Poll Question: How many people in your country have had COVID-19?

- Americans Answered: 20% (66M)

- Reality: 1% (3.3M)

- Poll Question: How many people in your country have died from COVID-19?

- Americans Answered: 9% (29.5M)

- Reality: 0.04% (131K)

Americans overstated the death number by 225 times.

Another poll showing similar trends.

Despite the extremely low risks (as detailed above) for children from this virus, people are frequently using deceptive, appeal-to-emotion fallacies along the lines of "think of the children". It seems that people are doing this due to one or more of:

Ignorance

Self-preservation/selfishness

Political motivations

r/LockdownSkepticism seems to be one of the few bastions of rational, objective, independent thought and information. According to the widespread propaganda on reddit you would expect that sub to only be MAGA extremists. Yet it is not. There is a myriad of information there from highly reputable sources (including many left-leaning ones) that are nowhere to be found on other reddit subs, simply because they are contradictory to the pro-shutdown propaganda that inundates virtually everywhere else on reddit.

Top links: https://old.reddit.com/r/LockdownSkepticism/top/ - https://archive.vn/uy2KZ

EDIT: A week after I created this post, CGP Grey, someone very popular on reddit, created a rational video on COVID-19 lockdowns. Typically his videos would get to the front page of reddit within a couple hours. This video though? After 1 hour my upvote was the only one. https://archive.vn/2YWmh#selection-3197.13-3201.1. This really typifies the behavior of redditors and coverage of COVID-19 here.

Sweden:

Sweden's reaction was by far the most sensible, yet they're forced to apologize because all anyone weighs are the COVID-19 deaths, and if you dare consider any other side effects from the shutdowns you get labeled a monster. https://www.snopes.com/ap/2020/06/03/to ... us-better/

Ignore the headline, see the comments: https://archive.vn/wip/JcFSb

Sweden, Which Never Had Lockdown, Sees COVID-19 Cases Plummet as Rest of Europe Suffers Spike (Jul 2020) https://archive.vn/wip/eCNOU

COVID appears done in Sweden. (Jul 2020) https://archive.vn/wip/ceKJa

Epidemiologist: Sweden’s COVID Response Isn’t Unorthodox. The Rest of the World’s Is (May 2020) https://fee.org/articles/epidemiologist ... orld-s-is/

Study between Finland and Sweden indicates school closings had no measurable impact on number of cases in children. https://www.folkhalsomyndigheten.se/con ... ildren.pdf

The scientist behind lockdown in the UK has admitted that Sweden has achieved roughly the same suppression of coronavirus without draconian restrictions (Jun 2020) https://www.telegraph.co.uk/news/2020/0 ... ce-uk-has/

Why Sweden’s COVID-19 Strategy Is Quietly Becoming the World’s Strategy (May 2020) https://fee.org/articles/why-sweden-s-c ... -strategy/

Norway PM regrets taking tough coronavirus lockdown measures (Jun 2020) https://au.news.yahoo.com/coronavirus-n ... 07536.html

Symptoms vs cause:

What we did and have been doing for decades is ignoring the problem (public health and chronic disease), and then only reacting to and addressing the symptoms.

That is an absolutely moronic thing to do. It makes me furious. It's a massively inefficient and wasteful allocation of resources. And making others suffer because of one group of people's poor decisions is extremely problematic. Removing the consequences of people's own poor decisions will only lead to continued poor decisions, and likely even worse ones.

Only 3% of the population even bothers to live a healthy lifestyle https://www.theatlantic.com/health/arch ... yle/475065. And now that consequences of that show up they want everyone to suffer to protect them from the consequences of their decisions.

This applies to universal healthcare as well. Spending on healthcare would be a tiny fraction of what it currently is if the majority of the population actually bothered to try and be healthy. I'm fully in favor of universal healthcare, but actions must be taken to reduce chronic disease and general poor health. Otherwise, irresponsible people are just sucking vast amounts of resources from responsible ones.

America’s obesity epidemic threatens effectiveness of any COVID vaccine https://ctmirror.org/2020/08/09/america ... d-vaccine/

Misallocation of resources:

Far more damaging things, that impact far more people, we've been ignoring: https://old.reddit.com/r/HumanMicrobiom ... ?context=3 - https://www.youtube.com/watch?v=Zk11vI-7czE

Where is all the outcry (plus trillions of dollars spent, and massive economic action) about those deaths plus the massive drops in quality of life? Quality of life can be argued to be even more important than death.

“Epidemiologists have tried to quantify this sort of loss with something they call the disability-adjusted life year. Simply put, this unit measures the estimated value of the years of healthy life lost to a disease.”

If you have a million dollars, do you spend it all to save one life, or do you spend it where it will statistically have the most impact and help the most people? Do you spend it all on a life that is ending soon or a life that has a long way to go? The former is what we've been doing with COVID.

The reaction to COVID-19 is furthering an already problematic history of overspending on end of life care: https://archive.vn/UbC0K#selection-293.18-293.19

Why people who care about the environment (especially young people) should protest COVID-19 shutdowns: https://archive.vn/S1IIC

CDC Director: Threat Of Suicide, Drugs, Flu To Youth ‘Far Greater’ Than Covid (Jul 2020) https://archive.vn/wip/bXM7U

Misc:

Besides ignorance and moderator manipulation, the following might explain some of the voting patterns on reddit.

https://archive.vn/Lj518#selection-1991.10-1991.11

/u/Sphinx91:

Reddit doesn't care. Reddit would rather have everything completely shut down to avoid even one single death , and then pat themselves on their back a job well done without looking at every single unintended consequences. The clusterfuck that is waiting for us at the end of all these "lockdowns" is gonna be way more damaging than the virus itself and I'm just waiting for this ride to end.

/u/PhineasC:

The vast majority of Redditors are 15-30 year old males with no kids. They literally have zero invested in this, and in some cases actually are students themselves who want to stay home and play video games all day. This is literally the last place to get the general public viewpoint on this issue.

An entire New Zealand city shuts down due to 4 cases (not deaths) of COVID-19: https://www.abc.net.au/news/2020-08-12/ ... n/12549920 and they're having trouble figuring out the source: https://www.todayonline.com/world/new-z ... d-auckland

How Fear, Groupthink Drove Unnecessary Global Lockdowns https://www.realclearpolitics.com/artic ... 43253.html

#stayathome is so popular because it can instantly transform you into a hero by literally doing nothing https://archive.vn/d3z49

As COVID-19 Cases Surge, Daily Deaths and the Case Fatality Rate Continue To Fall (Jul 2020) https://reason.com/2020/07/06/as-covid- ... e-to-fall/ - https://www.nytimes.com/2020/07/03/heal ... sting.html

Many COVID-19 deaths were likely people who would have died from flu: https://archive.vn/wip/BHOvP

List of questions that pro-shutdown people need to answer: https://archive.vn/M2WHH

Preface at the end!

Rightly so, redditors frequently criticize FOX News viewers, and even Republicans in general, for being anti-science, willfully ignorant, mindless sheep. Yet the behavior on reddit around COVID-19 has shown me that redditors themselves can be guilty of all the same behavior. Hysterical, ignorant, easily manipulated, emotional, reactionary, tribe mentality.

If one needed more evidence of the consequences of the majority of the population being poorly functioning, this has surely provided it.

You can see above how much information and complexity there is. Which is why it is so appalling and alarming that the majority of reddit seems to have reduced the complexity down to "virus bad, dying bad, stay home till virus goes away".

EDIT: And from the comments and voting in this thread it seems that a majority of redditors are displaying all this same behavior I just wrote about! It seems many of them did not even bother to read this post and review the evidence prior to commenting, which is quite a common behavior on reddit. Depressingly, that's exactly what the data shows as well: Facts are increasingly useless.

I've had the unfortunate experience of seeing this occur in many other instances, including parenting and healthcare, where people are only able to process "oh my god people are dying", and entirely unable to do any sort of objective, higher level, logical cost-benefit analysis that is based on facts and statistics. Instead, they simply react emotionally and drastically. The results of which are often vastly worse than had they not reacted at all. I was almost killed multiple times due to a person I know behaving in this way, and I've written about millions of other people being harmed due to this phenomenon [1].

I wanted to make this my title, but knew it would cause immediate downvotes before people even bothered to read the content:

The overreaction to COVID-19 is the most egregious misallocation of resources I've ever heard of in the entirety of human history. Objective arguments from a left-wing perspective.

I am constantly being accused of lack of empathy & compassion, and hatefulness. I have demonstrated that these accusations are not only false, but ironically, the stances and behaviors of the people leveling those accusations are what are harmful and uncompassionate.
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Re: U.S. government gave $3.7 million grant to Wuhan lab at

Postby admin » Fri Sep 11, 2020 1:32 am

Trump explains why he downplayed coronavirus risks to the American public
by Dylan Stableford and David Knowles
Yahoo News
September 9, 2020

President Trump on Wednesday acknowledged that he misled the American public about the threat of COVID-19 earlier this year in order to “reduce panic” about a virus that has so far killed nearly 200,000 people in the U.S.

Speaking to reporters at the White House, Trump was asked whether he misled the country by publicly downplaying the threat of the virus.

“Well, I think if you said ‘in order to reduce panic,’ perhaps that’s so,” Trump said. “The fact is I’m a cheerleader for this country. I love our country, and I don’t want people to be frightened. I don’t want to create panic, and certainly I’m not going to drive this country or the world into a frenzy. We want to show confidence. We want to show strength.”

According to audio excerpts from interviews that Washington Post journalist Bob Woodward conducted for his forthcoming book, “Rage,” Trump said in February that he knew COVID-19 was more deadly than the flu but wanted to “play it down” because “I don’t want to create a panic.”

With Trump’s own answers to Woodward’s questions captured on tape, the president did not attempt to deny that he downplayed the risks to the American people from the virus.

“We don’t want to jump up and down and start shouting that we have a problem that is a tremendous problem, scare everybody,” Trump added.

Asked how he can reassure Americans that they can trust what he is saying, Trump replied, “Well, I think that’s really a big part of trust. We have to have leadership. We have to show leadership, and the last thing you want to do is create a panic in the country. This was a horrible thing. It was sent to us by China.”

According to Johns Hopkins University, there have been more than 6.3 million confirmed COVID-19 cases in the United States, more by far than in any other country. Approximately 189,000 Americans have died from the virus, which originated in Wuhan, China.

Trump dismissed the suggestion that he could have saved American lives if he had been more forthright about the risks posed by the virus.

“I think if we didn’t do what we did, we would have had millions of people die,” the president said. “We closed up our country. We closed it up very, very quickly, very effectively. We, uh, did a job, we learned about this horrible disease along with the rest of the world, which had to learn about it, and then we opened it up and now we know the vulnerable, we know who it attacks, who it’s so vicious against, and I think we’ve done from every standpoint a[n] incredible job.”

Joe Biden, the Democratic nominee, quickly responded to Trump's remarks.

“I promise you that if I’m elected, I’ll always tell you the truth,” Biden tweeted. “I’ll listen to the experts and do everything I can to contain this virus. And I’ll always put your health and safety first — no matter the political cost.”
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Re: U.S. government gave $3.7 million grant to Wuhan lab at

Postby admin » Fri Sep 18, 2020 9:28 am

'Herd mentality': Trump says US 'rounding the corner' on coronavirus, doctors and scientists disagree
by Savannah Behrmann
USA TODAY
September 15, 2020

Image
[Trump] I am going to eat you.
"He tells it like it is", by Paul Noth


WASHINGTON – President Donald Trump claimed Tuesday during a televised town hall that "herd mentality" could make the coronavirus "disappear" with or without a vaccine.

During a 90-minute town hall hosted by ABC News in the must win battleground of Pennsylvania, Trump defended his repeated assertion that the virus will eventually disappear even without a vaccine, citing what he called "herd mentality," an apparent reference to "herd immunity."

ABC News' Chief Anchor George Stephanopoulos asked Trump whether the coronavirus "would go away without the vaccine?"

"Sure, over a period of time. Sure, with time it goes away --" Trump responded.

Stephanopoulos interjected: "-- And many deaths."

"And you'll develop, you'll develop herd -- like a herd mentality. It's going to be -- it's going to be herd developed -- and that's going to happen. That will all happen," Trump said.

Herd immunity is the theory that the virus is eradicated only after a high percentage of the population is infected, limiting its ability to spread.

Herd mentality, also known as mob mentality, rather means people can be influenced by the “herd” to act in ways that are emotional, rather than rational.

Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, who is the nation's leading infectious disease expert, has said the “death toll would be enormous” if the country attempted herd immunity.

For COVID-19, doctors believe 60% to 80% of the population needs natural antibodies, or to be vaccinated, to achieve herd immunity.

The U.S. has reported more than 6.5 million confirmed cases. The number needed to achieve herd immunity is far more, as the U.S. population is 328.2 million.

The Washington Post calculated that nearly three million Americans would have to die for the U.S. to reach herd immunity without a vaccine.


As of Tuesday night, more than 195,000 deaths Americans have died, according to data from John Hopkins University.

The White House earlier in September denied the Trump administration has ever considered a policy of "herd immunity."

"The herd immunity so-called theory was something made up in the fanciful minds of the media. That was never something that was ever considered here at the White House," press secretary Kayleigh McEnany told reporters during a White House Press briefing.


Trump also claimed Tuesday he believes "we're rounding the corner" on the coronavirus.

However, many scientists and doctors, including Fauci, have strongly disagreed with that assertion, expressing concerns of the coronavirus mixing with flu season.

“If you're talking about getting back to a degree of normality which resembles where we were prior to COVID, it's going to be well into 2021, maybe even towards the end of 2021," Fauci said recently.

Trump defended this thinking by naming former Stanford Neuroradiology Chief Dr. Scott Atlas.

Atlas has become a White House adviser on the coronavirus, and has publicly downplayed the virus. There were reports from The Washington Post that Atlas has been pushing herd immunity inside the White House, and Trump has been listening.


Andrew Bates, Director of Rapid Response for Democrat nominee Joe Biden's campaign, tweeted: "This is the *current* PRESIDENT of the United States, whose charged with keeping the American people safe. This would literally mean millions of deaths."

Andrew Bates @AndrewBatesNC
"This is the *current* PRESIDENT of the United States, whose charged with keeping the American people safe. This would literally mean millions of deaths."
Andrew Bates@AndrewBatesNC
"It would go away without the vaccine?"
"Sure, over a period of time. Sure, with time..."
"And many deaths."
"You'll develop a herd mentality."
6:37 PM - Sep 15, 2020


During the town hall, the president also repeatedly rejected the idea that he had downplayed the severity of the virus, despite recordings from Bob Woodward's interviews in which he told the journalist he thought downplaying it would help avoid a panic.

Contributing: John Fritze, David Jackson USA TODAY
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