session 6: potential risks of gof - biosafety (lipsitch)
TRANSCRIPT
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8/10/2019 Session 6: Potential Risks of GOF - Biosafety (Lipsitch)
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Risks of GOF studies to enhancemammalian transmissibility of novel
influenza, and the role of alternatives
Marc Lipsitch, DPhil
Professor of Epidemiology
Harvard School of Public Health
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Preliminaries
Personal views; not those of my funders whosupport work on pandemic risk (NIGMS MIDASprogram 2U54GM088558) or institution.
Similar calculations: Klotz and Sylvester 2014Front Pub Health, Lipsitch & Inglesby mBio2014
Focus on
biosafety not biosecuritynovel influenza gain-of-mammalian-transmissibility
studies, not corona or gain-of-pathogenicity
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Modern laboratory safety has apretty good record
1141 LAI and 24 deaths in literature1979-2005
Yet major breaches with real or potential risks
to populations can occur:Beijing SARS 2004. 2 primary, 7 secondary
casesTaiwan, Singapore SARS 2003: no secondary
casesFMDV release from Pirbright: major agricultural
consequences1977 influenza H1N1?
Harding and Byers 2006. in Biological
Safety Principles and Practices ed. DFleming & D Hunt. ASM Press
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Biosafety: occupational health orpublic health?
Vast majority of research ondangerous pathogens
Potential pandemic pathogens:novel, virulent, transmissible
90+% of NIAID budget including
>200 influenza projects
smallpox +
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At least 0.2% annual risk of lab-associated infection per BSL3 lab
US Select Agent labs 2004-10
>4 LAI / 2044 BSL3-lab-years = 0.2%/lab-yr
NIAID intramural labs:
3 LAI / 317 BSL3-worker-years
= 1%/ full-time BSL3-worker-year
2004-10 Henkel et al.Applied Biosafety 2012
U.S. Department ofHomeland Security,National Bio andAgro-Defense Facility,Final EnvironmentalImpactStatement, Appendix B(2007); www.dhs.gov/xlibrary/assets/nbaf_feis_appendix_b.pdf
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Risk: Probability x consequence
Probability of pandemic from one unit ofinfluenza transmissibility GOF research
x
Consequence of pandemic of GOFinfluenza strain
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Risk: Probability x consequence
Probability of pandemic from one unit ofGOF research
= Pr (Lab-acquired infection | 1 unit ofresearch)
xPr (Pandemic | 1 LAI)
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Risk: Probability x consequence
Probability of pandemic from one unit ofGOF research
>= 0.2% / BSL-3 year
x
Pr (Pandemic | 1 LAI)
2004-10 Henkel et al.
Applied Biosafety2012
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Risk: Probability x consequence
Probability of pandemic from one unit ofGOF research
>= 0.2% / BSL-3 year
x
5%-60% for flu-like R0J Lloyd-Smith et al.Nature2005M Lipsitch et al.Science2003
Merler, Ajelli et al. BMCMed2014
2004-10 Henkel et al.Applied Biosafety 2012
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Risk: Probability x consequence
Probability of pandemic from one unit ofGOF research
>= 0.2% / BSL-3 year
x
5%-60% for flu-like R0
~1 in 10 000 1 in 1000
per BSL3 lab-yr of GOF on flu
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Adjustments to ProbabilityEstimates
- Control measures (already factored into Merlerstudy)
- Vaccination, prophylaxis of lab workers (imperfect)
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BSL3+ vs BSL3- molecular biocontainment
+undercounting of infections, overcounting lab-yearsin US Select Agent program: limitations of Henkel etal.
+ lower standards in some other countries
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Risk: Probability xconsequence
Mortality consequence of a pandemic =
Expected pandemic attack ratex
Case-fatality risk
xGlobal population
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Risk: Probability xconsequence
Mortality consequence of a pandemic =
24-38%x
Case-fatality risk
xGlobal population
!"# %&'()*+& &, "-. !"#$/0123 456 7*889#:,;
"=*# 69:?"#@& /00A
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Risk: Probability xconsequence
Mortality consequence of a pandemic =
24-38%x
1%-60%
xGlobal population
Van Kerkhove et al. IORV2013; USGCommunity Mitigation Guidance 2007Van Kerkhove et al Science2012; Toner et al.
CID2013
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Risk: Probability xconsequence
Consequence of an H5N1 pandemic(mortality) =
24-38%x
1%-60%
x7,000,000,000
= 20 million 1.6 billion fatalities
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Adjustments to ConsequenceEstimates
- Virulence reduced even below 1% (cantassume a priori)
+ Non-mortality costs: nonfatal health loss,
$, loss of scientific credibility, schoolclosures etc.
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Risk: Probability x consequence
>= 10-4to 10-3/ BSL-3 lab-year
x
2x107to 1.6 x 109 fatalities | GOF pandemic =
2000-1,600,000 fatalities /BSL-3 lab-year using these(provisional) numbers
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The wrong way to frame the choice
+B
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Alternative ways to study anddefeatinfluenza
Approach Risk tolife
Cost Throughput /Statistical power
Generalizability
GOF on novel flu High $$$ - -
Defective viruses in
vitro
~0 $ +++ ++
Sequence analysis ofnatural bird vs. humanvs. passaged strains
Low $$ + +
Universal vaccine ~0 $$ ++ +++
Accelerate vaccineproduction; make
multiple vaccine seedstocks
~0 $$ ++ +++
Host-targetedtherapeutics
~0 $$$ ? +++
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Favors PPP Favors alternatives
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Favors GOF Favors alternatives
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(alternatives create nosignificant public healthrisk)
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modified from M Lipsitch & TV Inglesby mBio2014
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Following the deliberative process
Society for Safe Science
http://safesci.org
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Most promising science experiments
never get done Grants not funded
Benefits too small
Approach is not best way to get the knowledge
Budget not available
Human subjects review prohibits Risk to subjects too great
Animal welfare review prohibits
Harm to animals too great
Biosafety prohibits
Risk to investigators, facility too great. Smallpox, others Investigator discontinues one research approach to focus on a more
promising (or cheaper) one