Session 6: Potential Risks of GOF - Biosafety (Lipsitch)

8/10/2019 Session 6: Potential Risks of GOF - Biosafety (Lipsitch)

1/26

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


2/26

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


3/26

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


4/26

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 +


5/26

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


6/26

Risk: Probability x consequence

Probability of pandemic from one unit ofinfluenza transmissibility GOF research

x

Consequence of pandemic of GOFinfluenza strain


7/26


Probability of pandemic from one unit ofGOF research

= Pr (Lab-acquired infection | 1 unit ofresearch)

xPr (Pandemic | 1 LAI)


8/26



>= 0.2% / BSL-3 year

x

Pr (Pandemic | 1 LAI)

2004-10 Henkel et al.

Applied Biosafety2012


9/26



>= 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


10/26



>= 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


11/26

Adjustments to ProbabilityEstimates

- Control measures (already factored into Merlerstudy)

- Vaccination, prophylaxis of lab workers (imperfect)

-

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


12/26

Risk: Probability xconsequence

Mortality consequence of a pandemic =

Expected pandemic attack ratex

Case-fatality risk

xGlobal population


13/26



24-38%x

Case-fatality risk

xGlobal population

!"# %&'()*+& &, "-. !"#$/0123 456 7*889#:,;

"=*# 69:?"#@& /00A


14/26



24-38%x

1%-60%

xGlobal population

Van Kerkhove et al. IORV2013; USGCommunity Mitigation Guidance 2007Van Kerkhove et al Science2012; Toner et al.

CID2013


15/26


Consequence of an H5N1 pandemic(mortality) =

24-38%x

1%-60%

x7,000,000,000

= 20 million 1.6 billion fatalities


16/26

Adjustments to ConsequenceEstimates

- Virulence reduced even below 1% (cantassume a priori)

+ Non-mortality costs: nonfatal health loss,

$, loss of scientific credibility, schoolclosures etc.


17/26


>= 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


18/26

The wrong way to frame the choice

+B


19/26

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 $$$ ? +++


20/26

H-,&'#"=+&

"CC'*"@)&B ,*

I9 +:'*-*>;

JJJ

B9'+&:--"#@&K 9#:+

+"@@:#&K 8"(&

+"@@:#& B&&?B


21/26

H-,&'#"=+&

"CC'*"@)&B ,*

I9 +:'*-*>;

L#@'&"B&? B9'+&:--"#@&K

9#:+&'B"- +"@@:#&K 8"(&

+"@@:#& B&&?B

B9'+&:--"#@&K 9#:+

+"@@:#&K 8"(&

+"@@:#& B&&?B

Favors PPP Favors alternatives

H-,&'#"=+&

"CC'*"@)&B ,*

I9 +:'*-*>;

JJJ


22/26

H-,&'#"=+&

"CC'*"@)&B ,*

I9 +:'*-*>;

L#@'&"B&? B9'+&:--"#@&K

9#:+&'B"- +"@@:#&K 8"(&

+"@@:#& B&&?B

B9'+&:--"#@&K 9#:+

+"@@:#&K 8"(&

+"@@:#& B&&?B

Favors PPP Favors alternatives

M:B(

*N

JJJ

H-,&'#"=+&

"CC'*"@)&B ,*

I9 +:'*-*>;

JJJ


23/26

H-,&'#"=+&"CC'*"@)&B ,*

I9 +:'*-*>;

L#@'&"B&? B9'+&:--"#@&K

9#:+&'B"- +"@@:#&K 8"(&

+"@@:#& B&&?B

Favors GOF Favors alternatives

M:B(

*N

JJJ

(alternatives create nosignificant public healthrisk)

H-,&'#"=+&

"CC'*"@)&B ,*

I9 +:'*-*>;

JJJ

B9'+&:--"#@&K 9#:+

+"@@:#&K 8"(&

+"@@:#& B&&?B


24/26

H-,&'#"=+&

"CC'*"@)&B ,*

I9 +:'*-*>;

L#@'&"B&? B9'+&:--"#@&K

9#:+&'B"- +"@@:#&K 8"(&+"@@:#& B&&?B

B9'+&:--"#@&K 9#:+

+"@@:#&K 8"(&

+"@@:#& B&&?B

FavorsGOFFavorsalterna

tives

M:B(

*NJJJ

(alternatives create nosignificant public healthrisk)

H-,&'#"=+&

"CC'*"@)&B ,*

I9 +:'*-*>;

JJJ

modified from M Lipsitch & TV Inglesby mBio2014


25/26

Following the deliberative process

Society for Safe Science

http://safesci.org


26/26

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

Documents

Session 6: Potential Risks of GOF - Biosafety (Lipsitch)