1. Patrick J. Scannon, M.D., Ph.D. CSO, XOMA Stanford University, October 2015 Technology Impact on Biosecurity Policy and Practice “D.A. Henderson, Scientist Who Helped Eradicate Smallpox, Says U.S. Is Unprepared For Bioterrorism” Huffington Post, Feb 6, 2012 “California nurses go on strike over lack of Ebola preparedness” Fortune, Nov 11, 2014

2. Biosecurity - Technology - Public Policy  Biosecurity (adapted from NIH): Taking appropriate measures to address life sciences research (eg, human, animal, plant) with the potential to be misused to threaten public health or national security.  Technology (adapted from Merriam Webster): the science of the application of knowledge to practical purposes – often building upon prior generations of science and technologies  Public Policy (adapted from study.com): the means by which a government maintains order or addresses the needs of its citizens, through actions defined by its constitution.

3. Biotechnology Advances over Past Ten Years: Faster, Cheaper, Mobile and Global  Many biotechnologic advances: Accelerated research technologies: Accelerated development technologies Internet: Methodologies widely published  The Impact: Good: Greater innovation, faster and cheaper Bad: Greater innovation, faster and cheaper: non-state rogues

4. Biosecurity: Animals – Plants – Humans

5. Recent Biosecurity-Related Topics in Medical News

6. Key Biosecurity Public Policy Questions to Ask:  What is/should be the United States’ overarching policy for biosecurity, even if not formally stated? And what role does Technology play?

7. Some Desirable Properties of Public Policy  Forward looking and strategic guidance, ideally with declared objectives, from government to its society - guidance has some reasonable/likely life span  Guidance results in enhancing society’s protection or well being  Guidance anticipates scope  Guidance acknowledges all processes necessary to meet objectives  Guidance should recognize required leadership  Fiscally manageable and timely  Guidance is directional but also adaptive

8. Can’t write Public Policy in a Vacuum Written Here Needed Here

9. Key Biosecurity Public Policy Concerns  Management of concept of near-zero probability X high societal impact: Many known, and perhaps more unknown, all rare biothreats: what is real and what is “crying wolf”? Fear tactics quickly tachyphylax audiences.  Some factors concerning biothreats: natural vs intentional vs accidental causes, disease toxicity/pathology/mortality, disease speed in affected host, ease of dissemination across populations, impact on health care system – how to prioritize across so many possibilities?  Prevention versus treatment strategies: when is each appropriate?  Available resources – how much to allocate?  Long lead times and big costs with new drug development – how to allocate time?  Disease boundaries do not respect State boundaries – how encompassing should public policy be? Country-wide? Global?  Role of technologies: often rapidly evolving – how to capture in public policy?

10. Examples of Biothreats Anthrax: October 2001 Intentional Flu: 1997, 2005, 2011, 2015 & ongoing Natural Ebola: 2015 & Ongoing Natural Examples of Post Event Comments REGARDING THE “BIG ONE” Missed that Bullet… Hasn’t happened yet….. What are the odds: won’t happen on my watch…

11. NIAID Category A, B, and C Priority Pathogens Category A Priority Pathogens Bacillus anthracis (anthrax) Clostridium botulinum toxin (botulism)) Yersinia pestis (plague)) Variola major (smallpox) and other related pox viruses Francisella tularensis (tularemia)) Viral hemorrhagic fevers Arenaviruses Junin, Machupo, Guanarito, Chapare (new in fiscal year (FY) 14), Lassa, Lujo (new in FY 14) Bunyaviruses Hantaviruses causing Hanta Pulmonary syndrome, Rift Valley Fever, Crimean Congo Hemorrhagic Fever Flaviruses Dengue Filoviruses Ebola Marburg Category B Priority Pathogens Burkholderia pseudomallei (melioidosis) Coxiella burnetii (Q fever) Brucella species (brucellosis) Burkholderia mallei (glanders) Chlamydia psittaci (Psittacosis) Ricin toxin (Ricinus communis) Epsilon toxin (Clostridium perfringens) Staphylococcus enterotoxin B (SEB) Typhus fever (Rickettsia prowazekii) Food- and waterborne pathogens Bacteria Diarrheagenic E.colii Pathogenic Vibrios Shigella species Salmonella Listeria monocytogenes Campylobacter jejuni Yersinia enterocolitica Viruses Caliciviruses Hepatitis A Protozoa Cryptosporidium parvum Cyclospora cayatanensis Giardia lamblia Entamoeba histolytica Toxoplasma gondii Naegleria fowleri (new in FY 14) Balamuthia mandrillaris (new in FY 14) Fungi Microsporidia Mosquito-borne encephalitis viruses West Nile virus (WNV) LaCrosse encephalitis (LACV) California encephalitis Venezuelan equine encephalitis (VEE) Eastern equine encephalitis (EEE) Western equine encephalitis (WEE) Japanese encephalitis virus (JE) St. Louis encephalitis virus (SLEV) Category C Priority Pathogens Nipah and Hendra viruses Additional hantaviruses Tickborne hemorrhagic fever viruses Bunyaviruses Severe Fever with Thrombocytopenia Syndrome virus (SFTSV), Heartland virus Flaviruses Omsk Hemorrhagic Fever virus, Alkhurma virus, Kyasanur Forest virus Tickborne encephalitis complex flaviviruses Tickborne encephalitis viruses European subtype Far Eastern subtype Siberian subtype Powassan/Deer Tick virus Yellow fever virus Tuberculosis, including drug-resistant TB Influenza virus Other Rickettsias Rabies virus Prions Chikungunya virus Coccidioides spp. Severe acute respiratory syndrome associated coronavirus (SARS-CoV), MERS-CoV, and other highly pathogenic human coronaviruses (new in FY 14) Antimicrobial resistance Pharma will not proceed for rare IDs without USG Funding: NIH, CDC, DoD

12. Biothreats From Any Direction Not just on the NIAID Priority List + Global Realities Impacting Bioresponse Strategy Diseases do not recognize national borders Multiple Populations: Civilian (children, elders, immunocompromised), Military Inability to stockpile vaccines/therapies for all possible disease US Strategic National Stockpile (SNS): STRATEGIC CHALLENGES

13. Public Policy Requires Many Inputs for Cohesive Integration and Implementation TECHNOLOGIES TIME DEMAND INTEGRATION: Public Health Dept Hospitals 1 st Responders … PRIORITIZATION EFFECTIVE PUBLIC POLICY DISEASE(S)

14. Possible Barriers to the Inclusion of Transformational Technology into Policy  Only one of many variables which need integration  Policy Makers may not recognize what is reasonable to request  Technologies “move too fast” – when is good, good enough? Proven “Bird in the Hand” technologies: ready to go Unproven “Birds in the Bush” – what are risks?  Time/cost to develop and implement new technologies RESULT: Potential default to existent technologies which MAY not meet Policy Objectives – modify objectives?

15.  Can or should Technology affect Public Policy?  Can or should Public Policy affect Technology? Consider impact, cost, timing of increasing mfg capacity(10x mfg cGMP capacity), yield (10x vaccine/liter from fermenter), potency (1/10 dose)/person.

16. Technologies Encompass the Entire Biosecurity Path Rapid and distributed detection systems Rapid Discovery of new vaccines (prevention) and therapeutics (treatment) Development Manufacturing Clinical Trials Regulatory FDA approval Distribution Administration to Patients Technical Impacts at Each Step: Speed, Scale, Safety, Efficacy, Cost

17. From Another Angle: Same Need for Technology Bill Gates, N Eng J Med, 372;15 April 9, 2015

18. Getting to Some Answers What makes a rare biothreat disease “bad” for society? Mortality: 0% or 100% for individual, variable % for society High Morbidity: overwhelming the health care system, eg, ventilators, isolation units, trained personnel (3 shifts) Contagiousness: high transmission (plague, smallpox) vs low transmission (anthrax) Lack of existent prevention and treatment

19. Example 1: Disease Transmission, independent of disease, May Affect Policy

20. Example 2: Disease Morbidity, independent of disease, May Affect Policy

21. Disease Profiles, independent of disease, May Affect Policy  High transmission x high morbidity  High transmission x low morbidity  Low transmission x high morbidity  Low transmission x low morbidity: probably not a meaningful societal threat Necessary But Not Sufficient: How are bioresponses affected? Possible Profile Categories – each with different impact

22. Different Disease Categories Suggest Different Medical (Technical) Responses  Concept: Diseases with high transmission and substantial morbidities affecting large populations, especially where time is critical, may be best addressed by a “bioresponse” prevention plan which includes novel vaccines  Complementary Concept: Diseases with low transmission and substantial morbidities may be more practically approached by a “bioresponse” treatment plan which includes novel therapeutics

23. Impact of Technology: Two Scenarios for a highly contagious, high morbidity pathogen Scenario 1:  Previously unknown pathogen  No vaccine or therapy known Scenario 2  Known pathogen  Existent vaccine

24. The “Simple Case”: Scenario 2 Options  In Place Vaccine but Stores Insufficient  10X10,000 L bioreactors available  1 microgram dose, single vaccine (no booster required)  Availability 1: 100 million doses given by shot Availability 2: 1 billion doses given by pill How extensive would the public policy be for each?

25. Policy concerns (inversely proportional to number of doses and route of administration) 100,000,000 doses IM  Prioritization for administration (eg, first responders, elderly, children, military)  Availability of 100,000,000 needles, syringes and sufficient cold storage  Availability of hospitals, MDs, technicians…. 1 billion doses PO  Deliver everywhere ASAP  Make available to ROW

26. Conceptual Public Policy Bifurcation for Different Biothreats: Disease Transmission x Morbidity Requirement for Rapid Response High Transmission x High Morbidity Low Transmission x High Morbidity Technology Implications: Identification/Detection Rapid Vaccine Development Medical Supportive Care: Quantity + Quality Distribution/Administration Technology Implications: Identification/Detection Rapid Therapy Development

27.  Current focus appears to be on categories of diseases (eg, NIAID, CDC, CDC/USDA select agent/toxin listings) and specific diseases within.  Alternatively, “USG bioresponses to disease” driven by disease profile and technology, rather than disease specifics, may beneficially impact USG response, eg, vaccine, therapy and relative funding to support different scenarios. USG’s Overarching Biosecurity Policy?

28. Pathogen Response in place eg, SNS No Response in place, eg, new High Transmission, High Morbidity, eg, pandemic Low Transmission, High Morbidity, eg, containable Vaccine Therapy, eg, siRNA, mAb Technology-Driven Bioresponse to Pathogen Profile Provides Direction

29. Key Biosecurity Public Policy Questions to Ask:  What is/should be the United States’ overarching policy for biosecurity, even if not formally stated? And what role does Technology play?  Who is in charge? And do the involved departments know what the other departments’ responsibilities are?

30. Multiple Federal Agencies Are Involved: But who should be in charge of biosecurity?

31. Key Biosecurity Public Policy Questions to Ask:  What is the United States’ overarching policy for biosecurity? And what role does Technology play?  Who is in charge? And do the involved departments know what the other departments’ responsibilities are?  What does it take to be ready?

32. Preparing for unknown biothreats: Where to Start?  First, recognize and accept such biological threats can happen anywhere and anytime: natural, accidental, intentional  Assess our limitations on global scale, and determine which are addressable by investments in technology: Timely Biothreat identification Current Bioresponse Capabilities/ Capacities Public health care and logistical response structures – not made for rapid and large scale emergencies  Develop Overarching Biosecurity Public Policy as broadly as practical: Top down leadership with long term commitment Greater communication nationally and internationally Large and distributable technology platforms adaptable for rapid implementation when needed

33. Progress into Preparedness

34. “An epidemic is one of the few catastrophes that could set the world back drastically in the next few decades. By building a global warning and response system, we can prepare for it and prevent millions of deaths.” Bill Gates, N Eng J Med, 372;15 April 9, 2015 An example of an Overarching Biosecurity Public Policy Statement

35. My Viewpoint Responses cannot be developed for questions not asked. Biosecurity Public Policy makers should not permit public policy to be driven solely by present day technologies but, rather, must create the needed vision in order to challenge technologists to address biothreats both today and tomorrow.

38. An Adaptable Strategy for Addressing Unknown Biothreats on a Global Scale Depends on Technology Advances and Leadership at Every Step Cooperative communication network Early-warning biosurveillance Public Health response system for pandemics (Global)Vaccine/Therapy response plan Response plan for unknown biothreats International Cooperation of governments, policymakers, public health systems, industry and academia Prepared for the Unknown on Global Scale