UW Madison Lab Accident Reports to NIH

~,_,t.1rac,,,_~ ( - National Institutes of Health .. ;~~\.- December 24~ 2013 redacted by agreement I Associate Vice Chancellor for Research Policy University of Wisconsin 327 Bascom HalJ 3 500 Lincoln Drive Madison, WI 53 706-1380 Dearfedacted by agreement U.S. Public Health Service Bethesda, Maryland 20892 Office of Biotechnology Activities National Institutes of Health 6705 Rockledge Drive Suite 750, MSC 7985 Bethesda. MO 20892-7985 (301) 496-9838 (Phone) (301) 496-9839 (Fax) • hllp:/loba.od.nih.gov/ We are writing in reply to your correspondence of December 20. 2013, that responded to two letters from the National Institutes of Health (Nil-I) Oflicc of Biotechnology Activities (OBA), dated December t 6, 20 I 3. These two letters addressed two separate incidents involving recombinant DNA research with highly pathogenic avian influenza HPAl) HSNJ that have occurred recently in the ABSL3+ laboratory ot edacted by agreement In our December 16, 20 I 3, letters we detailed our concerns regarding the University of Wisconsin's Jack of a dedicated quarantine facility to house individual_s who have experienced a high-risk exposure to mammalian-transmissible strains of HPAI HSN I. We also conveyed our concerns regarding specific biosafety practices associated with these incidents. After reviewing the information you have submitted, NIH OBA has determined that the University of Wisconsin has adequately responded to our concerns. Detailed infonnation regarding your response appears below. Lack of a 1/edicated quarll11li11e facilitv Jn our December 16,2013, letter regarding the ncedlestick incident, we stated that to be compliant with the NIH G11ideli11esfor Research lnvolvi11g Recombi11a11t or Sy111hetic Nucleic Acid Molecules (Nllf Guidelines), the University of Wisconsin must find a dedicated quarantine facility outside of the individual's permanent residence (I) in which an individual e.xposcd to mammalian-transmissible HP Al H5N 1 can be salcly isolated for up to IO days, and (2) that can be decontaminated easily after the individual's depai1ure. In your response, you stated that the University of Wisconsin will utjlizc the University of Wisconsin Hospital as a quarantine facility in the event of a high-risk exposure to mammalian￾transmissible strains of HSN!. Your response also included an updated standard operating procedure (SOP) that reflects this change. •

redacted by agreement December 24, 2013 Page 2 Cm1L'l!ms rel"tiug to bio.wfetr pmclices Both of our December 16, 2013, letters conveyed our concerns regarding the biosafoty practices associated with each incidcnl. Spccific,11ly, we were eonccmc<l that a researcher's personal protective equipment did not cover his ankles while in the ABSL3+ laboratory, creating an opportunity for dermal exposure lo hazardous agents. We were also concerned that a researcher had used a needle to collect lissuc culture supernatant in violation of the University of Wisconsin's own policies, which 011ly pcnnit needles to he used in the ABSL3+ laboratory to anesthetize research animals, drnw blood from research animals, or inoculate eggs. With regard to the issue of bare skin, your response slates that the principal i nvcstigalor will require that high-top booties be worn umkrncath the researcher's tyvek suit and inside of the dedicated clogs. ·n1e dogs will then be covered with regular shoe covers. This change has been incorporated into the SOPs for the laboratory, and you have provided OBA a copy of that SOP. We also understand from your letter that you arc rcgucstin~ clarification regarding the issue of exposed skin in relation to Purified Air Pmvcrcd Respirators, which \Ve will respond to in a separate communication. With respect to the nccdlestick incident, your response states that the University has conducted two training sessions since this event. The first session was aimed al all current and future biocontainment laboratory researchers and was led by a senior scientist at the University of Wisconsin. The second session ,vas led by two senior scientists, and the slides from that training event have been included in your response. 1\dditionally, the SOPs for sharps use in lhc ABSL3+ laboratory have been revised to be more specific. The new SOP articulates that sharps will only be used when administering drugs to an animal or drawing blood from an animal. When either of these procedures are being performed with mammalian-transmissible influcn7..a viruses, two individuals will be required to be present for the procedure. With respect to the issues above, the University of Wisconsin response is now t:onsistcnt with the requirements of the NIH Guide!;nes. which arc a term and condition of the funding or this project. As such, the resumption of research involving mnmmalian-transmissiblc strains oflI5Nl is appropriate as our biosafety concerns have been addressed. In the meantime, i r you have any questions about this letter, please Ice! free to co11tacl us. s· ly, . uelinc ., M.D. i Cling Di })nice of Biotechnology Activities V

redacted by agreement December 24, 2013 Page 3 cc: Redacted by agreement Capt. Robbin Weyant, Ph.D., Director. Division of Sc Ice\ Agents and Toxins. CDC Freeda E. Isaac. D.V.M., Director, Agriculture Select Agent Program, USDA /\PHIS Amy P. Patterson, M.D., Associate Dircclor for Science Policy. Nll I Sally Rockey, Ph.D .. Deputy Director for E.xlrmnural Research, NII I Mary Kirker, Program Director, Grants Management Program. NIAID, NIH Matthew Fenton, Ph.D., Director, Division of Extramurnl Activities, NIAID, Nil-I Victoria Connors, Hranch ChicL Grants Management Program, NIAID, NIH Teresa Haugucl, Ph.D., Program Offic~r. NIA ID. NI 1-1 Dinne Dean, Director. Division of Grants Compliance and Oversight, OER, NIH

December 20, 2013 Jacqueline Corrigan-Curay, M.D., J.D. Acting Director Office of Biotechnology Activities National Institutes of Health 6705 Rockledge Drive Suite 750, MSC 7985 Bethesda, MD 20892 Dear Dr. Corrigan-Curay: TH£ UNIVERSITY ----q/---- WISCONSIN MADISON Thank you for the opportunity to respond to your letter dated December 16, 2013 regarding questions NIH OBA has about an incident at our institution where a researcher used a needle inappropriately and in the process acquired a needle stick. In response to this incident, there have been two training sessions so far to discuss this event. The first was a questions and answer session on November 19, 2013 involving all current and future biocontainment laboratory researchers. This was directed by a senior scientist and the University of Wisconsin Select Agent Program's trainer. They discussed the use the sharps in the containment labs. The second training session occurred on December 18, 2013 and was led by two senior scientists and the Select Agent Program trainer. The training materials are provided with this memo. In summary, the sharps standard operating procedure (SOP) has been revised to be more specific and modify current procedures to make them safer. Sharp needles will only be used for administering drugs to animals and drawing blood from animals. When either of these procedures are being done with reconstructed 1918 influenza virus or mammalians transmissible influenza viruses, two people will be required for the procedure. When inoculating eggs, only blunt or dispensing needles will be allowed. Lastly, the SOP was also updated to include the appropriate cleaning of necropsy tools. In regards to the second matter described in your letter, we have determined that your suggestion of a hospital isolation room at the University of Wisconsin Hospital is the best option to comply with the requirement to have a dedicated facility outside of a personal residence to quarantine. The University spent a significant amount of time enhancing our influenza exposure control plan in 2012. At that time, the University, our health care providers, and the Department of Public Health debated the best place for quarantine and determined that complications could arise with hospital quarantine. Based on these complications, they felt a home quarantine was appropriate for all exotic influenza viruses. When consulted about NIH OBA's requirement, our health care providers reiterated concerns but they have agreed to provide this service for us so our program is in compliance with the terms and conditions of the grant. Attached are the revised exposure control plan and exposure SOP reflecting these changes. The changes are effective immediately. Graduate School Bascom Hall University of Wisconsin-Jiaclison 500 Lincoln Drive :Madison, W'l 53706-1380 Dean's Office 608-262-1044 Fu:: 60S/262-5134 Graduate Admissions & Academic Sen-ices, Diversity Resources 608/262-2433, F:ax: 608i265-9505 Accounanc 608/:262-5835 Fu: 608/262-5134 Human Resources 608/262-5802 Fu: 608/262-5235 P.rofessio.nal De-.,eJopment & Engagement ~S/262-2433,. Fu:: 608/262-5134

Jacqueline Corrigan-Curay, J.D, M.D. December 20, 2013 Page 2 It should be noted no work has been performed with mammalian transmissible H5Nl viruses at the University of Wisconsin-Madison since the start of the moratorium in January 2012. Currently, there are no plans over the next several months to resume experiments with these viruses. University administration will be informed before the experiments with mammalian transmissible H5Nl viruses resume. Please contact me if you have any questions or concerns. Sincerely, Redacted by agreement Associate Vice Chancellor for Research Policy Attachments: IRI Sharps SOP Incident Follow-up Training Materials - November 19, 2013 Incident Follow-up Training Materials - December 18, 2013 IRl Exposure Plan (Overview) IRI Exposure Plan (SOP)

IRI SOP# 18 Sharps Injury from sharps is a significant concern in the BSL-3 laboratories. All work must be done in a manner that reduces the risk of sharp injuries. Sharps are laboratory items such as needles, scissors, and broken glassware. This SOP will list the precautions that must be taken when working with sharps. Needles Careful handling of needles is very important. Used needles must not be bent, sheared, broken, recapped, removed from disposable syringes or otherwise manipulated by hand before disposal. The used syringe with needle must go directly into a sharps disposal container. The sharps disposal container must be located at the work site. Do not overfill the sharps disposal containers. Once used syringes and other sharps reach the "fill-line", properly dispose of the container and start a new container. When possible, the use of safety glide needles is recommended when working with animals. Sharp needles should only be used for the following: administrating drugs to animals drawing blood from animals If the procedure is being performed on an animal infected with a recombinant virus with one or more genes from the 1918 virus or a mammalian transmissible influenza virus of avian origin, the procedure must be performed in the presence of another researcher. For the inoculation of eggs and harvesting virus from eggs, only dispensing needles are allowed. Necropsy tools Scissors used with forceps should be the primary tools used to perform necropsies. Instruments should be carefully and properly cleaned using a brush and stored in properly labeled, hard-walled containers when not in use. If necropsies are performed on animals infected with a recombinant virus with one or more genes from the 1918 virus or a mammalian transmissible influenza virus of avian origin, the procedure must be performed in the presence of another researcher. Broken Glassware Every effort must be made to minimize the use of glass in the BSL3 suites. Plastic containers and bottles must be substituted whenever possible. In the event that glass is broken, it must not be handled directly. Instead it should be picked up with tongs, forceps, or a broom and dustpan. Broken glass must be placed in a sharps container for autoclaving and disposal.

IRI Incident Follow-up Training November 19'", 2013 Trainers: Influenza Research Institute UW Environment Health and Safety Select agent researchers in Yoshi Kawaoka's laboratory attended a meeting on November 19th in response to two laboratory incidences that had recently took place in the containment labs of the IRI, a biohazardous spill, and a needle stick. - started the training session with an interactive power point regarding risk assessment and risk mitigation. As a group researchers were asked to list what the risks are for conducting the following three tasks: • Entry into a BSL-3 suite • Emptying the BSL-3 trash • Inoculating eggs in the BSL-3 Then researchers were asked for ways in which they mitigate the risks associated with those activities. - asked researchers to always ask themselves "is what I am doing safe?" and to be consciously thinking about all of their actions in BSL-3 also reiterated that if you are unsure or do not know what you are doing, ask someone before proceeding, and if you are doing a procedure that you have never done before in BSL-3 containment, you must discuss this procedure with - - before starting the research. The use of sharps in the BSL-2 and BSL-3 was reviewed. Each researcher was asked to fill out an assignment with the following questions on it: • Do you use disposable sharps (e.g., syringe needles, razor blades) for any of the research you perform in either the BSL-2 or BSL-3 laboratory? • If yes, please list the types of procedures that require sharps use. • Describe the methods you use to reduce the danger associated with sharps in your research. Researchers shared ways they mitigate risk when handling sharps in the BSL-3 containment laboratories. finished the session by discussing the biohazard spill incident. The researcher involved in the spill incident was asked to talk the group though exactly what happened and demonstrate was holding the plates when the incident occurred. Following the reenactment the researcher was interviewed a bout different aspects of the incident so that researchers cou Id learn firsthand what it might feel like to have an accidental spill. Here is a sampling of the questions asked: • Did you carry the plates any differently that day than you normally do? • What was the first thought that came to your mind when you dropped the plate? • Did you consult the spill protocol?

• What was the hardest or most challenging part of the spill clean-up process? • Did you have all of the spill supplies available and in the room with you for clean up? • Did you ever have a moment when you panicked? • What was running through your head? • What was your worst fear? Quarantine? • At what point did you contact your family? Were you updating them as things went along or did you wait until the final decision was made? Why? • What was the worst part of this process? • Is there a part of the process that you would change? • Is there anything that you would do differently? After the discussion researchers were reminded to take care of themselves both physically and mentally and that if they arc having an off day or feel like they are not fit to work in the laboratory they should say something and make arrangements to have a partner in the laboratory with them or arrange for someone else to take over their project.

Risk assessment and risk mitigation apply to every single thing you do in the BSL-3. laboratory.

Risk assessment: What are the dangers associated with each action you perform? Example: entry into a BSL-3 suite Example: emptying the trash Example: egg inoculation

Risk mitigation: How do you protect yourselfrom the dangers associated with a particular activity? Example: entry into the BSL-3 suite Example: emptying the trash Example: egg inoculation

Always ask yourself: Is what I am doing safe? . If you don't know: Ask someone before proceeding·

If you are performing aprocedure you've never done before in BSL-3, ... you must discuss this procedure with a senior scientist before starting. This applies even to procedures you have performed many times in BSL-2.

Sharps Training 12/18/2013 Points to Cover: Stress that sharp needles may only be used for drug injections or blood draws. Indicate the needle must never be manipulated once on the syringe. Infection of eggs: NO SHARP NEEDLES; only dispensing needles Do not hold egg in your hand; keep in egg holder lnjectables: Don't recap needle, use holder Work in pairs if animal is infected with certain viruses* Blood draws: Use of safety-lock needles: Work in pairs if animal is infected with certain viruses* Necropsies: Work In pairs Spread the work out if possible to avoid fatigue Avoid scalpels Use forceps to keep fingers away from sharps Work in pairs if animal is infected with certain viruses* Use a brush to dean tools Store tools in a hard-walled, labeled container when not in use. Keep the container in an easily visible location. Disposal of sharps inside the biosafety cabinet: Always keep a sharps container inside the BSC Do not overfill Do not place hands inside the opening of the sharps container Pull disinfectant into needles before dropping them into a sharps container. Close the container before removing from the BSC * Recombinant viruses with one or more genes from 1918 virus or transmissible HSNl or H7N9 viruses

Changes to the Use of Sharps SOP #18

Purpose of this training: 1) Reduce the use of sharps in the lab 2) Prevent accidents when sharps are u5 by modifying our practices

Areas Identified Where Sharps are Used

Areas Identified Where Sharps are Used Propagation of virus in eggs Injectable drugs Blood draws Necropsies

Areas Identfied Where Sharps are Used Propagation of virus in eggs - eliminate Injectable drugs - modify Blood draws - modify Necropsies - modify

Areas Identified Where Sharps are U Propagation of virus in eggs - eliminate

Areas Identified Where Sharps are Used Propagation of virus in eggs - eliminate All sharp needles have been removed from the 1918 lab and the HS lab. • ! -· .- - - l Do not bring any sharp need I 1 into these BSL-3 labs. ·,.1·, .. :~~· \ .. ,<--·, '.ih

Areas Identified Where Sharps are Used Propagation of virus in eggs - eliminate The use of dispensing needles is manda· • [ Both in BSL-2 and BSL-3, lfi 1i l !I .,,, 1 . ~, ~-;;_._. ·i~

Areas Identified Where Sharps are Used Propagation of virus in eggs - eliminate The use of dispensing needles is manda· If the gauge or length needs to be changed, please email

Areas Identified Where Sharps are Used Propagatio·n of virus _in eggs - modify

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Areas Identified Where Sharps are Used Propagation of virus in eggs - Any questions ?

Areas Identified Wher~ Sharps are Used Injectable drugs and blood draws

Areas Identified Where Sharps are Used Injectable drugs and blood draws - Sharp needles are required for these procedures - Modifications to be safer

Areas Identified Where Sharps are Used Injectable drugs Modifications to be safer Know where your needle is - Needle stand Do not· recap ;; I r .... , .. 'l.:)~:;-...... •, J\_ •..

Areas Identified Where Sharps are Used Blood draws - Modifications to be safe·r - I SafetyGlide Needles

Areas Identified Where Sharps are Used Injectable drugs and blood draws Keep fingers, hands, etc. away from the sharp end of the needle.

Areas Ide·ntified Where Sharps are Used Injectable drugs and blood draws Any questions ?

Areas Identified Where Sharps are Used Necropsies

Areas Identified Where Sharps are Used Necropsies - spread out the work - avoid scalpels - use forceps, not your fingers to pull/ RARC will set up training in Jan/Feb

Areas Identified Where Sharps are Used Necropsies - maintenance of necropsy tools Brushes to clean after use Hard-walled, labeled containers

Buddy System For any procedure involving sharps and any virus, it is recommended to have a research partner to assist.

Buddy System For any procedure involving sharps and any virus, it is recommended to have a research partner to assist. - BSL-3 animal lab tech

Buddy System It is REQUIRED to have another researcher present and assisting when sharps are being used when working with Transmissible avian influenza viruses Recombinant virus with 1 or more genes from 1918 virus

Disposi'ng of Sharps Immediately dispose of used sharps in a Sharps Container DO NOT OVERFILL

General Summary We need to communicate more Think about our actions Stay focus Cannot have more accidents But MUST report any incidents , even the most minor

Sharps Summary No sharps in the BSL-3 labs Dispensing needles for eggs Needle stands, SafetyGlide needles Working with a partner Do NOT overfill the used sharps container

Where do we go from here RARC animal training One-on-one training for sharps Standard virus propagation in eggs training

IRI SOP #48 Exposure Plan - Influenza Viruses At the Influenza Research Institute (IRI) the following influenza viruses are used in our BSL-3+ and BSL-3 Agriculture (Ag) laboratories: - Highly pathogenic avian influenza viruses such as H5N1 viruses - Human H2N2 viruses - H1N1 viruses such as 1918 "Spanish" influenza viruses - H7N9 viruses All viruses used at the IRI are susceptible to current antiviral therapies such as Tamiflu and Relenza. In addition, all laboratory researchers are immunized yearly with the seasonal influenza vaccine. When available, researchers will also receive a H5N1 influenza vaccine. In the event of an accidental exposure (i.e., a "known exposure") or the development of reportable influenza￾like symptoms (listed below) without a known exposure, individuals must follow the procedures outlined below. KNOWN EXPOSURE Examples of Known Exposures - Needle stick - Animal bite - Failure of personal protective equipment (PPE) - A large spill of infectious agent outside of a biosafety cabinet Response to Known Exposures o In the event of a mucosal exposure, wash the affected area with running water for 15 minutes. o In the event of a needle stick or an animal bite, spray the affected area with 70% EtOH, and then wash with running water for 15 minutes. o In the event of a large spill, follow the Large Biohazard Spill SOP (SOP #32). This type of a spill is a potential exposure/release and is reportable to the CDC. Each situation will be evaluated by Biosafety to determine the potential exposure risk to the individual and they will consult with the infectious disease doctors to determine whether or not antiviral medications should be prescribed or a quarantine period is necessary. o Notify the on-call scientist by calling the emergency iPhone researcher on the two-way radio. or by contacting a o The IRI on-call scientist will notify 1) alternative (ARO). and 2) the Responsible Official (RO) or o The RO or ARO will contact the Infectious Disease (ID) consult team by calling the University of Wisconsin (UW) hospital operator at __ The ID Consult team will determine what actions are required. The RO or ARO will also promptly notify all appropriate local, State, and Federal agencies. o If medical attention is needed (e.g., stiches), the on-call scientist will bring the exposed individual, who will be wearing an N-95 respirator without an exhalation valve, to the UW ER for medical attention.

o If the exposure is of "high risk" defined as an exposure of the respira~ory tract or mucous membranes with a recombinant virus containing one or more genes of the 1918 virus or a mammalian transmissible influenza virus of avian origin, the exposed individual will be quarantined in an isolation room at the University of Wisconsin Hospital. The on-call scientist will transport the exposed individual who will be wearing an N-95 respirator without an exhalation valve to the University of Wiscon$in Hospital. The individual will be quarantined until the Wisconsin Department of Public Health has determined it is appropriate for the individual to return to their personal residence. o If the exposure is of "high risk" defined as an exposure of the respiratory tract or mucous membranes with a non-transmissible influenza virus of avian origin,,the exposed individual will be quarantined to their personal residence provided they have started on the treatment dose of Tamiflu (75mg twice a day) within 5 hours of the time of exposure. o If the exposure is of "low to moderate risk" defined as an exposure not involving the respiratory tract or mucous membranes with any BSL-3 influenza virus, the exposed individual will be quarantined to their personal residence provided they have started on the treatment dose of Tamiflu (75mg twice a day) within 5 hours of the time of exposure. o Individuals will be prescribed antiviral medications by the ID consult team and will be quarantined for 4-14 days after the exposure, as determined by state health officials. Individuals will adhere to the guidelines in the University of Wisconsin "Quarantine and Isolation Policy." o During the quarantine period, throat gargles, throat swabs, and nasal swabs will be collected from the individual at the quarantine apartment twice a day (A.M. and P.M.) by trained UW staff from the individual and diagnostic testing will be performed as described below. rm addition, the quarantined individual will record their own bod tern erature (A.M. and P.M.) and email or phone this information to the on-call scientist and ~;,~!~~~i°Y The health of the individual will be monitored by medical professionals at the U unng vIsI ations. A daily summary of the· diagnostic tests and temperatures will be emailed to all parties involved. o If, during the home quarantine period, the individual develops influenza-like symptoms and/or tests positive for influenza virus, the individual, who will be wearing an N-95 respirator without an exhalation valve, will be transferred to the UW hospital for medical care in an isolation room. o If the individual does not develop any influenza-like symptoms and/or repeatedly tests negative for influenza virus, the individual will be released at the end of the quarantine period. UNKNOWN EXPOSURE WITH REPORTABLE INFLUENZA-LIKE SYMPTOMS If a researcher who has been working with the viruses previously listed, develops influenza symptoms within 1 0 da s after their last BSL-3 entry, the researcher must immediately contact the on-call scientist and Redacted by agreement Reportable Symptoms: Fever (temperature> 100° F) Myalgia - sore muscles, body aches Nonproductive cough - dry cough Rhinitis - runny nose Sore throat Conjunctivitis - red, swollen eyelids Fatigue (when clustered with other symptom(s)) Headache (when clustered with other symptom(s)) Response to Unknown Exposures with Reportable Symptoms:

o A throat gargle, throat swab, and nasal swab will be collected from the individual for diagnostic testing (see below). Samples that are positive for 1918 (H1), H2, HS, or H7 viruses will be split and sent to the Centers for Disease Control for independent verification of the results. o Home quarantine of all household members is required until the diagnostic tests come back negative. During this time period, individuals will adhere to the guidelines in the UW "Quarantine and Isolation Policy." o A positive diagnostic test for 1918 (H1 ), H2, HS, or H7 viruses will result in the transfer of the individual, who will be wearing an N-9S respirator without an exhalation valve, to the UW hospital for medical care. o Individuals must disclose the agents (i.e., viruses) that they have been working with to the ID consult team at the UW hospital. o The names of all people in contact with the infected individual will be provided to University Health Services within 48 hours. o If a researcher tests positive for 1918 (H1), H2, HS, or H7, then all other household members will be quarantined for 4-14 days, as determined by state health officials. o During the quarantine period, throat gargles, throat swabs, and nasal swabs will be collected from all household members twice a day (A.M. and P.M.) by trained UW staff. In addition, quarantined individuals will record their temperatures twice a day (A.M. and P.M.) and email or phone this information to the on-call scientist. The health of th~ individual will be monitored by medical professionals at the UW during home visitations. A daily summary of the diagnostic tests and temperatures will be emailed to all parties involved. o If during the quarantine, household member(s) develop influenza-like symptoms and/or test positive for influenza virus, the individual(s), who will be wearing an N-95 respirator without an exhalation valve, will be transferred to the UW hospital for medical care in an isolation room. o If household member(s) do not develop any influenza-like symptoms and/or test negative for influenza virus, the individual(s) will be released at the end of the end of the quarantine period. DIAGNOSTIC TESTING o Individuals must give the required samples for diagnostic testing. These include Throat gargles Throat swabs • Nasal swabs o Samples will be collected by trained members of the swab team (IRI researchers or other UW staff members). o A rapid diagnosis Directigen AB kit for influenza virus and established RT-PCR protocols will be conducted for H1, H2, H3, HS and H7 influenza viruses, as required, and will be completed within 8 hours from the sample collection. o Samples positive for 1918 (H1 ), H2, HS, or H7 will be split and sent to the Centers for Disease Control for the independent verification of results.

CALL SYSTEM FOR REPORTING KNOWN EXPOSURES AND INFLUENZA-LIKE SYMPTOMS The following people should be notified immediately after a known exposure occurs, or as soon as influenza￾like symptoms develop: o The IRI on-call scientist via the on-call iPhone 0 fedacted by agreement I o The on-call scientist will notify the RO or ARO at the Office of Biological Safety Contact Information: Principal Investigator Yoshihiro Kawaoka Responsible Official Alternate Responsible Official Alternate Responsible Official Scientist Scientist Researcher • Scientist Revised: 12/2013 redacted by agreement

December 20, 2013 Jacqueline Corrigan-Curay, M.D., J.D. Acting Director Office of Biotechnology Activities National Institutes of Health 6705 Rockledge Drive Suite 750, MSC 7985 Bethesda, MD 20892 Dear Dr. Corrigan-Curay: -THE UNIVERSITY WISCO_N_S1-N MADISON Thank you for the opportunity to respond to your letter dated December 16, 2013 regarding questions NIH OBA has about a small spill onto the floor of one our ABSL-3+ laboratories. Specifically, corrective action was requested in regards to exposed skin around the ankle of the researcher involved in the incident. In an effort to comply with the spirit of the guidelines and in response to your memo, the principle investigator of the laboratory where the spill occurred has ordered high-top booties that will be worn underneath the tyvek suit and inside of the dedicated clogs which will be covered with normal shoe covers. Included with this memo are copies of the updated standard operating procedures for entry into the principle investigator's laboratories incorporating the change with the PPE. A highest priority at UW-Madison is to assure that we are in complete compliance with federal regulations regarding select agent research. However, on occasion we have received mixed messages from agencies regarding aspects of our program, and this is a case in point. This was the first instance where we have been informed that our personal protective equipment (PPE) for RG3 influenza viruses was inadequate. Our researchers wear P APRs, tyveks, shoe covers, dedicated garden clogs, shoe covers, and two pairs of gloves. Our university's select agent program has been inspected IO separate times since the creation of the Federal Select Agent Program (FSAP) with 8 of those inspections involving RG3 influenza viruses. During these inspections, FSAP Inspectors from the Centers for Disease Control (CDC) and Animal and Plant Health Inspection Service (APHIS) enter into our laboratories wearing full PPE and exit in the same manner as our researchers do on daily basis. Our most recent FSAP inspection was in August 2013 and there was no mention of the PPE being inadequate. As required by the Federal Select Agent Program we notified the CDC and APHIS of the spill within a few hours of the incident and the report was reviewed by both agencies with APHIS handling the correspondence since the agent involved falls under their purview. We received a memo dated November 20, 2013 from an APHIS compliance manager, who reviewed our spill report that stated "At the time of incident the researcher was wearing appropriate personal protective equipment." Since our phone conference call with NIH on December 16, Graduate School Bascom Hall Univenity of Wiscomin-1.fadison 500 Lincoln Drive lfadison, \\'7153706-1380 Dean's Office 60B-262-1044 Fax: 608/262-5134 Graduate Admissions & Academic Sen-ices, Diversity Resources 608/26.2-2433, F.ar. 608/265-9505 Accounting 608/262-S83S Fax: 606/262-5134 HUD1an Resources 608/262-5802 l¼x: 608/262-5235 Profusional Development & Engagttn1ent 608/262-2433. F-ax: 608/26.2-5134

Jacqueline Corrigan-Curay, M.D., J.D. December 20, 2013 Page2 2013 we have received a more recent memo from AP HIS dated December 17, 2013 stating after further review, they are concerned about the bare skin. We are requesting clarification from NIH Office of Biotechnology Activities (OBA) in regards to this policy. Appendix G-II-C-5-a ( I) does not specifically mention the requirement of no exposed skin nor does it discuss the type of PAPR a researcher working with RG3 influcn:r.a viruses should wear. As you know, many PAPRs lack shrouds and leave the researcher's neck exposed. Does the no-bare-skin requirement apply for all RG3 influenza viruses including wild type viruses or just mutant/reassortant viruses? The reason we ask is we would like to be consistent across all RG3 influenza virus laboratories at our institution. Further, we assume that many other institutions engaged in RG3 influenza research use safeguards similar to ours. They also would benefit from clarification of exposed skin and PAPR requirements. Please contact me if you have any questions or concerns. Sincerely, Redacted by agreement Associate Vice Chancellor for Research Policy Attachments: Three SOPs for entry to facilities

Entry into BSL-3+ ( The normal hours of operation for the BSL-3 suites are from 6:00 a.m. to 10:00 p.m. If you are oin to be in the BSL-3 suites after 8:00 p.m., you must notify the person on-call at and noti edacted by agreement y email. IRI SOP#S Individuals working in the BSL-3+ suite must wear the following personal protective equipment (PPE): • - a water resistant Tyvek suit - disposable latex or nitrile exam gloves - dedicated shoes covered by a pair of shoe covers (blue) - a powered air purifying respirator (PAPR) must be worn when working with highly pathogenic avian influenza (HPAI) viruses. To ensure exposed .skin around the wrists and ankles is properly covered, researchers are required to wear long cuffed gloves and/or protective sleeves and white Tyvex foot covers. If you choose to wear an N100 respirator for work with Ebola~VP30 viruses or during periods when no virus materials are being used in the suite, you must also wear: - a hair cover - safety glasses PPE can be found in the clean gown room - along with posted signs listing the procedures for entering the BSL-3+ suite. Entry Procedure: 1) Fill-in the "BSL-3+ Sign-In/Out" sheet (Form# 13a). 2) Enter the clean gown room (-. turn on the In Use light, remove all street clothes, and change into scrubs. 3) Put on the white Tyvek foot covers, Tyvek suit, dedicated laboratory shoes covered by shoe covers (blue), tong cuffed gloves and/or protective sleeves and either a PAPR or an N100 with a hair cover and safety glasses. 4) Walk through shower into the dirty gown room-· 5) If you are wearing a PAPR: o Test the battery using the indicator strip on the back-side of the battery o Perform an airflow test to verify that the HEPA filter is not clogged • Insert the airflow indicator into the blower unit and turn the unit on • The middle of the test ball must pass the "6 cfm" line If the airflow test fails, select a different blower unit. Affix a label to the malfunctioning blower unit and report the test failure to the tab supervisor o Check to make sure the HEPA filter cover and hose is securely attached to the blower unit, and the hose is securely attached to the hood. In addition, make sure there are no tears or punctures in the hood. 6) Using the secure key access, enter the BSL-3 laboratory and turn off the In Use light. Revised 12/17 /2013jRedacted by agreement

IRI SOP# 7 Entry into ABSL-3+ ( ) The normal hours of operation for the BSL-3 suites are from 6:00 a.m. to 10:00 p.m. If you are going to be in the BSL-3 suites after 8:00 p.m., you must notify the person on-call at and notifyfedacted by agreement !byemai I. • Individuals working in the ABSL-3+ suite must wear the following personal protective equipment (PPE): a water resistant Tyvek suit disposable latex or nitrile exam gloves (two pairs of disposable gloves if working with animals) dedicated shoes covered by a pair of shoe covers (blue) a powered air purifying respirator (PAPR) must be worn when working with virus materials. To ensure exposed skin around the wrists and ankles is properly covered, researchers are required to wear long cuffed gloves and/or protective sleeves and white Tyvex foot covers. If you choose to wear a N 100 respirator during periods when no virus materials are being used in the suite, you must also wear: a hair cover safety glasses If you are working with potential mammalian transmissible influenza viruses, you must also wear: a second pair of disposable latex or nitrile exam gloves protective sleeves PPE can be found in the clean anterior room(-) of the ABSL-3+ suite along with posted signs listing the procedures for entering the ABSL-3+ suite. Entry Procedure: 1) Enter the men's or women's locker room ( 2) Remove all street clothes in the locker room and change into scrubs, shoe covers over your feet, hall shoes, and shoe covers over the hall shoes. 3) Bring a clean set of scrubs and a towel with you and then exit the locker rooms into the secure clean corridor. 4) Fill-in the "BSL-3+ Sign-In/Out" sheet (Form# 13b). 5) Turn on the In Use light, enter into clean gown room ( ) using the remove hall shoes. 6) Put on the white Tyvek foot covers, Tyvek suit, dedicated laboratory shoes covered by shoe covers (blue), long cuffed gloves and/or protective sleeves. If you choose to wear a N100 respirator, also put on a hair cover and safety glasses. If you are working with potential mammalian transmissible influenza viruses, you must also wear a second pair of disposable gloves and protective sleeves. 7) Walk through the shower. 8) If you are wearing a PAPR: o Test the battery using the indicator strip on the back-side of the battery

o Perform an airflow test to verify that the HEPA filter is not clogged Insert the airflow indicator into the blower unit and turn the unit on The middle of the test ball must pass the "6 cfm" line If the airflow test fails, select a different blower unit. Affix a label to the malfunctioning blower unit and report the test failure to the lab supervisor o Check to make sure the HEPA filter cover and hose is securely attached to the blower unit, and the hose is securely attached to the hood. In addition, make sure there are no tears or punctures in the hood. 9) Enter the BSL-3 laboratory through the dirty gown room(_), and turn off the In Use light. Revised 12/17/2013jRedacted by agreement

Entry into ABSL-3Ag The normal hours of operation for the BSL-3 suites are from 6:00 a.m. to 10:00 p.m. If you are going to be in the BSL-3 suites after 8:00 p.m., you must notify the person on-call at and notifylRedacted by agreement lby email. IRI SOP#9 Individuals working in the ABSL-3Ag suites must wear the following personal protective equipment (PPE): a water resistant Tyvek suit two pairs of disposable latex or nitrile exam gloves dedicated shoes covered by a pair of shoe covers (blue) a powered air purifying respirator (PAPR) must be worn when working with virus materials To ensure exposed skin around the wrists and ankles is properly covered, researchers are required to wear long cuffed gloves and/or protective sleeves and white Tyvex foot covers. lf you choose to wear an N100 respirator during periods when no virus materials are being used in the suite, you must also wear: a hair cover safety glasses If you are working with potential mammalian transmissible influenza viruses, you must also wear: protective sleeves PPE can be found in the clean gown room (- of the ABSL-3Ag suite along with posted signs listing the procedures for entering the ABSL-3Ag suite. 1) Enter the men's or women's locker room ( 2) Remove all street clothes in the locker room and change into scrubs, shoe covers over your feet, hall shoes, and shoe covers over the hall shoes. 3) Bring a clean set of scrubs and a towel with you and then exit the locker rooms into the secure clean corridor. 4) Fill-in the MBSL-3+ Sign-In/Out" sheet (Form# 13c). 5) Turn on the In Use light, enter into clean gown room (- using the remove hall shoes. 6) Put on the white Tyvek foot covers, Tyvek suit and long cuffed gloves and/or protective sleeves. If you choose to wear an N100 respirator, also put on a hair cover and the N100 respirator. • If you are working with potential mammalian-transmissible influenza viruses, you must also wear protective sleeves. 7) Leave the clean set of scrubs in a locker and take the towel with you. Enter the shower room through the Presray door (SOP# 10). Hang the towel on a hook on the clean side of the shower. 8) Walk through the shower and into the dirty gown room (- through the Presray door. 9) If wearing a PAPR: o Test the battery using the indicator strip on the back-side of the battery o Perform an airflow test to verify that the HEPA filter is not clogged

Insert the airflow indicator into the blower unit and turn the unit on The middle of the test ball must pass the "6 cfm" line If the airflow test fails. select a different blow unit. Affix a label to the malfunctioning blower unit and report the test failure to the lab supervisor o Check to make sure the HEPA filter cover and hose is securely attached to the blower unit, and the hose is securely attached to the hood. In addition, make sure there are no tears or punctures in the hood. 10) Put on the dedicated laboratory shoes, shoe covers (blue) over the shoes, and a second pair of disposable gloves. If wearing an N100, put on safety glasses. 11) Enter into ABSL-3Ag hallway and turn off the In Use light 12) Follow the posted signs on the inside of the laboratory doors that outline the procedures for changing shoe covers, outer gloves and protective sleeves every time you leave each laboratory. Revised 12/17/2013 redacted by agreement

, .......... (,-'!/-loo.&:J) National Institutes of Health December 17, 2013 redacted by agreement I Vice Chancellor for Research and Dean of the Graduate School University of Wisconsin 3 3 3 Bascom Hall 500 Lincoln Drive Madison, WI 53706-1380 Dear redacted by agreement U.S. Public Health Service Bethesda, Maryland 20892 Office of Biotechnology Activities National Institutes of Health 6705 Rockledge Drive Suite 750, MSC 7985 Bethesda, MO 20892-7985 (301) 496-9838 (Phone) (301) 496-9839 (Fax) http://oba.od.nih.gov/ We are writing in regard to two incidents involving recombinant research with highly pathogenic avian influenza HPAI) H5Nl that have occurred recently in the ABSL3+ laboratory of Dr. Redacted by agreement fter reviewing the details of these two incidents, NIH has significant concerns relating to the University of Wisconsin's apparent lack of a dedicated quarantine facility other.than the researcher's home. We also have concerns relating to the biosafety practices associated with these incidents. Our concerns are detailed below. Lack ofa dedicated quarantine facility In the needlestick incident that occurred on November 16, 2013, a decision was made to home quarantine the individual because the route of exposure (needlestick) was not expected to place the researcher at high risk for infection and this influenza strain, which contained the HA gene from H5Nl, was determined not to be a mammalian-transmissible strain. However, in conversations with the Universit of Wisconsin Alternate Responsible Official, 1=Re--d-'-act.,...e..,.d b,...y-ag-re-e-me-nt,......., edacted by egarding this inciden edacted by nformed us that all researchers exposed to H5Nl areement • areement . would be quarantined at home, regar ess o the risk of infection or whether the strain was mammalian-transmissible or not. In a subsequent phone conversation with the University of Wisconsin Senior Associate Dean for Research Redacted by agreement the lie for home isolation for all incidents was reiterated to us. We were told by edacted by agreement that the decision was based upon consultation with University of Wisconsin infectious disease experts and the state health department. We were also informed that the use of a hospital room for quarantine was rejected due to the stress it would place on the laboratory worker.

redacted by agreement December 16, 2013 Page2 The University of Wisconsin's policy on home quarantine communicated to us bylRedacted byagreementl F edacted by agreementjis not in keeping with what was communicated to us in fedacted by agreement I application to the Department of Health and Human Services to perform research with mammalian transmissible strains ofHPAI HSNl. In a May 6, 2013, plan provided to NIH, Dr. • ndicated that he had access to a "designated quarantine apartment" in which researc ers could be laced for 10-14 days in the event of an accidental exposure (Attachment A). Redacted by agreement ave indicated to OBA that there was a miscommunication between the PI and the University of Wisconsin administration regarding the availability and appropriateness of such a quarantine apartment. The University of Wisconsin's policy on home quarantine is inconsistent with the requirements for this research under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines), and under the terms agreed to by the University as a condition of funding this project. The University of Wisconsin must find a dedicated facility outside of the individual's permanent residence (1} in which an individual exposed to mammalian-transmissible HPAI HSNl can be safely isolated for up to 10 days, and (2) that can be decontaminated easily after the individual's departure. An isolation room in a hospital would also be appropriate. An individual's permanent residence is not appropriate when the risk of infection is high. For high risk exposures, it is critical to isolate the individual in a structure that does not have shared air exchange and can be quickly and efficiently decontaminated in the case of infection. In addition, if this structure is outside of a health care facility, there needs to be a plan in place regarding how this researcher could be safely transported to an isolation room in a health care facility, should he or she develop clinical symptoms, without the risk of exposure to other individuals. Concerns relating to hiosafetv practices In addition to the quarantine issue, NIH has significant concerns regarding the biosafety practices associated with both of the recent incidents. The November 16, 2013, needlestick incident occurred when the researcher used a needle to collect tissue culture supernatant in violation of the University of Wisconsin's own policies, which only permits needles to be used in the ABSL3+ laboratory to anesthetize research animals, draw blood from research animals, or inoculate eggs. It was unclear from the University's response why this individual was using a needle for this type of procedure. The University of Wisconsin report regarding the November 9, 2013, HPAI HSNl spill described the researcher as having two to three inches of exposed skin between where his tyvek suit ended and his shoe covers began. While it was reported that none of the spilled material landed on the researcher's bare skin, we made it clear in our letter (Attachment A) and in a phone conversation withfedacted by agreement I that having bare skin in the ABSL3+ laboratory was unacceptable under the containment requirements for this research specified in the NIH Guidelines. During that phone conversation, redacted by agreement I stated that the ABSL3+ laboratory had recently undergone a Select Agent inspection and the report from that inspection did not specifically mention a prohibition against working in the ABSL3+ laboratory

redacted by agreement December 16, 2013 Page3 with bare skin. We have discussed the issue of bare skin in the ABSL3+ laboratory with the United States Department of Agriculture (USDA) Select Agent Program, and they are in agreement that bare skin is unacceptable at this level of containment. Attachments B and Attachment C to this letter contain the NIH response to both HSN I incidents. These letters contain requests for action regarding the quarantine situation and our biosafety concerns. We would appreciate any assistance you can provide to ensure that these requests are answered by December 23, 2013. Finally, if your response is not received by this date or if does not fully address the issues we have described regarding a dedicated quarantine facility and inappropriate biosafety practices, as required by the terms and conditions of rant award, NIH will institute enforcement action(s) for the NIH gran Redacted by agreement !Redacted by agreement I Principal Investigator. Such actions could include disaUowance of costs, suspension, or termination of the grant award. If you have any questions, please feel free to contact us._ ---- .. 0 at:) --, c;;,,,r.7/--~ -z:_/ {,;~! 1? v. = - ,,-- 7#" /1/ / Amy f Patterson, M.D. Sally Rockey, Ph.D. Associate Director for Science Policy Deputy Director for Extramural Research National Institutes of Health National Institutes of Health cc: "-edacted by agreement Capt. Robbin Weyant, Ph.D., Director, Division of Select Agents and Toxins, CDC Freeda E. Isaac, D.V.M., Director, Agriculture Select Agent Program, USDA APHIS _ Jacqueline Corrigan-Curay, J.D., M.D., Acting Director, Office of Biotechnology Activities, NIH

ATTACHEMENT A MAY 6, 2013, UNIVERSITY OF WISCONSIN INFLUENZA RESEARCH INSTITUTE EXPOSURE PLAN (redacted)

IRI SOP#48 Exposure Plan - Influenza Viruses At the Influenza Research Institute (IRI) the following influenza viruses are used in our BSL-3+ and BSL-3 Agriculture (Ag) laboratories: All viruses used at the IRI are susceptible to current antiviral therapies such as Tamiflu and Relenza. In addition. all laboratory researchers are immunized yearly with the seasonal influenza vaccine. When available, researchers will also receive a HSN1 influenza vaccine. In the event of an accidental exposure (i.e., a "known exposure") or the development of reportable influenza￾like symptoms (listed below) without a known exposure, individuals must follow the procedures outlined below. KNOWN EXPOSURE Examples of Known Exposures - Needle stick - Ani ma I bite - Failure of personal protective equipment (PPE) - A large spill of infectious agent outside of a biosafety cabinet Response to Known Exposures o tn the event of a mucosa! exposure, wash the affected area with running water for 15 minutes. o In the event of a needle stick or an animal bite, spray the affected area with 70% EtOH, and then wash with running water for 15 minutes. o In the event of a large spill, follow the Large Biohazard Spill SOP (SOP #32). o Notify the on-call scientist by calling the on-call iPhone researcher on the two-way radio. or by contacting a o The IRI on-call scientist will notify 1 ~~-ed-act_e_d_bY __ ~land 2) the Responsible Official (RO) or ~qreement . alternative (ARO). o The RO or ARO will contact the Infectious Disease (ID) consult team by calling the University of Wisconsin (UW) hospital operator at -- The ID Consult team will determine what actions are required. The RO or ARO will also promptly notify all appropriate local, State, and Federal agencies. o If medical attention is needed (e.g., stiches), the on-call scientist will bring the exposed individual, who will be wearing an N-95 respirator without an exhalation valve, to the UW ER for medical attention. a If no medical attention is needed, the on-call scientist will bring the exposed individual, who will be wearing an N-95 respirator without an exhalation valve, to the designated "quarantine apartment."

o Individuals will be prescribed antiviral medications by the ID consult team and will be quarantined for 10-14 days after the exposure, as determined by state health officials. Individuals will adhere to the guidelines in the University of Wisconsin "Quarantine and Isolation Policy." o During the quarantine period, throat gargles, throat swabs, and nasal swabs will be collected from the individual at the quarantine apartment twice a day (A.M. and P.M.) by trained UW staff from the individual at the Quarantine Apartment and diagnostic testing will be performed as described below. ln addition, the quarantined individual will record their own body temperature (A.M. and P.M.) and email or phone this information to the on-call scientist and!Redacteooyagreement The health of the individual will be monitored by medical professionals at the UW during visitations at the quarantine apartment. A daily summary of the diagnostic tests and temperatures will be emailed to all parties involved. o If, during the quarantine period, the individual develops influenza-like symptoms and/or tests positive for influenza virus, the individual, who will be wearing an N-95 respirator without an exhalation valve, will be transferred by emergency medical services (EMS) to the UW hospital for medical care in an isolation room. o If the individual does not develop any influenza-like symptoms and/or repeatedly tests negative for influenza virus, the individual will be released at the end of the quarantine period. UNKOWN EXPOSURE WITH REPORTABE INFLUENZA-LIKE SYMPTOMS If a researcher who has been working with the viruses previously listed, develops influenza symptoms within 10 da s after their last BSL-3 entry, the researcher must immediately contact the on-call scientist and edacted by agreement Reportable Symptoms: Fever (temperature> 100° F) Myalgia Nonproductive cough Rhinitis Sore throat Conjunctivitis Fatigue (when clustered with other symptom(s)) Headache (when clustered with other symptom(s)) Response to Unknown Exposures with Reportable Symptoms: o A throat gargle, throat swab, and nasal swab will be collected from the individual for diagnostic testing (see below). Samples that are positive for 1918 (H1 ), H2, H5, or H7 viruses will be split and sent to the Centers for Disease Control for independent verification of the results. o Home quarantine of all household members is required until a minimum of two diagnostic tests from different samples come back negative. During this time period, individuals will adhere to the guidelines in the UW "Quarantine and Isolation Policy." o A positive diagnostic test for 1918 (H1), H2, H5, or H7 viruses will result in the transfer of the individual, who will be wearing an N-95 respirator without an exhalation valve, by EMS to the UW hospital for medical care. o Individuals must disclose the agents (i.e., viruses) that they have been working with to the ID consult team at the UW hospital. o The names of all people in contact with the infected individual will be provided to University

Health Services within 48 hours. o If a researcher tests positive for 1918 ( H 1), H2, H5, or H7, then all other household members will be quarantined for 10-14 days, as determined by state health officials. o During the quarantine period, throat gargles, throat swabs, and nasal swabs will be collected from all household members twice a day (A.M. and P.M.) by trained UW staff. In addition, quarantined individuals will record their temperatures twice a day (A.M. and P.M.) and email or phone this information to the on-call scientist. The health of the individual will be monitored by medical professionals at the UW during home visitations. A daily summary of the diagnostic tests and temperatures will be emailed to all parties involved. o If during the quarantine, household member(s) develop influenza-like symptoms and/or test positive for influenza virus, the individual(s), who will be wearing an N-95 respirator without an exhalation valve, will be transferred by EMS to the UW hospital for medical care in an isolation room. o If household member(s) do not develop any influenza-like symptoms and/or test negative for influenza virus, the individual(s) will be released at the end of the end of the quarantine period. DIAGNOSTIC TESTING o Individuals must give the required samples for diagnostic testing. These include Throat gargles • Throat swabs • Nasal swabs o Samples will be collected by trained UW laboratory staff members. o A rapid diagnosis Directigen AB kit for influenza virus and established RT-PCR protocols will be conducted for H1, H2, H3, H5 and H7 influenza viruses, as required, and will be completed within 8 hours from the sample collection. o Samples positive for 1918 (H1), H2, H5. or H7 will be split and sent to the Centers for Disease Control for the independent verification of results. CALL SYSTEM FOR REPORTING KNOWN EXPOSURES AND INFLUENZA-LIKE SYMPTOMS The following people should be notified immediately after a known exposure occurs, or as soon as influenza￾like symptoms develop: o The \RI on-call scientist via the on-call iPhone 0 !Redacted by agreement I o The on-call scientist will notify the RO or ARO at the Office of Biological Safety Contact Information:

---··--- - - --- -- - -- - . - - - - - -· - - -------- -~------ Revised: 05/06/2013IRedacted by agreement

ATTACHEMENT B NIH OBA RES~ONSE TO UNIVERSITY OF WISCONSIN'S NOVEMB,ER 9, 2013, HSNl SPILL

... ~., ( •> National Institutes of Health December 16, 2013 f edacted by agreement Associate Vice Chancellor for Research Policy University of Wisconsin 327 Bascom Hall 3 500 Lincoln Drive Madison, Wisconsin 53 706 Dear redacted by agreement U.S. Public Health Service Bethesda, Maryland 20892 Office of Biotechnology Activilles Natlonal Institutes of Health 6705 Rockledge Drive Suite 750, MSC 7985 Bethesda, MD 20892-7985 (301) 496-9838 (Phone) (301) 496-9839 (Fax) http://oba.od.nlh.gov/ We are following up on our series of teleconferences regarding your November 15, 2013, report to the National Institutes of Health (NIH) Office of Biotechnology Activities (OBA) describing a November 9, 2013, incident in which a University of Wisconsin researcher spilled approximately 8 mL ofH5Nl'-containing media onto the floor of the ABSL3+ laboratory. According to your report, the spill occurred shortly after the researcher collected H5Nl culture . supernatant samples into three 6-well tissue culture plates. The researcher stacked the three plates on top of each other and transported the plates from the biosafety cabinet to the tissue culture incubator. After opening the door of the incubator, the researcher dropped one of the 6- well plates onto the laboratory floor. Immediately following the spill, the researcher closed the door to the incubator and returned the well plates that were not dropped to the biosafety cabinet. The researcher then picked up the dropped plate and immersed it in a chemical disinfectant solution within the biosafety cabinet. He then saturated his outer gloves with 70-percent ethanol, disposed of them in the biohazrdous waste bin and donned a new pair of outer gloves. At this time, the researcher noticed some of the spilled material had landed on his Tyvek suit just below the knee. In response, he applied 70- • percent ethanol to both the arms and legs of the suit, his shoe covers, and the uncovered skin between the bottom of the suit and his shoes. Next, the researcher cleaned the spill by covering the affected area with paper towels soaked in chemical disinfectant. After allowing 20 minutes for the towels to soak up the spilled material, the researcher mopped the floor using a viral disinfectant. The biosafety cabinet and the tissue culture incubator were then decontaminated using 70-percent ethanol. All cleanup materials were placed in a biohazardous waste bag for autocJaving. When the spill was fully cleaned up, the researcher phoned the on-call scientist to report th<; incident, removed his personal protective equipment, and reported to the building conference room to wait for further instructions.

redacted by agreement December 16, 2013 Page2 When the on-call scientist received the notification of the spill, he phoned the Alternate Responsible Official (ARO) and left a message describing the situation. The ARO returned the call, and was brief ed. The ARO then called the researcher involved in the incident to obtain additional information. She infonned the researcher to remain in the conference room while she consulted with the University of Wisconsin infectious disease physician. After considering the facts of the incident, the infectious disease physician determined that treatment with antivirals would not be necessary. This determination was based on the fact that the appropriate disinfection procedures had been used, and the risk of infection from any skin exposure would be low. The ARO nonetheless insisted that the researcher be given a prescription for Tami flu as a precautionary measure. The infectious disease physician agreed, and a prescription was written for the researcher. At that time, the ARO called the researcher and informed him that he was cleared to leave the building, and quarantine would not be necessary. The researcher was instructed to self-monitor for any change in body temperature and report any feelings of illness he experienced. The researcher began the Tamiflu course of treatment on the afternoon of • November 9. To date, no symptoms of illness have been reported by the researcher. While the actions taken by the University of Wisconsin in response to this incident appear appropriate, we do not consider it acceptable biosafety practice to have uncovered skin in an ABSL3+ laboratory. It was unclear from your original report whether any of the spilled media splashed onto the bare ankles of the researcher. In subsequent communications, the University of Wisconsin informed us that the researcher did not spill any of the material on his ankles; the spill was limited to the researcher's Tyvek suit and the laboratory floor. That said, to be compliant with Appendix G-11-C-5-a-(l) of the NIH Guidelines, researchers must be fully covered with no exposed skin when perfonning research with RG3 influenza strains, including HPAI HSNl. We have discussed the issue of bare skin in the ABSL3+ laboratory with the United States Department of Agriculture (USDA) Select Agent Program, and they are in agreement that bare skin is unacceptable at this level of containment. The University must take immediate action to ensure that, in the future, no workers in this or any other high containment laboratories have exposed skin. Please provide us with a corrective action that details how the University of Wisconsin will address this deficiency no later than December 23, 2013. Please contact OBA staff by email at oba@od.nih.gov or by telephone at (301) 496-9838 if you have any questions. Sincerely, ~l; C 1· cque me om cting Director ffice of Biotechnology Act ities I I I ) I I I I I

redacted by agreement December 16, 2013 Page 3 cc: Redacted by agreement Capt. Robbin Weyant, Ph.D., Director, Division of Select Agents and Toxins, CDC Freeda E. Isaac, D.V.M., Director, Agriculture Select Agent Program, USDA APHIS Teresa Hauguel, Program Officer, NIAID, Nlli Amy P. Patterson, M.D., Associate Director for Science Policy, NIH Allan C. Shipp, Director of Outreach, Office of Biotechnology Activities, NIH Ryan Bayha, Senior Analyst for Science Policy Outreach, Office of Biotechnology Activities, NIH Kathryn Harris, Ph.D., RBP, Senior Outreach and Education Specialist (contractor), Office of Biotechnology Activities, NIH

ATTACHEMENT C NIH OBA RESPONSE TO UNIVERSITY OF WISCONSIN'S NOVEMBER 16, 2013, HSN! NEEDLESTICK

,,..pflQ .. {_J Ill)) National Institutes of Health December 16, 2013 !Redacted by agreement Associate Vice Chancellor for Research Policy University of Wisconsin 327 Bascom Hall 3 500 Lincoln Drive Madison, Wisconsin 53706 DearlRedacted by agreement U.S. Public Health Service Bethesda, Maryland 20892 Office of Blotechnology Activities National Institutes of Health 6705 Rockledge Drive Suite 750, MSC 7985 Bethesda, MD 20892-7985 {301) 496-9838 (Phone) (301) 496-9839 (Fax) http://oba.od.nlh.gov/ We are following up on our series of teleconferences regarding your November 17, 2013, and November 19, 2013, report to the National Institutes of Health (NIH) Office of Biotechnology Activities (OBA) describing a November 16, 2013, incident in which a University of Wisconsin researcher stuck himself with a syringe containing a recombinant fonn of HSN 1. The virus contained the HA gene from H5Nl while the remaining genes came from HlNl A/California (2009 HlNl) strain. The needlestick occurred in the ABSL3+ laboratory while the researcher was attempting to collect tissue culture supernatant. Immediately following the incident, the researcher sprayed the wound site with disinfectant and washed the site of the wound for fifteen minutes. The researcher contacted the laboratory manager and reported the exposure. The laboratory manager then infonned the Alternate Responsible Official (ARO) of the incident and requested that the University of Wisconsin infectious disease physician be contacted for a consultation. The laboratory manager called the researcher back and instructed him to put on a new pair of gloves, clean up his work area, follow the shower-out procedures, and report to the building conference room to await further instructions. After the ARO briefed the infectious disease physician on the exposure, the University determined that the researcher should be placed under quarantine at his home. The laboratory manager phoned the researcher's family members and informed them of the situation. The researcher's family was subsequently escorted to a hotel room for the duration of the researcher's quarantine. The researcher was provided with a prescription of Tami flu and was then driven home by the laboratory manager. During the transport from the laboratory to the researcher's house, the researcher wore a glove on the hand that had the puncture wound as well as an N-95 respirator. The following morning (November 17), nasal and throat swab testing began. To date, the researcher has not shown any signs or symptoms of illness.

!Redacted by agreement December 16, 2013 Page 2 This event raises several questions regarding the University of Wisconsin's policies and procedures. First, we learned in subsequent conversations with the University that the use of a needle for the collection procedure in question is a violation of the University of Wisconsin's own policies, which only permit needles to be used in the ABSL3+ laboratory to anesthetize research animals, draw blood from research animals, or inoculate eggs. It is unclear from your report why the researcher was using a syringe to coJJect a supernatant sample, when the use of sharps for that activity was prohibited. Your report indicated that the researcher would be retrained and the standard operating procedure for sharps use in the ABSL3+ will be rewritten to articulate more clearly the allowed uses of sharps. Please indicate when this training occurred and provide OBA copies of the training materials that were used, as well as your policy describing the use of needles in the ABSL3+ laboratory. In fi 11 . "th d edacted by agreement d" · al h Ith o ow-up conversat10ns w1 you an r---,-..,......,r--....,...-~ egar mg your occupahon ea plans, you state that all exposures, inclu mg ns exposures, would follow the same protocol, i.e. home isolation after removing the family from the house. Your decision was based upon consultation with your infectious disease experts and the state health department. You had rejected using a hospital room for quarantine beca ft ss on the laboratory worker. h. 1 · · h • d . Redacted by agreement ) ' • erfi T 1s po icy 1s not w at was commumcate to us 1 +TT"TT"r-n~.,,,,.,,~,,.._ pp 1cat10n to p arm research with mammalian transmissible strains of at was provided to the D artment of Health and Human Services. In a May 6, 2013, plan provided to NIH ;r~!~~~t that he had access to a "designated quarantine apartment" in which researc ers cou be placed for 10-14 days in the event of an accidental exposure. Since then, the University of Wisconsin's Associate Dean for Research and ARO have indicated to OBA that there was a miscommunication between the PI and the University administration regarding the availability and appropriateness of such a quarantine apartment. The University must f'md a dedicated facility outside of the individual's permanent residence (1) in which an individual can be safely isolated for up to 10 days, and (2) that can be decontaminated easily after the individual's departure. An isolation room in a hospital would be appropriate. An individual's permanent residence is not appropriate due to the fact that many residences are in buildings with high occupancy that share air exchange and other infrastructure. Please provide revised SOPs that reflect an appropriate quarantine arrangement. No research with mammalian transmissible H5Nl stains may be carried out until this plan is operationalized. Please provide all requested materials by December 23, 2013. You may contact OBA staffby email at oba@od.nih.gov or by telephone at (30 l) 496-9838 if you have any questions.

!Redacted by agreement December 16, 2013 Page 3 cc: edacted by agreement Capt. Robbin Weyant, P .D., Director, D1vis1on o Se ect Agents an Toxms, C Freeda E. Isaac, D.V.M., Director, Agriculture Select Agent Program, USDA APHIS Amy P. Patterson, M.D., Associate Director for Science Policy, NIH Allan C. Shipp, Director of Outreach, Office of Biotechnology Activities, NIH Ryan Bayha, Senior Analyst for Science Policy Outreach, Office of Biotechnology Activities, NIH Kathryn Hanis, Ph.D., RBP, Senior Outreach and Education Specialist (contractor), Office of Biotechnology Activities, NIH

(.::J-. IIIJD} National Institutes of Heallh December 16, 2013 redacted by agreement I Associate Vice Chancellor for Research Policy University of Wisconsin 327 Bascom Hall 3 500 Lincoln Drive Madison. Wisconsin 53706 Dear f edacted by agreement I U.S. Publlc Health Service Bethesda, Mary1and 20892 Office of Biotechnology Activities National lnsliltltes of Health 6705 Rockhtdge Drive Suite 750, MSC 7985 Bethesda, MO 20892-7985 (301) 496-9838 (Phone) (301) 496-9B39 ( Fax) http://oba.od.nlh.gov/ We are following up on our series of teleconferences regarding your November I 7, 2013, and November 19, 2013, report to the National Institutes of Health (NIH) Office of Biotechnology Activities (OBA) describing a November 16, 2013, incident in which a University of Wisconsin researcher stuck himself with a syringe containing a recombinant fonn of H5Nl. The virus contained the HA gene from H5N1 while the remaining genes came from HlNl A/California (2009 HlNl) strain. The needlestick occurred in the ABSL3+ laboratory while the researcher was attempting to collect tissue culture supernatant. Immediately following the incident, the researcher sprayed the wound site with disinfectant and washed the site of the wound for fifteen minutes. The researcher contacted the laboratory manager and reported the exposure. The laboratory manager then infonned the Alternate Responsible Official (ARO) of the incident and requested that the University of Wisconsin infectious disease physician be contacted for a consultation. The laboratory manager called the researcher back and instructed him to put on a new pair of gloves, clean up his work area, follow the shower-out procedures, and report to the building conference room to await further instructions. After the ARO briefed the infectious disease physician on the exposure, the University determined that the researcher should be placed under quarantine at his home. The laboratory manager phoned the researcher's family members and informed them of the situation. The researcher's family was subsequently escorted to a hotel room for the duration of the researcher's quarantine. The researcher was provided with a prescription of Tami flu and was then driven home by the laboratory manager. During the transport from the laboratory to the researcher's house, the researcher wore a glove on the hand that had the puncture wound as well as an N-95 respirator. The following morning (November 1 7), nasal and throat swab testing began. To date, the researcher has not shown any signs or symptoms of illness.

redacted by agreement December 16, 2013 Page2 This event raises several questions regarding the University of Wisconsin's policies and procedures. First, we learned in subsequent conversations with the University that the use of a needle for the col1ection procedure in question is a violation of the University of Wisconsin's own policies, which only permit needles to be used in the ABSL3+ laboratory to anesthetize research animals, draw blood from research animals, or inoculate eggs. It is unclear from your report why the researcher was using a syringe to collect a supernatant sample, when the use of sharps for that activity was prohibited. Your report indicated that the researcher would be retrained and the standard operating procedure for sharps use in the ABSL3+ will be rewritten to articulate more clearly the allowed uses of sharps. Please indicate when this training occurred and provide OBA copies of the training materials that were used, as well as yottr policy describing the use of needles in the ABSL3+ laboratory. redacted by agreement I . In follow-up conversations with you and.__ ____ ___.regarding your occupational health plans, you state that all exposures, including high risk exposures, would follow the same protocol, i.e. home isolation after removing the family from the house. Your decision was based upon consultation with your infectious disease experts and the state health department. You had rejected using a hospital room for quarantine because of the stress on the laboratory worker. This policy is not what was communicated to us in Redacted by agreemen pplication to perform research with mammalian transmissible strains of at was provid t the D artment of Health and Human Services. In a May 6, 2013, plan provided to NIH, R;r~!~~~ty ndicated that he had access to a "designated quarantine apartment" in which researc ers cou be placed for 10-14 days in the event of an accidental exposure. Since then, the University of Wisconsin's Associate Dean for Research and ARO have indicated to OBA that there was a miscommunication between the PI and the University administration regarding the availability and appropriateness of such a quarantine apartment. The University must f'md a dedicated facility outside of the individual's permanent residence (1) in which an individual can be safely isolated for up to 10 days, and (2) that can be decontaminated easily after the individual's departure. An isolation room in a hospital would be appropriate. An individual's permanent residence is not appropriate due to the fact that many residences are in buildings with high occupancy that share air exchange and other infrastructure. Please provide revised SOPs that reflect an appropriate quarantine arrangement. No research with mammalian transmissible H5Nl stains may be carried out until this plan is operationalized. Please provide all requested materials by December 23, 2013. You may contact OBA staff by email at oba@od.nih.gov or by telephone at (301) 496-9838 if you have any questions. turn~ (\ uray,M~p. g 1rec or J ice of Biotechnology Activities V

!Redacted by agreement December 16, 2013 Page 3 cc: Redacted by agreement Capt. Ro m Weyant, P .D., 1rector, D1v1S1on of Se ect Agents and Toxins, CDC Freeda E. Isaac, D.V.M., Director, Agriculture Select Agent Program, USDA APHIS Arny P. Patterson, M.D., Associate Director for Science Policy, NIH Allan C. Shipp, Director of Outreach, Office of Biotechnology Activities, NIH Ryan Bayha, Senior Analyst for Science Policy Outreach, Office of Biotechnology Activities, Nill Kathryn Harris, Ph.D., RBP, Senior Outreach and Education Specialist (contractor}, Office of Biotechnology Activities, NIH

Template for Reporting Incidents Involving Recombinant DNA to the NIH Office of Biotechnology Activities (OBA) The NIH Guidelines for Research Involvin~ Recombinant DNA Molecules (NIH Guidelines) states that" .. any significant problems, violations of the NII/ Guidelines, or any significant research-related accidents and illnesses" must be reported to NIH OBA within 30 days. Certain types of incidents must be reported on a more expedited basis. Spills or accident~ in BSL-2 laboratorics resulting in an overt exposure must be immediately reported to NIH OBA. Spills or accidents occurring in high containment (BSL-3 or BSL--4) laboratories resulting in an overt or potential exposure must be immediately reported to NIH OBA_ This template is intended to facilitate the reporting of incidents that occur during the conduct of research subject to the NIH Guidelines. Use of this template is not required and other formats may be acceptable. A separate template for reporting Human Gene Transfer Adverse Events is available at: http://www4.od.nih.gov/oba1rac/adverse __ event_ template.doc Please note that submitting this completed template to the NIii OBA does NOT fulfill the reporting requirements of other agencies. You should verify with the other parties to whom you must report whether the use ofthis template is acceptable. Completed reports may be sent via U.S. mail, courier service, e-mail, or facsimile to; Attention: Incident Reports NIH Office of Biotechnology Activities 6705 Rockledge Drive, Suite 750 Bethesda, Maryland 20892-7985 (For all non-USPS deliveries use Zip Code 20817) Telephone 301-496-9838 FAX 301-496-9839 E-mail: oba@od.nih.gov NIH OBA Incident Re(!orting Tem(!late Does this incident involve research X Yes subject to the MH Guidelines? If no, this incident docs not have to be rel"lClrted to OBA Institution name: University of Wisconsin - Madison Date of report: 11/19/13 Reporter name and position: Jim Turk Biological Safety Officer Reporter telephone: (608)263-9013 Reporter email: jturk@fpm.wisc.edu Date of Incident: 11116/13 Name of principal investigator: Yoshihiro Kawaoka

~--------------~-------------------- ------~ Is this an NIH funded project? X Yes No If yes, please provide What was the nature of incident? Did the institutional Biosafcty Committee (IBC) approve this research? If yes, please provide: What section(s) of the NIH Guidelines is the research su~ject to? Has a report of this incident been made to other federal or local agencies? If so, please indicate by checking the appropriate box. -Nill Grant or contract numberfedacted by agreement t,vill be forwarding the grant number for this specific project. NIH funding institute or center NJH program officer contact information (name, email etc.) Needle Stick XYes If yes, on what date? 04/04/2012 Approval date: 04/04/2012 Approved biosafcty level for the research: ABSL-3 Additional aonroval re(]uirements: Seclion 111-D-3-b, Section 111-D-4-b, Section 111-D-7 X CDC X USDA o FDA EPA OSHA u Research Funding Agency/Sponsor: (name) State/Local Public J lcalth Federal/State/ Local Law Enforcement X Other - please describe: City/County Public I lealth Please provide a narrative of the incident including a timelinc of events. The incident should be described in sufficient detail to allow for an understanding of the nature and consequences of the incident. Include the following information as applicable. A description of: • The recombinant agent or material involved. • ·inc incident/violation location (e.g. laboratory biosafety level, vivarium, non-laboratory space). • Who was involved in the incident/violation, including others present at the incident location? Note - please do not identify individuals by name. Prnvide only position titles (e.g., graduate student, post doc, animal care worker, facility maintenance worker). • Actions taken immediately following the incident/violation, and by whom, to limit any health or environmental consequences of the event. • The training received by the individual(s) involved and the date(s) the training was conducted. • The institutional or laboratory standard operating procedures (SOPs) for the research and whether there was any deviation from these SOPS at the time of the incident/violation. • Any deviation from the IBC approved containment level or other IBC approval conditions at the time of the incident/violation. • The personal protective equipment in use at the time of the incident/violation. • '!be occupational health requirements for laboratory personnel involved in the research. • Any medical advice/treatment/surveillance provided or recommended after the incident • Any injury or illness associated with the incident. 2

• Medical surveillance results (if not available at the time of initial report please indicate when results will be available). • Equipment failures. DESCRIPTION OF INDICENT: (use additional space as necessary) Needle Stick - November 16, 2013 ~ 18:20-18:30 -The researcher was working in the ABSL3+ laboratory and accidentally punctured skin with an 18 gauge needle with a reassortant virus on it, containing the HA from ANietnam/UT36250l/2010 (H5Nl) with the Nl98H mutation in the receptor binding site, and the rest of the genes from A/Califomia/04/2009 (H 1 N 1 ). The approximate concentration of the tissue culture supernatant on the syringe needle was ~10A8 pfu/ml. 18:34 -A co-worker called the on-call iPhone, the lab manager answered, this co-worker relayed that the researcher called out on the radio that help was needed because the researcher had stuck themself with a needle in the ABSL-3+ laboratory. The co-worker was in the BSL-3Ag suite. 18:36 - The lab manager called the researcher in. The researcher had sprayed the puncture site with disinfectant and had been running the site under water at the sink for 5 minutes. The lab manager instructed the researcher to squeeze a few more drops of blood out of the finger and continue running the site under water for another l O minutes, and then call back for the next set of instructions. 18:43 - The lab manager asked the co-worker to listen for the radio in case the researcher had any difficulty. 18 :46 - The lab manager called the ARO, relayed the situation, asks her to call the Infectious Disease doctors. 18:54- The ARO called the UW Hospital Operator and asked to page the ID Fellow on-call. 18: 5 4 - The lab manager called the researcher and gave the researcher the following instructions: put on new gloves, clean up the work area and then shower out normally. Do not hurry. Go upstairs, sit in the conference room and do not leave the building. 18:57 - The lab manager called a senior scientist in the lab to call the researcher's family and instruct them to start packing belongings to go to a hotel. 19: 19- ID Fellow called the ARO back and they discussed the situation. The Fellow paged the attending to get the prescription sent in. 19:28- The ID attending physician called the ARO and got the required information for the Tamiflu prescription. I jRedacted by 19:29 - The lab manager called1agreement o report what happened. 19:40 - The lab manager arrived at the IRI, spoke with the researcher, and arranged for a hotel 3

room for the researcher's family. 20:10 -The lab manager called Walgreens to make sure the Tamiflu prescription was ready for pickup and that Walgreens had the researcher's contact information and insurance information. 20: 15- The ID attending physician follows up with the ARO and asked for the lab manager's contact information. 20: 18 - The ID Attending Physician called the lab manager to check that there are issues with obtaining the Tamiflu prescription. 20:20 - Another co-worker went to pick up the prescription. 20:22- The ARO notified CDC DSAT via the Form 3 email address. 20:26-The ARO called the Director of University Health Services to explain the situation. The Director sent an email to UW housing to see if we could get the a show apartment for the family starting on Sunday. 20:31- The ARO called the City of Madison/Dane Public Health on-call pager. 20:32-The ARO called the Chief Medical Officer and State Epidemiologist for Wisconsin Department of Health. He confinned the quarantine would be 7 days and the individual should be taking a treatment dose of 75mg twice a day for 10 days. 20:34- The ARO talked to the City/Dane County Health on-call individuals and explains the situation. 20:35pm -The research took the first Tamiflu dosage, (~2 hours after the injury). The Tamiflu prescription was written for 75mg, once daily. (The lab manager voiced concern to the ARO about the prescription being the prophylaxis dosage and not the treatment dosage. The ARO had already spoken with the doctors about this, the Chief Medical Officer for Wisconsin Dept. of Public Health wanted the researcher on the treatment dosage (75mg twice a day for 10 days). The researcher was instructed to take one pill every 12 hours. 21 :00 - The researcher's family was pickup and driven to the hotel. 21 :30 - The researcher was driven home by the lab manager and was wearing a glove on the hand with the puncture wound and an N~95 mask with no exhalation valve. 21 :00-22:00 - The lab manager spoke to two of the lab scientists about beginning the nasal and throat swab sample testing the next morning. 21:55-Researcher took a reference body temperature: 98.1 F (axillary). November 17. 2013 4

8:00 - The researcher too the second Tamiflu dosage and body temperature was 98.2 F (axillary). 9:00 - The lab manager obtained the first throat and nasal swab samples. 10:00 - Scientists began sample testing. 12:00 -The rapid Directigen test results are negative. 16:00 -The researcher's family was moved to a show apartment available on campus. 18:00 - The lab manager obtained nasal swab and throat gargle samples. The test results are negative. 19:00 - The researcher's body temperature was 98.4 F (axillary). November 18 2013 7: 15 - The researcher's temperature was 97.9F 9:00 - The researcher's body temperature was 98.96F (axillary). The UW-Madison Occuptional Health nurse visited the researcher, drew blood, measured blood pressure and pulse (normal). The lab manager obtained nasal swab and throat gargle samples. These test results were negative. 11:00-The researcher's body temperature is 99.IF (by mouth). 13:00 -The researcher's temperature is 98.6F (by mouth). Daily updates are sent out by the ARO. Has the IBC reviewed this incident? X No If ves, orovide minutes Has the root cause for this incident XYes been identified? If yes, please describe: Employee failed to follow proper procedure, despite training. Describe measures taken by the institution to mitigate any problems identified. For measures identified but not yet taken, please include a timeline for their implementation: (use additional space as necessary) Employee will be retrained and SOPs will be rewritten to reflect a more direct and specific sharps policy. NIH OBA Oct08 5

Bayha, Ryan (NIH/OD) [E] From: Sent: To: Cc Subject: !Redacted by agreement Sunday, November 17, 2013 10;33 AM Office of Biotechnology Activities (NIH/OD) 'rbayha@od.nih.gov'; 'kharris@od.nih.gov';""fe_,,d-act'""ed"'"'b-y-ag-re-em_e_,,.nt-------, incident A needle stick occurred last night, Saturday, November 16th, involving a non-transmissible strain of influenza HSN!. Toe researcher immediately followed appropriate procedure. The ARO was contacted, followed by the RO, the CDC, myselfr and City/County public health (not necessarily in that order). The researcher received his first dose of Tamiflu less than two hours after the incident took place. Arrangements were immediately made to move the family of the researcher into a model apartment on campus, with which we have an agreement, and to quarantine the researcher at home. PCR will be run frequently to ensure immediate detection if it necessary. The Occupational medicine group on campus has also been notified and will monitor/follow-up with the researcher. This has been an exceptional response and everyone involved followed the procedures that have been put in place and rehearsed regularly. I have limited details at this point as I was out of town at the time of the incident, but did still speak with the ARO shortly after the incident. I will complete and submit a full report in the morning after being further briefed by the ARO involved in the case, Please let me know if you have any questions in the mean time. Redacted by agreement Assistant Director Biological Safety Officer UW-EH&S 30 East Campus Mall Madison, WI 53715 0 608 263-9013 C Redacted by agreement http://www. e hs. wi sc.edu/bio-newsletter.htm

I \ \ ' \ Template for Reporting Incidents Involving Recombinant DNA to the NIH Office of Biotechnology Activities (OBA) The Nil/ Guidelines for Research Involving Recombinant DNA Molecules (NIii Guidelines) states that" ... any significant problems, violations of the NIH Guidelines, or any significant research-related accidents and illnesses" must be reported to NIH OBA within 30 days. Certain types of incidents must be reported on a more expedited basis. Spills or accidents in BSL-2 laboratories resulting in an overt exposure must be immediately reported to NIH OBA. Spills or accidents occurring in high containment (BSL-3 or BSL-4) laboratories resulting in an overt or potential exposure must be immediately reported to NIH OBA. This template is intended to facilitate the reporting of incidents that occur during the conduct of research subject to the NIH Guidelines. Use of this template 1s not required and other formats may be acceptable. A separate template for reporting Human Gene Transfer Adverse Events is available at: http://www4.od.nih.gov/oba/rac/adverse_event template.doc Please note that submitting this completed template to the NIH OBA docs NOT fulfill the reporting requirements of other agencies. You should verify with the other parties to whom you must report whether the use of this template is acceptable. Completed reports may be sent via [J.S. mail, courier service, e-mail, or facsimile to: Attention: Incident Reports NIH Office of Biotechnology Activities 6705 Rockledge Drive, Suite 750 Bethesda, Maryland 20892- 7985 (For all non-USPS deliveries use Zip Code 20817) Telephone 301-496-9838 FAX 301-496-9839 E-mail: oba@od.nih.gov -- NIH OBA Incident Rei!orting Teml!late Does this incident involve research X Yes subiect to the NIH Guidelines? If no, this incident does not have to be reeortcd to OBA Institution name: University of Wisconsin - Madison - - Date of report: 11/09/2013 Reporter name and position: Jim Turk Biological Safety Officer Reporter telephone: (608)263-9013 Reporter email: jturk@fpm. wisc.cdu ---- Date of Incident: 11/09/2013 -- Name of principal investigator: Y oshihiro Kawaoka ---

\ \ ~-------------------.------------- ·--~----~-----·- ------~ ls this an NIH funded project? If yes, please provide What was the nature of incident? X Yes o No NIH Grant or contract number:fedacted _by I NIii funding institute or center NIH program officer contact information (name, email etc.) Small spill (dropped plate while placing in incubator) outside of BSC while wearing appropriate PPE. t---------------. - ·--+-----------------------<o-••-- Did the institutional Biosafety X Yes Committee (IBC) approve this If yes, on what date? 4/4/2012 research? 1-----------------------+------- If yes, please provide: Approval date: 4/4/2012 Approved biosafcty level for the research: ABSL-3+ t------------------+ _ _bc!_ditional approval requirem~~_ts: _____ _ What scction(s) of the NIH Guidelines is the research subject to? Has a report of Lhis incident been made to other federal or local agencies? lf so, please indicate by checking the appropriate box. III-D-1-a lll-D-2-a III-D-3-a Ill-D-3-b lll-D-4-b III-D-4-c( l) ' , , ' ' , III-0- 7-b, III-D-7-c, III-D-7d, Appendix G-11-B, Appendix G-II￾C-5c, Aooendix Q X CDC X USDA o FDA n EPA u OSHA n Research Funding Agency/Sponsor: (name) o State/Local Public Health n Federal/Statd Local Law Enforcement --please describ_e_:_____________ ___, Please provide a narrative of the incident including a timeline of events. The incident should be described in sufficient detail to allow for an understanding of the nature and consequences of the incident. Include the following information as applicable. A description of: • ]be recombinant agent or material involved. • The incident/violation location (e.g. laboratory biosafcty level, vivarium, non-laboratory space). • Who was involved in the incident/violation, including others present at the incident location? Note - please do not identify individuals by name. Provide only position titles (e.g., graduate student, post doc, animal care worker-, facility maintenance worker). • Actions taken immediately following the incident/violation, and by whom, to limit any health or environmental consequences of the event. • The training received by the individual(s) involved and the date(s) the training was conducted. • The institutional or laboratory standard operating procedures (SOPs) for the research and whether there was any deviation from these SOPS at the time of the incident/violation. • Any deviation from the IBC approved containment level or other JBC approval conditions at the time of the incident/violation. • The personal protective equipment in use at the time of the incident/violation. • The occupational health requirements for laboratory personnel involved in the research. • Any_medical advice/treatment/surveillance provided or recommcn~ed after the incident 2

• Any injury or illness associated with the incident. • Medical surveillance results (if not available at the time of initial report please indicate when results will be available). • Eauioment failures. DESCRIPTION OF INDICENT: (use additional space as necessary) The researcher was wearing a PAPR, scrubs, tyvek, shoe covers, dedicated shoes, another pair of shoe covers, and two pairs of gloves. All SOPs were followed I appropriately and the incident is considered a spill and not an exposure. All personnel are 1 trained on a regular basis in accordance with the select agent regulations and go through an extensive mentoring process. This incident will be used as a training session for the laboratory. The group will discuss what can be done to prevent a spill of this nature from occurring again. Mostly likely it will be as simple as changing the way the plates are carried to the incubator. Experiment set-up: The researcher was working in the ABSL-3+ suite performing growth j curve analysis of viruses containing mutations in the PB2 protein (part of the viral polymerase complex), in the virus strain background of A/Muscovy Duck/Vietnam/TY93/2007 (H5N1: referred to as 'TY93'). The viral hemagglutinin (HA) protein of this virus strain possesses a multi-basic cleavage site. Approximately 24 h prior to the incident (on November 8th, 2013), cells in 6-well tissue culture plates were infected at a multiplicity of 0.001 plaque forming units (PFU) per cell (~4 x 105 cells per well). Following the infection, infected cells were covered with approximately 2 ml of media per well, and cultures were incubated. The spill: The spill occurred during the collection of supernatant samples from the infected cultures at the 24 h time point (on the morning of November 9th, 2013). To collect the virus culture supernatant samples, three 6-well tissue culture plates were transferred by the researcher from the tissue culture incubator into a biosafety cabinet (BSC), and a sample was harvested from each well into 2 ml screw-cap tubes. Following sample collection, the researcher removed all three plates from the BSC (stacked on top of each other) for transfer back into the tissue culture incubator. After opening the I external door and the internal glass door of the incubator, the lower half of the tissue culture plate on the bottom of the 3-plate stack slipped from the researcher's hand and fell to the floor. Four wells of this plate were infected (2 wells each with two different virus mutants: TY93-PB2-627K and TY93-PB2-627V), so approximately 8 ml of virus￾containing media spilled onto the floor. Spill clean-up: 1. The researcher immediately closed the incubator doors and returned the plates that were not dropped to the BSC. These plates were later transferred back to the tissue culture incubator, following the spill clean-up procedure. 2. The researcher picked up the dropped plate bottom from the floor and immersed it in a container of 5% MicroChem Plus inside the SSC. 3

3. The researcher then saturated his outer gloves with 70% ethanol, disposed of them in the biohazard trash, and put on a new pair of outer gloves. 4. Following IRI SOP #33, the researcher covered the area of the spill (-3-inches in diameter) with paper towels, and then flooded the contaminated area and paper towels with freshly made 5% MicroChem Plus. 5. At this time, the researcher observed a few drops of liquid (i.e., media)~ek suit below the knee, so 70% ethanol to saturate both arms (in entirety) and both legs (from theknee aoWn) of the Tyvek suit, shoe covers, the bottoms of shoes, and 2-3 inches of exposed skin between the bottom of the Tyvek suit and the shoes (i.e., ankles). 6. After waiting 20 minutes, the researcher a. Transferred the disinfectant-soaked paper towels covering the spill into a biohazard autoclave bag inside a gray plastic bin. b. Removed and disposed of his outer gloves into the same biohazard bag. c. Donned a new pair of outer gloves. d. Secured the biohazard bag by tying a knot at the top. e. Sprayed the outside surface of the bag in 70% ethanQI. 7. The researcher prepared fresh 1 % Virkon S (from powder) and mopped the area of the floor affected by the spill with 1 % Virkon S. 8. The researcher saturated the outside surfaces of the tissue culture incubators with 70% ethanol, and cleaned up the BSC according to standard procedures. 9. The researcher contacted the on-call scientist via the emergency iPhone to obtain further instructions, and then exited the ABSL-3+ suite following the standard exit procedure. Additional details about the incident response and communication are described in Section IV below. 10. Following the researcher's exit from the ABSL-3+ suite, a second researcher entered the suite and autoclaved out the disposable trash from the gown room, as well as all trash inside the suite. IV. Incident Response Communication and Timeline 1. 6:30 a.m. - The researcher spilled -8 ml of virus-containing media on the floor of the ABSL-3+ suite (room 121 ), outside of BSC containment. 2. 6:30 - 6:54 a.m. - The researcher cleaned up the spill according to the steps described in SOP #33. 3. 6:55 a.m. -The researcher phoned the on-call scientist via the emergency iPhone. The researcher indicated to on-call scientist that a plate was dropped containing virus onto the floor, and further indicated that was used SOP #33 to clean uo the soill. The on￾4

call scientist asked the researcher to await further instructions within the ABSL-3+ suite. 4. 7:09 a.m. - The on-call phone researcher phoned the lab manager to relay information about the volume of the spill and to discuss how to proceed. Since the volume was close to the amount considered to be a "large" spill (large spills are > 10 ml, and can be considered a potential exposure), it was decided that additional consultation with the Alternate Responsible Official (ARO) would be required before a decision about quarantine could be made. 5. 7:15 a.m. - The on-call scientist phoned the ARO and left a message, describing the incident and asking to phone back as soon as possible. 6. 7:21 a.m. -The on-call scientist notified the researcher that additional consultation with the ARO was ongoing, and that the researcher should proceed to the conference room, avoid contact with other people, and wait for further instructions. 7. 7:35 a.m. - The ARO returned the on-call scientist phone call. The situation was summarized for the ARO. 8. 7:41 a.m. - The ARO called the researcher and they discussed the incident and the strains being used. The ARO instructed the researcher to stay in the conference room and while the necessary phone calls were made. 9. 7:52 a.m. - The ARO called the UW Hospital Operator and had the infectious disease fellow on-call paged. 10. 7:55 a.m. - The on-call scientist notified the Principal Investigator about the incident and the response up to this point. 11. 7:56 a.m. - The UW ID Fellow on-call, called the ARO. She explained the situation to him and he consulted with his attending physician. 12. 8:12 a.m. -The ARO phoned to the on-call scientist to give a situational update 13. 8:23 a.m. -The Pl replied to the on-call scientist to indicate the receipt of the information about the spill incident, and asked to be kept updated. 14. 8:28 a.m. - The UW ID Fellow called the ARO back and described that they would not treat the individual due to the appropriate disinfection performed by researcher and the risk of exposure through intact skin being very low. The ARO insisted however that the researcher be given a Tamiflu prescription as a precaution as well as for peace of mind. The UW ID Fellow agreed and called the researcher. 15. 8:31 a.m. - The ARO called the researcher and released the researcher from the building. The ARO double checked the well-being of the researcher. 5

16. 8:34 a.m. -The ARO phoned the on-call scientist to relay the ID Consult team decided to release the researcher without quarantine, and that there would be no need for a Tamiflu prescription. However, as noted above, the researcher requested Tamiflu anyway, and the UW ID Fellow stated that he would phone the researcher with the prescription. The ID Consult Team also instructed that the researcher self-monitor for any change in body temperature (every 12 h, at minimum) or feelings of illness, and The ARO instructed the researcher that such observations must be communicated to the ARO immediately upon observation. 17. The researcher took the first dose of Tamiflu in the afternoon, temperature remains normal and is in good health. Has the IBC reviewed this incident? X No If yes, provide minutes Has the root cause for this incident X Yes been identified? If yes, please describe: Employee dropped plates while placing in incubator. Describe measures taken by the institution to mitigate any problems identified. For measures identified but not yet taken, please include a timeline for their implementation: (use additional space as necessary) The researcher was wearing a PAPR, scrubs, tyvek, shoe covers, dedicated shoes, another pair of shoe covers, and two pairs of gloves. All SOPs were followed appropriately and the incident is considered a spill and not an exposure. All personnel are trained on a regular basis in accordance with the select agent regulations and go through an extensive mentoring process. This incident will be used as a training session for the laboratory. The group will discuss what can be done to prevent a spill of this nature from occurring again. Mostly likely it will be as simple as changing the way the plates are carried to the incubator. Spill clean-up: 1. The researcher immediately closed the incubator doors and returned the plates that were not dropped to the BSC. These plates were later transferred back to the tissue culture incubator, following the spill clean-up procedure. 2. The researcher picked up the dropped plate bottom from the floor and immersed it in a container of 5% MicroChem Plus inside the SSC. 3. The researcher then saturated his outer gloves with 70% ethanol, disposed of them in the biohazard trash, and put on a new pair of outer gloves. 4. FollowinQ IRI SOP #33, the researcher covered the area of the soill /~3-inches in 6

diameter) with paper towels, and then flooded the contaminated area and paper towels with freshly made 5% MicroChem Plus. 5. At this time, the researcher observed a few drops of liquid (i.e., media) on the Tyvek suit below the knee, so 70% ethanol to saturate both arms (io entirety) and both legs (from the knee down) of the Tyvek suit, shoe covers, the bottoms of shoes, and 2-3 inches of exposed skin between the bottom of the Tyvek suit and the shoes (i.e., ankles). 6. After waiting 20 minutes, the researcher a. Transferred the disinfectant-soaked paper towels covering the spill into a biohazard autoclave bag inside a gray plastic bin. b. Removed and disposed of his outer gloves into the same biohazard bag. c. Donned a new pair of outer gloves. d. Secured the biohazard bag by tying a knot at the top. e. Sprayed the outside surface of the bag in 70% ethanol. 7. The researcher prepared fresh 1 % Virkon S (from powder) and mopped the area of the floor affected by the spill with 1% Virkon S. 8. The researcher saturated the outside surfaces of the tissue culture incubators with 70% ethanol, and cleaned up the SSC according to standard procedures. 9. The researcher contacted the on-call scientist via the emergency iPhone to obtain further instructions, and then exited the ABSL-3+ suite following the standard exit procedure. Additional details about the incident response and communication are described in Section IV below. 10. Following the researcher's exit from the ABSL-3+ suite, a second researcher entered the suite and autoclaved out the disposable trash from the gown room, as well as all trash inside the suite. IV. Incident Response Communication and Timeline 1. 6:30 a.m. - The researcher spilled -8 ml of virus-containing media on the floor of the ABSL-3+ suite (room 121 ), outside of BSC containment. 2. 6:30 - 6:54 a.m. - The researcher cleaned up the spill according to the steps described in SOP #33. 3. 6:55 a.m. -The researcher phoned the on-call scientist via the emergency iPhone. The researcher indicated to on-call scientist that a plate was dropped containing virus onto the floor, and further indicated that was used SOP #33 to clean up the spill. The on￾call scientist asked the researcher to await further instructions within the ABSL-3+ suite. 4. 7:09 a.m. - The on-call phone researcher phoned the lab manager to relay information about the volume of the soill and to discuss how to oroceed. Since the volume was close 7

to the amount considered to be a "large" spill (large spills are > 10 ml, and can be considered a potential exposure), it was decided that additional consultation with the Alternate Responsible Official (ARO) would be required before a decision about quarantine could be made. 5. 7:15 a.m. - The on-call scientist phoned the ARO and left a message, describing the incident and asking to phone back as soon as possible. 6. 7:21 a.m. -The on-call scientist notified the researcher that additional consultation with the ARO was ongoing, and that the researcher should proceed to the conference room, avoid contact with other people, and wait for further instructions. 7. 7:35 a.m. - The ARO returned the on-call scientist phone call. The situation was summarized for the ARO. 8. 7:41 a.m. - The ARO called the researcher and they discussed the incident and the strains being used. The ARO instructed the researcher to stay in the conference room and while the necessary phone calls were made. 9. 7:52 a.m. - The ARO called the UW Hospital Operator and had the infectious disease fellow on-call paged. 10. 7:55 a.m. - The on-call scientist notified the Principal Investigator about the incident and the response up to this point 11. 7:56 a.m. - The UW ID Fellow on-call, called the ARO. She explained the situation to him and he consulted with his attending physician. 12. 8:12 a.m. - The ARO phoned to the on-call scientist to give a situational update 13. 8:23 a.m. - The Pl replied to the on-call scientist to indicate the receipt of the information about the spill incident, .and asked to be kept updated. 14. 8:28 a.m. - The UW ID Fellow called the ARO back and described that they would not treat the individual due to the appropriate disinfection performed by researcher and the risk of exposure through intact skin being very low. The ARO insisted however that the researcher be given a Tamiflu prescription as a precaution as well as for peace of mind. The UW ID Fellow agreed and called the researcher. 15. 8:31 a.m. - The ARO called the researcher and released the researcher from the building. The ARO double checked the well-being of the researcher. 16. 8:34 a.m. -The ARO phoned the on-call scientist to relay the ID Consult team decided to release the researcher without quarantine, and that there would be no need for a Tamiflu prescription. However, as noted above, the researcher requested Tamiflu an_yv,,a , and the UW ID Fellow stated that he would hone the researcher with the 8

prescription. The ID Consult Team also instructed that the researcher self"'.monitor for any change in body temperature (every 12 h, at minimum) or feelings of illness, and The ARO instructed the researcher that such observations must be communicated to the ARO immediately upon observation. 17. The researcher took the first dose of Tamiflu in the afternoon, temperature remains normal and is in good health. NIH OBA Oct08 9