II. BIOHAZARDOUS RESEARCH PROJECT REGISTRATION AND APPROVAL

A. Introduction

Each Principal Investigator (PI) is responsible for the preparation of a Memorandum of Understanding and Agreement (MUA) for all research involving biological materials or agents including the assignment of the required Biosafety Level to the proposed research. This includes research involving:

• Recombinant DNA, including experiments that are specifically exempt under the NIH Guidelines
  
• Bacterial, fungal, parasitic, or other potentially infectious agents
  
• Live viruses
  
• Human blood and tissue

The IBC will review all submitted MUAs; confirm, where applicable, that exempt status is appropriate for certain rDNA work; and consider approval for those MUAs that are complete and which provide for safe handling of potentially biohazardous materials under the appropriate Biosafety Level.

B. Registration and Approval Process

The annual registration and MUA approval process begins each fall with the distribution of the MUA registration materials by ORPA to the chairperson of each department conducting research with rDNA and other potentially infectious agents. Additional requirements referred to in the MUA for research involving live viruses or human blood or tissue, (as outlined below) will need to be fulfilled for final approval to be given.

The chart provided below indicates the steps involved in this process:

Copies of the MUA and Annual Registration forms can be downloaded from the ORPA web site at http://www.princeton.edu/~orpa1/ibc.htm or can be obtained from ORPA. To assist in the completion of the MUA, the Synopsis of Recombinant DNA Guidelines and Biosafety Policies is also provided at the above website or from ORPA. In addition, to assist the Principal Investigator in determining the appropriate Biosafety Level for the proposed research, the PI is directed to the Agent Summary Statements in the BMBL and Appendix B, classification of Human Etiologic Agents on the Basis of Hazard in the NIH Guidelines.

C. Additional Approvals and Requirements

Select Biological Agents and Toxins

The US Department of Health and Human Services (HHS) and the US Department of Agriculture (USDA) have developed a list of select biological agents and toxins that have the potential to pose a severe biosecurity threat to public health, animals, and agricultural crops. As directed by the US Patriot Act, HHS and USDA have adopted strict regulations for the obtaining, possession, use, or transfer of any of these selected agents. Failure to comply with the established regulations can result in significant civil and criminal penalties.

Therefore, any investigator considering the use of select agents or toxins must contact the University Biosafety Officer (Don Robasser at 8-6256 or robasser@princeton.edu) to discuss the specifics of the requirements. HHS regulations in 42 CFR Part 73 Possession, Use, and Transfer of Select Agents and Toxins and the companion USDA regulations in 9 CFR Part 121 require federal registration and inspection; restricted lab access; development of written and strictly followed safety and security plans; personnel background checks by the FBI (including fingerprinting); specialized training; strict recordkeeping and reporting of agent use, transfer, loss, or destruction.

In determining whether to use select agents, researchers are encouraged to give careful consideration to the personal responsibilities, financial costs, and lengthy application and permit process involved with compliance. Any plans for use of select agents could easily take several months to get the appropriate permits and approvals and establish the security and protocols necessary to comply with the regulations. Sources of research funds to cover the cost of facility security improvements will need to be identified.

There is a small quantity exemption available for some of the select toxins. If the aggregate amount of toxin in the possession of a researcher can be kept below the specified exempt quantity (see agent listing), most of the rules do not apply. It should be noted that even when taking advantage of the small quantity exemption, the investigator is required to establish an inventory system to ensure the limit is not exceeded. Regardless of the amount, the University Biosafety Officer must be contacted prior to beginning work

See Select Agents Program for more information about the select agent requirements.

 

Alphabetical List Of Select Agents And Toxins

( as per the Final Select Agent Rules published 3/18/05 )

Except for exclusions listed in the Appendix, the viruses, bacteria, fungi, toxins, genetic elements, recombinant nucleic acids, and recombinant organisms specified in this list are HHS, USDA or HHS/USDA overlap select agents and toxins.

• Abrin (HHS)
• African horse sickness virus (USDA, Animal)
• African swine fever virus (USDA, Animal)
• Akabane virus (USDA, Animal)
• Avian influenza virus (highly pathogenic) (USDA, Animal)
• Bacillus anthracis (Overlap)
• Bluetongue virus (exotic) (USDA, Animal)
• Botulinum neurotoxin producing strains of Clostridium (Overlap)
• Botulinum neurotoxins (Overlap)
• Bovine spongiform encephalopathy agent (USDA, Animal)
• Brucella abortus (Overlap)
• Brucella melitensis (Overlap)
• Brucella suis (Overlap)
• Burkholderia mallei (formerly Pseudomonas mallei) (Overlap)
• Burkholderia pseudomallei (Overlap)
• Camel pox virus (USDA, Animal)
• Central European Tick-borne encephalitis virus (HHS)
• Cercopithecine herpesvirus 1 (Herpes B virus) (HHS)
• Classical swine fever virus (USDA, Animal)
• Clostridium perfringens epsilon toxin (Overlap)
• Coccidioides immitis (Overlap)
• Coccidioides posadasii (HHS)
• Conotoxins (HHS)
• Cowdria ruminantium (Heartwater) (USDA, Animal)
• Coxiella burnetii (Overlap)
• Crimean-Congo haemorrhagic fever virus (HHS)
• Diacetoxyscirpenol (HHS)
• Eastern Equine Encephalitis virus (Overlap)
• Ebola viruses (HHS)
• Far Eastern Tick-borne encephalitis (HHS)
• Flexal virus (HHS)
• Foot-and-mouse disease virus (USDA, Animal)
• Francisella tularensis (Overlap)
• Goat pox virus (USDA, Animal)
• Guanarito, virus (HHS)
• Hendra virus (Overlap)
• Japanese encephalitis virus (USDA, Animal)
• Junin virus (HHS)
• Kyasanur Forest disease (HHS)
• Lassa fever virus (HHS)
• Liberobacter africanus (USDA, Plant)
• Liberobacter asiaticus (USDA, Plant)
• Lumpy skin disease virus (USDA, Animal)
• Machupo virus (HHS)
• Malignant catarrhal fever virus (Alcelaphine herpes virus type 1) (USDA, Animal)
• Marburg virus (HHS)
• Menangle virus (USDA, Animal)
• Monkeypox virus (HHS)
• Mycoplasma capricolum/ M. F38/M. mycoides capri (contagious caprine pleuropneumonia) (USDA, Animal)
• Mycoplasma mycoides mycoides (contagious bovine pleuropneumonia) (USDA, Animal)
• Newcastle disease virus (velogenic) (USDA, Animal)
• Nipah virus (Overlap)
• Omsk Hemorrhagic Fever (HHS)
• Peronosclerospora philippinensis (USDA, Plant)
• Peste des petits ruminants virus (USDA, Animal)
• Ralstonia solanacearum, race 3, biovar 2 (USDA, Plant)
• Ricin (HHS)
• Rickettsia prowazekii (HHS)
• Rickettsia rickettsii (HHS)
• Rift Valley fever virus (Overlap)
• Rinderpest virus (USDA, Animal)
• Russian Spring and Summer encephalitis (HHS)
• Sabia virus (HHS)
• Saxitoxin (HHS)
• Sclerophthora rayssiae var. zeae (USDA, Plant)
• Sheep pox virus (USDA, Animal)
• Shiga-like ribosome inactivating proteins (HHS)
• Shigatoxin (Overlap)
• Staphylococcal enterotoxins (Overlap)
• Swine vesicular disease virus (USDA, Animal)
• Synchytrium endobioticum (USDA, Plant)
• T-2 toxin (Overlap)
• Tetrodotoxin (HHS)
• Variola major virus (Smallpox virus) (HHS)
• Variola minor virus (Alastrim) (HHS)
• Venezuelan Equine Encephalitis virus (Overlap)
• Vesicular stomatitis virus (exotic) (USDA, Animal)
• Xanthomonas oryzae pv. oryzicola (USDA, Plant)
• Xylella fastidiosa (citrus variegated chlorosis strain) (USDA, Plant)
• Yersinia pestis (HHS)

Genetic Elements, Recombinant Nucleic Acids, and Recombinant Organisms

• Nucleic acids that can produce infectious forms of any of the select agent viruses.
• Recombinant nucleic acids that encode for the functional form(s) of any of the select agent toxins if the nucleic acids:
• can be expressed in vivo or in vitro, or
• are in a vector or recombinant host genome and can be expressed in vivo or in vitro.
• Select agents that have been genetically modified.

APPENDIX

Exclusions:

• Any select agent or toxin that is in its naturally occurring environment provided it has not been intentionally introduced, cultivated, collected, or otherwise extracted from its natural source.
• Non-viable select agent organisms or nonfunctional toxins.
• The following toxins (in the purified form or in combinations of pure and impure forms) if the aggregate amount under the control of a principal investigator does not, at any time, exceed the amount specified:

• 100 mg of Abrin
• 0.5 mg of Botulinum neurotoxins
• 100 mg of Clostridium perfringens epsilon toxin
• 100 mg of Conotoxins
• 1,000 mg of Diacetoxyscirpenol
• 100 mg of Ricin
• 100 mg of Saxitoxin
• 100 mg of Shigatoxin
• 100 mg of Shiga-like ribosome inactivating proteins
• 5 mg of Staphylococcal enterotoxins
• 100 mg of Tetrodotoxin
• 1,000 mg of T-2 toxin

• The following attenuated strains are exempt if used in basic or applied research, as positive controls, for diagnostic assay development, or the development of vaccines and therapeutics:

Coccidioides posadasii ∆chs5 strain

Conotoxins specifically excluded are: the class of sodium channel antagonist μ-conotoxins, including GIIIA; the class of calcium channel antagonist ω-conotoxins, including GVIA, GVII, MVIIA, MVIIC, and their analogs or synthetic derivatives; the class of NMDA-antagonist conantokins, including con-G, con-R, con-T and their analogs or synthetic derivatives; and the putative neurotensin agonist, contulakin-G and its synthetic derivatives.

Yersinia pestis strains which are Pgm - due to a deletion of a 102-kb region of the chromosome termed the pgm locus (i.e., ∆pgm). Examples are Y. pestis strain E.V. or various substrains such as EV 76. Yersinia pestis strains (e.g., Tjiwidej S and CDC A1122) devoid of the 75 kb low-calcium response (Lcr) virulence plasmid.

Bacillus anthracis strains devoid of both plasmids pX01 and pX02 & Bacillus anthracis strains devoid of the plasmid pX02 (e.g., Bacillus anthracis Sterne, pX01 +pX02 -).

Brucella abortus Strain 19 & Brucella abortus strain RB51 (vaccine strain). Coxiella burnetii Phase II, Nine Mile Strain, plaque purified clone 4.

Francisella tularensis subspecies novicida (also referred to as Francisella novicida) strain, Utah 112 (ATCC 15482) & Francisella tularensis subspecies holartica LVS (live vaccine strain; includes NDBR 101 lots, TSI-GSD lots, and ATCC 29684) & Francisella tularensis ATCC 6223 (also known as strain B38).

Rift Valley fever virus, MP-12 vaccine strain.

Venezuelan Equine Encephalitis (VEE) virus vaccine candidate strain V3526 & Venezuelan equine encephalitis virus, TC-83 strain.

Highly pathogenic avian influenza (HPAI) virus, recombinant vaccine reference strains of the H5N1 and H5N3 subtypes.

Japanese encephalitis virus, SA14-14-2 strain..

The medical use of toxins for patient treatment is exempt.

 

Live Viruses

Individuals who will be working with certain live viruses in the laboratory must successfully complete the web-based training and medical review and informed consent process prior to such work. Further information and directions for completing this process are found in the Live Virus Worker Program Instructions and Requirements.

Successful completion of the web training will be automatically recorded in the training data base and the training will conclude by directing the individual to complete the necessary forms and medical review.

Completing this live virus worker process:

• Provides the individual with information on the risks and the necessary safety measures associated with the work
  
• Acknowledges the individual’s acceptance of risks and responsibilities for the work
  
• Initiates the necessary medical review provided through Employee Health at McCosh Health Center

The procedure to be followed by the live virus worker to complete this process is outlined in the chart that follows:

The live virus worker informs the PI and Employee Health when the worker:

• Becomes pregnant
  
• Is exposed to live virus by accident or injury
  
• Has a change in immune status

Human Blood and Tissue

In any laboratory where work involves the use of and/or exposure to human blood, certain other body fluids, or unfixed human tissue, there is the danger of exposure to bloodborne pathogens, the disease-causing microorganisms that may be found in such material. Work with any of these materials in a laboratory setting usually requires that workers be enrolled in the Bloodborne Pathogens Program. The BBP Program ensures compliance with the federal Occupational Health and Safety Administration (OSHA) Bloodborne Pathogens Standard (29 CFR 1910.1030).

The Bloodborne Pathogens Program requires each department or laboratory to develop an Exposure Control Plan that documents how the risk of exposure will be reduced or eliminated. Specifically, the Plan:

• Defines who has potential exposure and what tasks or duties cause exposure
• Indicates the engineering and work practice controls in place
• Describes the personal protective equipment provided and used
• Describes the good housekeeping practices initiated
• Provides for the offer of hepatitis B (HBV) vaccination to those exposed
• Provides for medical follow-up after exposure
• Provides for proper hazard signage and labeling
• Provides for initial and annual training and necessary record-keeping
  

EHS has developed a model plan that can be tailored to the needs of the department or lab. A copy of the model plan can be found at http.//web.princeton.edu/sites/ehs/biosafety/Training/BBPExposureControl.htm.

As part of this plan, the potentially exposed individuals must:

• Complete the on-line interactive web-based training, Protection Against Bloodborne Pathogen, which includes offer of Hepatitis B vaccination and registration in the Bloodborne Pathogens Program
  
• Use appropriate personal protective equipment and follow established safe work practices
  
  
• Report all exposures to the Employee Health at McCosh Health Center for post-exposure treatment

The following chart indicates the steps a PI must take to obtain approval of work using human blood and tissue:

In addition, when blood or tissue donors are involved, the Principal Investigator must:

• Submit the research proposal through ORPA to the Review Panel for Human Subjects.
  
• Get the informed consent of prospective donors and inform them of the requirement for pre-testing every six months for HIV and hepatitis B and C.
  Donors will not be able to donate without agreeing to pre-testing.
  
• Contact Employee Health at McCosh Health Center to arrange for pre-testing. (Drawing of blood and pre-testing is performed only by McCosh personnel.) After test results are confirmed negative, then up to 200 ml of blood can be drawn for research. If the results are positive, then blood would
  not be drawn for research use. New Jersey law requires that the treating physician notify the proper state agency regarding persons who have tested positive for HIV, and this will be done by McCosh personnel.
  
• NOTE: McCosh will monitor the donors’ charts. The investigator’s grant will be charged for costs of pre-testing and blood draws.
  
• Get assurance that, when human blood or blood products are received from sources outside the University, donors (or blood products) have been
  tested for HIV and hepatitis B and C and found to be negative. When such testing is impractical or impossible, requests for exemptions to this
  requirement are to be made to the Biosafety Committee.

Biohazards Associated with Animal Handling

When research involves exposure to and handling of animals, there are considerations that must be given to the potential allergens, zoonoses, and physical hazards, e.g. bites and scratches, that may be encountered by researchers and staff.

All staff, faculty, and students who have direct contact with animals are enrolled in the Occupational Health and Safety Program. Enrollment is initiated by the individual completing the web-based training, Health and Safety for Animal Workers.

Successful completion of the web training will be automatically recorded in the training data base and the training will conclude by directing the individual to complete the necessary forms and medical review. The web training and medical review must be completed before the individual will be provided access to the animal facility.

The medical review includes:

• Update of tetanus immunizations
  
• TB screening for primate workers
  
• Discussion of allergen exposure and potential zoonoses
  
• What to do if bitten, or after other injury with animals or contaminated caging/equipment
  
• Vaccination for zoonoses, when indicated and available
  
• Completion of the Animal Worker Personnel Information Form and the Health History Form.

Personnel also receive training by the Campus Veterinarian in biomethodology and safe handling techniques for those animals with which they will have contact.

All research involving the care and handling of animals is reviewed and approved by the Institutional Animal Care and Use Committee (IACUC). Hazards associated with animal exposure are addressed through this committee.

IACUC Protocol Forms and attachments need to be completed and submitted to ORPA. The necessary forms can be found and completed online.

The following chart indicates the steps of the review and approval process:

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