Biosafety Directive for Human Immunodeficiency Virus (HIV) and Human T-cell Lymphotropic Virus Type 1 (HTLV-1)
January 21, 2014
TABLE OF CONTENTS
- 1.0 BACKGROUND
- 2.0 PATHOGEN DESCRIPTIONS AND RISK GROUPS
- 3.0 CONTAINMENT LEVEL REQUIREMENTS
- 4.0 ADDITIONAL BIOSAFETY REQUIREMENTS
- 5.0 BIOSAFETY CONSIDERATIONS
- 6.0 CONTACT AND ADDITIONAL INFORMATION
- 7.0 GLOSSARY
- 8.0 REFERENCES AND RESOURCES
- Acquired Immunodeficiency Syndrome
- Adult T-cell Leukemia
- Biological Safety Cabinet
- Canadian Biosafety Standards and Guidelines
- Canadian Food Inspection Agency
- Containment Level (i.e., CL2, CL3, CL4)
- CL2 Large Animal Facility
- HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis
- High Efficiency Particulate Air
- Human Immunodeficiency Virus
- Human T-cell Lymphotrophic Virus (type 1)
- Laboratory Acquired Infection
- Local Risk Assessment
- Public Health Agency of Canada
- Pathogen Safety Data Sheet
- Risk Group (i.e., RG1, RG2, RG3, RG4)
- Simian Immunodeficiency Virus
- Standard Operating Procedure
Biosafety is defined as the containment principles, technologies, and practices that are implemented to prevent unintentional exposure to pathogens and toxins, or their accidental release. The application of appropriate biosafety principles and practices is fundamental to ensuring the safe and secure handling and storage of infectious materials and the protection of the public. National biosafety standards and guidelines pertaining to human and terrestrial animal pathogens and toxins are currently provided in the Government of Canada's Canadian Biosafety Standards and Guidelines (CBSG), 1st editionFootnote 1 referred to as the CBSG' for the remainder of the Directive.
The CBSG describes the physical containment and operational practices required for handling infectious material according to containment level (CL). Pathogens that have had pathogen risk and CL assessments completed have been assigned an appropriate risk group (RG) and CL. For the majority of pathogens, the CL and RG of the pathogen are the same (e.g., RG2 pathogens are handled at CL2), but there are some exceptions. As part of the pathogen risk assessments and containment level assessments conducted by the Public Health Agency of Canada (the Agency) and the Canadian Food Inspection Agency (CFIA ), or local risk assessments conducted by regulated parties, the CLs may change when the pathogen has been modified, the original conditions of use have changed, or the risks associated with a pathogen itself have changed. These CL changes reflect the risk mitigation strategies to address the specific modification of the pathogen or conditions of use. In general, many of the physical containment and operational practice requirements at CL3 are aimed at reducing the risks associated with airborne or aerosol-transmitted pathogens. As such, certain physical and/or operational requirements at CL3 for activities involving pathogens not known to be transmissible by inhalation are sometimes derogated. As stated in the CBSG, derogations are determined based on the work involved and the pathogen in question, and would be stipulated in the importation permit and/or otherwise communicated by the Agency or CFIA using another mechanism, and in this case a Biosafety Directive.
The human immunodeficiency virus (HIV) and the human T-cell lymphotropic virus type 1 (HTLV-1) are examples of RG3 pathogens where the pathogen risk and CL assessments have been revisited by the Agency in conjunction with HIV/HTLV specialists based on current risks associated with activities involving these pathogens. It has been determined that HIV & HTLV-1 can be safely handled at CL2/CL2-Ag with specific additional operational requirements (see Section 4.0). This Biosafety Directive is intended to provide a comprehensive overview of the risk assessment outcomes, subsequent CL decisions, and considerations that have been made for those working with HIV and HTLV-1. The Biosafety Directive for HIV and HTLV-1 is to be used in conjunction with the CBSG.
HIV is an enveloped, spherical virus that is around 80–100 nm in length, and has a linear, single-stranded positive-sense RNA genome.Footnote 2 The retrovirus exists as two types, HIV-1 and HIV-2.Footnote 3 HIV-1 is the more common type, and it is divided into four groups, M, N, O, and P, based on homology of nucleotide sequences and the originating cross-species transmission.Footnote 4 HIV-1 groups N, O, and P are considered rare, and group M accounts for an estimated 98% of infections worldwide.Footnote 4
HIV-2 is common in Portugal and West Africa, but its prevalence is increasing in other parts of the world as well. The virus is related more closely to simian immunodeficiency virus (SIV) (75% similarity) than to HIV-1 (42%).Footnote 5 HIV-2 infection does not appear to be as easily transmitted and immunodeficiency takes longer to develop. Unlike HIV-1 which is highly infectious in the acute stage, HIV-2 infectiousness increases in the later stages of acquired immunodeficiency syndrome (AIDS) and the highly infectious stage is shorter when compared with HIV-1.
High rates of HIV infection are observed in Africa, Asia, and Europe.Footnote 6 As of 2011, the Agency estimates 71,300 individuals are infected with HIV in Canada, an 11.4% increase from 2008.Footnote 7
The initial, acute stage of HIV-1 infection results in flu-like symptoms that can last for 3-5 weeks and typically includes lymphadenopathy, malaise, high plasma viremia, and an initial decrease in CD4+ T cells.8,9 As infection progresses to the clinical latency stage that can last for years, immune responses lead to a decrease in circulating virus and restoration of CD4+ T cell numbers. In the absence of treatment, viral replication continues, leading to the gradual loss of CD4+ T cells. When the number of CD4+ T cells becomes insufficient to maintain effective immunity, the likelihood of opportunistic infections and neoplasia increases. As CD4+ T cell numbers fall to very low levels, the disease progresses to acquired immunodeficiency syndrome (AIDS), with symptoms of lymphadenopathy, weight loss, chronic diarrhea, and nervous system diseases (including dementia, myopathy and pain). Progression to disease depends on viral factors such as the strain or isolate, infectious dose, and viral load. Without treatment, AIDS develops in the majority of people within 10 years after infection.Footnote 10 Globally, tuberculosis (TB) is the leading cause of death in patients with AIDS, as it causes mortality in one third of HIV-infected individuals worldwide, and patients with HIV are also about 30% more likely to develop TB disease than those without infection.Footnote 11
The natural host of HIV is humans, and experimental infection with HIV-1 is possible in the chimpanzee, gibbon ape, and rabbit.Footnote 12 HIV cannot replicate outside of the host, and is extremely susceptible to drying.Footnote 13 The infectious dose of HIV remains unknown. Since the primary route of transmission is through sexual transmission and parenteral inoculation, it is unlikely that a major HIV epidemic would occur upon the release of the virus from the laboratory environment.
Up until 2002, 106 cases of occupationally acquired HIV infections were documented, where 57 were of healthcare workers in the United States, 35 in Europe, and 14 elsewhere (there were 3 cases from Canada).Footnote 14 Two hundred and thirty eight (238) cases of possible occupationally acquired infections have also been reported. Risks of acquiring infection in the laboratory environment include direct exposure of mucus membranes or breaks in the skin to the blood or bodily fluids of infected humans or animals. The most common exposure is needle stick injury, which causes about 80% of all laboratory acquired infections (LAI); however, it is reported that the infection rate associated with this type of exposure is 0.3-0.5%.Footnote 15
Vaccine development has not yet been successful due to the ever-changing genetic and antigenic properties of HIV-1. There are now more than 25 effective antiviral drugs available for use; however, the emergence of drug-resistant HIV strains threatens to limit the effects of antiviral treatments.Footnote 16, Footnote 17 Additionally, in cases of exposure, there are effective post-exposure prophylaxis regimes and guidelines to follow.Footnote 18, Footnote 19
HTLV, also known as human T-cell leukemia virus is a complex human C-type retrovirus that is spherical in structure with a diameter of approximately 100 nm.Footnote 20 The core of HTLV is electron-dense and contains 2 positive-sense single stranded RNA genomes that upon infection are converted to DNA by reverse transcription and inserted into the host genome to cause persistent infection.Footnote 21 Unlike other retroviruses such as HIV, which increases its progeny by replication of the virus itself, HTLV increases its copy number by proliferation of infected cells.Footnote 22, Footnote 23
Four distinct HTLV types have been identified, all of which resulted from the zoonotic transmission of simian retroviruses from simian to human hosts.Footnote 21 HTLV-1 is the only virus among the 4 types to be linked to human disease: adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is estimated that 10-20 million individuals worldwide are infected with HTLV-1.Footnote 20, Footnote 21, Footnote 23, Footnote 24 HTLV-1 infection is endemic in southern Japan, the Caribbean, parts of Africa (Gabon and Nigeria), the Middle East, South America (Panama, Colombia, Venezuela, Brazil and Bolivia), the Pacific Melanesian islands, and Papua New Guinea.Footnote 24 The number of HTLV-1 cases in Canada is unknown; however, it is reported as rare.Footnote 25, Footnote 26 HTLV-1 infections have been described in Amerindians from coastal regions of British ColombiaFootnote 25, and in Nunavut.Footnote 26
The main hosts of HTLV-1 are humans; however, HTLV-1 is also able to infect rabbits, rats and monkeys.Footnote 27 While the infectious dose of HTLV-1 remains unknown, the main mode of transmission is through direct contact of contaminated body fluids with mucous membranes or breaks in the skin (e.g., abrasions, lacerations, etc.). Even though the transmission of HTLV-1 from animals to humans would be rare, it could occur from animal bites or scratches, or contact of infected body fluids with mucous membranes. There is documentation of HTLV infection of a laboratory worker following accidental needle stick puncture.Footnote 28
ATL is a serious disorder involving malignancy of T-lymphocytes. There are 4 types that are based on clinical presentation. The acute type involves increased numbers of T-cells, skin lesions, systemic lymphadenopathy and hepatosplenomegaly. The lymphoma type is characterized by prominent systemic lymphadenopathy with few abnormal cells in the blood. Both the acute and lymphoma types have poor outcomes with a median survival time of about one year. In chronic ATL, the white cell count is mildly elevated and skin lesions, lymphadenopathy and hepatosplenomegaly are sometimes present. Smoldering ATL is characterized by a few ATL cells and the absence of other clinical features commonly associated with ATL. Generally, the chronic types of ATL progress to an acute form within a few years.Footnote 22,Footnote 25,Footnote 27
Development of ATL is strongly linked to childhood infection and has an estimated incubation period anywhere between 20-60 years, with about 2-6% of infected individuals developing the disease. Footnote 20,Footnote 22
HAM/TSP is a chronic demyelinating disorder characterized by muscle weakness in the extremities, sensory disturbances, urinary incontinence, impotence, and lower back pain.Footnote 20-22,Footnote 25,Footnote 27 This is a progressively disabling condition and with time, the patient may become wheelchair bound, and death may result from secondary complications.Footnote 22 The median incubation period of HAM/TSP is 3.3 years, with less than 1% of HTLV-1 infected patients having the condition.Footnote 29 Although the majority of HTLV-1 infected patients remain asymptomatic, they are still capable of transmitting the virus.Footnote 27 There is no cure for HTLV-1 infection, and effective and long-term therapeutic protocols are lacking for HTLV-1 associated diseases.
RG determination is based on the outcome of a pathogen risk assessment which assesses the inherent risk of a pathogen utilizing risk factors such as; pathogenicity, infectious dose, and communicability. The categories range from RG1 (low individual and low community risk) to RG4 (high individual and high community risk). A full list of pathogen risk factors and the definitions of the RG levels can be found in the CBSG.
In collaboration with a group of experts, the Agency performed pathogen risk assessments for both HIV and HTLV-1 and based on the risk factors associated with the pathogens outlined in the previous sections, it was determined that both viruses will remain in the RG3 category. The CBSG defines a RG3 pathogen as one that poses a high risk to the health of individuals and/or animals and a low risk to public health. RG3 pathogens are likely to cause serious disease in a human or animal. Effective treatment and preventive measures are usually available and the risk of spread of disease caused by these pathogens is low for the public.Footnote 1 The RG determination for HIV and HTLV-1 is in line with assessments that have been completed by international counterparts as shown in Table 1.
|Country||HIV Risk Group||HTLV Risk Group|
|Australia/New Zealand 2002||3||3|
|United Kingdom 2004||3||3|
|European Community 2000||3||3|
|National Institute of Health (NIH) 2002||3||3|
The CBSG reflects the harmonization of the operational and physical containment requirements for human and terrestrial animal pathogens and toxins. This section will reiterate the types of work that are included for each containment column (i.e., CL2) and the distinction between the animal containment zones. More detailed information can be found in the CBSG.
An animal containment zone refers to a series of co-located animal rooms/cubicles, as well as associated corridors and support rooms (e.g., storage and preparation areas) of equal CL, serviced by a single entry/exit. In a “small animal containment zone” (SA zone), animals are housed in primary containment caging. The room encompassing these cages is referred to as an “animal room”. Generally, SA zones follow the same requirements as those for laboratory work areas and are represented under the CL2 or CL3 columns (Table 2).
In a “large animal containment zone” (LA zone), the room itself provides the primary containment. The room or space housing the animals is referred to as an “animal cubicle”. When small-sized animals are not housed in primary containment caging (e.g., chickens in pens), they are considered to be housed in an LA zone and the room and containment requirements provide the appropriate risk mitigation. The CBSG provides distinct columns for LA zones at CL2 and CL3, labelled CL2-Agriculture (CL2-Ag) and CL3-Ag, respectively.
|Type of work area(s)||CL2 Footnote 2.1||CL2-Ag Footnote 2.1||CL3||CL3-Ag||CL4|
|Laboratory work areas||Yes||NO||Yes||NO||Yes|
|Large scale production areas||Yes||NO||Yes||NO||Yes|
|SA zones (including animal rooms) Footnote 2.2||Yes||NO||Yes||NO||Yes|
|LA zones Footnote 2.2 (including animal cubicles and PM rooms)||NO||Yes||NO||Yes||Yes|
CL determination provides the end-user with a description of the minimum physical containment and operational practices required for handling pathogens safely in a laboratory setting. CLs range from a basic laboratory to CL4 (maximum containment facility). Please see the CBSG for full descriptions of the CLs.
For the majority of pathogens, the CL and RG of the pathogen are the same (e.g., RG2 pathogens are handled at CL2), but there are some exceptions. For example, certain physical and/or operational requirements at CL3 for activities involving RG3 pathogens not known to be transmissible by inhalation can sometimes be derogated.
The risk assessments for HIV and HTLV-1 clearly indicate that both pathogens have the ability to produce serious disease in humans. However, the assessments also report that transmission is largely dependent on parenteral inoculation and contact with mucous membranes; survival of the virus outside the host is limited and occurs only under ideal conditions; airborne transmission is not possible; and the risk for laboratory users as well as the environment is limited. It has also been determined that the culturing (propagation) or in vivo work involving either pathogen does not increase the risk for the laboratory user and that proper handling and operational practices can mitigate the risk.
Based on the risk assessments completed by the Agency in conjunction with HIV and HTLV-1 specialists, it has been determined that HIV and HTLV-1 can be safely handled at CL2/CL2-Ag with specific additional operational requirements. See Table 3 for the containment categories, Section 4 for the additional requirements that are to be followed in order to work at CL2/CL2-Ag, and Section 5 for additional biosafety considerations for working with HIV and HTLV-1. For a complete listing of the operational and physical containment requirements, please refer to Part I Chapters 3 and 4 of the CBSG.
|Sample Type and Activity||Minimum
Non-Propagative Clinical/Diagnostic Activities
|■ Footnote 3.1|
Propagative in vitro Activities
|■ Footnote 3.1|
|In vivo Work Activities||■ Footnote 3.1 Footnote 3.2|
HIV and HTLV-1 can be safely handled in a CL2 or CL2-Ag zone that meets the physical and operational requirements described in Part I Chapters 3 and 4 of the CBSG, as well as the additional requirements noted below.
- Centrifugation of infectious material to be carried out in sealed safety cups (or rotors) that are unloaded in a BSC (CBSG R4.6.27). Where this is not possible, additional precautions (e.g., PPE and/or safety equipment, splash guards) are to be in place to prevent exposure to infectious materials due to spills, splashes, or similar events.
- All activities involving open vessels of infectious material to be conducted in a certified BSC or other appropriate primary containment device (CBSG R4.6.24); and
- An additional layer of protective clothing to be donned prior to work with infectious material in accordance with entry procedures (CBSG R4.4.6). An additional layer of protective clothing (e.g., solid-front gowns with tight-fitting wrists, second pair of gloves, waterproof aprons or head covers) provides additional protection and guards against exposure following a tear that compromised, or a spill that contaminated, the outer protective layer.
- An additional layer of protective clothing to be donned prior to work with infected animals, in accordance with entry procedures (CBSG R4.4.6).
The importance of requirements surrounding the completion of LRAs is provided in the CBSG. Many of the requirements in the CBSG are risk and performance-based and as such, are dependent on the LRA performed. Based on the risks associated with work involving HIV and/or HTLV-1, the following list of CBSG requirements are being highlighted to assist with the development of LRAs and standard operating procedures (SOPs). Although these requirements or parts thereof are listed as CL2/CL2-Ag operational requirements in Part I Chapter 4 of the CBSG, they are critical for the safe handling of HIV and HTLV-1 and are highlighted and expanded upon here to facilitate the development of LRAs and associated procedures.
- Good microbiological practices to be employed (CBSG R4.6.18);
- Use of needles, syringes, and other sharp objects to be strictly limited (CBSG R4.6.9). Where possible, plasticware should be used instead of glassware; Applicable provincial/territorial legislation should be consulted to determine local requirements for the use of safety-engineered needles;
- A certified BSC to be used for procedures that may produce infectious aerosols or aerosolized toxins when aerosol generation cannot be contained through other methods; or that involve high concentrations of infectious material or toxins (CBSG R4.6.23);
- Face protection to be used where there is a risk of exposure to splashes or flying objects (CBSG R4.4.2);
- Open wounds, cuts, scratches, and grazes to be covered with waterproof dressings (CBSG R4.6.6);
- Procedures to be in place to prevent a leak, drop, spill, or similar event, during the movement of infectious material within the containment zone, or between containment zones within a building (CBSG R4.6.29);
- A medical surveillance program, based on an overarching risk assessment and LRAs, to be developed, implemented, and kept up to date (CBSG R4.2.1). The surveillance plan should include a protocol for the evaluation of potentially exposed personnel to receive post exposure prophylactic treatment; and
- Disinfectants effective against the infectious material in use to be available and used in the containment zone (CBSG R4.8.2).
Please note that this Directive is based on currently available scientific evidence and is subject to review and change as new information becomes available. If the Directive is amended, the Agency will communicate the updated information to the impacted regulated parties and distribute the amended Directive. For more information on this Directive please contact:
The following list is an excerpt from the CBSG pertaining to terms referenced in this Directive. A comprehensive list of terms and their definitions can be found in the Glossary in Part II Chapter 21 of the CBSG.
|Animal cubicle||A room or space designed to house an animal (or animals) where the room itself serves as primary containment. Generally, these spaces are used to house large-sized animals (e.g., livestock, deer).|
|Animal room||A room designed to house animals in primary containment caging. Generally, these spaces are used to house small-sized animals (e.g., mice, rats, rabbits).|
|Biological safety cabinet (BSC)||A primary containment device that provides protection for personnel, the environment and the product (depending on BSC class), when working with biological material.|
|Biosafety||Containment principles, technologies and practices that are implemented to prevent unintentional exposure to infectious material and toxins, or their accidental release.|
|Containment||The combination of physical design parameters and operational practices that protect personnel, the immediate work environment and the community from exposure to biological material.|
|Containment level (CL)||Minimum physical containment and operational practice requirements for handling infectious material or toxins safely in laboratory and animal work environments. There are four containment levels ranging from a basic laboratory (CL1) to the highest level of containment (CL4).|
|Containment zone||A physical area that meets the requirements for a specified containment level. A containment zone can be a single room (e.g., CL2 laboratory), a series of co-located rooms (e.g., several non-adjoining but lockable CL2 laboratory work areas), or it can be comprised of several adjoining rooms (e.g., CL3 suite comprised of dedicated laboratory areas and separate animal rooms/ cubicles). Dedicated support areas, including anterooms, showers and dirty change rooms, may be part of the containment zone.|
|Derogation||An allowable decrease in the physical and/or operational requirements when conducting specific activities with certain pathogens. The derogations would be stipulated in the importation permit or otherwise communicated by the Agency and the CFIA.|
|Disinfection||Process that eliminates most forms of living microorganisms; disinfection is much less lethal to infectious material than sterilization.|
|Good microbiological laboratory practice||A basic code of practice applicable to all types of laboratory work with biological material. These practices serve to protect and prevent contamination of laboratory workers, the laboratory environment, and the samples in use. Reference posters on good microbiological practices are available from the Agency.|
|Infectious dose||The amount of pathogen required to cause an infection in the host, measured in number of organisms.|
|In vitro||Latin for within glass, in vitro refers to experimentation involving components of a living organism within an artificial environment (e.g., manipulation of cells in petri dish).|
|In vivo||Latin for within the living, in vivo refers to experimentation conducted within the whole living organisms (e.g., studying the effect of antibiotic treatment in animal models).|
|Large animal containment zone (LA zone)||Animal containment zone comprised of one or several co-located or adjoining rooms of equal containment level where animals are housed in animal cubicles (i.e., the room itself provides the primary containment). An LA zone may include, for example, rooms housing mice or raccoons in open cages, or livestock or deer housed in cubicles|
|Large-sized animal||Refers to the physical size of the animal. In general, large-sized animals cannot be housed in primary containment caging. For example, cows and sheep are large-sized animals.|
|Local risk assessment (LRA)||Site-specific risk assessment used to identify hazards based on the infectious material or toxins in use and the activities being performed. This analysis provides risk mitigation and risk management strategies to be incorporated into the physical containment design and operational practices of the facility.|
|Operational practice requirements||Administrative controls and procedures followed in a containment zone to protect personnel, the environment, and ultimately the community from infectious material or toxins, as outlined in Part I, Chapter 4 in the CBSG.|
|Pathogen||A microorganism, nucleic acid, or protein capable of causing disease in humans and/or animals. Examples of human pathogens are listed in Schedules 2 to 4 or in Part 2 of Schedule 5 of the Human Pathogens and Toxins Act, but these are not exhaustive lists. Examples of animal pathogens can be found by visiting the CFIA website.|
|Pathogen risk assessment||The determination of the risk group and appropriate physical containment and operational practice requirements needed to safely handle the infectious material or toxins in question.|
|Pathogen safety data sheet (PSDS)||Technical document describing the hazardous properties of pathogens and recommendations for the safe handling of them. A PSDS may include information such as pathogenicity, drug susceptibility, first aid treatment, PPE, and risk group classification. PSDSs were formally called material safety data sheets for infectious material.|
|Pathogenicity||The ability of a pathogen to cause disease in a human and/or animal host.|
|Personal protective equipment (PPE)||Equipment and/or clothing worn by personnel to provide a barrier from infectious material or toxins, thereby minimizing the risk of exposure. PPE may include, but is not limited to, lab coats, gowns, full-body suits, gloves, protective footwear, safety glasses, safety goggles, masks and respirators.|
|Physical containment requirements||Physical barriers in the form of engineering controls and facility design used to protect personnel, the environment, and, ultimately, the community from infectious material or toxins, as outlined in Part I, Chapter 3 of the CBSG.|
|Primary containment||Ensures the protection of personnel and laboratory work areas from exposure to infectious material and toxins. This is accomplished by the provision of a physical barrier between the individual and/or the work environment and the infectious material or toxins. Examples include BSCs, glove boxes, animal micro-isolators, and animal cubicles.|
|Primary Containment caging||Animal caging serving as a primary containment device to prevent the release of infectious material and toxins (e.g., ventilated filter-top cages and ventilated micro-isolator cage rack system, with or without HEPA).|
|Primary containment device||Device and/or equipment that is designed to prevent the release of infectious material or toxins and to provide primary containment (i.e., provide a physical barrier between the individual and/ or the work environment and the biological material). The most common primary containment device is a BSC.|
|Propagation||The act of multiplying pathogens under controlled laboratory conditions.|
|Risk group (RG)||The classification of biological material based on its inherent characteristics, including pathogenicity, risk of spread, and availability of effective prophylactic and/or therapeutic treatments.|
|Small-sized animal||Refers to the physical size of the animal. In general, small-sized animals can be housed in primary containment caging. For example, mice, rats, and rabbits are small-sized animals. Some small-sized animals cannot be housed in primary containment caging (e.g., chickens); instead, they must be handled in an LA zone.|
|Small animal containment zone (SA zone)||Animal containment zone comprised of one or several co-located or adjoining rooms of equal containment level where animals are housed in animal rooms inside primary containment caging (e.g., microisolators). An SA zone may contain, for example, mice, rats, rabbits, ferrets or nonhuman primates, provided that they are housed in primary containment caging.|
|Virulence||The degree/severity of a disease caused by a pathogen.|
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