New substances: risk assessment summary 22301
Overview
Notified organism: Rosenblumvirus phage CIP-212 targeting Staphylococcus aureus
Schedule of the New Substances Notification Regulations (Organisms) [NSNR(Organisms)]: Schedule 1 - Information Required in Respect of Micro-organisms
Organism type: Bacteriophage
Use: Manufacture of CIP-212 to treat a prosthetic joint infection (PJI) caused by S. aureus in a single patient
Anticipated quantity: confidential and not for disclosure
Assessment level of concern:
- Human health hazard: Low
- Human exposure: Low
- Environmental hazard: Low
- Environmental exposure: Medium
Assessment conclusion under section 64 of the Canadian Environmental Protection Act, 1999 (CEPA): Low risk, not suspected to be toxic
Category: Eligible for addition to the Domestic Substances List
Recommended action: None
Waivers: Requested for information elements 5(a)(i), 5(a)(ii), and 6(b) of Schedule 1 of the NSNR(Organisms), under paragraph 106(8)(a) of CEPA
Synopsis
CIP-212 is an unmodified, naturally occurring, lytic bacteriophage that targets S. aureus. It was notified for manufacture and use in Canada for the treatment of S. aureus PJI in one designated patient.
Other potential uses could include:
- in commercial drug products to treat any S. aureus infection in humans
- in commercial drug products to treat S. aureus infection in animals
- in products intended for biofilm removal including wastewater treatment
- as a food preservative to prevent S. aureus contamination
Despite the medium potential exposure of the environment to CIP-212 from potential uses, there is no evidence to suggest a risk of adverse effects to the environment and the general population from intended and potential uses.
Based on this assessment, CIP-212 is not suspected to meet criteria in paragraphs 64(a), (b), or (c) of CEPA.
Waivers requested for information elements 5(a)(i) and 5(a)(ii) of Schedule 1 of the NSNR(Organisms) for the data from tests conducted on aquatic species and terrestrial species, respectively, were granted. Information gathered from such tests to determine whether the organisms are toxic or capable of becoming toxic on aquatic and terrestrial species is not necessary given that the notified organism is an unmodified, naturally occurring, lytic bacteriophage that does not contain toxin, virulence, and antibiotic resistance genes or genes associated with temperate lifestyle (such as integrase genes) which could lead to bacterial pathogenesis.
In addition, a waiver requested for information element 6(b) of Schedule 1 of the NSNR(Organisms) for the data from tests of antibiotic susceptibility was granted. Information gathered from such tests to determine whether the organism is susceptible to antibiotics is not necessary given that the notified organism does not carry antiviral susceptibility or resistance genes.
Background information
CIP-212 is a naturally occurring (meaning not genetically modified), obligate lytic bacteriophage targeting S. aureus. It was notified for its manufacture in a single contained facility in Canada and subsequently used to treat a PJI caused by S. aureus in a single designated patient at a Canadian hospital. Upon intra-articular and intravenous administrations, CIP-212 is expected to target and kill S. aureus via its lytic activity, thereby controlling the bacterial infection in the treated patient.
Hazard assessment
The environmental and human health hazard potential of CIP-212 is determined to be low because:
- CIP-212 is a naturally occurring lytic bacteriophage
- the identity of CIP-212 was verified by notifier using whole genome sequence analysis
- test data provided by the notifier indicated that CIP-212 can only target S. aureus strains; it did not infect other Staphylococcus species in the test, including S. succinus, S. chromogenes, S. simulans and S. epidermidis
- bacteriophages can penetrate or interact with eukaryotic cells leading to inflammatory responses in phage-treated human patients
- these responses are not expected to occur in the untreated general population
- CIP-212 is not anticipated to replicate, cause infections or any other adverse effects in terrestrial or aquatic plants, invertebrates or vertebrates, including humans
- the Public Health Agency of Canada generally considers bacteriophages as Risk Group 1 pathogens for terrestrial animals and humans, meaning they present low individual and community risk
- whole genome sequence analysis and host-specificity test results provided by the notifier also suggested that CIP-212 is non-replicative in humans and does not have the potential to become toxic or virulent
- CIP-212 lacks the ability to integrate its genetic material into the host bacteria or to transfer it to another bacterium
- horizontal gene transfer between the notified phage and other organisms in the environment is unlikely
- the notifier did not provide preclinical animal studies on the notified organism
- published literature on other S. aureus phages using mice, rats and rabbit models have reported no adverse effects to treated animals.
- notifier provided pre-clinical toxicity data using rats treated with lytic bacteriophage cocktail targeting Salmonella enterica serovar Typhimurium where no adverse effects were observed
- published clinical studies with other S. aureus phages have reported only mild and clinically manageable health effects and similar health effects may be expected in patientsFootnote 1 treated with CIP-212
- currently there is no antiviral treatment available for CIP-212
- CIP-212 is a phage lacking the capability to induce infection in both animals and humans, and adverse effects are not expected in the general population
Hazards related to micro-organisms used in the workplace should be classified accordingly under the Workplace Hazardous Materials Information System (WHMIS)Footnote 2 .
Exposure assessment
The indirect human exposure potential of CIP-212 is determined to be low, whereas the environmental exposure potential is determined to bet medium, because:
- CIP-212 will be manufactured in a Containment Level 2 (CL-2) facility following a well-established phage production protocol and formulated as a drug product
- CIP-212 will be transported in a frozen state, in properly labelled secured containers to a Canadian hospital for the purposes of treating a single patient with a PJI
- CIP-212 will be administered to the patient via intra-articular injection and/or via intravenous infusion, by trained professionals under the controlled conditions at the clinical site
- the notifier indicated that materials used to dilute, transfer, or contain CIP-212 solutions at the clinical site will be discarded as regular waste or biohazard waste
- any unused drug product will be disposed of following the institutional biohazard waste management procedures
- since CIP-212 is intended only for use in a single patient via injection or infusion over a limited course of treatment, the exposure of the environment and the general population to CIP-212 from the notified use is expected to be negligible, if any
- phages, in general, can be viable for several months to years at 4°C
- phages are susceptible to extreme temperatures and pH in the environment and cannot replicate without their bacterial host
- potential uses of CIP-212 could include its use as a commercial drug, food preservative, or in biofilm-removal applications (such as wastewater treatment)
- general population exposure remains low because phages replicate only in their host bacteria, whereas environmental exposure may increase at the point of introduction due to potential larger application volumes and localized releases
- CIP-212 is naturally occurring where its host thrives
Risk characterization
When used as notified in a medical setting, release to the environment and human exposure to the phage is not expected. The risk assessment also considered exposures due to the possibility of future commercial uses, as a commercial drug product, food preservative, or in products intended for biofilm removal including wastewater treatment. These potential uses were determined to have a low potential for exposure to humans and a medium potential for environmental exposures.
Based on the low hazard potential of the substance and the outcome of the assessment, the environmental and human health risks associated with the manufacture and use of CIP-212 for its intended or potential uses is low.
Risk assessment conclusion
There is no evidence to suggest a potential risk of adverse environmental or human health effects for the environment and general population in Canada from the manufacture and the intended or potential uses of CIP-212. The risk to the environment and human health associated with CIP-212 is not suspected to meet criteria in paragraphs 64(a), (b), or (c) of CEPA. No further action is recommended.