Discussion

Novel gene therapies represent a significant breakthrough in the care of many medical conditions. Gene therapies utilizing viral vectors to deliver the genetic material present unique IPC considerations not present with traditional pharmaceutical formulations in the clinical setting, specifically concerning environmental disinfection and personal protective equipment. The NIH Recombinant DNA Guidelines, United States Pharmacopeia Chapters 800, and the sixth edition of Biosafety in Microbiological and Biomedical Laboratories (BMBL) offer the general framework of working with viral vectors, and they are often used as a reference for risk assessment for human gene transfer research. ^{Reference Blind, McLeod and Campbell9} However, no single guidance document has comprehensive information about disinfection practices, shedding, and risk assessment when using these vector systems in a healthcare setting. Additionally, limited data on shedding requires organizations to work with their Institutional Biosafety Committee (IBC) and healthcare epidemiology teams to develop policies specific to their centers. ^{Reference Eisenman, Debold and Riddle3,Reference Ghosh, Brown and Jenkins4} In the last few years, several local IBCs have been requiring study teams to collect shedding data during the early phase of clinical trials. Hopefully, as there is growth in the field of human gene transfer in the coming few years more information related to shedding will be available. In general, most healthcare facilities recommend universal/standard precautions with patient material between 14 and 30 days after administration for both healthcare staff and direct family members. ^{Reference Blind, McLeod and Campbell9}

A hierarchy originally designed by Earle H Spaulding defines common disinfectants as either high-, intermediate-, or low level, based on their ability to kill various microorganisms. Disinfection protocols in the patient setting are extrapolated from this rational approach provided by Spaulding and from data generated from wild-type viruses in basic research studies. When placed on untreated plastic, recombinant AAV and adenoviral vectors were recoverable by cell culture for 3 and 14 days, respectively. ^{Reference Reuter, Fang and Ly39} Common oxidative disinfectants include peroxides, peroxygen-persulfate types, peroxide-peracetic acid, and chlorine-based disinfectants. These disinfectants have been found to successfully eliminate adenoviral vectors in research studies. These disinfectants have an appropriate spectrum of activity against some of the most common viruses in a research facility, given that any organism of equal or greater sensitivity than that of AVs likely also will be inactivated by these products. ^{Reference McDonnell and Burke40}

Similarly, the Environmental Protection Agency has a list of disinfectants for emerging viral pathogens that provides endorsement and kill claims based on active ingredient, virus type, and surfaces which are utilized for risk assessment during clinical trials by organizations. ⁴¹ Based on this information, most therapies utilizing AV, AAV, or plasmid DNA vectors require disinfection with 1% sodium hypochlorite solution, with the need for prolonged contact times causing concern for damage to surfaces with repetitive long-term use. ^{Reference Ghosh, Brown and Jenkins4,41} Similarly, center-wise policies related to disinfection are developed in consultation with local IBCs and infection prevention teams based on data gathered related to shedding. Herpesvirus can be inactivated with 70% alcohol solutions as well, presenting fewer material surface incompatibility concerns. ^{Reference Dickinson, Marsh and Shao37} Non-surface-based disinfectant options including hydrogen peroxide vapor and UV irradiation may also play a role in viral gene vector therapy disinfection protocols, however, effectiveness is dependent upon multiple factors including burden of organic matter which limits their usage as a primary disinfection agent.

Duration and extent of viral shedding varies with individual therapeutics, though data are limited. ^{Reference Eisenman and Swindle1,Reference Eisenman, Debold and Riddle3,Reference Ghosh, Brown and Jenkins4} Standard precautions, including covering site of inoculation, should be utilized in patients treated with viral vector gene therapies. Additional transmission-based precautions with contact, droplet, and eye precautions should be employed when viral vectors are administered via aerosol. Immunocompromised healthcare workers or household contacts should avoid contact with patients treated with attenuated, replication-competent herpes viral vectors during the shedding period. ^{Reference Bulcha, Wang and Hong8,Reference Blind, McLeod and Campbell9,42} When working with viral vector gene therapies, clinical staff should wear appropriate personal protective equipment, including gowns, gloves, and eye or respiratory protection, and should further be educated on the potential risks of percutaneous exposure through accidental needlestick. ^{Reference Hernandez7,Reference Blind, McLeod and Campbell9}

Commercially approved agents may provide healthcare teams with some product-specific disinfection and spill-related recommendations within their package inserts. Nadofaragene firadenovec, an AV-mediated therapy, recommends sodium hypocholorite with 0.5% active chlorine or 6% hydrogen preroxide solution with a contact time of 15 minutes to treat any local spill. ⁴³ Talimogene laherparepvec notes that any surface that comes in contact with the product should be treated with a virucidal agent, such as 1% sodium hypochlorite or 70% isopropyl alcohol. ⁴² In the absence of clinical regulatory recommendations to support broad IPC methods for all commercial and clinical research therapies, institutions must develop local policies and procedures to cover a variety of operational scenarios.

Standardized, consistent, and easily interpreted recommendations must be established to ensure the safety of healthcare workers handling these products. Current handling recommendations for viral-based gene therapies should be derived from the United States Pharmacopeia Chapters 800, commercially available gene therapy package inserts, the Center for Disease Control and Prevention’s Biosafety in Microbiological and Biomedical Laboratories (BMBL, 6 ^th Edition), and the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. ^{Reference Blind, McLeod and Campbell9} Table 4 provides institutional recommendations for infection control methods when handling or preparing viral-based gene therapies in a healthcare system.

Table 4. An infection prevention and control strategy based on single-center experience

In this review, we highlight some of the challenges pharmacy and healthcare staff face regarding the use of virus-based gene therapies. The heterogeneity of methodology in studies included in this review precludes definitive recommendations of a single best infection control approach to these gene therapies, and further study will be needed as new products become available for patient use. Current advancements in gene therapy have opened the door to cures at a molecular level for many genetic diseases. The design of new experimental viral vectors with emerging technologies and the rate at which gene therapies are approved highlight the critical role of pharmacists, healthcare epidemiologists, infection preventionists, and biosafety professionals in identifying overall risk and operationalizing acceptable policies, predominantly in the absence of a consensus framework for the risk assessment process.