The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Animal Studies
Reference | Physical Exam | Adverse Events | Distribution | Laboratory Assessment | Immune Response | |||||||
Inflammation | Ig Production | |||||||||||
Animal Studies | Hematology | Liver Function | Kidney Function | Electrolytes | Cell Infiltration | Cytokine | ||||||
Dufour et al., 2019 [15] | ||||||||||||
Fong et al., 2019 [17] | ||||||||||||
Drilling et al., 2017 [16] | ||||||||||||
Drilling et al., 2014 [21] | ||||||||||||
Reference | Subjective Data | Physical Exam | Adverse Event | Imaging | Distribution | Lab Exam. | Immune Response | |||||
System Inflammation | Ig Production | |||||||||||
Case Reports | Hematology | Liver Function | Kidney Function | Electrolyte | CRP or ESR | Cytokine | ||||||
Lebeaux et al., 2021 [22] | ||||||||||||
Ferry et al., 2020 [23] | ||||||||||||
Bao et al., 2020 [24] | ||||||||||||
Cano et al., 2020 [25] | ||||||||||||
Rostkowska et al., 2020 [26] | ||||||||||||
Doub et al., 2020 [27] | ||||||||||||
Rubalskii et al., 2020 [28] | ||||||||||||
Gainey et al., 2020 [29] | ||||||||||||
Aslam et al., 2019 [30] | ||||||||||||
Nir-Paz et al., 2019 [31] | ||||||||||||
Tkhilaishvili et al., 2019 [32] | ||||||||||||
Onsea et al., 2019 [33] | ||||||||||||
Corbellino et al., 2019 [34] | ||||||||||||
Susan et al., 2019 [35] | ||||||||||||
Gilbey et al., 2019 [36] | ||||||||||||
Law et al., 2019 [37] | ||||||||||||
RM et al., 2019 [38] | ||||||||||||
Kuipers et al., 2019 [39] | ||||||||||||
Fish et al., 2018 [40] | ||||||||||||
Ferry et al., 2018 [41] | ||||||||||||
Hoyle et al., 2018 [42] | ||||||||||||
Chan et al., 2018 [43] | ||||||||||||
Duplessis et al., 2019 [10] | ||||||||||||
LaVergne et al., 2018 [44] | ||||||||||||
Ferry et al., 2018 [45] | ||||||||||||
Ujmajuridze et al., 2018 [46] | ||||||||||||
Schooley et al., 2017 [47] | ||||||||||||
Zhvania et al., 2017 [48] | ||||||||||||
Jennes et al., 2017 [49] | ||||||||||||
Fish et al., 2016 [50] | ||||||||||||
Fadlallah et al., 2015 [51] | ||||||||||||
Rose et al., 2014 [52] | ||||||||||||
Khawaldeh et al., 2011 [53] | ||||||||||||
Kvachadze et al., 2011 [54] | ||||||||||||
Letkiewicz et al., 2009 [55] | ||||||||||||
Clinical Trials | ||||||||||||
Leitner et al., 2020 [56] | ||||||||||||
Grubb et al., 2020 [57] | ||||||||||||
Fabijan et al., 2020 [58] | ||||||||||||
Ooi et al., 2019 [59] | ||||||||||||
Febvre et al., 2019 [60] | ||||||||||||
Gindin et al., 2018 [61] | ||||||||||||
McCallin et al., 2018 [62] | ||||||||||||
Sarker et al., 2017 [63] | ||||||||||||
McCallin et al., 2013 [64] | ||||||||||||
Sarker et al., 2012 [65] | ||||||||||||
Rhoads et al., 2009 [66] | ||||||||||||
Patrick et al., 2018 [67] | ||||||||||||
Sarker et al., 2016 [68] | ||||||||||||
Wright et al., 2009 [69] |
3.2. Case Reports
3.3. Clinical Trials
4. Discussion
4.1. Potential Impact of Phage Therapy
4.1.1. Impact of Phage on the Microbiome
4.1.2. Endotoxin Release Associated with Bacterial Lysis
4.1.3. Impact of Phages on Immune Activation
4.2. Potential Contaminants from Bacterial Components within Phage Preparations
4.3. Potential Chemical Contaminants from Phage Preparation and Purification
4.4. The Current Safety and Toxicity Monitoring Associated with Phage Preparations
Reference | Titration | Characterization | Composition & Purity | ||||
---|---|---|---|---|---|---|---|
Animal Studies | PFU | Genotype | Protein Profile | Sterility | Endotoxin | Host Cell DNA | Other Toxins |
Dufour et al., 2019 [15] | |||||||
Fong et al., 2019 [17] | |||||||
Drilling et al., 2017 [16] | |||||||
Drilling et al., 2014 [21] | |||||||
Chhibber et al., 2008 [115] | |||||||
Jongsoo et al., 2019 [116] | |||||||
Chang et al., 2018 [113] | |||||||
Gelman et al., 2018 [117] | |||||||
Cheng et al., 2017 [118] | |||||||
Oechslin et al., 2016 [18] | |||||||
Galtier et al., 2016 [81] | |||||||
Jun et al., 2014 [20] | |||||||
Takemura-Uchiyama et al. 2014 [119] | |||||||
Osanai, et al. 2012 [120] | |||||||
Pouillot, et al. 2012 [121] | |||||||
Ľubomíra Tóthová et al. 2011 [122] | |||||||
Hung, et al. 2011 [123] | |||||||
Hawkins, et al. 2010 [124] | |||||||
Sunagar, et al. 2010 [19] | |||||||
Nishikawa, et al. 2008 [125] | |||||||
Case Reports | |||||||
Lebeaux et al., 2021 [22] | |||||||
Ferry et al., 2020 [23] | |||||||
Bao et al., 2020 [24] | |||||||
Cano et al., 2020 [25] | |||||||
Rostkowska et al., 2020 [26] | |||||||
Doub et al., 2020 [27] | |||||||
Rubalskii et al., 2020 [28] | |||||||
Gainey et al., 2020 [29] | |||||||
Aslam et al., 2019 [30] | |||||||
Nir-Paz et al., 2019 [31] | |||||||
Tkhilaishvili et al., 2019 [32] | |||||||
Onsea et al., 2019 [33] | |||||||
Corbellino et al., 2019 [34] | |||||||
Susan et al., 2019 [35] | |||||||
Gilbey et al., 2019 [36] | |||||||
Law et al., 2019 [37] | |||||||
RM et al., 2019 [38] | |||||||
Duplessis et al., 2019 [10] | |||||||
Kuipers et al., 2019 [39] | |||||||
LaVergne et al., 2018 [44] | |||||||
Ferry et al., 2018 [41] | |||||||
Fish et al., 2018 [40] | |||||||
Ferry et al., 2018 [45] | |||||||
Hoyle et al., 2018 [42] | |||||||
Chan et al., 2018 [43] | |||||||
Ujmajuridze et al., 2018 [46] | |||||||
Schooley et al., 2017 [47] | |||||||
Zhvania et al., 2017 [48] | |||||||
Jennes et al., 2017 [49] | |||||||
Fish et al., 2016 [50] | |||||||
Fadlallah et al., 2015 [51] | |||||||
Rose et al., 2014 [52] | |||||||
Khawaldeh et al., 2011 [53] | |||||||
Kvachadze et al., 2011 [54] | |||||||
Letkiewicz et al., 2009 [55] | |||||||
Clinical Trials | |||||||
Leitner et al., 2020 [56] | |||||||
Grubb et al., 2020 [57] | |||||||
Fabijan et al., 2020 [58] | |||||||
Ooi et al., 2019 [59] | |||||||
Febvre et al., 2019 [60] | |||||||
Gindin et al., 2018 [61] | |||||||
McCallin et al., 2018 [62] | |||||||
Sarker et al., 2017 [63] | |||||||
McCallin et al., 2013 [64] | |||||||
Sarker et al., 2012 [65] | |||||||
Rhoads et al., 2009 [66] | |||||||
Patrick et al., 2018 [67] | |||||||
Sarker et al., 2016 [68] | |||||||
Wright et al., 2009 [69] |
4.5. Optimization of Safety and Toxicity Monitoring in Phage Therapy
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Safety Monitoring | Safety Endpoints |
---|---|
General assessment | Vital signs; physical exam; subjective symptoms |
Labs—Chemistry | Liver function; kidney function; electrolytes; glucose; CRP |
Labs—Hematology | CBC with differential; ESR |
Pharmacology | Absorption; distribution; excretion; metabolism endpoints (e.g., LE50, ED50, TI) |
Immune Response | Non-specific and specific immune responses (e.g., DC, inflammatory factor level; phage specific antibodies) |
Phage Parameters | Phage Preparation Measurements |
---|---|
Identify | Morphology |
Potency | Titer |
Sequencing | Genotype; Protein profile |
Bacterial contaminants | Viable bacteria; Endotoxin; Enterotoxin B; Bacterial DNA |
Other impurities | CsCl |
Others | Sterile; PH; shelf time; suspended buffer; osmotic pressure |
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Liu, D.; Van Belleghem, J.D.; de Vries, C.R.; Burgener, E.; Chen, Q.; Manasherob, R.; Aronson, J.R.; Amanatullah, D.F.; Tamma, P.D.; Suh, G.A. The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies. Viruses 2021, 13, 1268. https://doi.org/10.3390/v13071268
Liu D, Van Belleghem JD, de Vries CR, Burgener E, Chen Q, Manasherob R, Aronson JR, Amanatullah DF, Tamma PD, Suh GA. The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies. Viruses. 2021; 13(7):1268. https://doi.org/10.3390/v13071268
Chicago/Turabian StyleLiu, Dan, Jonas D. Van Belleghem, Christiaan R. de Vries, Elizabeth Burgener, Qingquan Chen, Robert Manasherob, Jenny R. Aronson, Derek F. Amanatullah, Pranita D. Tamma, and Gina A. Suh. 2021. "The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies" Viruses 13, no. 7: 1268. https://doi.org/10.3390/v13071268