Overview of Viral
Vector Shedding

Vector shedding is the release of virus-based gene therapy products from the patient through one or all of the following routes: excreta (faeces), secreta (urine, saliva, nasopharyngeal fluids, etc.), and skin (pustule, sores, wounds)1

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Biodistribution

Shedding is distinct from biodistribution, which refers to the spread of vector DNA within the patient’s body after administration and its localisation and persistence in tissues, body fluids, or organs1,2

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Vector Shedding

Shedding, which refers to how a product is excreted or released from the patient’s body, may be observed as a result of biodistribution2

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Viral vectors are currently the preferred method of delivery for gene therapies compared with non-viral delivery systems3

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Approximately 70% of ongoing gene therapy clinical trials for rare genetic diseases utilise viral vectors4

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Currently, all of the gene therapies approved by the FDA or EMA are viral-based gene therapy products3,5–11

Replication Capabilities of Viral Vectors

Replication-deficient viral vectors

Replication-deficient viral vectors are engineered to be devoid of most of the viral sequences and hence lack the genetic information for replication; however, they do retain the capacity for introducing genes of interest into target cells12,13

Some wild-type viruses like adeno-associated virus are naturally replication deficient and need co-infection with other helper viruses to be able to replicate12

Replication-competent viral vectors

Replication-competent viral vectors retain characteristics of the parent virus that enable them to multiply12

These viruses are currently most often being applied in cancer therapy12

A few examples include herpes simplex virus, reovirus, and adenovirus14

Safety concerns associated with vector shedding are extremely low for replication-deficient viral vectors1,15

Shedding of replication-deficient viral vectors is expected to be low, of a limited duration, and associated with a lower potential for release as infectious viruses1

While it is unknown whether limited exposure to a replication-deficient vector is sufficient to generate an antibody response, there is a potential risk of seroconversion* in people who come into contact with patients dosed with a gene therapy, which could have future implications16,17

  • In exposed individuals, it could limit the possibility of future use of a gene therapy containing the same vector16
  • In the event of exposure in an antibody-negative mother, there may be the subsequent risk of future seropositive† pregnancies17
Alipogene tiparvovec‡ Replication-deficient AAV118
Autologous CD34+ cells encoding the human ADA cDNA sequence§ Replication-deficient ɣ-retroviral vector19
Axicabtagene ciloleucel§ Replication-deficient ɣ-retroviral vector20
Recombinant human p53§ Replication-deficient adenovirus21
Onasemnogene abeparvovec§ Replication-deficient AAV922
Tisagenlecleucel§ Replication-deficient lentiviral vector23
Voretigene neparvovec§ Replication-deficient AAV224

*Seroconversion is the development of detectable antibodies in the blood that are directed against an infectious agent;26 †Seropositive is the presence of a specific antibody in serum;27 ‡Alipogene tiparvovec is no longer marketed due to extremely limited usage;28 §Please refer to local prescribing information.
AAV, adeno-associated virus; ADA, adenosine deaminase; CD, cluster of differentiation; cDNA; complementary DNA.

Safety concerns associated with vector shedding are a potential concern for replication-competent viral vectors1,15

Because replication-competent viral vectors retain the ability to replicate, they are likely to shed more effectively and for a longer period into the environment compared with replication-deficient viral vectors15

  • This shed vector may be infectious, raising the possibility of transmission of the virus-based gene therapy product to untreated individuals (e.g. close contacts and healthcare professionals)1

To understand the potential risk of transmission and help evaluate measures to prevent transmission, shedding studies in the target population are being conducted1
Talimogene laherparepvec§ Replication-competent HSV-125

§Please refer to local prescribing information.

References

  1. U.S. Food and Drug Administration. Design and analysis of shedding studies for virus or bacteria-based gene therapy and oncolytic products. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-and-analysis-shedding-studies-virus-or-bacteria-based-gene-therapy-and-oncolytic-products. Accessed 10 September 2019.
  2. Salmon F, et al. Expert Rev Clin Pharmacol 2014;7(1):53–65.
  3. Ginn SL, et al. J Gene Med 2018;20(5):e3015.
  4. Nyamay’Antu A, et al. Cell Gene Insights 2019;5(S1):51–57.
  5. BioPharm International. 1 May 2004. Available at: http://www.biopharminternational.com/genesis-gendicine-story-behind-first-gene-therapy. Accessed 10 September 2019.
  6. Autologous CD34+ cells encoding the human adenosine deaminase (ADA) cDNA sequence® [product information]. 2021. Available at: https://www.ema.europa.eu/en/documents/product-information/strimvelis-epar-product-information_en.pdf. Accessed 16 March 2021.
  7. Tisagenlecleucel® [product information]. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product-information_en.pdf. Accessed 16 March 2021.
  8. Axicabtagene ciloleucel® [product information]. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/yescarta-epar-product-information_en.pdf. Accessed 16 March 2021.
  9. Onasemnogene abeparvovec® [product information]. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/zolgensma-epar-product-information_en.pdf. Accessed 12 March 2021.
  10. Talimogene laherparepvec® [product information]. 2020. Available at: https://www.ema.europa.eu/en/documents/product-information/imlygic-epar-product-information_en.pdf. Accessed 16 March 2021.
  11. Voretigene neparvovec® [product information]. 2021. Available at: https://www.ema.europa.eu/en/documents/product-information/luxturna-epar-product-information_en.pdf. Accessed 16 March 2021.
  12. Baldo A, et al. Curr Gene Ther 2013;13(6):385–394.
  13. Bouard D, et al. Br J Pharmacol 2009;157(2):153–165.
  14. Saini V, et al. Adv Gene Mol Cell Ther 2007;1(1):30–43.
  15. van den Akker E, et al. Curr Gene Ther 2013;13(6):395–412.
  16. Petrich J, et al. J Pharm Prac 2020;33(6):846–855.
  17. Al-Zaidy SA, Mendell JR. Ped Neuro 2019;100:3–11.
  18. European Medicines Agency. Alipogene tiparvovec. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/glybera-epar-public-assessment-report_en.pdf. Accessed 16 March 2021.
  19. European Medicines Agency. Autologous CD34+ cells encoding the human ADA cDNA sequence. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/strimvelis-epar-public-assessment-report_en.pdf. Accessed 16 March 2021.
  20. European Medicines Agency. Axicabtagene ciloleucel. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/yescarta-epar-public-assessment-report_en.pdf. Accessed 16 March 2021.
  21. Goswami R, et al. Front Oncol 2019;9:297.
  22. European Medicines Agency. Onasemnogene abeparvovec. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/zolgensma-epar-public-assessment-report_en.pdf. Accessed 16 March 2021.
  23. European Medicines Agency. Tisagenlecleucel. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/kymriah-epar-public-assessment-report_en.pdf. Accessed 16 March 2021.
  24. European Medicines Agency. Voretigene neparvovec. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/luxturna-epar-public-assessment-report_en.pdf. Accessed 16 March 2021.
  25. European Medicines Agency. Talimogene laherparepvec. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/imlygic-epar-public-assessment-report_en.pdf. Accessed 16 March 2021.
  26. MedicineNet. Medical Definition of Seroconversion. Available at: https://www.medicinenet.com/script/main/art.asp?articlekey=9388. Accessed 10 September 2019.
  27. Collins Dictionary. Seropositive. Available at: https://www.collinsdictionary.com/us/dictionary/english/seropositive. Accessed 10 September 2019.
  28. UniQure. Press release. 20 April 2017. Available at: http://uniqure.com/GL_PR_Glybera%20withdrawal_FINAL_PDF.pdf. Accessed 16 March 2021.