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 (feces), 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 localization 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 utilize viral vectors4

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Currently, all of the gene therapies approved by the FDA or EMA are viral-based gene therapy products3,5–10

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 cells11,12

Some wild-type viruses like adeno-associated virus (AAV) are naturally replication deficient and need
co-infection with other helper viruses to be able to replicate11

Replication-competent viral vectors

Replication-competent viral vectors retain characteristics of the parent virus that enable them to multiply11

These viruses are currently most often being applied in cancer therapy11

A few examples include herpes simplex virus (HSV), reovirus, and adenovirus13

Safety concerns associated with vector shedding is extremely low for replication-deficient viral vectors

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 viruses15

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 AAV119
Autologous CD34+ cells encoding the human ADA cDNA sequence† Replication-deficient ɣ-retroviral vector20
Axicabtagene ciloleucel‡ Replication-deficient ɣ-retroviral vector21
Gendicine Replication-deficient adenovirus22
Onasemnogene abeparvovec-xioi Replication-deficient AAV923,24
Tisagenlecleucel§ Replication-deficient lentiviral vector25
Voretigene neparvovec-rzyl Replication-deficient AAV226

Safety concerns associated with vector shedding is a potential concern for replication-competent viral vectors15,16

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 vectors18

  • 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)15

To understand the potential risk of transmission and help evaluate measures to prevent transmission, shedding studies in the target population are conducted15

Talimogene laherparepvec# Replication-competent HSV-127

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 September 10, 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:e3015;
      4. Nyamay’Antu A, et al. Cell Gene Insights 2019;5(S1):51–57;
      5. BioPharm International. May 1, 2004. Available at: http://www.biopharminternational.com/genesis-gendicine-story-behind-first-gene-therapy. Accessed September 10, 2019;
      6. Strimvelis® [summary of product characteristics]. 2016. Available at: https://www.ema.europa.eu/en/documents/product-information/strimvelis-epar-product-information_en.pdf. Accessed August 14, 2019;
      7. Kymriah™ [package insert]. 2018. Available at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kymriah.pdf. Accessed September 10, 2019;
      8. European Medicine Agency. Yescarta: Assessment Report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/yescarta-epar-public-assessment-report_en.pdf. Accessed September 10, 2019;
      9. Zolgensma® [package insert]. 2019. Available at: https://www.avexis.com/content/pdf/prescribing_information.pdf. Accessed September 10, 2019;
      10. U.S. FDA. News release. May 24, 2019. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease. Accessed August 14, 2019.
      11. Baldo A, et al. Curr Gene Ther 2013;13:385–394;
      12. Bourd D, et al. Br J Pharmacol 2009;157:153–165;
      13. Saini V, et al. Adv Gene Mol Cell Ther 2007;1(1):30–43;
      14. Goswami R, et al. Front Oncol 2019;9:297.
      15. 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 September 10, 2019;
      16. Petrich J, et al. J Pharm Prac 2019; doi: 10.1177/0897190019854962 [Epub ahead of print];
      17. Al-Zaidy SA, Mendell JR. Ped Neuro 2019; doi: 10.1016/j.pediatrneurol.2019.06.007 [Epub ahead of print];
      18. van den Akker E, et al. Curr Gene Ther 2013;13:395–412;
      19. European Medicines Agency. Glybera. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/glybera-epar-public-assessment-report_en.pdf. Accessed September 10, 2019;
      20. European Medicines Agency. Strimvelis®. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/strimvelis-epar-public-assessment-report_en.pdf. Accessed September 10, 2019;
      21. European Medicine Agency. Yescarta®. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/yescarta-epar-public-assessment-report_en.pdf. Accessed September 10, 2019;
      22. Goswami R, et al. Front Oncol 2019;9:297;
      23. Zolgensma® [package insert]. 2019. Available at: https://www.avexis.com/content/pdf/prescribing_information.pdf. Accessed  September 10, 2019;
      24. ClinicalTrials.gov. NCT03306277. Available at: https://clinicaltrials.gov/ct2/show/NCT03306277. Accessed September 10, 2019;
      25. European Medicines Agency. Kymriah™. Assessment report. Available at: https://www.ema.europa.eu/en/documents/assessment-report/kymriah-epar-public-assessment-report_en.pdf. Accessed September 10, 2019;
      26. Luxturna™ [package insert]. 2017. Available at: http://sparktx.com/LUXTURNA_US_Prescribing_Information.pdf. Accessed September 10, 2019;
      27. Imlygic® [package insert]. 2015. Available at: https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/imlygic/imlygic_pi.pdf. Accessed September 10, 2019;