Recombinant viruses driving game-changing therapies

Jörg Schneider

by Jörg Schneider

Recombinant viruses are indispensable for many novel biotherapeutics product classes such as CAR-T cells, gene therapies, stem cell therapies, oncolytic viruses, gene-edited cells and novel preventive and therapeutic vaccines. The ability of viruses to enter cells and deliver genetic information has evolved over millennia. This tried and tested feature still makes them the best in class gene transfer vehicles. Viruses evolved to enter cells and deliver genetic information to manipulate the host cell metabolism. As every organism has at least one matching virus, it is no wonder that viruses represent the most diverse lifeform on earth (Suttle, 2013). For the development of AMTPs, the main classes of gene transfer viruses are adeno-associated virus (AAV) and retro-and lentiviruses because they have been developed to minimalistic versions that only carry sequences to deliver and maintain expression of genetic information. The diversity of virus families used for oncolytic and vaccine approaches is even more diverse and includes members from a range of different virus families such as poxviruses, paramyxoviruses, adenoviruses, herpesviruses and parvoviruses (see Table 1 for more details). While each recombinant virus vector technology has its unique features for development and testing, there are common development principles which are outlined in regulatory guidelines.

For example, extensive characterisation and QC testing is required for recombinant viral vectors for human clinical trials. This assures that each batch of the investigational product meets pre-determined specifications for purity, potency, safety and identity. Furthermore, these QC tests should be sufficiently precise and accurate to provide the clinical investigation team and regulatory authorities with confidence regarding batch-to-batch consistency and comparability. The evolution from pre-clinical animal studies, to early- and then late-phase clinical studies, and ultimately to commercialisation, correlates with the development, qualification and validation of a broad range of QC tests to ensure sufficient characterisation of each investigational product.

Similarly, during clinical development, manufacturing process improvements and multi-lot experience enable progressive tightening of specifications. One of the challenges of characterisation and QC testing of viral vectors is the high degree of complexity of this class of biologics. The manufacture of viral vectors used in gene therapy needs to comply with cGMP. In Europe, the recently issued “Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products” provides an adequate basis to support companies in their development from IMP to late-stage products. For example, while product QC testing for safety attributes of an investigational product (sterility, absence of mycoplasma and adventitious viral contaminants) must be established and validated from the beginning of clinical development, certain product characterisation tests may be performed using non-validated assays and broad specifications, with the regulatory expectation of full assay validation and progressive tightening of specification to occur in a timely manner during clinical development. Similarly, it is recognised that process changes, including process optimisation and scale-up, are likely to occur during clinical development of most investigational products (van der Loo & Wright, 2016).

Due to their proven ability to deliver genetic information, acceptable safety profile and several approved products, we clearly see a further expansion of the pipeline of virus-based therapies.

Biopharma Excellence´s services cover all aspects of recombinant virus vector development, and we have successfully supported many customers in Europe and the US. You are developing recombinant virus-based product? Don’t hesitate to contact us to guarantee your success.

Table 1: Selection of gene therapies and their development and regulatory status (adapted from Sinclair et al., 2018)

ALL = acute lymphocytic/lymphoblastic leukaemia; AAV = adeno-associated virus; ADA-SCID = adenosine deaminase severe combined immunodeficiency; BCL = B cell lymphoma; CAR-T = chimeric antigen receptor T-cells; CALD = cerebral adrenoleukodystrophy; DLBCL = diffuse large B cell lymphoma; HSV = herpes simplex virus; LHON = Leber hereditary optical neuropathy; MD = muscular dystrophy; MLD = metachromatic leukodystrophy; MM = multiple myeloma; MPS IIIA = Sanfilippo syndrome type A; OA = osteoarthritis; Plas = plasmid; RR = Relapsed/Refractory; SCD = sickle cell disease; SMA = spinal muscular atrophy; SS = synovial sarcoma; WAS = Wiskott-Aldrich syndrome; X-CGD = X-linked chronic granulomatous disease.

a Initiating trials.

b OTL-101 has received a Rare Pediatric Disease Designation.

c Conditional Market Authorisation in EU.


  • Sinclair, A., Islam, S., & Jones, S. (2018). Gene therapy: an overview of approved and pipeline technologies. In CADTH Issues in Emerging Health Technologies: Canadian Agency for Drugs and Technologies in Health.

  • Suttle, C. A. (2013). Viruses: unlocking the greatest biodiversity on Earth. Genome, 56(10), 542-544.

  • van der Loo, J. C., & Wright, J. F. (2016). Progress and challenges in viral vector manufacturing. Human molecular genetics, 25(R1), R42-R52.

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