Accelerating manufacturing to enable large-scale supply of a new adenovirus-vectored vaccine within 100 days
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Abstract
The Coalition for Epidemic Preparedness Innovations’ ‘100-day moonshot’ aspires to launch a new vaccine within 100 days of pathogen identification. Here, we describe work to optimize adenovirus vector manufacturing for rapid response, by minimizing time to clinical trial and first large-scale supply, and maximizing the output from the available manufacturing footprint.
We describe a rapid viral seed expansion workflow that allows vaccine release to clinical trials within 60 days of antigen sequence identification, followed by vaccine release from globally distributed sites within a further 40 days. We also describe a new perfusion-based upstream production process, designed to maximize output while retaining simplicity and suitability for existing manufacturing facilities. This improves upstream volumetric productivity of ChAdOx1 nCoV-19 by around four-fold and remains compatible with the existing downstream process, yielding drug substance sufficient for 10000 doses from each liter of bioreactor capacity.
Transition to a new production process across a large manufacturing network is a major task. In the short term, the rapid seed generation workflow could be used with the existing production process. We also use techno-economic modelling to show that, if linear scale-up were achieved, a single cleanroom containing two 2000 L bioreactors running our new perfusion-based process could supply bulk drug substance for around 120 million doses each month, costing <0.20 EUR/dose. We estimate that a manufacturing network with 32000 L of bioreactor capacity could release around 1 billion doses of a new vaccine within 130 days of genomic sequencing of a new pathogen, in a hypothetical ‘surge campaign’ with suitable prior preparation and resources, including adequate fill-and-finish capacity.
This accelerated manufacturing process, along with other advantages such as thermal stability, supports the ongoing value of adenovirus-vectored vaccines as a rapidly adaptable and deployable platform for emergency response.
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SciScore for 10.1101/2021.12.22.473478: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources CELLS AND VACCINE: All experiments used a previously described research cell bank of T-REx-293 human embryonic kidney (HEK) cells stably expressing the tetracycline repressor protein (ThermoFisher) (4). HEKsuggested: CLS Cat# 300192/p777_HEK293, RRID:CVCL_0045)Initial T-REx-293 cell density was 0.5 to 2 × 106 viable cells/mL in a working volume of or 3 L. T-REx-293suggested: RRID:CVCL_D585)Residual host-cell DNA was quantified using the previously reported qPCR method, with a lower limit of quantification of 100 pg/mL for intact HEK293 cell DNA (4). HEK293suggested: CLS Cat# …SciScore for 10.1101/2021.12.22.473478: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources CELLS AND VACCINE: All experiments used a previously described research cell bank of T-REx-293 human embryonic kidney (HEK) cells stably expressing the tetracycline repressor protein (ThermoFisher) (4). HEKsuggested: CLS Cat# 300192/p777_HEK293, RRID:CVCL_0045)Initial T-REx-293 cell density was 0.5 to 2 × 106 viable cells/mL in a working volume of or 3 L. T-REx-293suggested: RRID:CVCL_D585)Residual host-cell DNA was quantified using the previously reported qPCR method, with a lower limit of quantification of 100 pg/mL for intact HEK293 cell DNA (4). HEK293suggested: CLS Cat# 300192/p777_HEK293, RRID:CVCL_0045)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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