With a potential finishing line suddenly appearing over the horizon, getting competitors to the end of this global SARS-CoV-2 vaccine race depends as much on the condition of the track and the riders themselves as it does on the vaccine candidates. Don't forget after all, that the end isn't a viable vaccine, the real finishing post is an entire vaccinated population. And, when it comes to managing the whole picture, the UK has as much to give as it does to gain.
Here, Nigel Whittle and Stephen Guy look at how the UK labs market is shaping up to test and deliver vaccines at unparalleled scale as the final mad dash to a COVID-19 free society hots up.
In recent months the world’s attention has been focused on the efforts of the scientific community and the pharmaceutical industry to come up with a vaccine to help us escape the COVID-19 pandemic. The effort has been immense and progress that normally takes 10 years has been cut down to 10 months. With an estimated 300 vaccine candidates and dozens of clinical trials taking place, there are now some clear front runners.
Pfizer and BioNTech have announced 95% efficacy for its vaccine from the final analysis of a 43,000-person study, and importantly 94% efficacy in people aged over 65. Moderna’s interim findings also demonstrated 95% efficacy and can be more easily stored and transported. The Pfizer/BioNTech collaboration is to ask the US Food and Drug Administration for emergency use authorisation and Moderna will follow suit. The FDA has said it will review any emergency use authorisation requests as early as the start of December and the same moves are happening around the world.
Accelerating the vaccine development process to such an extent has necessitated carrying out certain stages in parallel. For example, millions of doses of vaccine are being manufactured by pharmaceutical companies ‘at-risk’, without knowing the efficacy of the vaccine, while in other cases, national governments are shouldering much of the final risk. The UK government so far has ordered 340 million doses of vaccines from several manufacturers, with the hope at least one will prove successful.
Currently, the most advanced vaccine candidates come from four different classes: adenoviral vector vaccines, mRNA vaccine, inactivated whole virus vaccines and protein adjuvant vaccines. But coming up with an effective vaccine is just the start. All these vaccine candidates have their own manufacturing challenges at unprecedented scale.
The UK’s capability to manufacture vaccines received a substantial boost with the announcement of a £100 million investment into a state-of-the-art Cell and Gene Therapy Catapult Manufacturing Innovation Centre. This is not due to open until December 2021 in Braintree, but will possess state-of-the art capabilities to produce millions of doses of vaccine each month. Once complete, the facility will have the capacity to produce enough doses to serve the entire UK population.
The centre will complement the Vaccines Manufacturing and Innovation Centre (VMIC), a new, not for profit research company within the national scientific infrastructure providing strategic vaccine development and manufacturing capability. The company is supported by its three founding members: the University of Oxford, Imperial College and the London School of Hygiene and Tropical Medicine, with a £93 million investment from the government. The government has invested an additional £38 million to establish a rapid deployment facility.
Technical issues of vaccine development
The rapid development of vaccines and other similar biologics is a challenging task and one requiring all the processes to be critically analysed and optimised. One of these challenges is creating high quality master and working cell banks and the scale-up of cells to support early phase clinical trials.
The origin of biologics-based therapies begins with the generation of a small number of modified cells that possess some form of therapeutic benefit. This may be in expressing a particular protein or other biochemical entity, or as in cell therapy or regenerative medicine, the actual cell itself.
The small number of modified cells are ‘scaled-up’ to a higher number in microtiter plates or small flasks, and manual or automated cell picking methods used to identify and extract the healthiest cells. Once a suitable and healthy colony of cells is established, the next step is to expand the cells at sufficient volume to create a ‘master cell bank’ that may comprise of 10s of millions of cells. This may be achieved by seeding the original cell colony (or cell line) into multiple flasks containing cell media and incubating over a few days, and then harvesting.
A master cell bank can then be created by pooling the output of multiple flasks and dispensing them into cryovials, achieved manually or with the use of automation. After creating these cryovials, they are tracked and then stored at low temperatures typically ranging down to -196?C. Tracking is conventionally achieved by reading a 2D code on the base of the cryovial using a scanner.
To create working cell banks comprising of 100s of millions of cells, a series of cryovials from the master cell bank are defrosted and seeded into multiple flasks containing cell media and incubating over a few days, and then harvested. This process is then repeated to create the working cell bank, and the cryovials stored at ultra-low temperatures.
A critical aspect of this process is to manage the workflow and to ensure that the master and working cell banks can be stored and retrieved effectively and reliably. At the Plextek and Design Momentum Partnership, for example, we are exploring technologies to enhance the tracking of cryovials for the generation of master and working cell banks; and techniques for potentially gathering more information than is presently available on the cryovials’ local environment. The aim is to better ensure the reliability and quality of master and working cell banks.
Once the working cell bank is established, it’s then possible to start manufacturing small to medium batches of cells to support testing, including early stage clinical trials. Depending on the therapeutic method, the cells may at this stage be adherent cells or suspension cells.
If suspension cells, the next step may be to defrost and pool the contents of the cryovials from the working cell bank and to scale-up into larger volumes, comprising maybe billions of cells using small scale bioreactors.
If adherent cells, the next step is to defrost and pool the contents of the cryovials from the working cell bank and to scale-up into larger volumes, comprising billions of cells, using flask-based technologies such as the Cell Factory™, CellSTACK®, HYPERStack® and CELLdisc™ systems. In some applications it may be possible to grow the adherent cells on micro-carriers and expand within small scale bioreactors.
With flask-based systems in particular, when filled, these items can be heavy and very difficult to manipulate. They can also rely on manual processes to fit and extract tubing, attach and detach sensors and filters and monitor how well the processes are progressing.
At the Plextek and Design Momentum Partnership we are also exploring collaborative robotics technologies to help perform these processes; so, the benefits of the operator interaction are maintained whilst also making use of automation to perform repetitive and heavy lifting tasks.
Unlike industrial robots, they are equipped with a combination of sophisticated sensors and internal electromechanical design elements making them safe to work alongside. Scientists can interact with them in close quarters without any separation requirements, which has sweeping implications on how laboratory automation is configured, as well as the range of workflows and places they can be deployed. That makes it possible to both shrink the overall size of the system and allow it to be easily reconfigured as needed. This is just the start. The next generation will have autonomous mobility and be capable of moving to various locations around a facility to perform different functions.
Nigel Whittle (left) is Head of Medical & Healthcare at Plextek and Stephen Guy (right) is Principal Consultant at Design Momentum