CM – Membranes unlock the potential to increase cell-free vaccine production

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By Jane Byrne
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22-Apr-2021
– Last updated on
22-Apr-2021 at 12:30 GMT

Related tags:
Cell lines, vaccine, cold chain

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In February, the researchers unveiled a new bioproduction platform – called In Vitro Conjugate Vaccine Expression (iVAX) – that they had developed. This platform is designed to quickly produce storage-stable vaccines at the point of treatment to ensure that they are not wasted due to transport or storage errors.

In a new study published today [22. April] was published in Nature Communications, the team discovered that enriching cell-free extracts with cell membranes – the components needed to make conjugated vaccines – significantly increased the yields of this platform.

The work, they said, does it the prerequisites for quickly producing drugs at 40,000 doses per liter per day against emerging antibiotic-resistant bacteria and against new viruses, which cost around US $ 1 per dose. At that rate, the team could produce 40 million doses per day with a 1,000 liter reactor and reach 1 billion doses in less than a month, the synthetic biologists found.

BioPharma reporter caught up with Michael Jewett, who did the Study conducted. He is Professor of Chemical Engineering and Biotechnology at the McCormick School of Engineering in the Northwest and Director of the Northwestern Center for Synthetic Biology. « This work will transform the way vaccines are made, including bio-readiness and pandemic response, » he said.

« IVAX is based on cell-free protein expression. Cell-free protein expression – the synthesis of proteins in crude extracts without living intact cells – offers a convincing solution to existing limitations in cell-based production. “

“ With iVAX-based cell-free systems, these limitations are eliminated. Indeed, iVAX offers a new approach. iVAX is a cell-free platform for the portable, on-demand and scalable production of conjugated protective vaccines. “

The iVAX platform is made possible by cell-free synthetic biology, in which researchers remove the outer wall or membrane of a cell and reuse its internal machinery. Then they put this reused machine in a test tube and freeze it. Adding water triggers a chemical reaction that activates the cell-free system, making it a catalyst for making usable drugs when and where they are needed. The platform has a shelf life of six months or more, eliminating the need for complicated supply chains and extreme cooling. This makes them a powerful tool for remote or low-resource settings.

The previous study by the Northwestern team showed synthesis of conjugate vaccines at around 20 micrograms per milliliter, said Jewett.  » Higher yields and lower costs could enable even better access, improve disaster responsiveness, enable timely response to emerging / pandemic threats, and enable distributed organic production anywhere in the world and even beyond. We have addressed this in this new paper. “

In previous work, Jewett’s team used the iVAX platform to create conjugated vaccines to protect against bacterial infections. At the time, they used Escherichia coli molecular machines to make a vaccine dose in an hour, which cost about $ 5 per dose. « It was still too expensive and the yields weren’t high enough. We set a goal of $ 1 per dose and we met that goal. By increasing the yields and lowering the cost, we thought we could Drugs may provide better access to lifesaving. « 

How did the team use the iVAX platform to produce conjugated vaccines at a much lower cost?

The team said the key to achieving that goal is Cell membrane that is normally discarded in cell-free synthetic biology. When membranes break apart, they naturally reassemble into vesicles, spherical structures that contain important molecular information. The researchers said they characterized these vesicles and found that increasing the concentration of vesicles could be useful in making components for protein therapeutics such as conjugate vaccines that bind a sugar moiety, unique to a pathogen, to a carrier protein. By learning to recognize this protein as a foreign substance, the body knows how to build an immune response to attack it if it is encountered again, they said.

However, attaching this sugar to the carrier protein is a difficult one, complex process. The team found that the cell membrane contained machines that allowed the sugar to more easily attach to the proteins. By enriching vaccine extracts with this membrane-bound machinery, the researchers were able to significantly increase the yields of usable vaccine doses.

“In iVAX, membrane vesicles are formed during cell lysis, which enable cell-free glycoprotein synthesis. We hypothesized that increasing the vesicle concentration in the cell-free system would increase membrane-bound components and improve glycosylation efficiency. Here we have shown that extract processing offers a handle to enrich extracts with vesicles. An increase in the vesicle concentrations enriched with glycosylation machinery improves glycoprotein synthesis by a factor of 5 to over 100 mg / l. This will reduce the total cost of iVAX from originally around $ 5 per dose to $ 1 per dose, ”Jewett explained.

While there is no company dedicated to iVAX technology yet, it is on the horizon, said he us. Jewett founded SwiftScale Biologics to help speed the time to market for protein therapeutics, including glycated protein therapeutics.

“I believe the commercialization of cell-free synthesized vaccines is on the horizon. It is important that iVAX consists of detoxified lysates that contain endotoxin levels that are well below those in FDA-approved products. While further safety and efficacy studies will be required, we are delighted with the robustness and consistency of cell-free synthesized products. In particular, cell-free systems enable consistent product quality by avoiding stochastic cell growth and mutation problems associated with cell-based manufacturing. « 

Jewett said that conjugated vaccines combine a weak antigen, such as the polysaccharide antigen of a pathogenic bacterium, with a strong antigen, an immunogenic carrier protein, to trigger an immune response.

 » This approach has been very successful at Reacts to polysaccharide antigens from bacteria for protection. However, cell-free systems generally offer exciting opportunities for the production of vaccine antigens from viruses, such as proteins – the spike protein – that trigger an immune response. This can be done quickly and with reagents in stock to respond to pandemic threats. The ability to easily save, distribute and activate freeze-dried cell-free systems by simply adding water or a catalog of freeze-dried DNA templates opens up new possibilities for needs-based, agile and modular bioproduction. « 

 » Drug-resistant bacteria are predicted to threaten up to 10 million lives a year by 2050, requiring new strategies to develop and distribute antibiotics and vaccines. .

“Conjugate vaccines are one of the safest and most effective ways to prevent life-threatening bacterial infections. In principle, conjugated vaccines can be developed for many bacterial pathogens and have so far proven to be more than 90% effective. For example, the implementation of meningococcal and pneumococcal conjugate vaccines has significantly reduced the incidence of bacterial meningitis and pneumonia worldwide. “

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