Cell membranes can boost the production of protein-based vaccines

Synthetic biologists from Northwestern Engineering have cracked open a cellular membrane, identifying a new method to boost the production yields of protein-based vaccines by five times and thus considerably expanding access to possibly life-saving drugs.

Cell Membranes can Boost the Production of Protein-Based Vaccines
Michael Jewett. Image Credit: Northwestern University.

In February 2021, the team launched a novel biomanufacturing platform that can rapidly create shelf-stable vaccines at the point of care, making sure that they are not discarded because of errors in storage or transportation.

In their latest analysis, the researchers found that the production yields of their freeze-dried platform increased considerably when they enriched cell-free extracts with cellular membranes—the components required to make conjugate vaccines.

The new study sets the stage to quickly develop drugs that address the growing antibiotic-resistant bacteria, and also novel viruses at 40,000 doses per liter for each day, costing around $1 for each dose.

At that speed, the researchers could employ a 1000-liter reactor (roughly the size of a huge garden waste bag) to produce 40 million doses for each day, touching 1 billion doses within a month.

Certainly, in the time of COVID-19, we have all realized how important it is to be able to make medicines when and where we need them. This work will transform how vaccines are made, including for bio-readiness and pandemic response.”

Michael Jewett, Study lead, McCormick School of Engineering, Northwestern University

The study was published in the Nature Communications journal on April 22nd, 2021.

Jewett is also a professor of chemical and biological engineering, and director of the Center for Synthetic Biology at Northwestern University. The co-first authors of the study are Jasmine Hershewe and Katherine Warfel, who are both graduate students in Jewett’s laboratory.

Called in vitro conjugate vaccine expression (iVAX), the novel manufacturing platform was achieved through cell-free synthetic biology—a process where the outer wall (or membrane) of a cell is removed and its internal machinery is repurposed. The team placed this repurposed machinery into a test tube and then freeze-dried it.

The addition of water triggers a chemical reaction that stimulates the cell-free system, converting it into a catalyst for producing usable drugs when and where it is required.

The platform remains shelf-stable for six months or longer and prevents the necessity for extreme refrigeration and complicated supply chains, rendering it a robust tool for low-resource and remote environments.

In an earlier analysis, Jewett’s research team applied the iVAX platform to create conjugate vaccines to protect against infections caused by bacteria. During that time, the team repurposed the molecular machinery from Escherichia coli to make one vaccine dose in an hour that costs around $5 for each dose.

It was still too expensive, and the yields were not high enough, We set a goal to reach $1 per dose and reached that goal here. By increasing yields and lowering costs, we thought we might be able to facilitate greater access to lifesaving medicines.”

Michael Jewett, Study lead, McCormick School of Engineering, Northwestern University

Jewett and his research team later discovered that the key to achieving that goal lies inside the membrane of the cell, which is generally discarded in cell-free synthetic biology. When the membranes are split apart, they naturally look like vesicles—spherical structures that carry crucial molecular information.

The team defined these vesicles and observed that increasing the level of vesicles could be useful for creating components for protein therapeutics, including conjugate vaccines. Such vaccines work by binding a sugar unit—that is exclusive to a pathogen—to a carrier protein. As the body learns to detect that protein as a foreign substance, it learns how to trigger an immune response to fight it when encountered again.

But it is a difficult and complex process to bind this sugar unit to the carrier protein. The team eventually discovered that the cell’s membrane included machinery that allowed the sugar unit to bind to the proteins more easily. The researchers enriched the vaccine extracts with this membrane-bound machinery and considerably increased the production yields of usable vaccine doses.

For a variety of organisms, close to 30 percent of the genome is used to encode membrane proteins. Membrane proteins are a really important part of life. By learning how to use membrane proteins effectively, we can really advance cell-free systems.”

Neha Kamat, Study Co-Author and Assistant Professor of biomedical engineering, McCormick School of Engineering, Northwestern University

Kamat is also an expert on cell membranes.

Source:
Journal reference:

Hershewe, J. M., et al. (2021) Improving cell-free glycoprotein synthesis by characterizing and enriching native membrane vesicles. Nature Communications. doi.org/10.1038/s41467-021-22329-3.

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