Cell-free protein synthesis systems for vaccine design and production

In 2018, the World Health Organization called for accelerated R&D on a list of priority diseases with no efficacious drugs or vaccines. The list includes numerous viral diseases that have the potential to cause future public health crises such as Nipah, Zika, severe acute respiratory syndrome, and Ebola diseases [1]. In addition, it has been difficult to generate vaccines for diseases caused by pathogens such as human immunodeficiency virus, dengue virus, influenza virus, and Plasmodium parasites. This difficulty is due to broad sequence diversity, potential exacerbation of disease in individuals previously never infected, antigenic drift, and the complexity of parasite life stages, respectively 2, 3, 4. Current strategies to manufacture vaccines, such as live attenuated, inactivated, subunit, conjugate, and virus-like particle (VLP) vaccines, have limitations that hinder development, efficacy, and widespread global use (Table 1). Major constraints include the risk associated with live pathogens, long production times, the need for cold chain manufacturing, or the requirement of living cellular hosts that ultimately limit the reach of vaccine distribution or increase the costs and time required to produce vaccines 5, 6, 7, 8. Without effective tools to develop vaccines to address the myriad of pathogenic threats, we are vulnerable to ongoing and future epidemics.

Traditional vaccines are typically produced in a recombinant host and can lead to many of the aforementioned issues. With advancements in synthetic biology, we can now produce proteins outside of a cell. Specifically, cell-free protein synthesis (CFPS) systems provide a platform to circumvent many of the issues associated with current vaccine production strategies. CFPS uses extracted transcriptional and translational machinery from cells to synthesize proteins of interest in vitro, without requiring a cellular host. CFPS systems are derived from either crude cell extracts or purified recombinant translation factors and supplemented with energy sources, salts, amino acids, nucleotides, cofactors, and additional reagents if necessary 15, 16. While CFPS systems have been predominantly used for the design of biosensors [17], high-throughput prototyping [18], metabolic engineering [19], and therapeutics [20], its use for vaccine development and production is still an emerging area. CFPS features such as the lack of a cellular host, an open environment, and rapid protein production have the potential to overcome drawbacks in current production techniques and expand opportunities in vaccine development.

In this review, we highlight the advantages of CFPS systems for vaccine development and production. We discuss examples of how the valuable features of CFPS have been harnessed to generate a variety of vaccines as well as how the technology is beneficial as a tool in vaccine discovery. Last, we discuss existing challenges in cell-free vaccine production that need to be addressed in order to expand the use of this technology for development of potent vaccines.

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