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The Power of Recombinant Proteins in the Age of COVID-19

During the SARS-COV-2 pandemic, investigators quickly zeroed onto the viral Spike protein as a critical target for therapeutic development, including vaccines and monoclonal antibody drugs. Additionally, for diagnostics, receptor-binding domain (RBD) fragments, Spike protein trimer, and Nucleocapsid (N) protein are some of the SARS-CoV-2 proteins leveraged for developing various ELISA and Lateral Flow immunoassays. Hence, recombinant proteins have been essential to the fast advances we have seen in developing vaccines, antibodies, and diagnostics in the age of COVID-19. This expedited recombinant protein production has been only possible due to well-honed bioprocessing strategies.

Based on the COVID-19 Vaccine Tracker, a total of thirteen SARS-CoV-2 vaccines are approved or authorized for use in various countries. Over forty vaccines continue to progress through clinical testing, including ten vaccine candidates based on SARS-CoV-2 recombinant proteins such as full-length Spike protein, Spike fragments, or RBD (Pollet et al. 2021). Among these, Novavax’s recombinant protein nanoparticle vaccine, NVX-CoV2373, was produced by expressing a codon-optimized Spike synthetic gene in Sf9 insect cells (Guebre-Xabier et al. 2020, Keech et al. 2020, Tian et al. 2021). However, other recombinant protein vaccine candidates have been produced by expression of the Spike protein or RBD fragments in what has been called the “workhorse in biopharmaceutical protein production,” the Chinese Hamster Ovary (CHO) cells (Pollet et al. 2021).

SARS-CoV-2 Vaccine Candidates based on Recombinant Proteins Expressed in CHO cells

Vaccine Candidate Immunogen Sponsor Clinical Progress
ZF2001 RBD  Anhui Zhifei Longcom Biopharmaceutical/Institute of Microbiology, Chinese Academy of Sciences Phase 3
Nanocovax Spike  Nanogen Biopharmaceutical Phase 1/2
SCB-2019 Spike  GSK, Sanofi, Clover Biopharmaceuticals  Phase 1
MVC-COV1901 Spike  Medigen Vaccine Biologics Corporation/NIAID/Dynavax Phase 1

In addition to their use in vaccine development, CHO cells have enabled the production of SARS-CoV-2 neutralizing monoclonal antibody drugs for treating patients with mild to moderate COVID-19. For example, the first two FDA Emergency Use Authorizations (EUAs) for recombinant monoclonal antibody drugs were granted to Regeneron’s casirivimab and imdevimab, and Eli Lilly’s Bamlanivimab and Etesevimab, all produced in CHO cells.

Using mammalian cells, such as CHO cells, in bioprocessing has become an increasingly favored approach primarily due to their ability to produce proteins with human-like post-translational modifications (e.g., glycosylation). A definite advantage for recombinant SARS-CoV-2 Spike protein production, as each monomer is heavily glycosylated with ~20 N- and O-glycosylation sites (Pino et al. 2020).

Additionally, CHO cells’ high expression capacity, combined with their tolerance to various culture conditions, make them ideal for workflows involving “difficult-to-express” proteins (Dumont et al. 2016). This was recently demonstrated in work by Johari et al. 2020, where improved vector engineering strategies, mild hypothermic culture conditions, and use of small bioactive molecules supported CHO cells’ high-yield production of stable Spike protein trimer, suitable for immunoassay development.

Considering the long history of CHO cells in the generation of biotherapeutics, dating back to the production of tissue plasminogen activator in 1986, it is not surprising that CHO cells have served as an effective vehicle expediting the production of proteins for COVID-19 treatment and diagnostics (Dumont et al. 2016). As new SARS-CoV-2 variants emerge worldwide, production of SARS-CoV-2 recombinant proteins to support vaccine boosters and diagnostic immunoassays will be a continued necessity.

Reference


Dumont, J., Euwart, D., Mei, B., Estes, S. & Kshirsagar, R. Human cell lines for biopharmaceutical manufacturing: history, status, and future perspectives. Critical Reviews in Biotechnology (2016) doi:10.3109/07388551.2015.1084266.

Guebre-Xabier, M. et al. NVX-CoV2373 vaccine protects cynomolgus macaque upper and lower airways against SARS-CoV-2 challenge. Vaccine (2020) doi:10.1016/j.vaccine.2020.10.064.

Johari, Y. B. et al. Production of trimeric SARS-CoV-2 spike protein by CHO cells for serological COVID-19 testing. Biotechnol. Bioeng. (2021) doi:10.1002/bit.27615

Juraszek, J. et al. Stabilizing the closed SARS-CoV-2 spike trimer. Nat. Commun. (2021) doi:10.1038/s41467-020-20321-x.

Keech, C. et al. Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. N. Engl. J. Med. (2020) doi:10.1056/nejmoa2026920.

Pino, P. et al. Trimeric SARS-CoV-2 spike proteins produced from CHO cells in bioreactors are high-quality antigens. Processes (2020) doi:10.3390/pr8121539.

Pollet, J., Chen, W. H. & Strych, U. Recombinant protein vaccines, a proven approach against coronavirus pandemics. Advanced Drug Delivery Reviews (2021) doi:10.1016/j.addr.2021.01.001.