A team of scientists has engineered the spike protein of the SARS-CoV-2 virus – a critical component of potential COVID-19 vaccines – to be more environmentally stable and generate larger yields in the lab. By solving problems with protein instability that have held back vaccine research, the new spike protein design could accelerate the development of desperately needed vaccines and diagnostics for COVID-19. As the race for a COVID-19 vaccine continues, most researchers have focused on targeting the spike protein, the viral component that allows the SARS-CoV-2 virus to enter and infect human cells in the lungs and gut. Scientists have modified the wild-type spike protein into variants such as S-2P to improve its ability to generate immune responses, as well as to be produced in greater quantities. However, even these improved versions remain finicky for researchers, as they are still unstable and can be difficult to produce on a large scale in mammalian cells. To navigate these roadblocks, Ching-Lin Hsieh and colleagues analyzed the cryo-EM structure of the spike protein and studied the effects of various changes to the protein’s chemistry, such as substituting in amino acids called prolines. After analyzing 100 spike protein designs, the authors uncovered 26 substitutions that made the protein more stable and able to be expressed in higher quantities. Hsieh et al. combined the most effective proline substitutions into a variant they named HexaPro, which was expressed 10 times higher than S-2P in human cells. HexaPro also withstood temperatures of 55°C for 30 minutes, could be stored at room temperature for 2 days, and remained stable during multiple cycles of freezing and thawing. “The high yield and enhanced stability of HexaPro should enable industrial production of subunit vaccines and could also improve DNA or mRNA-based vaccines,” the team concludes.
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