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In a revolutionary step for vaccine development, researchers have successfully managed to synthesize the vaccine adjuvant QS-21 completely using engineered yeast strains. This breakthrough may solve the long-standing shortage of this critical component, typically derived from the Chilean soapbark tree, Quillaja saponaria. Due to the tree’s limited availability and the labor-intensive extraction process, QS-21 has remained a bottleneck for expanding vaccine production.
QS-21 is known for its potent capability to enhance immune responses to vaccines, making it a critical ingredient in several important vaccines, including GSK’s malaria (Mosquirix) and shingles (Shingrix) vaccines, as well as Novavax’s COVID-19 vaccine. However, harvesting QS-21 from soapbark trees is not sustainable and has led to stringent regulations by governments to protect these trees from deforestation. These regulations further restrict the supply of QS-21, pushing scientists to explore alternative production methods.
In a study reported by Nature, a team of researchers led by Jay D. Keasling and his colleagues managed to use engineered yeast to replicate the complex biosynthetic pathway of QS-21. This process involves fine-tuning the yeast’s native pathways and integrating 38 heterologous enzymes from six different species. The biosynthetic pathway spans seven enzyme families and mimics how plants compartmentalize these pathways from the endoplasmic reticulum to the cytosol in yeast. This level of molecular engineering in yeast to produce QS-21 is unprecedented.
Yuzhong Liu, Xixi Zhao, Fei Gan, Xiaoyue Chen, and their colleagues were able to fine-tune the expression of these enzymes within the engineered yeast, resulting in the successful synthesis of QS-21 and its structural derivatives. The yeast-based production could potentially meet the increasing global demand for the adjuvant without adversely impacting natural resources.
Adjuvants are vital in enhancing the efficacy of vaccines by stimulating stronger immune responses. While aluminium hydroxide (alum) has been the most widely used adjuvant since its discovery in the 1920s, QS-21 has shown superior immunoactivity and has been included in many clinical trials due to its efficacy and safety profile. Over 120 clinical trials have tested QS-21, demonstrating its robust potential in vaccine formulations.
Despite the excitement surrounding its use, the traditional extraction of QS-21 from soapbark trees poses significant environmental and practical challenges. These trees take decades to mature and provide QS-21 only at minimal levels. Therefore, this synthetic biology approach using engineered yeast, which allows for quicker production and potentially higher yields, could transform the industry.
The engineered yeast strain, identified as JWy601, underwent a modified mevalonate-based isoprenoid biosynthetic pathway to produce the triterpene core of QS-21. Researchers induced galactose expression to overexpress the necessary enzymes, leading to significant production of β-amyrin, a precursor in the pathway. By borrowing and integrating enzymes from different plants and optimizing their function within the yeast, the team efficiently synthesized QS-21.
This innovation could dramatically change how vaccine adjuvants are produced, reducing dependence on plant extraction and allowing for more scalable and controlled production processes. While the yeast-derived QS-21 yield is currently slightly lower than what is naturally obtained from the soapbark tree, it is far faster, making industrial-scale production viable. This development could similarly pave the way for biomanufacturing other complex natural products sustainably.
Eradicating dependence on the soapbark tree for QS-21 production also aligns with environmental and ethical considerations, as continuous extraction from these trees is unsustainable and destructive.
While further improvements in strain engineering and downstream processing are needed to maximize production efficiency, the successful demonstration of QS-21 synthesis in engineered yeast marks a significant milestone. It sets the stage for higher yields and more accessible production, supporting global vaccine manufacturing and delivery.
Information Box:
– QS-21 is an adjuvant derived from the soapbark tree, used to enhance immune responses in vaccines.
– Traditional methods of extracting QS-21 are labor-intensive and damaging to the environment.
– Engineered yeast strains have now been used to synthesize QS-21, promising a more sustainable and scalable approach.
– The engineered yeast contains 38 heterologous enzymes from six species, meticulously crafted to mimic plant biosynthesis pathways.
– QS-21 is part of major vaccines like GSK’s Shingrix and Mosquirix and Novavax’s COVID-19 vaccines.
– This breakthrough may ease the bottleneck in vaccine production caused by the limited availability of QS-21.
References:
Reference 1: Complete biosynthesis of QS-21 in engineered yeast, Nature.com
Reference 2: Mark Williams Digital News Report
Reference 3: Travis K, The Scientist, January 2007