Vaccines for Group A Streptococcus: Recombinant production platform for universal ‘dual-hit’ Group A Streptococcus glycoconjugate-vaccines
Updated on 5 March 2021
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- Synthetic RhaPS
- Targets across GAS serotypes
- Uses bulk bacterial fermentation
- High yield & homogeneity
- Modular production platform
- Expandable platform for human and veterinary pathogens
Researchers at the University of Dundee have developed a novel method for the recombinant production of universal Group A Streptococcus (GAS) glycoconjugate vaccine candidates.
This approach allows hijacking of the Protein Glycan Coupling Technology (PCGT) currently used to produce glycoconjugate vaccine candidates for pathogenic bacteria, including Streptococcus pneumoniae. The team has produced the first recombinant GAS 'dual-hit' glycoconjugate vaccine candidate system. This method produces high yield and high purity of recombinantly produced GAS rhamnose polysaccharides (RhaPS) conjugated to protein carriers of choice.
Antimicrobial options for effectively controlling, treating and preventing Streptococcus pyogenes (Group A Streptococcus, GAS) infections are becoming more limited due to emerging antibiotic resistance, pandemic development and the evolution of hyper virulent strains. There is an urgent unmet need for the development of a safe, effective and universal prophylactic vaccine candidate for GAS. GAS kills more than 500,000 people worldwide each year.
For a vaccine to be capable of targeting all of >150 different GAS serotypes, a ubiquitous and universally conserved GAS target needs to be identified. The only target that is 100% conserved in all GAS isolates is the Group A Carbohydrate (GAC), a peptidoglycan-anchored rhamnose-polysaccharide (RhaPS) from GAS. The GAC is essential to bacterial survival and contributes to GAS ability to infect the human host. The GAC polyrhamnose (RhaPS) backbone is a validated vaccine candidate protecting in the animal model GAS infections and showed no cross-reactivity with human tissue.
Currently, RhaPS vaccine development has been limited to chemical and enzymatic extraction methods from streptococcal bacteria, as well as chemical conjugation to an acceptor compound. This method is costly for vaccine development as it is both labour intensive and requires many quality control steps.
The Dundee research team identified the key priming steps in the biosynthetic pathway of the GAC virulence determinant and have developed a modular production platform compatible with the synthetic production of RhaPS in E. coli. They produce pure RhaPS glycoconjugates via the efficient and low-cost Protein Glycan Coupling Technology (PGCT). The methodology provides a number of novel solutions to producing glycoconjugates of high quality and yield that serve as vaccine candidates to target all GAS serotypes. The platform allows the recombinant conjugation of the polyrhamnose to any acceptor protein of choice and a tightly regulated carbohydrate length to produce high quality and homogenous vaccine candidates. The recombinant approach has thus many advantages to the use of natively produced and extracted RhaPS.
The researchers have recently shown that recombinantly produced RhaPS induce GAS specific antibodies in mice and that RhaPS trigger a carbohydrate specific immune response. This suggests that this method produces vaccines with long-lasting immunity. Preclinical work is now continuing apace with a Wellcome Trust Innovator Award.
GB filing 1908528.1Priority date 13 June 2019. PCT publication 17 December 2020.
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