Universal protection against Streptococcus pneumoniae by recombinant glycoconjugate vaccines

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Vaccines are a critical component of defence against infectious disease, and have eliminated some of the most dangerous diseases that have faced humanity. This is increasingly the case in low income countries, where vaccines can transform the likelihood of healthy childhoods. Streptococcus pneumoniae can cause life-threatening diseases such as pneumonia, septicaemia and meningitis. S. pneumoniae is responsible for significant morbidity and mortality worldwide with over one million deaths of children annually. The emergence and rapid spread of antibiotic-resistant S. pneumoniae strains has further emphasised the need for prevention of S. pneumoniae infections. An inexpensive, broad-range, long-lasting pneumococcal vaccine is a current global imperative, and be of most impact to LMIC countries as this is where existing vaccines are often under utilised and S. pneumoniae infections remain a significant cause of childhood mortality and morbidity. A defining characteristic of a successful vaccine is the ability to evoke long-lasting protective immunity with minimal side effects. The most successful human vaccines are often glycoconjugates, which are combinations of a protein coupled to a sugar glycan, as these provide multiple triggers for the immune system, and increases the lifetime of the vaccine. Examples of current human glycoconjugate vaccines include vaccines against Haemophilus influenzae, Neisserria meningitidis and S. pneumoniae strains. These vaccines are made chemically which is time consuming and expensive. Furthermore, the current pneumococcus glycoconjugate vaccines only protect against a fraction of all S. pneumoniae strains. Ideally, to improve the proportion of all S. pneumoniae strains that the vaccine protects against, a glycoconjugate vaccine against S. pneumoniae should link the sugar component to S. pneumoniae proteins that are present in all strains, but to date this has proved technically challenging to achieve.Recently, we have developed a new approach for constructing glycoconjugate vaccines involving genetically altering the bacterium E. coli so that they act as cellular factories for the production of glycoconjugate vaccines. This is termed Protein Glycan Coupling Technology (PGCT), and involves making an E. coli strain that can produce the candidate protein and glycan, along with an enzyme that couples the protein and glycan together to produce an inexhaustible and inexpensive supply of vaccine. PGCT can produce purified vaccine in a one-step purification procedure, which reduces costs, and because multiple combinations of protein and glycans can be produced, a greater flexibility in the range of vaccines can be generated and tested. However, as yet we do not know the best S. pneumoniae proteins to use in a vaccine made using PGCT that are able to induce the highest level of protection against S. pneumoniae infections. In this study we will use new technologies to systematically screen all S. pneumoniae proteins to identify the best candidates for a "double hit" glycoconjugate vaccine consisting of a S. pneumoniae protein coupled to S. pneumoniae glycan (capsular polysaccharide). We will select the top 50 candidates from the screen to test which can be linked using PGCT to S. pneumoniae capsule glycan to make effective recombinant glycoconjugates. The most promising vaccines will then be tested in mouse models of S. pneumoniae infection to find which ones are best able to prevent infections. The new vaccines generated will also be compared to the efficacy of market leading vaccines such as Prevenar13. These experiments will identify the most suitable proteins for inclusion in a novel S. pneumoniae vaccine made using PGCT, or for other novel vaccine approaches. Additionally, the development of PGCT in this study will provide the expertise and knowledge base to make the technology more widely applicable for making glycoconjugate vaccines against other important infectious agents.