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The introduction of type b Haemophilus influenzae conjugate vaccines into routine vaccination schedules has significantly reduced the burden of this disease; however, widespread use in developing countries is constrained by vaccine costs, and there is a need for a simple and high-yielding manufacturing process. The vaccine is composed of purified capsular polysaccharide conjugated to an immunogenic carrier protein. To improve the yield and rate of the reductive amination conjugation reaction used to make this vaccine, some of the carboxyl groups of the carrier protein, tetanus toxoid, were modified to hydrazides, which are more reactive than the ε -amine of lysine. Other reaction parameters, including the ratio of the reactants, the size of the polysaccharide, the temperature and the salt concentration, were also investigated. Experimental design was used to minimize the number of experiments required to optimize all these parameters to obtain conjugate in high yield with target characteristics. It was found that increasing the reactant ratio and decreasing the size of the polysaccharide increased the polysaccharide:protein mass ratio in the product. Temperature and salt concentration did not improve this ratio. These results are consistent with a diffusion controlled rate limiting step in the conjugation reaction. Excessive modification of tetanus toxoid with hydrazide was correlated with reduced yield and lower free polysaccharide. This was attributed to a greater tendency for precipitation, possibly due to changes in the isoelectric point. Experimental design and multiple regression helped identify key parameters to control and thereby optimize this conjugation reaction.

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BackgroundStreptococcus agalactiae, or group B streptococcus (GBS), is a gram-positive streptococcal bacterium that is well-recognised as one of the leading causes of infant death, particularly in the early neonatal period (the first week of life). An estimated one in five pregnant women around the world carries GBS bacteria in their gastrointestinal or genitourinary tracts and vertical transmission from colonised mothers can lead to invasive disease in their offspring. A recent study conservatively estimated that out of 410,000 GBS cases globally every year, there are at least 1 47 000 stillbirths and infant deaths. Despite being home to only 13% of the world’s population, Africa has the highest GBS disease burden, with 54% of estimated cases and 65% of stillbirths and infant deaths.An effective GBS vaccine, given during pregnancy, is a promising strategy to protect against GBS disease. Currently, no licensed vaccine exists to prevent it, but scientific evaluation of feasibility is favourable. The leading vaccine candidates are capsular polysaccharide-protein conjugate vaccines. Evidence suggests maternal immunisation with a safe and effective GBS vaccine may reduce the disease risk in neonates and young infants.The Biovac Institute was established as a private-public partnership and is the only Southern African vaccine manufacturer. Located in Cape Town, South Africa, Biovac’s mission is to become a leading vaccine developer and producer in South Africa to increase capacity in Africa which only has four other vaccine manufacturers.In collaboration with PATH, an international health organisation, and other partners, Biovac is developing a multivalent conjugate vaccine against GBS. The first stage of the project involves the development of biopharmaceutical manufacturing processes and analytical tests, the preparation of clinical trial product, and execution of a first-in-human clinical trial.This presentation will provide an overview of the project, progress to date, and the path to commercialisation.