Although it does not sound threatening, diarrhoea is one of the leading causes of infant mortality in the world. The EU-funded STOPENTERICS project is developing innovative vaccines against two of the most common pathogens behind this neglected disease.
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Neglected infectious diseases exact a heavy toll on the globe’s poorest citizens in developing countries. Diarrhoeal diseases are the second leading cause of mortality worldwide in children under the age of five. Each year there are around 600 000 deaths due to severe, dehydrating diarrhoea and dysentery. Millions more are hospitalised, while untold numbers of children suffer from diarrhoeal disease-associated malnutrition and its adverse effects on physical and cognitive development, which perpetuate the cycle of poverty with serious social and economic consequences.
But it need not be so. Diarrhoeal diseases can be prevented through vaccination but a huge effort remains necessary to develop a vaccine against each of the biggest killers.
The EU-funded STOPENTERICS project is striving to develop candidate vaccines against two of the most common causes of diarrhoea: Shigella and enterotoxigenic E. coli (ETEC). Together, they account for at least one billion cases of diarrhoea annually. Estimates suggest that Shigella and ETEC are responsible for almost one-third of child deaths from diarrhoea, as well as many deaths in older age groups. Results from the Global Enterics Multicentre Study (GEMS) confirmed that both ETEC and Shigella remain among the top four pathogens causing moderate-to-severe diarrhoea among children in Africa and South Asia.
Led by France’s renowned Institut Pasteur, STOPENTERICS brought together 15 partners from across Europe, the Middle East, Asia and Africa. The 60-month project sought to create a paradigm shift in the approach to developing vaccines for these two pathogens by breaking the dogma surrounding serotype-specific protection and by improving the immunogenicity of some antigens already identified.
To do so, the project took a multidisciplinary approach, integrating genomics, transcriptomics, proteomics, high-throughput technologies and synthetic chemistry. More specifically, STOPENTERICS aimed at providing a proof-of-concept, in human subjects, of two newly available vaccine candidates against Shigella.
One vaccine candidate was made of protein vesicles derived from the membrane of the bacterium Shigella sonnei, the predominant strain in lower income countries. It was produced under good manufacturing procedures (GMP) to allow its use in humans. Upon testing in a phase 1 clinical trial, this vaccine candidate was shown to be safe and immunogenic.
The second vaccine candidate was a glycoconjugate made of protein and sugars. A synthetic sugar mimicking the main sugar component of the bacterial surface of Shigella flexneri 2a – the predominant endemic strain in low-income countries – was coupled to tetanus toxoid, a protein classically used in commercialised glycoconjugate vaccines. This vaccine candidate was successfully produced under GMP conditions. The phase 1 clinical trial will start next spring.
With respect to ETEC, the focus was placed on the identification of new correlates of protection and of ETEC-specific proteins shared by a diverse set of strains to develop a cross-protective vaccine.
“STOPENTERICS is a strong sign of the EU’s commitment to controlling neglected infectious diseases affecting the poorest populations,” says Philippe Sansonetti, a professor at Institut Pasteur involved in the project. “The clinical trials will hopefully confirm that innovative approaches can be applied to immunise against the most prevalent bacterial aetiologies of diarrhoea, Shigella and ETEC.”
But this is just the start. “STOPENTERICS’ partners see the current programme as the beginning of a long-term endeavour that should soon see these candidate vaccines extensively tested in endemic areas and further developed,” Sansonetti says.