Despite the need for a vaccine to prevent malaria, particularly in infants and young children, R&D efforts to date have been plagued by a lack of protective efficacy, particularly related to the duration of protection. Even the most advanced vaccine candidate, GlaxoSmithKline’s (GSK’s) subunit vaccine Mosquirix (RTS,S/AS01), possesses clear drawbacks in its ability to effectively protect those who are most vulnerable to severe infections.
Fortunately, researchers have recently identified that carbohydrates play a key role in the functionality of antigens that are currently the targets of malaria vaccines. By genetically disrupting O-fucosyltransferase (POFUT2), in the study published September, 2017 Lopaticki and colleagues were able to demonstrate that preventing the glycosylation of certain proteins could prevent malarial parasite development and infections. POFUT2 activity was shown to be fundamental to the stabilization of a group of surface proteins found on malaria parasites during several stages of their lifecycle. Therefore, GlobalData believes the inclusion of carbohydrates into current developmental vaccines has the potential to significantly increase their efficacy.
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Malaria is a life-threating infection that is caused by the Plasmodium family of parasites, which are transmitted to humans through infected female Anopheles mosquitoes. According to the World Health Organization (WHO), malaria is estimated to have infected 212 million people, causing 429,000 deaths worldwide in 2015, 70% of these in children under five years old. The most common form of the malarial parasite, P. falciparum, is primarily found in sub-Saharan Africa and is also responsible for the majority of worldwide serious infections and deaths.
Currently, there are no WHO-licensed vaccines for the prevention of malaria, but some are in the later stages of clinical development. The most promising malaria vaccine candidate is GSK’s Mosquirix, which is a subunit vaccine consisting of P. falciparum circumsporozoite proteins (CSP) with hepatitis B surface antigen virus-like particles, and is co-formulated with a proprietary chemical adjuvant, AS01. Mosquirix is set to be examined in a pilot study involving over 750,000 children starting in 2018. However, the efficacy results from Phase III trials have shown that less than 40% of participants taking Mosquirix were protected from malaria.
One approach to improving vaccine efficacy would involve introducing another antigenic component. Toward this end, researchers demonstrated that by genetically disrupting the POFUT2 enzyme in P. falciparum parasites, the parasites could not develop in the mosquitos and the sporozoites were rendered ineffective at infecting humanized liver cells in mice. This effect upon parasite development is due to the blocking O-glycosylation of CSP and TRAP proteins, which is vital to the stabilization of these proteins. This demonstrates the importance of carbohydrates in the functionality of CSP and TRAP proteins. Both proteins are the main focus of current vaccine development efforts, as targeting this pathway has the potential to substantially improve the efficacy of malaria vaccines.
Based on past failures with other subunit vaccines, an exclusively carbohydrate-based malaria vaccine is unlikely to be successful. However, these results highlight the potential for combining carbohydrates, specifically those targeting the POFTU2 pathway, with vaccines that are already in clinical development. Through the additional mode of action and the targeting of multiple parasitic life-stages, GlobalData believes carbohydrates could lead to novel malaria vaccines that offer stronger and more durable protection than those currently in clinical development.
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