Exploring the potential role of the schistosome cercarial elastase as a candidate vaccine for schistosomiasis

• Main Author: El Faham, Marwa
• Published: University of Nottingham 2012
• Subjects: 616.963
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581996

An effective vaccine against schistosomiasis remains an unfulfilled goal. A concept I am investigating is to target immune responses at molecules that are poorly immunogenic during normal infection, as such antigens might be the Achilles' heel of the organism. The Schistosoma mansoni cercarial elastase (SmCE) is one such molecule: antibodies which neutralize this enzyme might abort the infection at an early stage and my hypothesis is that such antibodies may be induced if SmCE is administered in an inactivated form. I aimed in this work to improve the levels of protection obtained in previous experiments with recombinant elastase. I have generated a His-tagged recombinant SmCE (His-CE) which is enzymatically inactive. Immunization of BalbjC mice with His-CE on aluminum hydroxide induced significant levels of specific anti-SmCE IgG antibodies within two weeks of the first immunization. The IgG subtype profile (lgGl> IgG2a, IgG2b) was indicative of a ThljTh2-like immune response skewed towards Th2. Immunized mice showed at least 40% reduction in the mean worm burden when compared to the control group of mice in 3 out of 4 mouse experiments. We have generated an active elastase fused to the mouse IgG2a-Fc region (CE-Fc), which was found to be immunogenic and promoted a partly protective anti-elastase IgG response in BalbjC mice. A plasmid encoding for an inactive CE-Fc was constructed by site-directed PCR mutagenesis, which is expected to be more immunogenic should used in future work. In this work, we showed that the native CE cleaves mouse IgG and human IgGjlgA, and potentially exists in a polymeric form. Finally, a computer model for SmCE was constructed and used to map computer- predicted B-cell epitopes for the molecule. The epitopes identified in the vicinity of the active site can be used to synthesize a multi-epitope DNA- string vaccine in future work.