Characterization of a multicomponent live, attenuated Shigella flexneri vaccine
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Published on: February 27, 2019
BreOnna C DeLaine1, Tao Wu1, Christen L Grassel1
1Institute for Global Health, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Insights
New Shigella flexneri vaccines (CVD 1213, CVD 1215, CVD 1208S) show promise for preventing diarrheal disease. A multivalent vaccine combining these strains could offer broad protection against multiple serotypes.
Area of Science:
- Microbiology
- Vaccinology
- Infectious Diseases
Background:
- Shigella flexneri causes significant diarrheal disease in children globally.
- Current prevention strategies lack broad-spectrum efficacy due to multiple serotypes.
- No licensed Shigella flexneri vaccine is available.
Purpose of the Study:
- To evaluate the safety and immunogenicity of live attenuated Shigella flexneri vaccine candidates.
- To assess the potential of a multivalent vaccine for broad protection against Shigella flexneri.
Main Methods:
- Development of live attenuated Shigella flexneri strains (CVD 1213, CVD 1215, CVD 1208S) with guaBA operon mutations.
- In vitro and in vivo testing for auxotrophy, replication defects, and cytokine induction.
- Virulence attenuation assessment using the guinea pig Serény test.
- Evaluation of serotype-specific antibody responses and protection against challenge.
Main Results:
- Vaccine candidates were auxotrophic for guanine and defective in intracellular replication.
- Strains induced cytokine production and were attenuated in virulence.
- Immunization elicited robust, serotype-specific antibody responses.
- A mixed inoculum conferred protection against homologous and heterologous serotypes.
Conclusions:
- CVD 1213, CVD 1215, and CVD 1208S are promising vaccine candidates.
- A multivalent vaccine combining these strains could provide broad protection against Shigella flexneri.
- Further development is warranted for a comprehensive Shigella flexneri vaccine.
Abstract:
Shigella flexneri is a leading cause of diarrheal disease in children under five in developing countries. There is currently no licensed vaccine and broad spectrum protection requires coverage of multiple serotypes. The live attenuated vaccines CVD 1213 and CVD 1215 were derived from two prominent S. flexneri serotypes: S. flexneri 3a and S. flexneri 6. To provide broad-spectrum immunity, they could be combined with CVD 1208S, a S. flexneri 2a strain that demonstrated promising results in phase I and II clinical trials. Each strain contains a mutation in the guaBA operon. These vaccine candidates were tested in vitro and in vivo and were found to be auxotrophic for guanine and defective in intracellular replication, but capable of inducing cytokine production from both epithelial cells and macrophages. Both strains were attenuated for virulence in the guinea pig Serény test and induced robust serotype-specific antibody responses following immunization. Each strain induced homologous serotype protection against challenge and a mixed inoculum of the three S. flexneri vaccines conferred protection against all three virulent wild-type strains. These data support the use of CVD 1213, CVD 1215 and CVD 1208S in a multivalent vaccine to confer broad protection against disease caused by Shigella flexneri.
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