Characterization of a multicomponent live, attenuated Shigella flexneri vaccine.
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.
Institute for Global Health, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
BreOnna C
BC
DeLaine
Institute for Global Health, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Tao
T
Wu
Institute for Global Health, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Christen L
CL
Grassel
Institute for Global Health, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Avital
A
Shimanovich
Institute for Global Health, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Marcela F
MF
Pasetti
Institute for Global Health, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Myron M
MM
Levine
Institute for Global Health, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA ebarry@medicine.umaryland.edu.
Eileen M
EM
Barry
D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004405:Dysentery, Bacillary / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D006168:Guinea Pigs; D006801:Humans; D007114:Immunization; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D010957:Plasmids / Q000235:genetics; D022281:Shigella Vaccines / Q000276:immunology*; D012763:Shigella flexneri / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology*; D014774:Virulence
D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D022281:Shigella Vaccines; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic
Shigella flexneri; diarrheal disease; live attenuated; vaccine