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Auxotrophic live oral Shigella flexneri vaccine protects monkeys against challenge with S. flexneri of different
A Kärnell1, H Sweiha, A A Lindberg
1Karolinska Institute, Department of Clinical Bacteriology, Huddinge Hospital, Sweden.
Abstract:
The aromatic-dependent live Shigella flexneri Y strain SFL114, attenuated by a Tn10-inactivated aroD gene, was given as an oral vaccine to 14 Macaca fascicularis monkeys. A significant clinical attenuation of SFL114 was seen (p = 0.0058) as all vaccinated monkeys tolerated 2 x 10(10)-1 x 10(11) bacteria of SFL114, whereas four out of seven monkeys orally given 1 x 10(11) of the virulent parent strain SFL1 developed shigellosis. The average excretion time for SFL114 and SFL1 were 2 and 18 days, respectively. As seen endoscopically SFL1 caused colonic lesions, whereas SFL114 did not. Histopathologic examination of colonic biopsies showed that SFL114 induced only slight acute inflammation, whereas SFL1 caused severe acute inflammation (p less than 0.01). The vaccine strain SFL114 elicited significant species-specific serum immune responses (p less than 0.005) as seen in enzyme immune assays using lipopolysaccharides from S. flexneri serotypes Y, 1b, and 2a and Escherichia coli K-12 as antigens. The titres were comparable to those seen in monkeys given virulent S. flexneri strains. Western blot analyses showed that many prevaccination sera contained antibodies directed against the invasion plasmid-coded polypeptides. However, after vaccination with SFL114 increased amounts of such anti-polypeptide antibodies were seen, particularly in sera from monkeys having a low prevaccination antibody level. SFL114 also elicited a significant species-specific (p less than 0.025) local intestinal sIgA response against the homologous lipopolysaccharide antigen. Vaccinated monkeys were clinically protected against an oral challenge with 1-2 x 10(11) live, virulent S. flexneri strains of any of serotypes Y (strain SFL1), 1b (strain SFL27), or 2a (strain M4243).(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
An oral vaccine using an attenuated Shigella flexneri Y strain (SFL114) proved safe and effective in non-human primates. Vaccinated monkeys showed no illness and were protected against virulent Shigella challenge, indicating a promising new vaccine candidate.
Area of Science:
- Microbiology
- Vaccinology
- Immunology
Background:
- Shigella flexneri causes shigellosis, a severe diarrheal disease.
- Development of effective oral vaccines against Shigella is a global health priority.
- Attenuated bacterial strains are a promising strategy for live oral vaccine development.
Purpose of the Study:
- To evaluate the safety and immunogenicity of an orally administered, attenuated Shigella flexneri Y strain (SFL114) in Macaca fascicularis.
- To assess the protective efficacy of SFL114 against challenge with virulent Shigella flexneri strains of multiple serotypes.
Main Methods:
- Oral vaccination of monkeys with live, attenuated SFL114.
- Clinical assessment, endoscopic evaluation, and histopathologic examination of colonic biopsies.
- Measurement of species-specific serum and intestinal immunoglobulin A (sIgA) responses.
- Challenge studies with virulent Shigella flexneri strains (serotypes Y, 1b, 2a).
Main Results:
- SFL114 was clinically attenuated, well-tolerated at high doses, and showed significantly reduced excretion time and colonic inflammation compared to the virulent parent strain.
- Vaccination with SFL114 induced significant species-specific serum immune responses and local intestinal sIgA.
- Vaccinated monkeys were clinically protected against oral challenge with virulent S. flexneri of serotypes Y, 1b, and 2a.
Conclusions:
- The attenuated Shigella flexneri Y strain SFL114 is a safe and immunogenic oral vaccine candidate.
- SFL114 confers protection against homologous and heterologous serotypes of virulent Shigella flexneri in a primate model.
- This study supports the further development of SFL114 as a live oral Shigella vaccine.