Evaluation of the Safety, Tolerability and Immunogenicity of ShigETEC, an Oral Live Attenuated Shigella-ETEC Vaccine in Placebo-Controlled Randomized Phase 1 Trial.

Petra Girardi,Valéria Szijártó,Orsolya Korda,Tamás Henics,Krisztina Szarka,Shushan Harutyunyan,Eszter Nagy,Katharina Glaninger,Frank J Malinoski,Gábor Kardos,Denes Pall,Gábor Nagy,Irene Neuhauser

doi:10.3390/vaccines10020340

Petra Girardi, Valéria Szijártó + Show 11 more

Open Access

https://doi.org/10.3390/vaccines10020340

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Abstract

Background: Shigella spp. and enterotoxigenic Escherichia coli (ETEC) cause high morbidity and mortality worldwide, yet no licensed vaccines are available to prevent corresponding infections. A live attenuated non-invasive Shigella vaccine strain lacking LPS O-antigen and expressing the ETEC toxoids, named ShigETEC was characterized previously in non-clinical studies. Methods: ShigETEC was evaluated in a two-staged, randomized, double-blind and placebo-controlled Phase I clinical trial. A single dose of increasing amounts of the vaccine was given to determine the maximum tolerated dose and increasing number of immunizations were administered with an interval based on the duration of shedding observed. Results: Oral immunization with ShigETEC was well tolerated and safe up to 4-time dosing with 5 × 1010 colony forming units. ShigETEC induced robust systemic immune responses against the Shigella vaccine strain, with IgA serum antibody dominance, as well as mucosal antibody responses evidenced by specific IgA in stool samples and in ALS (Antibodies in Lymphocyte Supernatant). Anti- ETEC toxin responses were detected primarily in the 4-times immunized cohort and for the heat-labile toxin correlated with neutralizing capacity. Conclusion: ShigETEC is a promising vaccine candidate that is scheduled for further testing in controlled human challenge studies for efficacy as well as in children in endemic setting for safety and immunogenicity.

Highlights

Shigella spp. and enterotoxigenic Escherichia coli (ETEC) are leading causes of enteral diseases among children living in endemic countries with poor hygienic conditions [1,2]
Stage 1, 48 subjects (2 vaccine recipients to each placebo recipient) were enrolled sequentially in 4 ascending dose groups (12 subjects per group) to receive a single oral dose of the ShigETEC vaccine starting at a dose of 1 × 109 colony forming units (CFU) (Cohort 1A), followed by 1 × 1010 CFU
Participants In Stage 1 of the Phase 1 clinical trial, 68 subjects were screened of which 48 subjects were randomized and sequentially enrolled in 4 ascending dose groups (12 subjects per group) to receive a single oral dose of the ShigETEC vaccine starting in the first group, 1A, at a dose, of 1 × 109 Colony Forming Units (CFU) of vaccine or a placebo, followed by 1 × 1010 CFU, 5 × 1010 CFU and 2 × 1011 CFU per dose in groups 1B, 1C and 1D, respectively

Summary

Introduction

Shigella spp. and enterotoxigenic Escherichia coli (ETEC) are leading causes of enteral diseases among children living in endemic countries with poor hygienic conditions [1,2]. An annual 200 million episodes of ETEC and Shigella diarrhea are estimated in children under the age of 5 [3]. Mortality rates from intestinal infections have decreased recently, Shigella spp. and ETEC were reported to be responsible for an estimated >210,000 and >50,000 deaths, respectively, in 2016 worldwide [1]. Shigella spp. and enterotoxigenic Escherichia coli (ETEC) cause high morbidity and mortality worldwide, yet no licensed vaccines are available to prevent corresponding infections. A live attenuated non-invasive Shigella vaccine strain lacking LPS O-antigen and expressing the ETEC toxoids, named ShigETEC was characterized previously in non-clinical studies. Conclusion: ShigETEC is a promising vaccine candidate that is scheduled for further testing in controlled human challenge studies for efficacy as well as in children in endemic setting for safety and immunogenicity

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