Live Attenuated S. Typhimurium Vaccine with Improved Safety in Immuno-Compromised Mice

Balamurugan Periaswamy,Mrutyunjay Suar,Emma Slack,Andrew J Grant,Vikalp Vishwakarma,Wolf-Dietrich Hardt,Michael Mcclelland,Helene L Andrews-Polymenis,Lisa Maier,Marcus Kremer,Dipshikha Chakravortty

doi:10.1371/journal.pone.0045433

Abstract

Live attenuated vaccines are of great value for preventing infectious diseases. They represent a delicate compromise between sufficient colonization-mediated adaptive immunity and minimizing the risk for infection by the vaccine strain itself. Immune defects can predispose to vaccine strain infections. It has remained unclear whether vaccine safety could be improved via mutations attenuating a vaccine in immune-deficient individuals without compromising the vaccine's performance in the normal host. We have addressed this hypothesis using a mouse model for Salmonella diarrhea and a live attenuated Salmonella Typhimurium strain (ssaV). Vaccination with this strain elicited protective immunity in wild type mice, but a fatal systemic infection in immune-deficient cybb −/− nos2 −/− animals lacking NADPH oxidase and inducible NO synthase. In cybb −/− nos2 −/− mice, we analyzed the attenuation of 35 ssaV strains carrying one additional mutation each. One strain, Z234 (ssaV SL1344_3093), was >1000-fold attenuated in cybb −/− nos2 −/− mice and ≈100 fold attenuated in tnfr1 −/− animals. However, in wt mice, Z234 was as efficient as ssaV with respect to host colonization and the elicitation of a protective, O-antigen specific mucosal secretory IgA (sIgA) response. These data suggest that it is possible to engineer live attenuated vaccines which are specifically attenuated in immuno-compromised hosts. This might help to improve vaccine safety.

Highlights

Bacterial infections are a worldwide health burden
We have focused on vaccine design against non-typhoidal Salmonella enterica (NTS), i.e. Salmonella enterica subspecies 1 serovar Typhimurium
Typhimurium diarrhea, a systemic spread of the parental LAV (ssaV) mutant lacking a structural protein of the Type III Secretion System-2 (TTSS-2), was a safe vaccine eliciting protective mucosal immunity in wt C57BL/6 mice [28,29,30], but causes lethal infection in isogenic cybb2/2nos22/2 animals

Summary

Introduction

Bacterial infections are a worldwide health burden. The rise of resistance against the current antibiotics and the limited availability of novel drug targets [1] have fuelled the interest in prophylactic approaches including live attenuated bacterial vaccines (LAV). Until today there are only surprisingly few LAV approved for human use; Ty21a against Salmonella Typhi, CVD 103-HgR for Vibrio cholerae, and the BCG vaccine against Mycobacterium tuberculosis infections [4,5,6,7] This scarcity of approved LAV is attributable at least in part to the safety concerns arising from the risk of fulminant infections which may be caused by the vaccine strains in immunocompromised individuals, like those suffering from immunosuppressive infections (e.g. HIV) or genetic disease (e.g. CGD, chronic granulomatous disease). This safety problem could be solved, if one could identify mutations which ‘‘super’’-attenuate the LAV in immuno-compromised individuals without compromising its performance in the immune-proficient host. It has remained unclear whether it is possible to design such a superattenuated live attenuated vaccine (saLAV)

Methods

Results

Conclusion