Alpha-galactosylceramide enhances mucosal immunity to oral whole-cell cholera vaccines

Christopher J H Davitt,Michael Lebens,Aqel Albutti,Craig P Mcentee,Ivan S Coulter,Joshua Tobias,Stephanie Longet,Vincenzo Aversa,Stefan Nordqvist,Becky Hackett,Monica Rosa,Ed C Lavelle,Jan Holmgren

doi:10.1038/s41385-019-0159-z

Christopher J H Davitt, Michael Lebens + Show 11 more

Open Access

https://doi.org/10.1038/s41385-019-0159-z

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Abstract

Cholera is a severe diarrheal disease caused by the bacterium Vibrio cholerae (V. cholerae) that results in 3–4 million cases globally with 100,000–150,000 deaths reported annually. Mostly confined to developing nations, current strategies to control the spread of cholera include the provision of safe drinking water and improved sanitation and hygiene, ideally in conjunction with oral vaccination. However, difficulties associated with the costs and logistics of these strategies have hampered their widespread implementation. Specific challenges pertaining to oral cholera vaccines (OCVs) include a lack of safe and effective adjuvants to further enhance gut immune responses, the complex and costly multicomponent vaccine manufacturing, limitations of conventional liquid formulation and the lack of an integrated delivery platform. Herein we describe the use of the orally active adjuvant α-Galactosylceramide (α-GalCer) to strongly enhance intestinal bacterium- and toxin-specific IgA responses to the OCV, Dukoral® in C57BL/6 and BALB/c mice. We further demonstrate the mucosal immunogenicity of a novel multi-antigen, single-component whole-cell killed V. cholerae strain and the enhancement of its immunogenicity by adding α-GalCer. Finally, we report that combining these components and recombinant cholera toxin B subunit in the SmPill® minisphere delivery system induced strong intestinal and systemic antigen-specific antibody responses.

Highlights

Cholera is mostly caused by enteric infections with Vibrio cholerae (V. cholerae) of the El Tor biotype and O1 serogroup.[1,2] The disease is endemic in large parts of South-East Asia and Africa and has caused major outbreaks in many developing countries
In order to evaluate the ability of α-GalCer to increase immune responses to an Oral cholera vaccines (OCVs), intestinal, and systemic antigen-specific antibody responses after oral vaccination with Dukoral® alone or combined either with α-GalCer or cholera toxin (CT) were compared in female C57BL/6 mice
This enhancement of intestinal antibody responses by α-GalCer was observed systemically with both bacteria- and CTBspecific IgA titres in serum being significantly higher after administration of the Dukoral® adjuvanted with α-GalCer compared to the vaccine alone and similar to the vaccine adjuvanted with CT (Fig. 1c, d)

Summary

Introduction

Cholera is mostly caused by enteric infections with Vibrio cholerae (V. cholerae) of the El Tor biotype and O1 serogroup (and in rare cases V. cholerae El Tor of serogroup O139).[1,2] The disease is endemic in large parts of South-East Asia and Africa and has caused major outbreaks in many developing countries. Oral cholera vaccines (OCVs) have proved effective against endemic cholera after vaccination and have been shown to reduce cholera incidence in outbreaks by >50%.3. Dukoral® was the first whole-cell killed (WCK) OCV to be licensed globally. It is composed of WCK bacteria of the different serotypes (Inaba and Ogawa) and biotypes (Classical and El Tor) of the. Three other licensed WCK OCVs, Orc-VaxTM, ShancholTM, and Euvichol contain the same WCK V. cholerae O1 strains as Dukoral® along with WCK bacteria of the O139 serotype.[4] unlike Dukoral® these do not contain CTB.[4]

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