An oral cholera vaccine in the prevention and/or treatment of inflammatory bowel disease

PLOS ONE RESEARCH ARTICLE An oral cholera vaccine in the prevention and/or treatment of inflammatory bowel disease Marine Meunier ID1*, Adrian Spillmann2, Christel Rousseaux3, Klaus Schwamborn1☯, Melissa Hanson1☯ 1 VALNEVA SE, Saint-Herblain, France, 2 VALNEVA AUSTRIA GMBH, Vienna, Austria, 3 Intestinal Biotech Development, Faculté de Médicine—Pole Recherche, Lille, France a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Meunier M, Spillmann A, Rousseaux C, Schwamborn K, Hanson M (2023) An oral cholera vaccine in the prevention and/or treatment of inflammatory bowel disease. PLoS ONE 18(8): e0283489. https://doi.org/10.1371/journal. pone.0283489 Editor: Imad Al Kassaa, Fonterra Coop / Lebanese University, LEBANON Received: April 12, 2023 Accepted: August 12, 2023 Published: August 28, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0283489 Copyright: © 2023 Meunier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data for this study are within the paper and its Supporting Information files. ☯ These authors contributed equally to this work. * Abstract The oral cholera vaccine WC-rBS consists of 4 different inactivated strains of Vibrio cholerae (LPS source) admixed with recombinant cholera toxin B subunit. Because of its unique composition and anti-inflammatory properties reported for both CTB and low doses of LPS from other Gram-negative bacteria, we speculated that WC-rBS might have anti-inflammatory potential in a chronic autoimmune disease such as inflammatory bowel diseases. First in vitro endotoxin tolerance experiments showed the surprising WC-rBS potential in the modulation of inflammatory responses on both PBMCs and THP1 cells. WC-rBS was further evaluated in the Dextran Sodium Sulfate colitis mouse model. Administrated orally at different dosages, WC-rBS vaccine was safe and showed immunomodulatory properties when administered in a preventive mode (before and during the induction of DSS colitis) as well as in a curative mode (after colitis induction); with improvement of disease activity index (from 27 to 73%) and histological score (from 65 to 88%). Interestingly, the highest therapeutic effect of WC-rBS vaccine was observed with the lowest dosage, showing even better anti-inflammatory properties than mesalamine; an approved 5-aminosalicylic acid drug for treating IBD patients. In summary, this is the first time that a prophylactic medicine, safe and approved for prevention of an infectious disease, showed a benefit in an inflammatory bowel disease model, potentially offering a novel therapeutic modality for IBD patients. Introduction Inflammatory bowel disease (IBD) is an autoimmune disease characterized by the loss of immune tolerance for normal bacteria present in the gut microbiome. Therefore, the immune system of IBD patients attacks bacteria and induces chronic inflammation, which has been linked to increased cancer risk [1]. The global prevalence of IBD has been increasing since 2000, and IBD now affects up to 1 in 200 individuals in Western countries [2]. IBD encompasses two distinct disorders, Crohn’s disease (CD) and ulcerative colitis (UC), which differ in pathophysiology, affected parts of the gastrointestinal (GI) tract, symptoms, complications, PLOS ONE | https://doi.org/10.1371/journal.pone.0283489 August 28, 2023 1 / 15 PLOS ONE Funding: The author(s) received no specific funding for this work Competing interests: Marine Meunier, Adrian Spillmann, Klaus Schwamborn and Melissa Hanson were all employees of the Valneva group when the work was done. The Swedish subsidiary of the Valneva group owns Dukoral®, i.e. the WCrBS vaccine. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Cholera vaccine in IBD disease course and management. CD is characterized by discontinuous intestinal lesions anywhere in the GI tract, and involves chronic, relapsing transmural inflammation that can lead to chronic abdominal pain, diarrhea, obstruction and/or perianal lesions. UC affects only the colon, the lesions are continuous, and inflammation is superficial, which can lead to erosions, ulcers, and bloody diarrhea. Depending on the severity of the disease, different drugs can be administrated for the treatment of IBD such as corticosteroids, aminosalicylates, biologics, supportive medications, and immunosuppressive drugs. Especially, mesalamine is a safe and well tolerated aminosalicylate anti-inflammatory drug widely used as a first-line therapy in IDB patients [3]. Despite multiple options available for IBD patients [4]–considering the strong side effects and high relapse rates for current therapies–there remains a large unmet need to improve IBD outcomes with safe and effective treatments. The WC-rBS vaccine (Dukoral1, Valneva, Solna, Sweden) is an orally administrated vaccine for the prevention of cholera and in some countries also indicated to help prevent diarrhea caused by heat-labile toxin-producing enterotoxigenic E. coli (LT-producing ETEC). It consists of 4 different inactivated strains of Vibrio cholerae (V. cholerae) admixed with recombinant cholera toxin B subunit (rCTB). CTB is part of the cholera toxin (CT) secreted by the bacterium V. cholerae. In its pentameric form, it is responsible for the toxin binding to intestinal epithelial cells via ganglioside GM1. The monomeric A subunit (CTA) is responsible of the secretory effects of the toxin leading to diarrhea. CTB can be produced recombinantly (henceforth referred to as rCTB) or purified from whole cholera toxin (henceforth referred to as CTB). The immunomodulatory properties of CTB/rCTB have been reported in several studies for different diseases [5–7]. In vitro, Burkart et al [8] demonstrated that pre-exposure of monocytes (Mono Mac 6 cells) or PBMCs to CTB prevented a proinflammatory reaction to a subsequent LPS challenge with significantly lower levels of secreted pro-inflammatory TNFα, IL6, IL12 cytokines and transient elevated secretion levels of the anti-inflammatory cytokine IL-10. In the context of Behcet’s disease (an inflammatory disorder leading to uveitis as a major complication), Phipps et al indicated the induction of uveitis in Lewis rats when orally administered with an HSP60-derived peptide; whereas administration of a fusion protein of rCTB linked to an HSP60-derived peptide prevented uveitis development. This indicated a tolerogenic role of rCTB [9]. In a subsequent human clinical trial, thre (...truncated)