A Double Mutant Heat-Labile Toxin from Escherichia coli, LT(R192G/L211A), Is an Effective Mucosal Adjuvant for Vaccination against Helicobacter pylori Infection

Abstract

bHelicobacter pylori infection in the stomach is a common cause of peptic ulcer disease and is a strong risk factor for the development of gastric adenocarcinoma, yet no effective vaccine against H. pylori infection is available to date. In mice, mucosal vaccination with H. pylori antigens when given together with cholera toxin (CT) adjuvant, but not without adjuvant, can induce protective immune responses against H. pylori infection. However, the toxicity of CT precludes its use as a mucosal adjuvant in humans. We evaluated a recently developed, essentially nontoxic double mutant Escherichia coli heat-labile toxin, LT(R192G/ L211A) (dmLT), as a mucosal adjuvant in an experimental H. pylori vaccine and compared it to CT in promoting immune responses and protection against H. pylori infection in mice. Immunization via the sublingual or intragastric route with H. pylori lysate antigens and dmLT resulted in a significant decrease in bacterial load after challenge compared to that in unimmunized infection controls and to the same extent as when using CT as an adjuvant. Cellular immune responses in the sublingually immunized mice known to correlate with protection were also fully comparable when using dmLT and CT as adjuvants, resulting in enhanced in vitro proliferative and cytokine responses from spleen and mesenteric lymph node cells to H. pylori antigens. Our results suggest that dmLT is an attractive adjuvant for inclusion in a mucosal vaccine against H. pylori infection.

Cholera Toxin, and the Related Nontoxic Adjuvants mmCT and dmLT, Promote Human Th17 Responses via Cyclic AMP–Protein Kinase A and Inflammasome-Dependent IL-1 Signaling

“…Multiple attempts have been made to mutate CT or LT in ways that could provide molecules with little or absent enterotoxicity and yet retained adjuvanticity (1,3). Double-mutant LT (dmLT), with more than a 100-fold reduced enterotoxicity compared with native LT, was recently developed (4) and shown to enhance immune responses to various vaccines in animal models (4)(5)(6)(7)(8). Furthermore, dmLT was also shown to be safe and adjuvant-active when tested alone or together with an enteric vaccine in humans via the oral route (9,10).…”

Avances en la búsqueda de la vacuna contra Helicobacter pylori

“…Uno de ellos demostró que el CTA1-DD, un derivado de la TC, podría llegar a ser tan eficaz como esta, con la ventaja de tener una muy baja toxicidad 70 . El otro consiguió una eficacia tan alta como la de la TC usando una TL con Doble Mutación en su subunidad A (DMTL, por sus siglas en inglés) 71 . Las mutaciones consistían en el reemplazo de una arginina por una glicina en la posición 192, y en el de una leucina por una alanina en la posición 211.…”

“…La importancia esencial de esta nueva molécula es que carece de efectos tóxicos. En este estudio se consiguió una reducción de 84 veces la carga bacteriana en ratones inmunizados con DMTL con antígenos de un lisado de H. pylori, tras someterlos a una carga bacteriana, en comparación a ratones no inmunizados, mientras que la reducción en ratones inmunizados con TC con los mismos antígenos lisados de H. pylori fue de 81 veces la carga bacteriana presente en no inmunizados 71 . Estas moléculas prometen ser excelentes adyuvantes al ser potentes y bastante seguras de utilizar.…”

“…La exposición al antígeno y al adyuvante a través de rutas directas al conducto gastrointestinal, como la mucosa sublingual o la vía intranasal, han sido las de mayor éxito hasta ahora 14,71 .…”

Immune Response to Helicobacter pylori

“…Cellular immune responses in the sublingually route resulting in enhanced in vitro proliferative and cytokine responses from spleen and mesenteric lymph node cells to H. pylori antigens. Thus, dmLT is an attractive adjuvant for inclusion in a mucosal vaccine against H. pylori infection [88].…”