Immunity Provided by an Outer Membrane Vesicle Cholera Vaccine Is Due to O-Antigen-Specific Antibodies Inhibiting Bacterial Motility

Abstract

An outer membrane vesicle (OMV)-based cholera vaccine is highly efficacious in preventing intestinal colonization in the suckling mouse model. Immunity from OMVs comes from immunoglobulin (Ig), particularly IgG, in the milk of mucosally immunized dams. Anti-OMV IgG renders Vibrio cholerae organisms immotile, thus they pass through the small intestine without colonizing. However, the importance of motility inhibition for protection and the mechanism by which motility is inhibited remain unclear. By using both in vitro and in vivo experiments, we found that IgG inhibits motility by specifically binding to the O-antigen of V. cholerae. We demonstrate that the bivalent structure of IgG, although not required for binding to the O-antigen, is required for motility inhibition. Finally, we show using competition assays in suckling mice that inhibition of motility appears to be responsible for most, if not all, of the protection engendered by OMV vaccination, thus providing insight into the mechanism of immune protection.

Dissecting serotype-specific contributions to live oral cholera vaccine efficacy

“…In conjunction with the observation of serotype-bias in FROI, these data support the idea that anti-O-antigen antibodies are the direct effectors responsible for vaccine-mediated suppression of colonization 5,47 and suggest that determination of the molecular bases of serotype-biased V.…”

Oral immunization with a probiotic cholera vaccine induces broad protective immunity againstVibrio choleraecolonization and disease in mice

“…The observation that exposure of HaitiV-immunized dams to SPF-derived pups during the cross-fostering experiments led to the elimination of detectable HaitiV in feces supports the prediction that this vaccine will not stably colonize humans. It is an open question whether transient exposure of naïve mice to HaitiV will also stimulate protective immunity, as has been shown in the context of vaccination with V. cholerae outer membrane vesicles [51,52]. The streptomycin-treated mouse model of V. cholerae colonization, which allows for temporary intestinal colonization, may also be useful to investigate the duration of colonization required for immunity [53].…”

“…The combination of the neonatal survival assay with the oral GF vaccination model builds on existing knowledge of these mice to assay both the immunogenicity and protective efficacy of live OCV candidates [38]. This model may be a useful addition to existing approaches that probe the molecular bases of vaccine-mediated mucosal protection against pathogens, a topic with significant translational potential that remains poorly understood [52,54]. A recent report employing a similar maternal-infant transmission model in the context of intraperitoneally-delivered heat-killed Citrobacter rodentium highlights the versatility of assessing vaccine protective efficacy using the infant progeny of immunized animals as readouts [55].…”

A Critical Region in the FlaA Flagellin Facilitates Filament Formation of the Vibrio cholerae Flagellum

“…humans during V. cholerae infection (5). Moreover, protective antibody responses specifically inhibit flagellum-mediated motility (6), emphasizing the important role motility plays during V. cholerae infection. Flagellum-mediated chemotaxis is suppressed during infection, which leads to an increase in intestinal colonization and a transient hyperinfectivity that is thought to enhance transmission and stimulate epidemic spread (7,8).…”