Research Article: Anti-O-specific polysaccharide (OSP) immune responses following vaccination with oral cholera vaccine CVD 103-HgR correlate with protection against cholera after infection with wild-type Vibrio cholerae O1 El Tor Inaba in North American volunteers

Date Published: April 6, 2018

Publisher: Public Library of Science

Author(s): Kamrul Islam, Motaher Hossain, Meagan Kelly, Leslie M. Mayo Smith, Richelle C. Charles, Taufiqur Rahman Bhuiyan, Pavol Kováč, Peng Xu, Regina C. LaRocque, Stephen B. Calderwood, Jakub K. Simon, Wilbur H. Chen, Douglas Haney, Michael Lock, Caroline E. Lyon, Beth D. Kirkpatrick, Mitchell Cohen, Myron M. Levine, Marc Gurwith, Jason B. Harris, Firdausi Qadri, Edward T. Ryan, Pamela L. C. Small.

Abstract: BackgroundCholera is an acute voluminous dehydrating diarrheal disease caused by toxigenic strains of Vibrio cholerae O1 and occasionally O139. A growing body of evidence indicates that immune responses targeting the O-specific polysaccharide (OSP) of V. cholerae are involved in mediating protection against cholera. We therefore assessed whether antibody responses against OSP occur after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and whether such responses correlate with protection against cholera.MethodologyWe assessed adult North American volunteers (n = 46) who were vaccinated with 5 × 108 colony-forming units (CFU) of oral cholera vaccine CVD 103-HgR and then orally challenged with approximately 1 × 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961, either 10 or 90 days post-vaccination.Principal findingsVaccination was associated with induction of significant serum IgM and IgA anti-OSP and vibriocidal antibody responses within 10 days of vaccination. There was significant correlation between anti-OSP and vibriocidal antibody responses. IgM and IgA anti-OSP responses on day 10 following vaccination were associated with lower post-challenge stool volume (r = −0.44, P = 0.002; r = −0.36, P = 0.01; respectively), and none of 27 vaccinees who developed a ≥1.5 fold increase in any antibody isotype targeting OSP on day 10 following vaccination compared to baseline developed moderate or severe cholera following experimental challenge, while 5 of 19 who did not develop such anti-OSP responses did (P = 0.01).ConclusionOral vaccination with live attenuated cholera vaccine CVD 103-HgR induces antibodies that target V. cholerae OSP, and these anti-OSP responses correlate with protection against diarrhea following experimental challenge with V. cholerae O1.Trial NCT01895855

Partial Text: Vibrio cholerae can be characterized into over 200 serogroups [1]. V. cholerae serogroups O1 and O139 are the causes of epidemic cholera, a severe dehydrating illness of humans [2]. V. cholerae O1 and O139 are noninvasive intestinal pathogens that express cholera toxin within the intestine of infected humans. Cholera toxin (CT) is an ADP-ribosylating protein that binds to intestinal epithelial cells, resulting in increased intracellular cAMP, and subsequent chloride, sodium, and water excretion by intestinal epithelial cells, resulting in the secretory diarrhea characteristic of cholera [3, 4]. The mechanistic mediators of protection against cholera are poorly defined. Immune responses against CT do not mediate meaningful protective immunity against cholera [5–7]. Protection against cholera is serogroup specific, two major serogroups of V. cholerae O1 are Ogawa and Inaba and serospecificity is mediated by the O-specific polysaccharide (OSP) component of lipopolysaccharide (LPS) [6, 8]. Currently, the best correlate of protection against cholera is the vibriocidal antibody response [9, 10]. The vibriocidal response can largely be adsorbed away by incubating serum with purified V. cholerae OSP, suggesting that OSP is the prime antigenic target assessed by the vibriocidal assay [11].

In this study, we found that recipients of live attenuated oral cholera vaccine CVD 103-HgR develop prominent immune responses targeting V. cholerae O-specific polysaccharide (OSP), and that these responses correlate with protection against moderate or severe diarrhea following experimental challenge with wild type V. cholerae O1. Antibodies targeting OSP induced by vaccination with CVD 103-HgR were largely of the IgM and IgA isotypes. Since V. cholerae is a noninvasive mucosal pathogen of the human intestine, IgM and IgA immune responses would be predicted to be the most pertinent isotypes involved in mechanistically mediating protection against cholera, since both IgM and IgA are actively secreted into the intestinal lumen by intestinal epithelial cells [17–19].