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

ABSTRACTCurrent oral cholera vaccines induce lower levels of protective efficacy and shorter durations of protection in young children than in adults. Immunity against cholera is serogroup specific, and immune responses toVibrio choleraelipopolysaccharide (LPS), the antigen that mediates serogroup-specific responses, are associated with protection against disease. Despite this, responses againstV. choleraeO-specific polysaccharide (OSP), a key component of the LPS responsible for specificity, have not been characterized in children. Here, we report a comparison of polysaccharide antibody responses in children from a region in Bangladesh where cholera is endemic, including infants (6 to 23 months,n= 15), young children (24 to 59 months,n= 14), and older children (5 to 15 years,n= 23) who received two doses of a killed oral cholera vaccine 14 days apart. We found that infants and young children receiving the vaccine did not mount an IgG, IgA, or IgM antibody response toV. choleraeOSP or LPS, whereas older children showed significant responses. In comparison to the vaccinees, young children with wild-typeV. choleraeO1 Ogawa infection did mount significant antibody responses against OSP and LPS. We also demonstrated that OSP responses correlated with age in vaccinees, but not in cholera patients, reflecting the ability of even young children with wild-type cholera to develop OSP responses. These differences might contribute to the lower efficacy of protection rendered by vaccination than by wild-type disease in young children and suggest that efforts to improve lipopolysaccharide-specific responses might be critical for achieving optimal cholera vaccine efficacy in this younger age group.

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Comparison of Immune Responses to the O-Specific Polysaccharide and Lipopolysaccharide of Vibrio cholerae O1 in Bangladeshi Adult Patients with Cholera

Clinical and Vaccine Immunology ◽

10.1128/cvi.00321-12 ◽

2012 ◽

Vol 19 (11) ◽

pp. 1712-1721 ◽

Cited By ~ 38

Author(s):

Russell A. Johnson ◽

Taher Uddin ◽

Amena Aktar ◽

M. Mohasin ◽

Mohammad Murshid Alam ◽

...

Keyword(s):

Bovine Serum Albumin ◽

Immune Responses ◽

Vibrio Cholerae ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Content Type ◽

Specific Polysaccharide ◽

Vibrio Cholerae O1 ◽

Human Immune ◽

El Tor

ABSTRACTImmunity againstVibrio choleraeO1 is serogroup specific, and serogrouping is defined by the O-specific polysaccharide (OSP) part of lipopolysaccharide (LPS). Despite this, human immune responses toV. choleraeOSP have not previously been characterized. We assessed immune responses againstV. choleraeOSP in adults with cholera caused byV. choleraeO1 El Tor serotype Inaba or Ogawa in Dhaka, Bangladesh, using O1 OSP-core–bovine serum albumin (OSPc:BSA) conjugates; responses targeted OSP in these conjugates. Responses of Inaba-infected patients to Inaba OSP and LPS increased significantly in IgG, IgM, and IgA isotypes from the acute to convalescent phases of illness, and the responses correlated well between OSP and LPS (R= 0.86, 0.73, and 0.91, respectively;P< 0.01). Plasma IgG, IgM, and IgA responses to Ogawa OSP and LPS in Ogawa-infected patients also correlated well with each other (R= 0.60, 0.60, and 0.92, respectively;P< 0.01). Plasma IgM responses to Inaba OSP and Ogawa OSP correlated with the respective serogroup-specific vibriocidal antibodies (R= 0.80 and 0.66, respectively;P< 0.001). Addition of either OSPc:BSA or LPS, but not BSA, to vibriocidal assays inhibited vibriocidal responses in a comparable and concentration-dependent manner. Mucosal IgA immune responses to OSP and LPS were also similar. Our study is the first to characterize anti-OSP immune responses in patients with cholera and suggests that responses targetingV. choleraeLPS, including vibriocidal responses that correlate with protection against cholera, predominantly target OSP. Induction of anti-OSP responses may be associated with protection against cholera, and our results may support the development of a vaccine targetingV. choleraeOSP.

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Vibrio cholerae O1 Ogawa detoxified lipopolysaccharide structures as inducers of cytokines and oxidative species in macrophages

Journal of Medical Microbiology ◽

10.1099/jmm.0.013599-0 ◽

2010 ◽

Vol 59 (2) ◽

pp. 158-164 ◽

Cited By ~ 8

Author(s):

Ema Paulovičová ◽

Elena Kováčová ◽

Slavomír Bystrický

Keyword(s):

Vibrio Cholerae ◽

Ex Vivo ◽

Peritoneal Macrophages ◽

Cholera Vaccine ◽

Specific Polysaccharide ◽

Vibrio Cholerae O1 ◽

Mouse Peritoneal Macrophages ◽

Oxidative Species ◽

Necrosis Factor ◽

Pro Inflammatory Cytokines

Multidrug resistance in several strains of Vibrio cholerae has encouraged anti-cholera vaccine developmental attempts using various subcellular moieties. In order to examine the immunological efficacy of detoxified LPS (dLPS)-derived saccharide immunogens, ex vivo activation of mouse peritoneal macrophages (MΦs) was investigated. The immunomodulatory effect was evaluated via induction of the pro-inflammatory cytokines tumour necrosis factor-α, interleukin (IL)-1α and IL-6 and acceleration of nitric oxide (NO) and reactive oxygen species (ROS). Immunologically active structures triggered mouse peritoneal MΦs to secrete cytokines and release NO/ROS, even at concentrations as low as 12.5 μg ml−1. It was found that the O-specific polysaccharide moiety was more immunologically efficient than the glycolipid one, probably due to the position of 3-deoxy-d-manno-octulosonic acid. The results revealed effective structure–immunomodulating relationships of dLPS-derived moieties that are desirable in subcellular anti-cholera vaccine design.

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Randomized, Double-Blind, Placebo-Controlled, Multicentered Trial of the Efficacy of a Single Dose of Live Oral Cholera Vaccine CVD 103-HgR in Preventing Cholera following Challenge with Vibrio cholerae O1 El Tor Inaba Three Months after Vaccination

Infection and Immunity ◽

10.1128/iai.67.12.6341-6345.1999 ◽

1999 ◽

Vol 67 (12) ◽

pp. 6341-6345 ◽

Cited By ~ 101

Author(s):

Carol O. Tacket ◽

Mitchell B. Cohen ◽

Steven S. Wasserman ◽

Genevieve Losonsky ◽

Sofie Livio ◽

...

Keyword(s):

Vibrio Cholerae ◽

Protective Efficacy ◽

Mercury Resistance ◽

Cholera Vaccine ◽

Double Blind ◽

Double Blind Placebo ◽

Oral Cholera Vaccine ◽

K 12 ◽

El Tor ◽

Placebo Recipients

ABSTRACT CVD 103-HgR is a live oral cholera vaccine strain constructed by deleting 94% of the gene for the enzymatically active A subunit of cholera toxin from classical Inaba Vibrio cholerae O1 569B; the strain also contains a mercury resistance gene as an identifying marker. This vaccine was well tolerated and immunogenic in double-blind, controlled studies and was protective in open-label studies of volunteers challenged with V. cholerae O1. A randomized, double-blind, placebo-controlled, multicenter study of vaccine efficacy was designed to test longer-term protection of CVD 103-HgR against moderate and severe El Tor cholera in U.S. volunteers. A total of 85 volunteers (50 at the University of Maryland and 35 at Children's Hospital Medical Center/University of Cincinnati) were recruited for vaccination and challenge with wild-type V. cholerae El Tor Inaba. Volunteers were randomized in a double-blind manner to receive, with buffer, a single oral dose of either CVD 103-HgR (2 × 108to 8 × 108 CFU) or placebo (killed E. coli K-12). About 3 months after immunization, 51 of these volunteers were orally challenged with 105 CFU of virulent V. cholerae O1 El Tor Inaba strain N16961, prepared from a standardized frozen inoculum. Ninety-one percent of the vaccinees had a ≥4-fold rise in serum vibriocidal antibodies after vaccination. After challenge, 9 (39%) of the 23 placebo recipients and 1 (4%) of the 28 vaccinees had moderate or severe diarrhea (≥3-liter diarrheal stool) (P < 0.01; protective efficacy, 91%). A total of 21 (91%) of 23 placebo recipients and 5 (18%) of 28 vaccinees had any diarrhea (P < 0.001; protective efficacy, 80%). Peak stoolV. cholerae excretion among placebo recipients was 1.1 × 107 CFU/g and among vaccinees was 4.9 × 102 CFU/g (P < 0.001). This vaccine could therefore be a safe and effective tool to prevent cholera in travelers.

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Construction and Evaluation of a Safe, Live, Oral Vibrio cholerae Vaccine Candidate, IEM108

Infection and Immunity ◽

10.1128/iai.71.10.5498-5504.2003 ◽

2003 ◽

Vol 71 (10) ◽

pp. 5498-5504 ◽

Cited By ~ 66

Author(s):

Weili Liang ◽

Shixia Wang ◽

Fenggang Yu ◽

Lijuan Zhang ◽

Guoming Qi ◽

...

Keyword(s):

Vibrio Cholerae ◽

Protective Antigen ◽

Vaccine Candidate ◽

Rabbit Model ◽

Housekeeping Gene ◽

Cholera Vaccine ◽

Oral Cholera Vaccine ◽

Toxigenic Strains ◽

El Tor ◽

Full Protection

ABSTRACT IEM101, a Vibrio cholerae O1 El Tor Ogawa strain naturally deficient in CTXΦ, was previously selected as a live cholera vaccine candidate. To make a better and safer vaccine that can induce protective immunity against both the bacteria and cholera toxin (CT), a new vaccine candidate, IEM108, was constructed by introducing a ctxB gene and an El Tor-derived rstR gene into IEM101. The ctxB gene codes for the protective antigen CTB subunit, and the rstR gene mediates phage immunity. The stable expression of the two genes was managed by a chromosome-plasmid lethal balanced system based on the housekeeping gene thyA. Immunization studies indicate that IEM108 generates good immune responses against both the bacteria and CT. After a single-dose intraintestinal vaccination with 109 CFU of IEM108, both anti-CTB immunoglobulin G and vibriocidal antibodies were detected in the immunized-rabbit sera. However, only vibriocidal antibodies are detected in rabbits immunized with IEM101. In addition, IEM108 but not IEM101 conferred full protection against the challenges of four wild-type toxigenic strains of V. cholerae O1 and 4 μg of CT protein in a rabbit model. By introducing the rstR gene, the frequency of conjugative transfer of a recombinant El Tor-derived RS2 suicidal plasmid to IEM108 was decreased 100-fold compared to that for IEM101. This indicated that the El Tor-derived rstR cloned in IEM108 was fully functional and could effectively inhibit the El Tor-derived CTXΦ from infecting IEM108. Our results demonstrate that IEM108 is an efficient and safe live oral cholera vaccine candidate that induces antibacterial and antitoxic immunity and CTXΦ phage immunity.

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Induction of systemic, mucosal and memory antibody responses targeting Vibrio cholerae O1 O-specific polysaccharide (OSP) in adults following oral vaccination with an oral killed whole cell cholera vaccine in Bangladesh

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0007634 ◽

2019 ◽

Vol 13 (8) ◽

pp. e0007634 ◽

Cited By ~ 1

Author(s):

Aklima Akter ◽

Pinki Dash ◽

Amena Aktar ◽

Sultana Rownok Jahan ◽

Sadia Afrin ◽

...

Keyword(s):

Vibrio Cholerae ◽

Antibody Responses ◽

Cholera Vaccine ◽

Oral Vaccination ◽

Whole Cell ◽

Specific Polysaccharide ◽

Vibrio Cholerae O1

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The gut microbiota and development of Vibrio cholerae -specific long-term memory B cells in adults after whole-cell killed oral cholera vaccine

Infection and Immunity ◽

10.1128/iai.00217-21 ◽

2021 ◽

Author(s):

Denise Chac ◽

Taufiqur R. Bhuiyan ◽

Amit Saha ◽

Mohammad M. Alam ◽

Umme Salma ◽

...

Keyword(s):

B Cells ◽

Gut Microbiota ◽

Immune Responses ◽

Vibrio Cholerae ◽

Memory B Cells ◽

Health Concern ◽

Cholera Vaccine ◽

Vaccine Adjuvants ◽

Oral Cholera Vaccine

Cholera is a diarrheal disease caused by Vibrio cholerae that continues to be a major public health concern in populations without access to safe water. IgG- and IgA-secreting memory B cells (MBC) targeting the V. cholerae O-specific polysaccharide (OSP) correlate with protection from infection in persons exposed to V. cholerae and may be a major determinant of long-term protection from cholera. Shanchol, a widely used oral cholera vaccine (OCV), stimulates OSP MBC responses in only some people after vaccination, and the gut microbiota is a possible determinant of variable immune responses observed after OCV. Using 16S rRNA sequencing of feces from the time of vaccination, we compared the gut microbiota among adults with and without MBC responses to OCV. Gut microbial diversity measures were not associated with MBC isotype and OSP-specific responses, but individuals with a higher abundance of Clostridiales and lower Enterobacterales were more likely to develop an MBC response. We applied protein-normalized fecal supernatants of high and low MBC responders to THP-1-derived human macrophages to investigate the effect of microbial factors at the time of vaccination. Feces from individuals with higher MBC responses induced significantly different IL-1β and IL-6 levels than individuals with lower responses, indicating that the gut microbiota at the time of vaccination may “prime” the mucosal immune response to vaccine antigens. Our results suggest that the gut microbiota could impact immune responses to OCVs, and further study of microbial metabolites as potential vaccine adjuvants is warranted.

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