Immune Responses to the O-Specific Polysaccharide Antigen in Children Who Received a Killed Oral Cholera Vaccine Compared to Responses following Natural Cholera Infection in Bangladesh

Abstract

g Current 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 to Vibrio cholerae lipopolysaccharide (LPS), the antigen that mediates serogroup-specific responses, are associated with protection against disease. Despite this, responses against V. cholerae O-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 to V. cholerae OSP or LPS, whereas older children showed significant responses. In comparison to the vaccinees, young children with wild-type V. cholerae O1 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.

O-Specific Polysaccharide-Specific Memory B Cell Responses in Young Children, Older Children, and Adults Infected with Vibrio cholerae O1 Ogawa in Bangladesh

“…We have also found that OSP serum responses are much more prominent following naturally acquired disease than following vaccination with oral killed cholera vaccine, especially in young children (30,31). This may in part be due to the fact that OSP is a polysaccharide and as such is a T cell-independent antigen.…”

“…Oral killed cholera vaccines are safe and protective and are significant assets in global cholera control strategies. Unfortunately, protection afforded by oral killed cholera vaccines is of lower magnitude and of shorter duration in children under 5 years of age than that in older children and adults and than that afforded by naturally acquired disease in children 5 years of age and younger (22,23,31,43). We have also previously shown that vaccination with an oral killed cholera vaccine (Dukoral; whole-cell oral cholera vaccine supplemented with 1 mg/dose of recombinant nontoxic cholera toxin B subunit [CtxB]; WCrBS; Crucell, Sweden) in the youngest children is associated with a proregulatory (interleukin-10 [IL-10]) response, versus a proinflammatory (IL-17, interferon gamma, and IL-13) response seen in young children with naturally acquired cholera (47), and that OSP-specific memory B cell responses following oral killed cholera vaccination of adults are markedly blunted following vaccination compared to what occurs following naturally acquired disease (30).…”

“…We assessed OSP-, LPS-, and CtxB-specific IgA, IgG, and IgM antibody responses in plasma by using enzyme-linked immunosorbent assay (ELISA) procedures, as previously described (9,31,32,35). Briefly, we coated 96-well polystyrene plates (Nunc F; Nunc, USA) with V. cholerae O1 Ogawa OSPc-bovine serum albumin (BSA) (1 g/ml) dissolved in carbonate buffer (pH 9.6 to 9.8), or O1 Ogawa LPS (2.5 g/ml) dissolved in phosphate-buffered saline (PBS) (pH 7.2 to 7.4) or coated with 0.3 nmol of ganglioside GM1/ml, followed by recombinant CtxB subunit (0.5 g/ml) (gift from A. M. Svennerholm, University of Gothenburg, Gothenburg, Sweden) (36)(37)(38).…”

“…We have also previously shown that baseline plasma IgA antibody levels and circulating IgG memory B cell (MBC) responses to V. cholerae O1 LPS correlate with protection against cholera in household contacts of cholera patients (21,29). We have recently developed the technology to isolate V. cholerae O1 OSP, and since serogroup specificity is determined by OSP, we have begun evaluating OSP responses in cholera patients (30)(31)(32)(33). We have found that OSP serum and mucosal responses occur in patients with cholera, that the OSP response correlates with vibriocidal and LPS responses, and that the vibriocidal response can be largely adsorbed away by OSP (30)(31)(32).…”

Immune Responses to O-Specific Polysaccharide and Lipopolysaccharide of Vibrio cholerae O1 Ogawa in Adult Bangladeshi Recipients of an Oral Killed Cholera Vaccine and Comparison to Responses in Patients with Cholera

“…[22][23][24][25] Despite this, OSP responses during wild-type disease or after vaccinaton have only recently begun to be characterized. 26,27 Here, we extend this analysis to adult recipients of an oral killed cholera vaccine, WC-rBS (Dukoral), in Dhaka, Bangladesh, and compare responses after vaccination with those induced in adult patients with cholera caused by V. cholerae O1 Ogawa, the serotype circulating in Dhaka during the study period.…”