Abstract
Serum vibriocidal antibody assays have long been used to evaluate the immunogenicity of cholera vaccines formulated with killed whole-cell Vibrio cholerae. However, the antibody isotypes responsible for the serum vibriocidal activity are not fully characterized. In this study, we examined 20 clinical serum samples obtained from human subjects who had been vaccinated with a killed, whole-cell cholera vaccine and a positive control, human convalescent sera with high vibriocidal activity, to determine which isotype antibody is associated with the vibriocidal activity. Antibody isotypes from pooled convalescent sera were fractionated by size-exclusion column chromatography, and the major vibriocidal activity was detected in the IgM fraction. Depletion of IgM antibodies in the convalescent sera produced a significant (P<0.05) decrease in vibriocidal activity (16-fold decrease), whereas only a small change was observed with depletion of IgG or IgA. In addition, anti-LPS IgM antibody showed the highest correlation with vibriocidal activity (Spearman correlation coefficient r = 0.846) among antibody isotypes against heat-killed V. cholerae, lipopolysaccharide (LPS), or major outer membrane protein (Omp U), while total IgG, IgA, or IgM antibody level was not correlated with vibriocidal activity in the 20 human clinical serum samples. Furthermore, human convalescent sera significantly (P<0.001) inhibited the attachment of V. cholerae to HT-29, a human intestinal epithelial cell in vitro. Interestingly, IgM-depleted convalescent sera could not effectively inhibit bacterial adherence compared with non-depleted sera (P<0.05). Finally, bacterial adhesion was significantly inhibited by sera with high vibriocidal titer compared with low-titer sera (P = 0.014). Collectively, we demonstrated that anti-V. cholerae LPS IgM is highly correlated with serum vibriocidal activity and it could be a surrogate antibody isotype representing protective antibodies against V. cholerae.
Highlights
Vibrio cholerae causes acute diarrhea by cholera toxin-mediated intestinal fluid secretion in humans
Serum vibriocidal antibody titer has been widely used to evaluate protective immunity to cholera in populations suffering from infection or in those administered cholera vaccines [28, 29]
We found that total IgG, IgA, or IgM antibody level was not associated with vibriocidal titer, but V. cholerae LPS-specific IgM was highly correlated with its bactericidal activity in the clinical specimen
Summary
Vibrio cholerae causes acute diarrhea by cholera toxin-mediated intestinal fluid secretion in humans. Humoral immunity rather than cellular immunity has been considered to play a role in protection against cholera because the bacteria do not invade the intestinal epithelial barrier and are unable to survive intracellularly [1]. Specific antibodies against V. cholerae are known to play a role in protection in humans, there is no direct evidence as to which antibody isotype is the most important to provide immunity against cholera. Secretory IgA and serum IgG, have been shown to provide protective immunity against V. cholerae infection [5, 6], and LPS-specific IgA is increased in the sera and intestinal fluids from patients and vaccinated individuals [7,8,9]. Significant levels of V. cholerae LPS-specific serum IgG are augmented in response to V. cholerae infection [10,11,12]
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