Abstract
Analyses of stool from patients with acute watery diarrhea (AWD) using sensitive molecular diagnostics have challenged whether fecal microbiological cultures have acceptably high sensitivity for cholera diagnosis. If true, these findings imply that current estimates of the global burden of cholera, which rely largely on culture-confirmation, may be underestimates. We conducted a vaccine probe study to evaluate this possibility, assessing whether an effective killed oral cholera vaccine (OCV) tested in a field trial in a cholera-endemic population conferred protection against cholera culture-negative AWD, with the assumption that if cultures are indeed insensitive, OCV protection in such cases should be detectable. We re-analysed the data of a Phase III individually-randomized placebo-controlled efficacy trial of killed OCVs conducted in Matlab, Bangladesh in 1985. We calculated the protective efficacy (PE) of a killed whole cell-only (WC-only) OCV against first-episodes of cholera culture-negative AWD during two years of post-dosing follow-up. In secondary analyses, we evaluated PE against cholera culture-negative AWD by age at vaccination, season of onset, and disease severity. In this trial 50,770 people received at least 2 complete doses of either WC-only OCV or placebo, and 791 first episodes of AWD were reported during the follow-up period, of which 365 were culture-positive for Vibrio cholerae O1. Of the 426 culture-negative AWD episodes, 215 occurred in the WC group and 211 occurred in the placebo group (adjusted PE = -1.7%; 95%CI -23.0 to 13.9%, p = 0.859). No measurable PE of OCV was observed against all or severe cholera culture-negative AWD when measured overall or by age and season subgroups. In this OCV probe study we detected no vaccine protection against AWD episodes for which fecal cultures were negative for Vibrio cholera O1. Results from this setting suggest that fecal cultures from patients with AWD were highly sensitive for cholera episodes that were etiologically attributable to this pathogen. Similar analyses of other OCV randomized controlled trials are recommended to corroborate these findings.
Highlights
An estimated 2.9 million cases and 95 000 deaths occur each year due to cholera, caused primarily by Vibrio cholerae (V. cholerae) O1, in endemic countries [1]
One pivotal article demonstrated that culture failed to detect cholera in one-third of the cholera-positive stool specimens confirmed by other methods
We used oral cholera vaccine as a probe to investigate the reliability of conventional culture as a diagnostic for cholera by measuring the effectiveness of the vaccine against cholera culture-negative acute watery diarrhea
Summary
An estimated 2.9 million cases and 95 000 deaths occur each year due to cholera, caused primarily by Vibrio cholerae (V. cholerae) O1, in endemic countries [1]. The authors postulated that failure of culture methods to isolate V. cholerae may be caused by bacterial inactivation by in vivo vibriolytic action of the phages and/or prevention by host-induced mechanisms. In light of this conclusion, one implication is that the current estimates of cholera disease burden that are based on culture-confirmed cholera may be significant underestimates, and that a reassessment of past and recent cholera studies may be needed to guide public health policy on cholera control measures in countries affected by cholera
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