PLoS Neglected Tropical Diseases
(Accessed 16 Mar 2019)
Use of oral cholera vaccine as a vaccine probe to determine the burden of culture-negative cholera
Justin Im, Md. Taufiqul Islam, Faisal Ahmmed, Deok Ryun Kim, Yun Chon, K Zaman, Ashraful Islam Khan, Mohammad Ali, Florian Marks, Firdausi Qadri, John D. Clemens
Research Article | published 14 Mar 2019 PLOS Neglected Tropical Diseases
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.
Conventional microbiological culture has remained a relatively uncontested ‘gold standard’ for the diagnosis of cholera; however, emerging methods, including sensitive molecular tests, challenge the current paradigm. One pivotal article demonstrated that culture failed to detect cholera in one-third of the cholera-positive stool specimens confirmed by other methods. This finding underscored the absence of a reliable reference test, further complicated by newer tests outperforming the gold standard, leaving no suitable comparator. In this study, 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. We did not find any evidence of protection, implying that the culture diagnostics used were reliable. The dynamics of cholera transmission require a rapid response, and ascertaining the best rapid diagnostic test for early detection of outbreaks will maximize the effectiveness of chronically limited resources in high risk regions. As techniques advance, well-designed studies should be implemented to systematically evaluate their merit against established methods, and improved diagnostics, including rapid diagnostics and microbiological culture, should be implemented into cholera control programs to reduce cholera transmission by creating a better trigger for outbreak response.