Research Article: Use of oral cholera vaccine as a vaccine probe to determine the burden of culture-negative cholera

Date Published: March 14, 2019

Publisher: Public Library of Science

Author(s): 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, Mathieu Picardeau.

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.

Partial Text: 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]. Until now, microbiological cultures of stools have provided an accepted gold standard for diagnosing cholera in patients with diarrhoea. Such cultures, particularly when done with alkaline peptone water overnight enrichment, have been regarded as having very high diagnostic sensitivity, as well as high diagnostic specificity. However, one influential paper has questioned the notion that conventional fecal cultures have high sensitivity in diagnosing cholera [2].

In this trial 25 416 individuals were vaccinated with at least two doses of WC-only OCV, and 25 354 received at least two doses of placebo. Of the 50 770 people vaccinated with either WC-only OCV or placebo, 791 first episodes of AWD from 786 patients during two years of follow-up among which 365 were culture-positive for V. cholerae O1. Of the remaining 426 first episodes of culture-negative AWD, 215 (50.5%) occurred in recipients vaccinated with WC and 211 (49.5%) occurred in placebo recipients (Fig 1). A majority of the cases, 373 (87.6%) occurred in individuals ≥5 years.

Using OCV as a vaccine probe to detect culture-negative cholera during the first two years of follow-up in a placebo-controlled, randomized trial in Matlab, we failed to detect OCV protection against all episodes of cholera culture-negative AWD, by age groups, for cholera season, or by disease severity. In contrast, analyses showed 51.7% PE against culture confirmed cholera in patients with AWD during the same interval of follow-up. Before discussing the interpretation of these findings, it is important to address the limitations of our study.