Research Article: Use of Oral Cholera Vaccines in an Outbreak in Vietnam: A Case Control Study

Date Published: January 25, 2011

Publisher: Public Library of Science

Author(s): Dang Duc Anh, Anna Lena Lopez, Vu Dinh Thiem, Shannon L. Grahek, Tran Nhu Duong, Jin Kyung Park, Hye Jung Kwon, Michael Favorov, Nguyen Tran Hien, John D. Clemens, Edward Ryan.

Abstract: BackgroundKilled oral cholera vaccines (OCVs) are available but not used routinely for cholera control except in Vietnam, which produces its own vaccine. In 2007–2008, unprecedented cholera outbreaks occurred in the capital, Hanoi, prompting immunization in two districts. In an outbreak investigation, we assessed the effectiveness of killed OCV use after a cholera outbreak began.Methodology/Principal FindingsFrom 16 to 28 January 2008, vaccination campaigns with the Vietnamese killed OCV were held in two districts of Hanoi. No cholera cases were detected from 5 February to 4 March 2008, after which cases were again identified. Beginning 8 April 2008, residents of four districts of Hanoi admitted to one of five hospitals for acute diarrhea with onset after 5 March 2008 were recruited for a matched, hospital-based, case-control outbreak investigation. Cases were matched by hospital, admission date, district, gender, and age to controls admitted for non-diarrheal conditions. Subjects from the two vaccinated districts were evaluated to determine vaccine effectiveness. 54 case-control pairs from the vaccinated districts were included in the analysis. There were 8 (15%) and 16 (30%) vaccine recipients among cases and controls, respectively. The vaccine was 76% protective against cholera in this setting (95% CI 5% to 94%, P = 0.042) after adjusting for intake of dog meat or raw vegetables and not drinking boiled or bottled water most of the time.Conclusions/SignificanceThis is the first study to explore the effectiveness of the reactive use of killed OCVs during a cholera outbreak. Our findings suggest that killed OCVs may have a role in controlling cholera outbreaks.

Partial Text: Cholera is increasingly being reported, and more countries are now experiencing outbreaks [1], some lasting for several months. In 2001, the World Health Organization (WHO) recommended the use of oral cholera vaccines (OCV) in populations at risk in endemic areas but not reactively once an outbreak has begun [2]. While this recommendation has been updated in March 2010, to include reactive use of these vaccines [3], OCVs have only been used for reactive cholera control in 2000, when a live attenuated OCV (CVD-103HgR) was used in an outbreak in Micronesia [4]. The CVD-103HgR was assessed to be effective in this outbreak, although this was an observational study. In contrast, CVD-103HgR conferred no protection in the only randomized controlled efficacy trial of this vaccine [5], and this vaccine is no longer manufactured. There is one internationally licensed killed oral cholera vaccine, the recombinant B subunit killed OCV (rBS-WC, Dukoral, Crucell/SBL), but it has not been routinely adopted for public health use due to its high cost, limited duration of protection and logistic issues with vaccine administration. A variant of this oral vaccine, containing only killed whole cells (Vibrio cholerae O1 and O139) is manufactured in Vietnam following technology transfer from Swedish scientists. Vietnam is the only country in the world to use an OCV in its public health system for cholera control. Since 1997, this killed OCV (ORC-Vax) has been licensed and produced locally by the Company for Vaccine and Biological Production (VaBiotech) in Hanoi. The vaccine was found to confer 66% protection against an El Tor cholera outbreak occurring eight months following vaccination among all individuals aged 1 year and older [6] and 50% protection, three to five years after vaccination [7]. It is safe, inexpensive, and easy to administer [8]. Packaged in five-dose vials, each 1.5 ml liquid vaccine dose is drawn and squirted into the mouth by a syringe without a needle. Each dose contained: 5.0×1010 formalin-killed V. cholerae Inaba, El Tor strain Phil 6973; 2.5×1010 heat-killed V. cholerae Ogawa, classical strain Cairo 50; 2.5×1010 formalin-killed V. cholerae Inaba, classical strain 569B; and 5.0×1010 formalin-killed V. cholerae O139 strain 4260B. After oral administration, individuals are asked to drink water, but no oral buffer is required. Given in two doses, one to four weeks apart, it may be given to individuals aged one year and older.

A matched, hospital-based, case-control investigation was conducted from 8 April to 10 June, 2008. Hanoi has nine urban districts with a population of ∼2.9 million [12]. Hospitalized patients from the two vaccinated districts – Hoang Mai and Thanh Xuan, as well as the unvaccinated districts – Dong Da and Cau Giay were invited to participate in the outbreak investigation (Figure 3). These districts have a combined population of ∼1 million [12]. These districts have similar population characteristics, environmental conditions and epidemiological data from past cholera outbreaks. Residents of these districts are also served in common and have equal chances of attending five hospitals including the National Institute of Infectious and Tropical Disease (NIID) Hospital, Bach Mai District Hospital, Saint Paul Hospital, Dong Da District Hospital and Transportation Hospital. Case and control exposure histories of subjects from Hoang Mai and Thanh Xuan , were compared for evaluation of risk factors and effectiveness of killed OCV use during the outbreak, the results of which are presented here.

We enrolled 126 matched pairs of cases and controls for the outbreak investigation; one matched pair was excluded when on review the case definition was not met by the case (Figure 4). After exclusion of this matched pair, among cases, the ages ranged from 17 to 86 years old while the control age range was 15 to 80 years old. Thirty-seven percent of cases had vomiting and 76% had some or severe dehydration on admission. Among those with severe dehydration, only one was vaccinated. Of the 99 cases whose stools were tested, 74 subjects had culture confirmed V. cholerae O1 (75%). Only one vaccine recipient had culture confirmed cholera. Table 1 shows the causes of hospitalization for the controls.

This is the first study to report on the use of killed OCV in an outbreak situation. While a significant association was detected between receipt of at least one dose of the killed OCV and protection against cholera, our study has several limitations.