The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study

Background: In 2013, a stockpile of oral cholera vaccine (OCV) was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both. Methods and Findings: Using mathematical models we determined the minimum relative single-dose efficacy (MRSE) at which single-dose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%–56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%). This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%–88%) for two doses and 44% (95% CI −27% to 76%) for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%–88%), which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943–86,205) cases in Zimbabwe, 78,317 (95% PI 57,435–100,150) in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490–3,170) cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted in past epidemics are based on severely limited single-dose efficacy data and may not fully capture uncertainty due to imperfect surveillance data and uncertainty about the transmission dynamics of cholera in each setting. Conclusions: Reactive vaccination campaigns using a single dose of OCV may avert more cases and deaths than a standard two-dose campaign when vaccine supplies are limited, while at the same time reducing logistical complexity. These findings should motivate consideration of the trade-offs between one- and two-dose campaigns in resource-constrained settings, though further field efficacy data are needed and should be a priority in any one-dose campaign. Modelling the efficacy of single-dose cholera vaccination in resource-limited settings.Background: Cholera—a bacterial gut infection caused by Vibrio cholerae—is a major global killer. Every year, epidemics (outbreaks) of cholera make 2 to 3 million people ill and kill about 100,000 people. People get cholera by eating food or drinking water contaminated with feces from an infected person, so cholera epidemics occur in places with poor sanitation such as slums and refugee camps. Earthquakes, floods, and other natural disasters that disrupt water and sanitation systems can also trigger cholera epidemics. Most people who become infected with V. cholerae have no or mild symptoms, but they may shed bacteria in their feces for up to two weeks. Other infected individuals develop severe diarrhea, producing profuse watery feces. The standard treatment for cholera is replacement of the fluids and salts lost through diarrhea by drinking an oral rehydration fluid or, in the worst cases, by fluid replacement directly into a vein. With prompt treatment, less than 1% of patients die, but untreated patients with severe cholera can die from dehydration within hours of developing symptoms. Why Was This Study Done?: The best way to control cholera is to ensure that everyone has access to safe water and good sanitation, but this is often impossible in poor countries, in refugee camps, or after natural disasters. In 2013, the World Health Organization created a global stockpile of an oral cholera vaccine (a preparation given by mouth that stimulates the immune system to attack V. cholerae) for use in cholera outbreaks. The licensed protocol for the currently stockpiled vaccine requires two doses of the vaccine to be given two weeks apart, but it can be difficult to ensure that everyone at risk of infection receives two doses. Moreover, the stockpile contains only one to two million doses of vaccine, which would have been insufficient to protect every individual at risk of infection in several recent cholera outbreaks. Here, the researchers use mathematical modeling to investigate whether one dose of oral cholera vaccine, rather than two doses, could be used to maximize the health impact of cholera vaccination and minimize logistical barriers to cholera vaccination during cholera outbreaks. What Did the Researchers Do and Find?: The researchers used cholera transmission models to determine the “minimum relative single-dose efficacy” (MRSE), the threshold at which single-dose vaccination campaigns begun after an outbreak has started (reactive vaccination) are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. The researchers report that, at the start of an epidemic, the MRSE is between 35% and 56%. That is, a single dose of vaccine must be at least 35%–56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine. By searching the literature, the researchers estimated that the short-term protection against infection provided by oral cholera vaccines is 77% for two doses and 44% for one dose—a one-dose relative efficacy of 57%, which is above the MRSE estimate. Finally, the researchers used their models to project that, in three recent cholera outbreaks, a single-dose campaign could have prevented between 1.1 and 1.2 times more cases of cholera than a two-dose campaign using the same amount of vaccine. What Do These Findings Mean?: The finding that the relative single-dose efficacy of oral cholera vaccination is above the estimated MRSE suggests that one-dose reactive vaccination campaigns might avert more cases and deaths than a standard two-dose campaign when vaccine supplies are limited. The accuracy of this and other study findings is limited, however, by the assumptions used to build the mathematical models and by the quality of the data used to run them. In particular, a lack of data on the efficacy of single-dose vaccination limits the ability to apply these findings. Thus, before one-dose campaigns are used widely, more data on the effectiveness on one-dose vaccination must be obtained. Notably, by increasing herd immunity (the vaccination of a significant portion of a population provides some protection for individuals in the population who have not been vaccinated), one-dose campaigns are likely to provide better population-level protection than two-dose campaigns. On the other hand, the individual who is given one rather than two vaccine doses is more vulnerable to cholera illness if exposed to cholera-causing bacteria. Strategies that balance the trade-off between individual- and population-level benefits must be carefully considered to ensure the best future use of the oral cholera vaccine stockpile. Moreover, every effort should be made to increase the size and availability of this stockpile. Additional Information: This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001867.