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.


All-or-Nothing Vaccination Model
With all-or-nothing vaccination θ 1 (i.e. VE) of the individuals vaccinated with dose 1 are expected to be 100% protected from infection. In this two-dose all-or-nothing model, we create states for unvaccinated (subscript 0), single-dose vaccinated (subscript 1), two-dose vaccinated (subscript 2). Only those individuals who have received a first dose are at risk of receiving a second dose. With the second vaccination, 1−θ2 1−θ1 of those unprotected from the first dose (S 1 ) remain unprotected moving to S 2 . The additional individuals protected per second dose given to an unprotected first dose recipient is: additional protected with second dose = total protected after 2-doses This model can be described by the following system of differential equations:

Susceptibility-Reducing Vaccine Model (V E S )
Our first leaky vaccine model (V E S ) reduces the risk of infection by θ · in all vaccinees. Figure S1-1 illustrates the model structure and flows between states; with circles representing states and edges representing rates of transition from one state to another.
Figure S1-1: Flow diagram of susceptibility-reducing vaccine model V E S Model The following system of equations describes the V E S vaccine model: The second leaky model considered reduces the probability (1 − θ · ) of an individual progressing to severe symptomatic disease required the addition of a mildly-symptomatic/asymptomatic class (A). This model is described by the system of ordinary differential equations below and additional parameters are shown in Table S1-2. Probability of asymptomatic infection without OCV 0 assumed κ Reduced infectiousness for asymptomatic/mildly symptomatic 0.9 assumed The following system of equations describes the leaky severity-reducing vaccine model:

Two-path Transmission Model
Cholera is thought to spread via two modes of transmission, a 'fast' route dominated by person-to-person transmission, and a 'slow' route where transmission is mediated through the environment. 5 The mix of these two modes help dictate the time course of the epidemic by modifying the generation time distribution (i.e. distribution of time between infector-infected pairs). In the primary analyses we consider a subset of this model where transmission is 100% fast. Here we also consider this full two-path model to explore the impact of varying contributions of environmentally mediated (slow) transmission. The slow path is conceptualized as a series of infectious compartments which leads to a gamma (Erlang) distributed infectious period ( Figure S1-2). Vaccine is implemented within this model as a leaky vaccine that reduces vaccinees susceptibility to infection (V E S ). Figure S1-2: Flow diagram of two-path model. Rates from infectious compartments shown as grey edges for visualization purposes.
The infectious period distribution was fit to empirical data on the survival of Vibrio cholerae (Figures S1-3 and S1-4) by minimizing the squared difference between the observations and the survival function of a gamma distribution. 6 We found the best fit to include three compartments (n slow = 3, see section Supplemental Text S4) each with a mean residence time of 7.5 days (γ = 1 7.5 See Supplemental Text S4).