Fractional Dosing of Yellow Fever Vaccine to Extend Supply: A Modeling Study

Background: The ongoing yellow fever (YF) epidemic in Angola strains the global vaccine supply, prompting WHO to adopt dose sparing for its vaccination campaign in Kinshasa in July–August 2016. Although a 5-fold fractional-dose vaccine is similar to standard-dose vaccine in safety and immunogenicity, efficacy is untested. There is an urgent need to ensure the robustness of fractional-dose vaccination by elucidating the conditions under which dose fractionation would reduce transmission. Methods: We estimate the effective reproductive number for YF in Angola using disease natural history and case report data. With simple mathematical models of YF transmission, we calculate the infection attack rate (IAR, the proportion of population infected over the course of an epidemic) under varying levels of transmissibility and five-fold fractional-dose vaccine efficacy for two vaccination scenarios: (i) random vaccination in a hypothetical population that is completely susceptible; (ii) the Kinshasa vaccination campaign in July–August 2016 with different age cutoff for fractional-dose vaccines. Findings: We estimate the effective reproductive number early in the Angola outbreak was between 5·2 and 7·1. If vaccine action is all-or-nothing (i.e. a proportion VE of vaccinees receives complete and the remainder receive no protection), n-fold fractionation can dramatically reduce IAR as long as efficacy VE exceeds 1/n. This benefit threshold becomes more stringent if vaccine action is leaky (i.e. the susceptibility of each vaccinee is reduced by a factor that is equal to the vaccine efficacy VE). The age cutoff for fractional-dose vaccines chosen by the WHO for the Kinshasa vaccination campaign (namely, 2 years) provides the largest reduction in IAR if the efficacy of five-fold fractional-dose vaccines exceeds 20%. Interpretation Dose fractionation is a very effective strategy for reducing infection attack rate that would be robust with a large margin for error in case fractional-dose VE is lower than expected

Prolonging herd immunity to cholera via vaccination: Accounting for human mobility and waning vaccine effects

Background: Oral cholera vaccination is an approach to preventing outbreaks in at-risk settings and controlling cholera in endemic settings. However, vaccine-derived herd immunity may be short-lived due to interactions between human mobility and imperfect or waning vaccine efficacy. As the supply and utilization of oral cholera vaccines grows, critical questions related to herd immunity are emerging, including: who should be targeted; when should revaccination be performed; and why have cholera outbreaks occurred in recently vaccinated populations? Methods and findings We use mathematical models to simulate routine and mass oral cholera vaccination in populations with varying degrees of migration, transmission intensity, and vaccine coverage. We show that migration and waning vaccine efficacy strongly influence the duration of herd immunity while birth and death rates have relatively minimal impacts. As compared to either periodic mass vaccination or routine vaccination alone, a community could be protected longer by a blended “Mass and Maintain” strategy. We show that vaccination may be best targeted at populations with intermediate degrees of mobility as compared to communities with very high or very low population turnover. Using a case study of an internally displaced person camp in South Sudan which underwent high-coverage mass vaccination in 2014 and 2015, we show that waning vaccine direct effects and high population turnover rendered the camp over 80% susceptible at the time of the cholera outbreak beginning in October 2016. Conclusions: Oral cholera vaccines can be powerful tools for quickly protecting a population for a period of time that depends critically on vaccine coverage, vaccine efficacy over time, and the rate of population turnover through human mobility. Due to waning herd immunity, epidemics in vaccinated communities are possible but become less likely through complementary interventions or data-driven revaccination strategies

Revaccination strategies to maximize duration of herd immunity (DHI).

<p>(<b>A</b>) Recurring mass vaccination events (arrows) with 100% coverage of susceptible people every year (dashed line) or two years (dotted line) is shown to periodically achieve then lose herd immunity, designated by the horizontal line at <i>R</i>_<i>e</i> = 1. Faded horizontal bars show times with herd immunity under each strategy and the total DHI is annotated to the right of each. (<b>B</b>) Routine vaccination of 2.4% (green), 3.6% (teal), or 4.8% (purple) of the population per month achieve herd immunity for 0, 4.4, and 4.3 years, respectively. (<b>C</b>) A “Mass and Maintain” strategy with one-time vaccination at 75% coverage followed by routine vaccination of 2.4% (green), 3.6% (teal), or 4.8% (purple) of the population per month can render herd immunity for 1.6, 5.2, and 4.3 years, respectively. The following are held constant for all simulations: population size = 10,000; maximum vaccine courses = 30,000; <i>R</i>₀ = 1.5; migration rate = ; and birth and death rates = .</p

Vaccine targeting optimized in settings with intermediate rates of migration.

<p>Vaccine impact, as measured by the difference in the cumulative probability of an outbreak comparing a mass kOCV campaign (coverage 100%) versus no vaccination, is shown to reach maxima (triangles) at intermediate levels of mobility (x axis). The time since vaccination (colored lines) modifies these maxima. Grey dashed lines denote the estimated migration rates for Calcutta, Bentiu PoC Camp, and Dhaka. In this example, <i>R</i>₀ = 1.5 and the average probability that a migrant is infected is 1/<i>N</i>, where <i>N</i> is the population size.</p

Relative contribution of four potential drivers of waning herd immunity in Bentiu PoC Camp.

<p>Relative contribution of four potential drivers of waning herd immunity in Bentiu PoC Camp.</p

Dynamics of population susceptibility and herd immunity.

<p>Dynamics following mass vaccination (100% coverage) with kOCV (left column) or a hypothetical vaccine with VE = 1 indefinitely (right column). (<b>A-B</b>) Population susceptibility increases over time in the presence of migration rates of (solid line), (dashed line), and zero (dotted). (<b>C-D</b>) The effective reproductive number changes over time with X(t) differently for settings with basic reproductive numbers of 2 (red), 1.5 (green), and 1 (blue). (<b>E-F</b>) The probability that a single case sparks an outbreak of more than 10 cases. Birth and death rates are set to zero in each simulation.</p

Bentiu PoC Camp case study.

<p>(<b>A</b>) Reported population size of the Bentiu PoC Camp (blue line), approximate number of people vaccinated assuming two-dose coverage (green bars), and monthly case counts from October to January (inset grey bars). IOM began reporting entries and exits in December 2015, which are represented by the faint green and red ribbons around the blue line. (<b>B</b>) The proportion susceptible over time (green line) decreases due to mass vaccination events and increases over time since vaccination. (<b>C</b>) The probability that a single case sparks an outbreak of more than 10 cases increases with <i>X</i>(<i>t</i>) and R₀, as represented by line color: R₀ = 1 (blue); 1.5 (green); 1.8 (black); and 2 (red). For reference, R_e = 0 yields an outbreak probability of 0; R_e = 1.01 yields a probability of 0.25; R_e = 1.35 yields a probability of 0.50; R_e = 1.84 yields a probability of 0.75; and R_e>4.66 yields an outbreak probability over 99%.</p

Incubation periods impact the spatial predictability of cholera and Ebola outbreaks in Sierra Leone

Forecasting the spatiotemporal spread of infectious diseases during an outbreak is an important component of epidemic response. However, it remains challenging both methodologically and with respect to data requirements, as disease spread is influenced by numerous factors, including the pathogen’s underlying transmission parameters and epidemiological dynamics, social networks and population connectivity, and environmental conditions. Here, using data from Sierra Leone, we analyze the spatiotemporal dynamics of recent cholera and Ebola outbreaks and compare and contrast the spread of these two pathogens in the same population. We develop a simulation model of the spatial spread of an epidemic in order to examine the impact of a pathogen’s incubation period on the dynamics of spread and the predictability of outbreaks. We find that differences in the incubation period alone can determine the limits of predictability for diseases with different natural history, both empirically and in our simulations. Our results show that diseases with longer incubation periods, such as Ebola, where infected individuals can travel farther before becoming infectious, result in more long-distance sparking events and less predictable disease trajectories, as compared to the more predictable wave-like spread of diseases with shorter incubation periods, such as cholera.This work was supported by Award U54GM088558 from the National Institute of General Medical Sciences.Peer reviewe