Real-time dynamic modelling for the design of a cluster-randomized phase 3 Ebola vaccine trial in Sierra Leone.

BACKGROUND: Declining incidence and spatial heterogeneity complicated the design of phase 3 Ebola vaccine trials during the tail of the 2013-16 Ebola virus disease (EVD) epidemic in West Africa. Mathematical models can provide forecasts of expected incidence through time and can account for both vaccine efficacy in participants and effectiveness in populations. Determining expected disease incidence was critical to calculating power and determining trial sample size. METHODS: In real-time, we fitted, forecasted, and simulated a proposed phase 3 cluster-randomized vaccine trial for a prime-boost EVD vaccine in three candidate regions in Sierra Leone. The aim was to forecast trial feasibility in these areas through time and guide study design planning. RESULTS: EVD incidence was highly variable during the epidemic, especially in the declining phase. Delays in trial start date were expected to greatly reduce the ability to discern an effect, particularly as a trial with an effective vaccine would cause the epidemic to go extinct more quickly in the vaccine arm. Real-time updates of the model allowed decision-makers to determine how trial feasibility changed with time. CONCLUSIONS: This analysis was useful for vaccine trial planning because we simulated effectiveness as well as efficacy, which is possible with a dynamic transmission model. It contributed to decisions on choice of trial location and feasibility of the trial. Transmission models should be utilised as early as possible in the design process to provide mechanistic estimates of expected incidence, with which decisions about sample size, location, timing, and feasibility can be determined.

The social contact hypothesis under the assumption of endemic equilibrium: Elucidating the transmission potential of VZV in Europe.

The basic reproduction number R0 and the effective reproduction number R are pivotal parameters in infectious disease epidemiology, quantifying the transmission potential of an infection in a population. We estimate both parameters from 13 pre-vaccination serological data sets on varicella zoster virus (VZV) in 12 European countries and from population-based social contact surveys under the commonly made assumptions of endemic and demographic equilibrium. The fit to the serology is evaluated using the inferred effective reproduction number R as a model eligibility criterion combined with AIC as a model selection criterion. For only 2 out of 12 countries, the common choice of a constant proportionality factor is sufficient to provide a good fit to the seroprevalence data. For the other countries, an age-specific proportionality factor provides a better fit, assuming physical contacts lasting longer than 15 min are a good proxy for potential varicella transmission events. In all countries, primary infection with VZV most often occurs in early childhood, but there is substantial variation in transmission potential with R0 ranging from 2.8 in England and Wales to 7.6 in The Netherlands. Two non-parametric methods, the maximal information coefficient (MIC) and a random forest approach, are used to explain these differences in R0 in terms of relevant country-specific characteristics. Our results suggest an association with three general factors: inequality in wealth, infant vaccination coverage and child care attendance. This illustrates the need to consider fundamental differences between European countries when formulating and parameterizing infectious disease models.

Assessing the risk of measles resurgence in a highly vaccinated population: Belgium anno 2013.

Despite long-standing two-dose measles-mumps-rubella (MMR) vaccination, measles outbreaks still occur in highly vaccinated European populations. For instance, large measles outbreaks occurred in France (2008­13), the United Kingdom (2012­13) and the Netherlands (2012). Based on a multicohort model approach, using spatial serological survey data, MMR vaccination coverage data and data on social contacts, we found effective reproduction numbers significantly higher than 1 for measles in Belgium. This indicates that at one of the expected re-introductions, a measles outbreak is likely to spread, especially when it occurs during school term. The predicted average effective reproduction number increased over a 30-year time span from 1.3 to 2.2 and from 1.9 to 3.2 for basic reproduction numbers of 12 and 18, respectively. The expected relative measles incidence was highest in infants under one year of age, in adolescents and young adults. In conclusion, gradually increasing proportions of susceptible adolescents and young adults provide through their highly active social life an avenue for measles to resurge in large outbreaks upon re-introduction in Belgium, especially during school terms. Infants form an important vulnerable group during future measles outbreaks.

Maternal mumps antibodies in a cohort of children up to the age of 1 year.

UNLABELLED: The duration of the presence of maternal mumps antibodies in a prospective cohort study is presented. Immunoglobulin G against mumps was portioned with a commercial ELISA test (Euroimmun® anti-mumps Virus AT ELISA, Germany) on samples from 213 mother-child pairs at seven time points between pregnancy and 12 months of age. Non-linear mixed models were used to model maternal antibody decay in infants. The model-based median time to loss of antibodies was 3.6 months. The median child-specific time to loss of antibodies in children of naturally immune women (3.8 months) and children of vaccinated women (2.4 months) differed significantly (p = 0.025). The log antibody level of the mother and the log birth weight were correlated with the duration of maternal antibodies in infants (p < 0.0001). CONCLUSION: Children of vaccinated women loose maternal mumps antibodies significantly earlier in life compared to children of naturally infected women. If early administration (<12 months) of the combined measles, mumps, and rubella vaccine is needed, maternal mumps antibodies are not expected to interfere with infant humoral vaccine responses.