Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!)

Ana Maria Henao-Restrepo, Anton Camacho, Ira M Longini, Conall H Watson, W John Edmunds, Matthias Egger, Miles W Carroll, Natalie E Dean, Ibrahima Diatta, Moussa Doumbia, Bertrand Draguez, Sophie Duraff our, Godwin Enwere, Rebecca Grais, Stephan Gunther, Pierre-Stéphane Gsell, Stefanie Hossmann, Sara Viksmoen Watle, Mandy Kader Kondé, Sakoba Kéïta, Souleymane Kone, Eewa Kuisma, Myron M Levine, Sema Mandal, Thomas Mauget, Gunnstein Norheim, Ximena Riveros, Aboubacar Soumah, Sven Trelle, Andrea S Vicari, John-Arne Røttingen, Marie-Paule Kieny


December 23, 2016



rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa.

The Long-Term Safety, Public Health Impact, and Cost-Effectiveness of Routine Vaccination with a Recombinant, Live-Attenuated Dengue Vaccine (Dengvaxia): A Model Comparison Study

Stefan Flasche, Mark Jit, Isabel Rodrıguez-Barraquer, Laurent Coudeville, Mario Recker, Katia Koelle, George Milne, Thomas J. Hladish, T. Alex Perkins, Derek A. T. Cummings, Ilaria Dorigatti, Daniel J. Laydon, Guido España, Joel Kelso, Ira Longini, Jose Lourenco, Carl A. B. Pearson, Robert C. Reiner, Luis Mier-y-Teran-Romero, Kirsten Vannice, Neil Ferguson

PLOS Medicine

November 29, 2016



Large Phase III trials across Asia and Latin America have recently demonstrated the efficacy of a recombinant, live-attenuated dengue vaccine (Dengvaxia) over the first 25 mo following vaccination. Subsequent data collected in the longer-term follow-up phase, however, have raised concerns about a potential increase in hospitalization risk of subsequent dengue infections, in particular among young, dengue-naïve vaccinees. We here report predictions from eight independent modelling groups on the long-term safety, public health impact, and cost-effectiveness of routine vaccination with Dengvaxia in a range of transmission settings, as characterised by seroprevalence levels among 9-y-olds (SP9). These predictions were conducted for the World Health Organization to inform their recommendations on optimal use of this vaccine.

Methods and Findings

The models adopted, with small variations, a parsimonious vaccine mode of action that was able to reproduce quantitative features of the observed trial data. The adopted mode of action assumed that vaccination, similarly to natural infection, induces transient, heterologous protection and, further, establishes a long-lasting immunogenic memory, which determines disease severity of subsequent infections. The default vaccination policy considered was routine vaccination of 9-y-old children in a three-dose schedule at 80% coverage. The outcomes examined were the impact of vaccination on infections, symptomatic dengue, hospitalised dengue, deaths, and cost-effectiveness over a 30-y postvaccination period. Case definitions were chosen in accordance with the Phase III trials.

All models predicted that in settings with moderate to high dengue endemicity (SP9 ≥ 50%), the default vaccination policy would reduce the burden of dengue disease for the population by 6%–25% (all simulations: –3%–34%) and in high-transmission settings (SP9 ≥ 70%) by 13%–25% (all simulations: 10%– 34%). These endemicity levels are representative of the participating sites in both Phase III trials. In contrast, in settings with low transmission intensity (SP9 ≤ 30%), the models predicted that vaccination could lead to a substantial increase in hospitalisation because of dengue. Modelling reduced vaccine coverage or the addition of catch-up campaigns showed that the impact of vaccination scaled approximately linearly with the number of people vaccinated. In assessing the optimal age of vaccination, we found that targeting older children could increase the net benefit of vaccination in settings with moderate transmission intensity (SP9 = 50%). Overall, vaccination was predicted to be potentially cost-effective in most endemic settings if priced competitively.

The results are based on the assumption that the vaccine acts similarly to natural infection. This assumption is consistent with the available trial results but cannot be directly validated in the absence of additional data. Furthermore, uncertainties remain regarding the level of protection provided against disease versus infection and the rate at which vaccine-induced protection declines.


Dengvaxia has the potential to reduce the burden of dengue disease in areas of moderate to high dengue endemicity. However, the potential risks of vaccination in areas with limited exposure to dengue as well as the local costs and benefits of routine vaccination are important considerations for the inclusion of Dengvaxia into existing immunisation programmes. These results were important inputs into WHO global policy for use of this licensed dengue vaccine.

Climate-driven endemic cholera is modulated by human mobility in a megacity

Javier Perez-Saez, Aaron A. King, Andrea Rinaldoa, Mohammad Yunus, Abu S.G. Faruquec, 
Mercedes Pascual

Advances in Water Resources

November 27, 2016


Although a differential sensitivity of cholera dynamics to climate variability has been reported in the spatially heterogeneous megacity of Dhaka, Bangladesh, the specific patterns of spread of the resulting risk within the city remain unclear. We build on an established probabilistic spatial model to investigate the importance and role of human mobility in modulating spatial cholera transmission. Mobility fluxes were inferred using a straightforward and generalizable methodology that relies on mapping population density based on a high resolution urban footprint product, and a parameter-free human mobility model. In accordance with previous findings, we highlight the higher sensitivity to the El Niño Southern Oscillation (ENSO) in the highly populated urban center than in the more rural periphery. More significantly, our results show that cholera risk is largely transmitted from the climate-sensitive core to the periphery of the city, with implications for the planning of control efforts. In addition, including human mobility improves the outbreak prediction performance of the model with an 11 month lead. The interplay between climatic and human mobility factors in cholera transmission is discussed from the perspective of the rapid growth of megacities across the developing world.

phylodyn: an R package for phylodynamic simulation and inference

Michael D. Karcher, Julia A. Palacios, Shiwei Lan, Vladimir N. Minin

Molecular Ecology Resources

November 21, 2016


We introduce phylodyn, an r package for phylodynamic analysis based on gene genealogies. The package's main functionality is Bayesian nonparametric estimation of effective population size fluctuations over time. Our implementation includes several Markov chain Monte Carlo-based methods and an integrated nested Laplace approximation-based approach for phylodynamic inference that have been developed in recent years. Genealogical data describe the timed ancestral relationships of individuals sampled from a population of interest. Here, individuals are assumed to be sampled at the same point in time (isochronous sampling) or at different points in time (heterochronous sampling); in addition, sampling events can be modelled with preferential sampling, which means that the intensity of sampling events is allowed to depend on the effective population size trajectory. We assume the coalescent and the sequentially Markov coalescent processes as generative models of genealogies. We include several coalescent simulation functions that are useful for testing our phylodynamics methods via simulation studies. We compare the performance and outputs of various methods implemented in phylodyn and outline their strengths and weaknesses. r package phylodyn is available at https://github.com/mdkarcher/phylodyn.

Drivers of Inter-individual Variation in Dengue Viral Load Dynamics

Rotem Ben-Shachar, Scott Schmidler, Katia Koelle

PLOS Computational Biology

November 17, 2016


Dengue is a vector-borne viral disease of humans that endemically circulates in many tropical and subtropical regions worldwide. Infection with dengue can result in a range of disease outcomes. A considerable amount of research has sought to improve our understanding of this variation in disease outcomes and to identify predictors of severe disease. Contributing to this research, patterns of viral load in dengue infected patients have been quantified, with analyses indicating that peak viral load levels, rates of viral load decline, and time to peak viremia are useful predictors of severe disease. Here, we take a complementary approach to understanding patterns of clinical manifestation and inter-individual variation in viral load dynamics. Specifically, we statistically fit mathematical within-host models of dengue to individual-level viral load data to test virological and immunological hypotheses explaining inter-individual variation in dengue viral load. We choose between alternative models using model selection criteria to determine which hypotheses are best supported by the data. We first show that the cellular immune response plays an important role in regulating viral load in secondary dengue infections. We then provide statistical support for the process of antibody-dependent enhancement (but not original antigenic sin) in the development of severe disease in secondary dengue infections. Finally, we show statistical support for serotype-specific differences in viral infectivity rates, with infectivity rates of dengue serotypes 2 and 3 exceeding those of serotype 1. These results contribute to our understanding of dengue viral load patterns and their relationship to the development of severe dengue disease. They further have implications for understanding how dengue transmissibility may depend on the immune status of infected individuals and the identity of the infecting serotype.

Cholera in Cameroon, 2000-2012: Spatial and Temporal Analysis at the Operational (Health District) and Sub Climate Levels

Moise C. Ngwa, Song Liang, Ian T. Kracalik, Lillian Morris, Jason K. Blackburn, Leonard M. Mbam, Simon Franky Baonga Ba Pouth, Andrew Teboh, Yang Yang, Mouhaman Arabi, Jonathan D. Sugimoto, John Glenn Morris, Jr.

PLOS Neglected Tropical Diseases

November 17, 2016



Recurrent cholera outbreaks have been reported in Cameroon since 1971. However, case fatality ratios remain high, and we do not have an optimal understanding of the epidemiology of the disease, due in part to the diversity of Cameroon’s climate subzones and a lack of comprehensive data at the health district level.


A unique health district level dataset of reported cholera case numbers and related deaths from 2000–2012, obtained from the Ministry of Public Health of Cameroon and World Health Organization (WHO) country office, served as the basis for the analysis. During this time period, 43,474 cholera cases were reported: 1748 were fatal (mean annual case fatality ratio of 7.9%), with an attack rate of 17.9 reported cases per 100,000 inhabitants per year. Outbreaks occurred in three waves during the 13-year time period, with the highest case fatality ratios at the beginning of each wave. Seasonal patterns of illness differed strikingly between climate subzones (Sudano-Sahelian, Tropical Humid, Guinea Equatorial, and Equatorial Monsoon). In the northern Sudano-Sahelian subzone, highest number of cases tended to occur during the rainy season (July-September). The southern Equatorial Monsoon subzone reported cases year-round, with the lowest numbers during peak rainfall (July-September). A spatial clustering analysis identified multiple clusters of high incidence health districts during 2010 and 2011, which were the 2 years with the highest annual attack rates. A spatiotemporal autoregressive Poisson regression model fit to the 2010–2011 data identified significant associations between the risk of transmission and several factors, including the presence of major waterbody or highway, as well as the average daily maximum temperature and the precipitation levels over the preceding two weeks. The direction and/or magnitude of these associations differed between climate subzones, which, in turn, differed from national estimates that ignored subzones differences in climate variables.


The epidemiology of cholera in Cameroon differs substantially between climate subzones. Development of an optimal comprehensive country-wide control strategy for cholera requires an understanding of the impact of the natural and built environment on transmission patterns at the local level, particularly in the setting of ongoing climate change.

Forecasting Epidemiological Consequences of Maternal Immunization

Ana I. Bento and Pejman Rohani

Clinical Infectious Diseases

December 1, 2016


Background. The increase in the incidence of whooping cough (pertussis) in many countries with high vaccination coverage is alarming. Maternal pertussis immunization has been proposed as an effective means of protecting newborns during the interval between birth and the first routine dose. However, there are concerns regarding potential interference between maternal antibodies and the immune response elicited by the routine schedule, with possible long-term population-level effects.

Methods. We formulated a transmission model comprising both primary routine and maternal immunization. This model was examined to evaluate the long-term epidemiological effects of routine and maternal immunization, together with consequences of potential immune interference scenarios.

Results. Overall, our model demonstrates that maternal immunization is an effective strategy in reducing the incidence of pertussis in neonates prior to the onset of the primary schedule. However, if maternal antibodies lead to blunting, incidence increases among older age groups. For instance, our model predicts that with 60% routine and maternal immunization coverage and 30% blunting, the incidence among neonates (0–2 months) is reduced by 43%. Under the same scenario, we observe a 20% increase in incidence among children aged 5–10 years. However, the downstream increase in the older age groups occurs with a delay of approximately a decade or more.

Conclusions. Maternal immunization has clear positive effects on infant burden of disease, lowering mean infant incidence. However, if maternally derived antibodies adversely affect the immunogenicity of the routine schedule, we predict eventual population-level repercussions that may lead to an overall increase in incidence in older age groups.

Containing Ebola at the Source with Ring Vaccination

Stefano Merler, Marco Ajelli, Laura Fumanelli, Stefano Parlamento, Ana Pastore y Piontti, Natalie E. Dean, Giovanni Putoto, Dante Carraro, Ira M. Longini Jr.,
M. Elizabeth Halloran, Alessandro Vespignani

PLOS Neglected Tropical Diseases

November 2, 2016


Interim results from the Guinea Ebola ring vaccination trial suggest high efficacy of the rVSV-ZEBOV vaccine. These findings open the door to the use of ring vaccination strategies in which the contacts and contacts of contacts of each index case are promptly vaccinated to contain future Ebola virus disease outbreaks. To provide a numerical estimate of the effectiveness of ring vaccination strategies we introduce a spatially explicit agent-based model to simulate Ebola outbreaks in the Pujehun district, Sierra Leone, structurally similar to previous modelling approaches. We find that ring vaccination can successfully contain an outbreak for values of the effective reproduction number up to 1.6. Through an extensive sensitivity analysis of parameters characterising the readiness and capacity of the health care system, we identify interventions that, alongside ring vaccination, could increase the likelihood of containment. In particular, shortening the time from symptoms onset to hospitalisation to 2–3 days on average through improved contact tracing procedures, adding a 2km spatial component to the vaccination ring, and decreasing human mobility by quarantining affected areas might contribute increase our ability to contain outbreaks with effective reproduction number up to 2.6. These results have implications for future control of Ebola and other emerging infectious disease threats.