Molecular Infectious Disease Epidemiology: Survival Analysis and Algorithms Linking Phylogenies to Transmission Trees

Eben Kenah, Tom Britton, M. Elizabeth Halloran, Ira M. Longini Jr

PLoS Computational Biology

April 12, 2016

ABSTRACT

Recent work has attempted to use whole-genome sequence data from pathogens to reconstruct the transmission trees linking infectors and infectees in outbreaks. However, transmission trees from one outbreak do not generalize to future outbreaks. Reconstruction of transmission trees is most useful to public health if it leads to generalizable scientific insights about disease transmission. In a survival analysis framework, estimation of transmission parameters is based on sums or averages over the possible transmission trees. A phylogeny can increase the precision of these estimates by providing partial information about who infected whom. The leaves of the phylogeny represent sampled pathogens, which have known hosts. The interior nodes represent common ancestors of sampled pathogens, which have unknown hosts. Starting from assumptions about disease biology and epidemiologic study design, we prove that there is a one-to-one correspondence between the possible assignments of interior node hosts and the transmission trees simultaneously consistent with the phylogeny and the epidemiologic data on person, place, and time. We develop algorithms to enumerate these transmission trees and show these can be used to calculate likelihoods that incorporate both epidemiologic data and a phylogeny. A simulation study confirms that this leads to more efficient estimates of hazard ratios for infectiousness and baseline hazards of infectious contact, and we use these methods to analyze data from a foot-and-mouth disease virus outbreak in the United Kingdom in 2001. These results demonstrate the importance of data on individuals who escape infection, which is often overlooked. The combination of survival analysis and algorithms linking phylogenies to transmission trees is a rigorous but flexible statistical foundation for molecular infectious disease epidemiology.

Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses

William T. Harvey, Donald J. Benton, Victoria Gregory, James P. J. Hall, Rodney S. Daniels, Trevor Bedford, Daniel T. Haydon, Alan J. Hay, John W. McCauley, Richard Reeve 

PLoS Pathogens

April 8, 2016

ABSTRACT

Determining phenotype from genetic data is a fundamental challenge. Identification of emerging antigenic variants among circulating influenza viruses is critical to the vaccine virus selection process, with vaccine effectiveness maximized when constituents are antigenically similar to circulating viruses. Hemagglutination inhibition (HI) assay data are commonly used to assess influenza antigenicity. Here, sequence and 3-D structural information of hemagglutinin (HA) glycoproteins were analyzed together with corresponding HI assay data for former seasonal influenza A(H1N1) virus isolates (1997–2009) and reference viruses. The models developed identify and quantify the impact of eighteen amino acid substitutions on the antigenicity of HA, two of which were responsible for major transitions in antigenic phenotype. We used reverse genetics to demonstrate the causal effect on antigenicity for a subset of these substitutions. Information on the impact of substitutions allowed us to predict antigenic phenotypes of emerging viruses directly from HA gene sequence data and accuracy was doubled by including all substitutions causing antigenic changes over a model incorporating only the substitutions with the largest impact. The ability to quantify the phenotypic impact of specific amino acid substitutions should help refine emerging techniques that predict the evolution of virus populations from one year to the next, leading to stronger theoretical foundations for selection of candidate vaccine viruses. These techniques have great potential to be extended to other antigenically variable pathogens.

Differential and enhanced response to climate forcing in diarrheal disease due to rotavirus across a megacity of the developing world

Pamela P. Martinez, Aaron A. King, Mohammad Yunus, 
A. S. G. Faruque, Mercedes Pascual

Proceedings of the National Academy of Sciences

March 28, 2016

ABSTRACT

The role of climate forcing in the population dynamics of infectious diseases has typically been revealed via retrospective analyses of incidence records aggregated across space and, in particular, over whole cities. Here, we focus on the transmission dynamics of rotavirus, the main diarrheal disease in infants and young children, within the megacity of Dhaka, Bangladesh. We identify two zones, the densely urbanized core and the more rural periphery, that respond differentially to flooding. Moreover, disease seasonality differs substantially between these regions, spanning variation comparable to the variation from tropical to temperate regions. By combining process-based models with an extensive disease surveillance record, we show that the response to climate forcing is mainly seasonal in the core, where a more endemic transmission resulting from an asymptomatic reservoir facilitates the response to the monsoons. The force of infection in this monsoon peak can be an order of magnitude larger than the force of infection in the more epidemic periphery, which exhibits little or no postmonsoon outbreak in a pattern typical of nearby rural areas. A typically smaller peak during the monsoon season nevertheless shows sensitivity to interannual variability in flooding. High human density in the core is one explanation for enhanced transmission during troughs and an associated seasonal monsoon response in this diarrheal disease, which unlike cholera, has not been widely viewed as climate-sensitive. Spatial demographic, socioeconomic, and environmental heterogeneity can create reservoirs of infection and enhance the sensitivity of disease systems to climate forcing, especially in the populated cities of the developing world.

Transmission dynamics of Ebola virus disease and intervention effectiveness in Sierra Leone

Li-Qun Fang, Yang Yang, Jia-Fu Jiang, Hong-Wu Yao, David Kargbo, Xin-Lou Li, Bao-Gui Jiang, Brima Kargbo, Yi-Gang Tong, Ya-Wei Wang, Kun Liu, Abdul Kamara, Foday Dafae, Alex Kanu, Rui-Ruo Jiang, Ye Sun, Ruo-Xi Sun, Wan-Jun Chen, Mai-Juan Ma, Natalie E. Dean, Harold Thomas, Ira M. Longini, Jr., M. Elizabeth Halloran, Wu-Chun Cao

Proceedings of the National Academy of Sciences

March 28, 2016

abstract

Sierra Leone is the most severely affected country by an unprecedented outbreak of Ebola virus disease (EVD) in West Africa. Although successfully contained, the transmission dynamics of EVD and the impact of interventions in the country remain unclear. We established a database of confirmed and suspected EVD cases from May 2014 to September 2015 in Sierra Leone and mapped the spatiotemporal distribution of cases at the chiefdom level. A Poisson transmission model revealed that the transmissibility at the chiefdom level, estimated as the average number of secondary infections caused by a patient per week, was reduced by 43% [95% confidence interval (CI): 30%, 52%] after October 2014, when the strategic plan of the United Nations Mission for Emergency Ebola Response was initiated, and by 65% (95% CI: 57%, 71%) after the end of December 2014, when 100% case isolation and safe burials were essentially achieved, both compared with before October 2014. Population density, proximity to Ebola treatment centers, cropland coverage, and atmospheric temperature were associated with EVD transmission. The household secondary attack rate (SAR) was estimated to be 0.059 (95% CI: 0.050, 0.070) for the overall outbreak. The household SAR was reduced by 82%, from 0.093 to 0.017, after the nationwide campaign to achieve 100% case isolation and safe burials had been conducted. This study provides a complete overview of the transmission dynamics of the 2014−2015 EVD outbreak in Sierra Leone at both chiefdom and household levels. The interventions implemented in Sierra Leone seem effective in containing the epidemic, particularly in interrupting household transmission.

Using age-stratified incidence data to examine the transmission consequences of pertussis vaccination

J.C. Blackwood, D.A.T. Cummings, S. Iamsirithaworn, P. Rohani

Epidemics

March 19, 2016

ABSTRACT

Pertussis is a highly infectious respiratory disease that has been on the rise in many countries worldwide over the past several years. The drivers of this increase in pertussis incidence remain hotly debated, with a central and long-standing hypothesis that questions the ability of vaccines to eliminate pertussis transmission rather than simply modulate the severity of disease. In this paper, we present age-structured case notification data from all provinces of Thailand between 1981 and 2014, a period during which vaccine uptake rose substantially, permitting an evaluation of the transmission impacts of vaccination. Our analyses demonstrate decreases in incidence across all ages with increased vaccine uptake – an observation that is at odds with pertussis case notification data in a number of other countries. To explore whether these observations are consistent with a rise in herd immunity and a reduction in bacterial transmission, we analyze an age-structured model that incorporates contrasting hypotheses concerning the immunological and transmission consequences of vaccines. Our results lead us to conclude that the most parsimonious explanation for the combined reduction in incidence and the shift to older age groups in the Thailand data is vaccine-induced herd immunity.

Cooperation between distinct viral variants promotes growth of H3N2 influenza in cell culture

Katherine S Xue, Kathryn A Hooper, Anja R Ollodart, Adam S Dingens, Jesse D Bloom

eLIFE

March 15, 2016

ABSTRACT

RNA viruses rapidly diversify into quasispecies of related genotypes. This genetic diversity has long been known to facilitate adaptation, but recent studies have suggested that cooperation between variants might also increase population fitness. Here, we demonstrate strong cooperation between two H3N2 influenza variants that differ by a single mutation at residue 151 in neuraminidase, which normally mediates viral exit from host cells. Residue 151 is often annotated as an ambiguous amino acid in sequenced isolates, indicating mixed viral populations. We show that mixed populations grow better than either variant alone in cell culture. Pure populations of either variant generate the other through mutation and then stably maintain a mix of the two genotypes. We suggest that cooperation arises because mixed populations combine one variant’s proficiency at cell entry with the other’s proficiency at cell exit. Our work demonstrates a specific cooperative interaction between defined variants in a viral quasispecies.

Transmissibility and Pathogenicity of Ebola Virus: A Systematic Review and Meta-analysis of Household Secondary Attack Rate and Asymptomatic Infection

Natalie E. Dean, M. Elizabeth Halloran, Yang Yang, Ira M. Longini

Clinical Infectious Diseases

March 13, 2016

abstract

Factors affecting our ability to control an Ebola outbreak include transmissibility of the virus and the proportion of transmissions occurring asymptomatically. We performed a meta-analysis of Ebola household secondary attack rate (SAR), disaggregating by type of exposure (direct contact, no direct contact, nursing care, direct contact but no nursing care). The estimated overall household SAR is 12.5% (95% confidence interval [CI], 8.6%–16.3%). Transmission was driven by direct contact, with little transmission occurring in its absence (SAR, 0.8% [95% CI, 0%–2.3%]). The greatest risk factor was the provision of nursing care (SAR, 47.9% [95% CI, 23.3%–72.6%]). There was evidence of a decline in household SAR for direct contact between 1976 and 2014 (P = .018). We estimate that 27.1% (95% CI, 14.5%–39.6%) of Ebola infections are asymptomatic. Our findings suggest that surveillance and containment measures should be effective for controlling Ebola.

Prediction, dynamics, and visualization of antigenic phenotypes of seasonal influenza viruses

Richard A. Neher, Trevor Bedford, Rodney S. Daniels, Colin A. Russell, Boris I. Shraiman

Proceedings of the National Academy of Sciences

March 4, 2016

Abstract

Human seasonal influenza viruses evolve rapidly, enabling the virus population to evade immunity and re-infect previously infected individuals. Antigenic properties are largely determined by the surface glycoprotein hemagglutinin (HA) and amino acid substitutions at exposed epitope sites in HA mediate loss of recognition by antibodies. Here, we show that antigenic differences measured through serological assay data are well described by a sum of antigenic changes along the path connecting viruses in a phylogenetic tree. This mapping onto the tree allows prediction of antigenicity from HA sequence data alone. The mapping can further be used to make predictions about the makeup of the future seasonal influenza virus population, and we compare predictions between models with serological and sequence data. To make timely model output readily available, we developed a web browser based application that visualizes antigenic data on a continuously updated phylogeny.

Quantifying and mitigating the effect of preferential sampling on phylodynamic inference

Michael D. Karcher, Julia A. Palacios, Trevor Bedford, Marc A. Suchard, Vladimir N. Minin

PLOS Computational Biology

March 3, 2016

Abstract

Phylodynamics seeks to estimate effective population size fluctuations from molecular sequences of individuals sampled from a population of interest. One way to accomplish this task formulates an observed sequence data likelihood exploiting a coalescent model for the sampled individuals' genealogy and then integrating over all possible genealogies via Monte Carlo or, less efficiently, by conditioning on one genealogy estimated from the sequence data. However, when analyzing sequences sampled serially through time, current methods implicitly assume either that sampling times are fixed deterministically by the data collection protocol or that their distribution does not depend on the size of the population. Through simulation, we first show that, when sampling times do probabilistically depend on effective population size, estimation methods may be systematically biased. To correct for this deficiency, we propose a new model that explicitly accounts for preferential sampling by modeling the sampling times as an inhomogeneous Poisson process dependent on effective population size. We demonstrate that in the presence of preferential sampling our new model not only reduces bias, but also improves estimation precision. Finally, we compare the performance of the currently used phylodynamic methods with our proposed model through clinically-relevant, seasonal human influenza examples.

Hemagglutinin Gene Clade 3C.2a Influenza A(H3N2) Viruses, Alachua County, Florida, USA, 2014–15

John A. Lednicky, Nicole M. Iovine, Joe Brew, Julia C. Loeb, Jonathan D. Sugimoto, Kenneth H. Rand, J. Glenn Morris

Emerging Infectious Diseases

January 29, 2016

ABSTRACT

Influenza A(H3N2) strains isolated during 2014–15 in Alachua County, Florida, USA, belonged to hemagglutinin gene clade 3C.2a. High rates of influenza-like illness and confirmed influenza cases in children were associated with a decrease in estimated vaccine effectiveness. Illnesses were milder than in 2013–14; severe cases were concentrated in elderly patients with underlying diseases.

The pertussis enigma: reconciling epidemiology, immunology and evolution

Matthieu Domenech de Cellès, 
Felicia M. G. Magpantay, Aaron A. King, Pejman Rohani

Proceedings B
Royal Society Publishing

January 13, 2016

ABSTRACT

Pertussis, a highly contagious respiratory infection, remains a public health priority despite the availability of vaccines for 70 years. Still a leading cause of mortality in developing countries, pertussis has re-emerged in several developed countries with high vaccination coverage. Resurgence of pertussis in these countries has routinely been attributed to increased awareness of the disease, imperfect vaccinal protection or high infection rates in adults. In this review, we first present 1980–2012 incidence data from 63 countries and show that pertussis resurgence is not universal. We further argue that the large geographical variation in trends probably precludes a simple explanation, such as the transition from whole-cell to acellular pertussis vaccines. Reviewing available evidence, we then propose that prevailing views on pertussis epidemiology are inconsistent with both historical and contemporary data. Indeed, we summarize epidemiological evidence showing that natural infection and vaccination both appear to provide long-term protection against transmission and disease, so that previously infected or vaccinated adults contribute little to overall transmission at a population level. Finally, we identify several promising avenues that may lead to a consistent explanation of global pertussis epidemiology and to more effective control strategies.

Seasonality and the effectiveness of mass vaccination

Dennis L. Chao,  Dobromir T. Dimitrov

Mathematical Biosciences and Engineering

November, 2015

Abstract

Many infectious diseases have seasonal outbreaks, which may be driven by cyclical environmental conditions (e.g., an annual rainy season) or human behavior (e.g., school calendars or seasonal migration). If a pathogen is only transmissible for a limited period of time each year, then seasonal outbreaks could infect fewer individuals than expected given the pathogen's in-season transmissibility. Influenza, with its short serial interval and long season, probably spreads throughout a population until a substantial fraction of susceptible individuals are infected. Dengue, with a long serial interval and shorter season, may be constrained by its short transmission season rather than the depletion of susceptibles. Using mathematical modeling, we show that mass vaccination is most efficient, in terms of infections prevented per vaccine administered, at high levels of coverage for pathogens that have relatively long epidemic seasons, like influenza, and at low levels of coverage for pathogens with short epidemic seasons, like dengue. Therefore, the length of a pathogen's epidemic season may need to be considered when evaluating the costs and benefits of vaccination programs.

Cholera Outbreak in Grande Comore: 1998–1999

Christopher Troeger, Jean Gaudart, Romain Truillet, Kankoe Sallah, Dennis L. Chao, Renaud Piarroux

The American Journal of Tropical Medicine and Hygiene

November 16, 2015

Abstract

In 1998, a cholera epidemic in east Africa reached the Comoros Islands, an archipelago in the Mozambique Channel that had not reported a cholera case for more than 20 years. In just a little over 1 year (between January 1998 and March 1999), Grande Comore, the largest island in the Union of the Comoros, reported 7,851 cases of cholera, about 3% of the population. Using case reports and field observations during the medical response, we describe the epidemiology of the 1998–1999 cholera epidemic in Grande Comore. Outbreaks of infectious diseases on islands provide a unique opportunity to study transmission dynamics in a nearly closed population, and they may serve as stepping-stones for human pathogens to cross unpopulated expanses of ocean.

Cholera Transmission in Ouest Department of Haiti: Dynamic Modeling and the Future of the Epidemic

Alexander Kirpich, Thomas A. Weppelmann, Yang Yang, Afsar Ali, J. Glenn Morris Jr., Ira M. Longini

PLOS Neglected Tropical Diseases

October 21, 2015

Abstract

In the current study, a comprehensive, data driven, mathematical model for cholera transmission in Haiti is presented. Along with the inclusion of short cycle human-to-human transmission and long cycle human-to-environment and environment-to-human transmission, this novel dynamic model incorporates both the reported cholera incidence and remote sensing data from the Ouest Department of Haiti between 2010 to 2014. The model has separate compartments for infectious individuals that include different levels of infectivity to reflect the distribution of symptomatic and asymptomatic cases in the population. The environmental compartment, which serves as a source of exposure to toxigenic V. cholerae, is also modeled separately based on the biology of causative bacterium, the shedding of V. cholerae O1 by humans into the environment, as well as the effects of precipitation and water temperature on the concentration and survival of V. cholerae in aquatic reservoirs. Although the number of reported cholera cases has declined compared to the initial outbreak in 2010, the increase in the number of susceptible population members and the presence of toxigenic V. cholerae in the environment estimated by the model indicate that without further improvements to drinking water and sanitation infrastructures, intermittent cholera outbreaks are likely to continue in Haiti.

The role of influenza in the epidemiology of pneumonia

Sourya Shrestha, Betsy Foxman, Joshua Berus, Willem G. van Panhuis, Claudia Steiner, Cécile Viboud, Pejman Rohani

NATURE Scientific Reports

October 21, 2015

ABSTRACT

Interactions arising from sequential viral and bacterial infections play important roles in the epidemiological outcome of many respiratory pathogens. Influenza virus has been implicated in the pathogenesis of several respiratory bacterial pathogens commonly associated with pneumonia. Though clinical evidence supporting this interaction is unambiguous, its population-level effects—magnitude, epidemiological impact and variation during pandemic and seasonal outbreaks—remain unclear. To address these unknowns, we used longitudinal influenza and pneumonia incidence data, at different spatial resolutions and across different epidemiological periods, to infer the nature, timing and the intensity of influenza-pneumonia interaction. We used a mechanistic transmission model within a likelihood-based inference framework to carry out formal hypothesis testing. Irrespective of the source of data examined, we found that influenza infection increases the risk of pneumonia by ~100-fold. We found no support for enhanced transmission or severity impact of the interaction. For model-validation, we challenged our fitted model to make out-of-sample pneumonia predictions during pandemic and non-pandemic periods. The consistency in our inference tests carried out on several distinct datasets, and the predictive skill of our model increase confidence in our overall conclusion that influenza infection substantially enhances the risk of pneumonia, though only for a short period.

The effects of a deleterious mutation load on patterns of influenza A/H3N2’s antigenic evolution in humans

 Katia Koelle, David A. Rasmussen

eLife

September 15, 2015

ABSTRACT

Recent phylogenetic analyses indicate that RNA virus populations carry a significant deleterious mutation load. This mutation load has the potential to shape patterns of adaptive evolution via genetic linkage to beneficial mutations. Here, we examine the effect of deleterious mutations on patterns of influenza A subtype H3N2’s antigenic evolution in humans. By first analyzing simple models of influenza that incorporate a mutation load, we show that deleterious mutations, as expected, act to slow the virus’s rate of antigenic evolution, while making it more punctuated in nature. These models further predict three distinct molecular pathways by which antigenic cluster transitions occur, and we find phylogenetic patterns consistent with each of these pathways in influenza virus sequences. Simulations of a more complex phylodynamic model further indicate that antigenic mutations act in concert with deleterious mutations to reproduce influenza’s spindly hemagglutinin phylogeny, co-circulation of antigenic variants, and high annual attack rates. 

Epidemic processes in complex networks

Romualdo Pastor-Satorras, Claudio Castellano, Piet Van Mieghem, Alessandro Vespignani

Reviews of Modern Physics

August 31, 2015

Abstract

In recent years the research community has accumulated overwhelming evidence for the emergence of complex and heterogeneous connectivity patterns in a wide range of biological and sociotechnical systems. The complex properties of real-world networks have a profound impact on the behavior of equilibrium and nonequilibrium phenomena occurring in various systems, and the study of epidemic spreading is central to our understanding of the unfolding of dynamical processes in complex networks. The theoretical analysis of epidemic spreading in heterogeneous networks requires the development of novel analytical frameworks, and it has produced results of conceptual and practical relevance. A coherent and comprehensive review of the vast research activity concerning epidemic processes is presented, detailing the successful theoretical approaches as well as making their limits and assumptions clear. Physicists, mathematicians, epidemiologists, computer, and social scientists share a common interest in studying epidemic spreading and rely on similar models for the description of the diffusion of pathogens, knowledge, and innovation. For this reason, while focusing on the main results and the paradigmatic models in infectious disease modeling, the major results concerning generalized social contagion processes are also presented. Finally, the research activity at the forefront in the study of epidemic spreading in coevolving, coupled, and time-varying networks is reported.

Positive selection in CD8+ T-cell epitopes of influenza nucleoprotein revealed by a comparative analysis of human and swine viral lineages

Heather M. Machkovech, Trevor Bedford, Marc A. Suchard, Jesse D. Bloom

Journal of Virology

August 26, 2015

ABSTRACT

Numerous experimental studies have demonstrated that CD8+ T-cells contribute to immunity against influenza by limiting viral replication. It is therefore surprising that rigorous statistical tests have failed to find evidence of positive selection in the epitopes targeted by CD8+ T-cells. Here we use a novel computational approach to test for selection in CD8+ T-cell epitopes. We define all epitopes in the nucleoprotein (NP) and matrix protein (M1) with experimentally identified human CD8+ T-cell responses, and then compare the evolution of these epitopes in parallel lineages of human and swine influenza that have been diverging since roughly 1918. We find a significant enrichment of substitutions that alter human CD8+ T-cell epitopes in the NP of human versus swine influenza, consistent with the idea that these epitopes are under positive selection. Furthermore, we show that epitope-altering substitutions to human influenza NP are enriched on the trunk versus the branches of the phylogenetic tree, indicating that viruses that acquire these mutations have a selective advantage. However, even in human influenza NP, sites in T-cell epitopes evolve more slowly than non-epitope sites, presumably because these epitopes are under higher inherent functional constraint. Overall, our work demonstrates that there is clear selection from CD8+ T-cells in human influenza NP, and illustrates how comparative analyses of viral lineages from different hosts can identify positive selection that is otherwise obscured by strong functional constraint.

Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial

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

the Lancet

July 31, 2015

Summary

Background A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa.

The ring vaccination trial: a novel cluster randomised controlled trial design to evaluate vaccine efficacy and effectiveness during outbreaks, with special reference to Ebola

Anton Camacho, Miles W Carroll, Natalie E Dean, Moussa Doumbia, W John Edmunds, Matthias Egger, Godwin Enwere, Yper Hall, Ana Maria Henao-Restrepo, Stefanie Hossman, Sakoba Keita, Mandy Kader Kondé, Ira M Longini, Sema Mandal, Gunnstein Norheim, Ximena Riveros, John-Arne Røttingen, Sven Trelle, Andrea S Vicari, Sara V Watle, Conall H Watson

BMJ

July 27, 2015

Abstract

A World Health Organization expert meeting on Ebola vaccines proposed urgent safety and efficacy studies in response to the outbreak in West Africa. One approach to communicable disease control is ring vaccination of individuals at high risk of infection due to their social or geographical connection to a known case. This paper describes the protocol for a novel cluster randomised controlled trial design which uses ring vaccination.

In the Ebola ça suffit ring vaccination trial, rings are randomised 1:1 to (a) immediate vaccination of eligible adults with single dose vaccination or (b) vaccination delayed by 21 days. Vaccine efficacy against disease is assessed in participants over equivalent periods from the day of randomisation. Secondary objectives include vaccine effectiveness at the level of the ring, and incidence of serious adverse events.

Ring vaccination trials are adaptive, can be run until disease elimination, allow interim analysis, and can go dormant during inter-epidemic periods.