Showing papers by "M. Elizabeth Halloran published in 2017"
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TL;DR: Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, it is shown that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers, which has major implications for vaccines against flaviviruses.
Abstract: For dengue viruses 1 to 4 (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern.
721 citations
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Broad Institute1, Massachusetts Institute of Technology2, Harvard University3, National Institutes of Health4, Oswaldo Cruz Foundation5, Florida State University College of Arts and Sciences6, Florida Department of Health7, University of the West Indies8, Universidad Nacional Autónoma de Honduras9, Industrial University of Santander10, University of Florida11, Massachusetts Department of Public Health12, Scripps Research Institute13, Scripps Health14, University of Edinburgh15, University of Washington16, Fred Hutchinson Cancer Research Center17, University of Córdoba (Spain)18, Michigan State University19
TL;DR: It is found that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections.
Abstract: Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention, much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections We identify mutations with possible functional implications for ZIKV biology and pathogenesis, as well as those that might be relevant to the effectiveness of diagnostic tests
304 citations
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TL;DR: A data-driven global stochastic epidemic model is used to analyze the spread of the Zika virus (ZIKV) in the Americas and it can be potentially used as a template for the analysis of future mosquito-borne epidemics.
Abstract: We use a data-driven global stochastic epidemic model to analyze the spread of the Zika virus (ZIKV) in the Americas. The model has high spatial and temporal resolution and integrates real-world demographic, human mobility, socioeconomic, temperature, and vector density data. We estimate that the first introduction of ZIKV to Brazil likely occurred between August 2013 and April 2014 (90% credible interval). We provide simulated epidemic profiles of incident ZIKV infections for several countries in the Americas through February 2017. The ZIKV epidemic is characterized by slow growth and high spatial and seasonal heterogeneity, attributable to the dynamics of the mosquito vector and to the characteristics and mobility of the human populations. We project the expected timing and number of pregnancies infected with ZIKV during the first trimester and provide estimates of microcephaly cases assuming different levels of risk as reported in empirical retrospective studies. Our approach represents a modeling effort aimed at understanding the potential magnitude and timing of the ZIKV epidemic and it can be potentially used as a template for the analysis of future mosquito-borne epidemics.
273 citations
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University of Washington1, University of Turku2, George Washington University3, University of Minnesota4, University of Georgia5, University of California, Los Angeles6, Mahidol University7, Harvard University8, Johns Hopkins University9, Washington State University10, University of Florida11, World Bank12, University of Basel13, Swiss Tropical and Public Health Institute14, Northeastern University15, University of London16, Public Health England17
TL;DR: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials.
Abstract: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods. Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects. Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials.
64 citations
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TL;DR: The two-dose HRV rotavirus vaccination program significantly reduced medically attended ARD in this low-resource population in Asia and was an open-label study with an observed-only control group (no placebo).
Abstract: Background
Rotavirus vaccines are now globally recommended by the World Health Organization (WHO), but in early 2009 WHO’s Strategic Advisory Group of Experts on Immunization reviewed available data and concluded that there was no evidence for the efficacy or effectiveness of a two-dose schedule of the human rotavirus vaccine (HRV; Rotarix) given early at 6 and 10 wk of age. Additionally, the effectiveness of programmatic rotavirus vaccination, including possible indirect effects, has not been assessed in low-resource populations in Asia.
Methods and findings
In Bangladesh, we cluster-randomized (1:1) 142 villages of the Matlab Health and Demographic Surveillance System to include two doses of HRV with the standard infant vaccines at 6 and 10 wk of age or to provide standard infant vaccines without HRV. The study was initiated November 1, 2008, and surveillance was conducted concurrently at Matlab Diarrhoea Hospital and two community treatment centers to identify children less than 2 y of age presenting with acute rotavirus diarrhea (ARD) through March 31, 2011. Laboratory confirmation was made by enzyme immunoassay detection of rotavirus antigen in stool specimens. Overall effectiveness of the HRV vaccination program (primary objective) was measured by comparing the incidence rate of ARD among all children age-eligible for vaccination in villages where HRV was introduced to that among such children in villages where HRV was not introduced. Total effectiveness among vaccinees and indirect effectiveness were also evaluated. In all, 6,527 infants were age-eligible for vaccination in 71 HRV villages, and 5,791 in 71 non-HRV villages. In HRV villages, 4,808 (73.7%) infants received at least one dose of HRV. The incidence rate of ARD was 4.10 cases per 100 person-years in non-HRV villages compared to 2.8 per 100 person-years in HRV villages, indicating an overall effectiveness of 29.0% (95% CI, 11.3% to 43.1%). The total effectiveness of HRV against ARD among vaccinees was 41.4% (95% CI, 23.2% to 55.2%). The point estimate for total effectiveness was higher against ARD during the first year of life than during the second (45.2% versus 28.9%), but estimates for the second year of life lacked precision and did not reach statistical significance. Indirect effects were not detected. To check for bias in presentation to treatment facilities, we evaluated the effectiveness of HRV against acute diarrhea associated with enterotoxigenic Escherichia coli; it was 4.0% (95% CI, −46.5% to 37.1%), indicating that bias likely was not introduced. Thirteen serious adverse events were identified among recipients of HRV, but none were considered related to receipt of study vaccine. The main limitation of this study is that it was an open-label study with an observed-only control group (no placebo).
Conclusions
The two-dose HRV rotavirus vaccination program significantly reduced medically attended ARD in this low-resource population in Asia. Protection among vaccinees was similar to that in other low-resource settings. In low-resource populations with high rotavirus incidence, large-scale vaccination across a wide population may be required to obtain the full benefit of rotavirus vaccination, including indirect effects.
Trial registration
ClinicalTrials.gov NCT00737503
45 citations
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TL;DR: After the 2014–2015 outbreak of chikungunya virus in the US Virgin Islands, the prevalence of persistent arthralgia was higher in case-patients than controls 6 and 12 months after disease onset.
Abstract: After the 2014-2015 outbreak of chikungunya virus in the US Virgin Islands, we compared the prevalence of persistent arthralgia among case-patients and controls. Prevalence was higher in case-patients than controls 6 and 12 months after disease onset. Continued vaccine research to prevent acute illness and long-term sequelae is essential.
41 citations
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TL;DR: The test-negative design (TND) is an appropriate method to measure RV effectiveness in low-income settings and was evaluated using randomized trials of RV in sub-Saharan Africa and Asia.
39 citations
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Biomedical Advanced Research and Development Authority1, University of California, Davis2, National Institutes of Health3, Johns Hopkins University4, Northeastern University5, Centers for Disease Control and Prevention6, Imperial College London7, University of Washington8, University of Florida9, Kessler Foundation10, National Center for Atmospheric Research11, University of Notre Dame12, University of California, San Francisco13
TL;DR: Given the projected low incidence of disease, the total number of participants, number of study sites, or duration of study follow-up may need to be increased to meet the efficacy study endpoints.
Abstract: Numerous Zika virus vaccines are being developed. However, identifying sites to evaluate the efficacy of a Zika virus vaccine is challenging due to the general decrease in Zika virus activity. We compare results from three different modeling approaches to estimate areas that may have increased relative risk of Zika virus transmission during 2017. The analysis focused on eight priority countries (i.e., Brazil, Colombia, Costa Rica, Dominican Republic, Ecuador, Mexico, Panama, and Peru). The models projected low incidence rates during 2017 for all locations in the priority countries but identified several sub-national areas that may have increased relative risk of Zika virus transmission in 2017. Given the projected low incidence of disease, the total number of participants, number of study sites, or duration of study follow-up may need to be increased to meet the efficacy study endpoints.
18 citations
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Fred Hutchinson Cancer Research Center1, University of Turku2, George Washington University3, University of Minnesota4, University of Georgia5, University of California, Los Angeles6, Mahidol University7, Harvard University8, University of Washington9, Johns Hopkins University10, Washington State University11, University of Florida12, World Bank13, Swiss Tropical and Public Health Institute14, Northeastern University15, University of London16
TL;DR: The adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly in emerging infectious disease, that more accurately reflects the dynamics of the transmission process is urged.
Abstract: Here we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly in emerging infectious disease, that more accurately reflects the dynamics of the transmission process. Interventions in infectious diseases can have indirect effects on those not receiving the intervention as well as direct effects on those receiving the intervention. Combinations of interventions can have complex interactions at the population level. These often cannot be adequately addressed with standard study designs and analytic methods. Simulations can help to accurately represent transmission dynamics in an increasingly complex world which is critical for proper trial design and interpretation. Some ethical aspects of a trial can also be quantified using simulations. After a trial has been conducted, simulations can be used to explore possible explanations for the observed effects. A great deal is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods and the conduct of clinical trials.
17 citations
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TL;DR: The feasibility of conducting a longitudinal, household-based study of meningococcal carriage in the African meningitis belt was demonstrated and it was demonstrated that the carriage prevalence was 5% during the cross-sectional screening visit.
16 citations
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01 Jan 2017
TL;DR: This chapter reviews causal inference problems pertinent to the study of infectious diseases, including time-varying confounding, interference, and surrogate measures of clinical outcomes.
Abstract: The potential outcomes framework for causal inference has proven valuable in the study of infectious diseases. Conversely, the context of infectious diseases has stimulated many methodological advances in causal inference. In this chapter, we review causal inference problems pertinent to the study of infectious diseases. These include time-varying confounding, interference, and surrogate measures of clinical outcomes. The test-negative study design and the relatively new (to epidemiology) methods of negative controls and regression discontinuity are also covered. Motivation for each topic is given along with examples of application.
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Broad Institute1, National Institutes of Health2, Oswaldo Cruz Foundation3, Florida State University College of Arts and Sciences4, Florida Department of Health5, University of the West Indies6, Universidad Nacional Autónoma de Honduras7, Industrial University of Santander8, University of Florida9, Massachusetts Department of Public Health10, Scripps Research Institute11, Scripps Health12, University of Edinburgh13, Massachusetts Institute of Technology14, Fred Hutchinson Cancer Research Center15, University of Córdoba (Colombia)16
TL;DR: It is found that ZIKV circulated undetected in many regions of the Americas for up to a year before the first locally transmitted cases were confirmed, highlighting the challenge of effective surveillance for this virus.
Abstract: Despite great attention given to the recent Zika virus (ZIKV) epidemic in the Americas, much remains unknown about its epidemiology and evolution, in part due to a lack of genomic data. We applied multiple sequencing approaches to generate 100 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analyzed the timing and patterns of introductions into distinct geographic regions, confirming phylogenetic evidence for the origin and rapid expansion of the outbreak in Brazil, and for multiple introductions from Brazil into Honduras, Colombia, Puerto Rico, other Caribbean islands, and the continental US. We find that ZIKV circulated undetected in many regions of the Americas for up to a year before the first locally transmitted cases were confirmed, highlighting the challenge of effective surveillance for this virus. We further characterize genetic variation across the outbreak to identify mutations with possible functional implications for ZIKV biology and pathogenesis.