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Epidemics of infectious diseases often occur in predictable limit cycles. Theory suggests these cycles can be disrupted by high amplitude seasonal fluctuations in transmission rates, resulting in deterministic chaos. However, persistent deterministic chaos has never been observed, in part because sufficiently large oscillations in transmission rates are uncommon. Where they do occur, the resulting deep epidemic troughs break the chain of transmission, leading to epidemic extinction, even in large cities. Here we demonstrate a new path to locally persistent chaotic epidemics via subtle shifts in seasonal patterns of transmission, rather than through high-amplitude fluctuations in transmission rates. We base our analysis on a comparison of measles incidence in 80 major cities in the prevaccination era United States and United Kingdom. Unlike the regular limit cycles seen in the UK, measles cycles in US cities consistently exhibit spontaneous shifts in epidemic periodicity resulting in chaotic patterns. We show that these patterns were driven by small systematic differences between countries in the duration of the summer period of low transmission. This example demonstrates empirically that small perturbations in disease transmission patterns can fundamentally alter the regularity and spatiotemporal coherence of epidemics.

Introduction: The purpose of this study was to examine county and state-level accidental poisoning mortality trends in Pennsylvania from 1979 to 2014. Methods: Crude and age-adjusted death rates were formed for age group, race, sex, and county for accidental poisonings (ICD 10 codes X40-X49) from 1979 to 2014 for ages 15+ using the Mortality and Population Data System housed at the University of Pittsburgh. Rate ratios were calculated comparing rates from 1979 to 2014, overall and by sex, age group, and race. Joinpoint regression was used to detect statistically significant changes in trends of age-adjusted mortality rates. Results: Rate ratios for accidental poisoning mortality in Pennsylvania increased more than 14-fold from 1979 to 2014. The largest rate ratios were among 35-44 year olds, females, and White adults. The highest accidental poisoning mortality rates were found in the counties of Southwestern Pennsylvania, those surrounding Philadelphia, and those in Northeast Pennsylvania near Scranton. Conclusions: The patterns and locations of accidental poisoning mortality by race, sex, and age group provide direction for interventions and policy makers. In particular, this study found the highest rate ratios in PA among females, whites, and the age group 35-44.

The enigmatic observation that the rapidly evolving influenza A (H3N2) virus exhibits, at any given time, a limited standing genetic diversity has been an impetus for much research. One of the first generative computational models to successfully recapitulate this pattern of consistently constrained diversity posits the existence of a strong and short-lived straintranscending immunity. Building on that model, we explored a much broader set of scenarios (parameterizations) of a transient strain-transcending immunity, ran long-term simulations of each such scenario, and assessed its plausibility with respect to a set of known or estimated influenza empirical measures. We evaluated simulated outcomes using a variety of measures, both epidemiological (annual attack rate, epidemic duration, reproductive number, and peak weekly incidence), and evolutionary (pairwise antigenic diversity, fixation rate, most recent common ancestor, and kappa, which quantifies the potential for antigenic evolution). Taking cumulative support from all these measures, we show which parameterizations of strain-transcending immunity are plausible with respect to the set of empirically derived target values. We conclude that strain-transcending immunity which is milder and longer lasting than previously suggested is more congruent with the observed short- and long-term behavior of influenza.

Background: The use of high quality disease surveillance data has become increasingly important for public health action against new threats. In response, countries have developed a wide range of disease surveillance systems enabled by technological advancements. The heterogeneity and complexity of country data systems have caused a growing need for international organizations such as the World Health Organization (WHO) to coordinate the standardization, integration, and dissemination of country disease data at the global level for research and policy. The availability and consistency of currently available disease surveillance data at the global level are unclear. We investigated this for dengue surveillance data provided online by the WHO. Methods and Findings: We extracted all dengue surveillance data provided online by WHO Headquarters and Regional Offices (RO’s). We assessed the availability and consistency of these data by comparing indicators within and between sources. We also assessed the consistency of dengue data provided online by two example countries (Brazil and Indonesia). Data were available from WHO for 100 countries since 1955 representing a total of 23 million dengue cases and 82 thousand deaths ever reported to WHO. The availability of data on DengueNet and some RO’s declined dramatically after 2005. Consistency was lacking between sources (84% across all indicators representing a discrepancy of almost half a million cases). Within sources, data at high spatial resolution were often incomplete. Conclusions: The decline of publicly available, integrated dengue surveillance data at the global level will limit opportunities for research, policy, and advocacy. A new financial and operational framework will be necessary for innovation and for the continued availability of integrated country disease data at the global level.

Background: In the current information age, the use of data has become essential for decision making in public health at the local, national, and global level. Despite a global commitment to the use and sharing of public health data, this can be challenging in reality. No systematic framework or global operational guidelines have been created for data sharing in public health. Barriers at different levels have limited data sharing but have only been anecdotally discussed or in the context of specific case studies. Incomplete systematic evidence on the scope and variety of these barriers has limited opportunities to maximize the value and use of public health data for science and policy. Methods: We conducted a systematic literature review of potential barriers to public health data sharing. Documents that described barriers to sharing of routinely collected public health data were eligible for inclusion and reviewed independently by a team of experts. We grouped identified barriers in a taxonomy for a focused international dialogue on solutions. Results: Twenty potential barriers were identified and classified in six categories: technical, motivational, economic, political, legal and ethical. The first three categories are deeply rooted in well-known challenges of health information systems for which structural solutions have yet to be found; the last three have solutions that lie in an international dialogue aimed at generating consensus on policies and instruments for data sharing. Conclusions: The simultaneous effect of multiple interacting barriers ranging from technical to intangible issues has greatly complicated advances in public health data sharing. A systematic framework of barriers to data sharing in public health will be essential to accelerate the use of valuable information for the global good.

Background: Agent based models (ABM) are useful to explore population-level scenarios of disease spread and containment, but typically characterize infected individuals using simplified models of infection and symptoms dynamics. Adding more realistic models of individual infections and symptoms may help to create more realistic population level epidemic dynamics.

Dengue vaccine development efforts have focused on the development of tetravalent vaccines. However, a recent Phase IIb trial of a tetravalent vaccine indicates a protective effect against only 3 of the 4 serotypes. While vaccines effective against a subset of serotypes may reduce morbidity and mortality, particular profiles could result in an increased number of cases due to immune enhancement and other peculiarities of dengue epidemiology. Here, we use a compartmental transmission model to assess the impact of partially effective vaccines in a hyperendemic Thai population. Crucially, we evaluate the effects that certain serotype heterogeneities may have in the presence of mass-vaccination campaigns.In the majority of scenarios explored, partially effective vaccines lead to 50% or greater reductions in the number of cases. This is true even of vaccines that we would not expect to proceed to licensure due to poor or incomplete immune responses. Our results show that a partially effective vaccine can have significant impacts on serotype distribution and mean age of cases. © 2013 The Authors.

Of the seven known species of human retroviruses only one, human T-cell lymphotropic virus type 4 (HTLV-4), lacks a known animal reservoir. We report the largest screening for simian T-cell lymphotropic virus (STLV-4) to date in a wide range of captive and wild non-human primate (NHP) species from Cameroon. Among the 681 wild and 426 captive NHPs examined, we detected STLV-4 infection only among gorillas by using HTLV-4-specific quantitative polymerase chain reaction. The large number of samples analyzed, the diversity of NHP species examined, the geographic distribution of infected animals relative to the known HTLV-4 case, as well as detailed phylogenetic analyses on partial and full genomes, indicate that STLV-4 is endemic to gorillas, and that rather than being an ancient virus among humans, HTLV-4 emerged from a gorilla reservoir, likely through the hunting and butchering of wild gorillas. Our findings shed further light on the importance of gorillas as keystone reservoirs for the evolution and emergence of human infectious diseases and provide a clear course for preventing HTLV-4 emergence through management of human contact with wild gorillas, the development of improved assays for HTLV-4/STLV-4 detection and the ongoing monitoring of STLV-4 among gorillas and for HTLV-4 zoonosis among individuals exposed to gorilla populations. © 2014 SSCC.

Background: Mathematical and computational models provide valuable tools that help public health planners to evaluate competing health interventions, especially for novel circumstances that cannot be examined through observational or controlled studies, such as pandemic influenza. The spread of diseases like influenza depends on the mixing patterns within the population, and these mixing patterns depend in part on local factors including the spatial distribution and age structure of the population, the distribution of size and composition of households, employment status and commuting patterns of adults, and the size and age structure of schools. Finally, public health planners must take into account the health behavior patterns of the population, patterns that often vary according to socioeconomic factors such as race, household income, and education levels. Results: FRED (a Framework for Reconstructing Epidemic Dynamics) is a freely available open-source agent-based modeling system based closely on models used in previously published studies of pandemic influenza. This version of FRED uses open-access census-based synthetic populations that capture the demographic and geographic heterogeneities of the population, including realistic household, school, and workplace social networks. FRED epidemic models are currently available for every state and county in the United States, and for selected international locations. Conclusions: State and county public health planners can use FRED to explore the effects of possible influenza epidemics in specific geographic regions of interest and to help evaluate the effect of interventions such as vaccination programs and school closure policies. FRED is available under a free open source license in order to contribute to the development of better modeling tools and to encourage open discussion of modeling tools being used to evaluate public health policies. We also welcome participation by other researchers in the further develo

The effect of school-based non-pharmaceutical interventions (NPIs) on influenza A and B transmission in children's households has not been estimated in published literature. We use data from a large school-based cluster randomized trial of improved hand and respiratory hygiene measures to explore the secondary transmission of influenza A and B in households of laboratory confirmed influenza cases. Data were taken from the Pittsburgh Influenza Prevention Project, a cluster-randomized trial of NPIs conducted in ten Pittsburgh, PA elementary schools during the 2007-2008 influenza season. We estimated two measures of influenza transmissibility in households; the susceptible infectious transmission probability, using variants of the Reed-Frost chain binomial model, and the secondary attack rate. We identified predictors of ILI using a logistic generalized estimating equation model. We estimate the secondary attack rates in intervention households to be 0.26 (95% confidence interval (CI) 0.19-0.34) compared to 0.30 (95% CI 0.23-0.38) in control households. Race and age were significant risk factors for secondary ILI acquisition in this study. We found no significant differences between the transmission probabilities for infectious individuals in intervention (0.19, 95% CI 0.14-0.25), and control households (0.22, 95% CI 0.16-0.29). Similarly, estimates for secondary attack rates and transmission probabilities for households with confirmed influenza A (0.31 and 0.22) were not significantly different from estimates from households with confirmed influenza B (0.25 and 0.20). While influenza A and B are thought to have different transmission characteristics, we find no significant differences in their transmissibility within households. Though our results suggest a potential effect, we found no statistically significant effect of school-based non-pharmaceutical interventions on transmission in symptomatic children's homes. © 2013 Elsevier B.V.

Dengue, a mosquito-borne virus of humans, infects over 50 million people annually. Infection with any of the four dengue serotypes induces protective immunity to that serotype, but does not confer long-term protection against infection by other serotypes. The immunological interactions between serotypes are of central importance in understanding epidemiological dynamics and anticipating the impact of dengue vaccines. We analysed a 38-year time series with 12 197 serotyped dengue infections from a hospital in Bangkok, Thailand. Using novel mechanistic models to represent different hypothesized immune interactions between serotypes, we found strong evidence that infection with dengue provides substantial short-term cross-protection against other serotypes (approx. 1-3 years). This is the first quantitative evidence that short-term cross-protection exists since human experimental infection studies performed in the 1950s. These findings will impact strategies for designing dengue vaccine studies, future multi-strain modelling efforts, and our understanding of evolutionary pressures in multi-strain disease systems. © 2013 The Author(s).

Background. It has been suggested that the true case-fatality rate of human H5N1 influenza infection is appreciably less than the figure of approximately 60% that is based on official World Health Organization (WHO)-confirmed case reports because asymptomatic cases may have been missed. A number of seroepidemiologic studies have been conducted in an attempt to identify such missed cases.Methods. We conducted a comprehensive literature review of all English-language H5N1 human serology surveys with detailed attention to laboratory methodology used (including whether investigators used criteria set by the WHO to define positive cases), laboratory controls used, and the clades/genotypes involved.Results. Twenty-nine studies were included in the analysis. Few reported using unexposed control groups and one-third did not apply WHO criteria. Of studies that used WHO criteria, only 4 found any seropositive results to clades/genotypes of H5N1 that are currently circulating. No studies reported seropositive results to the clade 2/genotype Z viruses that have spread throughout Eurasia and Africa.Conclusions. This review suggests that the frequency of positive H5 serology results is likely to be low; therefore, it is essential that future studies adhere to WHO criteria and include unexposed controls in their laboratory assays to limit the likelihood of false-positive results. © 2012 The Author.

Objectives. We examined the impact of access to paid sick days (PSDs) and stay-at-home behavior on the influenza attack rate in workplaces. Methods. We used an agent-based model of Allegheny County, Pennsylvania, with PSD data from the US Bureau of Labor Statistics, standard influenza epidemic parameters, and the probability of staying home when ill. We compared the influenza attack rate among employees resulting from workplace transmission, focusing on the effects of presenteeism (going to work when ill). Results. In a simulated influenza epidemic (R0 = 1.4), the attack rate among employees owing to workplace transmission was 11.54%. A large proportion (72.00%) of this attack rate resulted from exposure to employees engaging in presenteeism. Universal PSDs reduced workplace infections by 5.86%. Providing 1 or 2 "flu days"-allowing employees with influenza to stay home-reduced workplace infections by 25.33% and 39.22%, respectively. Conclusions. PSDs reduce influenza transmission owing to presenteeism and, hence, the burden of influenza illness in workplaces. © 2013 American Journal of Public Health.

This paper describes an international collaboration to carry out studies that contributed to the understanding of pathogenesis, diagnosis, treatment, and prevention of several diseases of public health importance for Thailand and the United States. In Kamphaeng Phet Province, Thailand, febrile syndromes, including encephalitis, hepatitis, hemorrhagic fever, and influenza-like illnesses, occurred commonly and were clinically diagnosed, but the etiology was rarely confirmed. Since 1982, the Kamphaeng Phet Provincial Hospital, the Thai Ministry of Public Health, and the US Army Component of the Armed Forces Research Institute of Medical Sciences, along with vaccine manufacturers and universities, have collaborated on studies that evaluated and capitalized on improved diagnostic capabilities for infections caused by Japanese encephalitis, hepatitis A, dengue, and influenza viruses. The collaboration clarified clinical and epidemiological features of these infections and, in large clinical trials, demonstrated that vaccines against Japanese encephalitis and hepatitis A viruses were over 90% efficacious, supporting licensure of both vaccines. With the introduction of Japanese encephalitis vaccines in Thailand's Expanded Program on Immunization, reported encephalitis rates dropped substantially. Similarly, in the US, particularly in the military populations, rates of hepatitis A disease have dropped with the use of hepatitis A vaccine. Studies of the pathogenesis of dengue infections have increased understanding of the role of cellular immunity in responding to these infections, and epidemiological studies have prepared the province for studies of dengue vaccines. Approximately 80 publications resulted from this collaboration. Studies conducted in Kamphaeng Phet provided experience that contributed to clinical trials of hepatitis E and HIV vaccines, conducted elsewhere. To provide a base for continuing studies, The Kamphaeng Phet-AFRIMS Virology Research Unit (KAVRU) was e

Objective. To develop a conceptual computational agent-based model (ABM) to explore community-wide versus spatially focused crime reporting interventions to reduce community crime perpetrated by youth. Method. Agents within the model represent individual residents and interact on a two-dimensional grid representing an abstract nonempirically grounded community setting. Juvenile agents are assigned initial random probabilities of perpetrating a crime and adults are assigned random probabilities of witnessing and reporting crimes. The agents' behavioral probabilities modify depending on the individual's experience with criminal behavior and punishment, and exposure to community crime interventions. Cost-effectiveness analyses assessed the impact of activating different percentages of adults to increase reporting and reduce community crime activity. Community-wide interventions were compared with spatially focused interventions, in which activated adults were focused in areas of highest crime prevalence. Results. The ABM suggests that both community-wide and spatially focused interventions can be effective in reducing overall offenses, but their relative effectiveness may depend on the intensity and cost of the interventions. Although spatially focused intervention yielded localized reductions in crimes, such interventions were shown to move crime to nearby communities. Community-wide interventions can achieve larger reductions in overall community crime offenses than spatially focused interventions, as long as sufficient resources are available. Conclusion. The ABM demonstrates that community-wide and spatially focused crime strategies produce unique intervention dynamics influencing juvenile crime behaviors through the decisions and actions of community adults. It shows how such models might be used to investigate community-supported crime intervention programs by integrating community input and expertise and provides a simulated setting for assessing dimensions of c

Pathogenesis studies of SIV infection have not been performed to date in wild monkeys due to difficulty in collecting and storing samples on site and the lack of analytical reagents covering the extensive SIV diversity. We performed a large scale study of molecular epidemiology and natural history of SIVagm infection in 225 free-ranging AGMs from multiple locations in South Africa. SIV prevalence (established by sequencing pol, env, and gag) varied dramatically between infant/juvenile (7%) and adult animals (68%) (p<0.0001), and between adult females (78%) and males (57%). Phylogenetic analyses revealed an extensive genetic diversity, including frequent recombination events. Some AGMs harbored epidemiologically linked viruses. Viruses infecting AGMs in the Free State, which are separated from those on the coastal side by the Drakensberg Mountains, formed a separate cluster in the phylogenetic trees; this observation supports a long standing presence of SIV in AGMs, at least from the time of their speciation to their Plio-Pleistocene migration. Specific primers/probes were synthesized based on the pol sequence data and viral loads (VLs) were quantified. VLs were of 104-106 RNA copies/ml, in the range of those observed in experimentally-infected monkeys, validating the experimental approaches in natural hosts. VLs were significantly higher (107-108 RNA copies/ml) in 10 AGMs diagnosed as acutely infected based on SIV seronegativity (Fiebig II), which suggests a very active transmission of SIVagm in the wild. Neither cytokine levels (as biomarkers of immune activation) nor sCD14 levels (a biomarker of microbial translocation) were different between SIV-infected and SIV-uninfected monkeys. This complex algorithm combining sequencing and phylogeny, VL quantification, serology, and testing of surrogate markers of microbial translocation and immune activation permits a systematic investigation of the epidemiology, viral diversity and natural history of SIV infection in wild

On the basis of positive preclinical data, we evaluated the safety and immunogenicity of an alphavirus replicon HIV-1 subtype C gag vaccine (AVX101), expressing a nonmyristoylated form of Gag, in two double-blind, randomized, placebo-controlled clinical trials in healthy HIV-1-uninfected adults. Escalating doses of AVX101 or placebo were administered subcutaneously to participants in the United States and Southern Africa. Because of vaccine stability issues, the first trial was halted prior to completion of all dose levels and a second trial was implemented. The second trial was also stopped prematurely due to documentation issues with the contract manufacturer. Safety and immunogenicity were evaluated through assessments of reactogenicity, reports of adverse events, and assessment of replication-competent and Venezuelan equine encephalitis (VEE) viremia. Immunogenicity was measured using the following assays: enzyme-linked immunosorbent assay (ELISA), chromium 51 ( 51Cr)-release cytotoxic T lymphocyte (CTL), gamma interferon (IFN-γ) ELISpot, intracellular cytokine staining (ICS), and lymphoproliferation assay (LPA). Anti-vector antibodies were also measured. AVX101 was well tolerated and exhibited only modest local reactogenicity. There were 5 serious adverse events reported during the trials; none were considered related to the study vaccine. In contrast to the preclinical data, immune responses in humans were limited. Only low levels of binding antibodies and T-cell responses were seen at the highest doses. This trial also highlighted the difficulties in developing a novel vector for HIV. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

Mathematical models can enhance our understanding of childhood infectious disease dynamics, but these models depend on appropriate parameter values that are often unknown and must be estimated from disease case data. In this paper, we develop a framework for efficient estimation of childhood infectious disease models with seasonal transmission parameters using continuous differential equations containing model and measurement noise. The problem is formulated using the simultaneous approach where all state variables are discretized, and the discretized differential equations are included as constraints, giving a large-scale algebraic nonlinear programming problem that is solved using a nonlinear primal-dual interior-point solver. The technique is demonstrated using measles case data from three different locations having different school holiday schedules, and our estimates of the seasonality of the transmission parameter show strong correlation to school term holidays. Our approach gives dramatic efficiency gains, showing a 40-400-fold reduction in solution time over other published methods. While our approach has an increased susceptibility to bias over techniques that integrate over the entire unknown state-space, a detailed simulation study shows no evidence of bias. Furthermore, the computational efficiency of our approach allows for investigation of a large model space compared with more computationally intensive approaches. © 2012 The Royal Society.

Background: States' pandemic influenza plans and school closure statutes are intended to guide state and local officials, but most faced a great deal of uncertainty during the 2009 influenza H1N1 epidemic. Questions remained about whether, when, and for how long to close schools and about which agencies and officials had legal authority over school closures. Methods. This study began with analysis of states' school-closure statutes and pandemic influenza plans to identify the variations among them. An agent-based model of one state was used to represent as constants a population's demographics, commuting patterns, work and school attendance, and community mixing patterns while repeated simulations explored the effects of variations in school closure authority, duration, closure thresholds, and reopening criteria. Results: The results show no basis on which to justify statewide rather than school-specific or community-specific authority for school closures. Nor do these simulations offer evidence to require school closures promptly at the earliest stage of an epidemic. More important are criteria based on monitoring of local case incidence and on authority to sustain closure periods sufficiently to achieve epidemic mitigation. Conclusions: This agent-based simulation suggests several ways to improve statutes and influenza plans. First, school closure should remain available to state and local authorities as an influenza mitigation strategy. Second, influenza plans need not necessarily specify the threshold for school closures but should clearly define provisions for early and ongoing local monitoring. Finally, school closure authority may be exercised at the statewide or local level, so long as decisions are informed by monitoring incidence in local communities and schools. © 2012 Potter et al.; licensee BioMed Central Ltd.

Hunting and butchering of wildlife in Central Africa are known risk factors for a variety of human diseases, including HIV/AIDS. Due to the high incidence of human exposure to body fluids of non-human primates, the significant prevalence of simian immunodeficiency virus (SIV) in non-human primates, and hunting/butchering associated cross-species transmission of other retroviruses in Central Africa, it is possible that SIV is actively transmitted to humans from primate species other than mangabeys, chimpanzees, and/or gorillas. We evaluated SIV transmission to humans by screening 2,436 individuals that hunt and butcher non-human primates, a population in which simian foamy virus and simian T-lymphotropic virus were previously detected. We identified 23 individuals with high seroreactivity to SIV. Nucleic acid sequences of SIV genes could not be detected, suggesting that SIV infection in humans could occur at a lower frequency than infections with other retroviruses, including simian foamy virus and simian T-lymphotropic virus. Additional studies on human populations at risk for non-human primate zoonosis are necessary to determine whether these results are due to viral/host characteristics or are indicative of low SIV prevalence in primate species consumed as bushmeat as compared to other retroviruses in Cameroon. © 2012 International Association for Ecology and Health.

Objectives. We investigated whether introducing the rotavirus and pneumococcal vaccines, which are greatly needed in West Africa, would overwhelm existing supply chains (i.e., the series of steps required to get a vaccine from the manufacturers to the target population) in Niger. Methods. As part of the Bill and Melinda Gates Foundation-funded Vaccine Modeling Initiative, we developed a computational model to determine the impact of introducing these new vaccines to Niger's Expanded Program on Immunization vaccine supply chain. Results. Introducing either the rotavirus vaccine or the 7-valent pneumococcal conjugate vaccine could overwhelm available storage and transport refrigerator space, creating bottlenecks that would prevent the flow of vaccines down to the clinics. As a result, the availability of all World Health Organization Expanded Program on Immunization vaccines to patients might decrease from an average of 69% to 28.2% (range=10%-51%). Addition of refrigerator and transport capacity could alleviate this bottleneck. Conclusions. Our results suggest that the effects on the vaccine supply chain should be considered when introducing a new vaccine and that computational models can help assess evolving needs and prevent problems with vaccine delivery.

Widespread avoidance of Measles-Mumps-Rubella vaccination (MMR), with a consequent increase in the incidence of major measles outbreaks, demonstrates that the effectiveness of vaccination programs can be thwarted by the public misperceptions of vaccine risk. By coupling game theory and epidemic models, we examine vaccination choice among populations stratified into two behavioral groups: vaccine skeptics and vaccine believers. The two behavioral groups are assumed to be heterogeneous with respect to their perceptions of vaccine and infection risks. We demonstrate that the pursuit of self-interest among vaccine skeptics often leads to vaccination levels that are suboptimal for a population, even if complete coverage is achieved among vaccine believers. The demand for measles vaccine across populations driven by individual self-interest was found to be more sensitive to the proportion of vaccine skeptics than to the extent to which vaccine skeptics misperceive the risk of vaccine. Furthermore, as the number of vaccine skeptics increases, the probability of infection among vaccine skeptics increases initially, but it decreases once the vaccine skeptics begin receiving the vaccination, if both behavioral groups are vaccinated according to individual self-interest. Our results show that the discrepancy between the coverages of measles vaccine that are driven by self-interest and those driven by population interest becomes larger when the cost of vaccination increases. This research illustrates the importance of public education on vaccine safety and infection risk in order to maintain vaccination levels that are sufficient to maintain herd immunity. © 2011 Elsevier Ltd.

Objective: Since states public health systems differ as to pandemic preparedness, this study explored whether such heterogeneity among states could affect the nations overall influenza rate. Design: The Centers for Disease Control and Prevention produced a uniform set of scores on a 100-point scale from its 2008 national evaluation of state preparedness to distribute materiel from the Strategic National Stockpile (SNS). This study used these SNS scores to represent each states relative preparedness to distribute influenza vaccine in a timely manner and assumed that "optimal" vaccine distribution would reach at least 35% of the states population within 4 weeks. The scores were used to determine the timing of vaccine distribution for each state: each 10-point decrement of score below 90 added an additional delay increment to the distribution time. Setting and Participants: A large-scale agent-based computational model simulated an influenza pandemic in the US population. In this synthetic population each individual or agent had an assigned household, age, workplace or school destination, daily commute, and domestic intercity air travel patterns. Main Outcome Measures: Simulations compared influenza case rates both nationally and at the state level under 3 Scenarios: no vaccine distribution (baseline), optimal vaccine distribution in all states, and vaccine distribution time modified according to state-specific SNS score. Results: Between optimal and SNS-modified scenarios, attack rates rose not only in low-scoring states but also in high-scoring states, demonstrating an interstate spread of infections. Influenza rates were sensitive to variation of the SNS-modified scenario (delay increments of 1 day versus 5 days), but the interstate effect remained. Conclusions: The effectiveness of a response activity such as vaccine distribution could benefit from national standards and preparedness funding allocated in part to minimize interstate disparities. Copyright © 2012 Lip

It is well-known that the distribution of immunity in a population dictates the future incidence of infectious disease, but this process is generally understood at individual or macroscales. For example, herd immunity to multiple pathogens has been observed at national and city levels. However, the effects of population immunity have not previously been shown at scales smaller than the city (e.g., neighborhoods). In particular, no study has shownlong-termeffects of population immunity at scales consistent with the spatial scale of person-to-person transmission. Here, we use the location of dengue patients' homes in Bangkok with the serotype of the infecting pathogen to investigate the spatiotemporal distribution of disease risk at small spatial scales over a 5-y period. We find evidence for localized transmission at distances of under 1 km. We also observe patterns of spatiotemporal dependence consistent with the expected impacts of homotypic immunity, heterotypic immunity, and immune enhancement of disease at these distances. Our observations indicate that immunological memory of dengue serotypes occurs at the neighborhood level in this large urban setting. These methods have broad applications to studying the spatiotemporal structure of disease risk where pathogen serotype or genetic information is known.

Background: Understanding the mechanism of influenza spread across multiple geographic scales is not complete. While the mechanism of dissemination across regions and states of the United States has been described, understanding the determinants of dissemination between counties has not been elucidated. The paucity of high resolution spatial-temporal influenza incidence data to evaluate disease structure is often not available. Methodology and Findings: We report on the underlying relationship between the spread of influenza and human movement between counties of one state. Significant synchrony in the timing of epidemics exists across the entire state and decay with distance (regional correlation = 62%). Synchrony as a function of population size display evidence of hierarchical spread with more synchronized epidemics occurring among the most populated counties. A gravity model describing movement between two populations is a stronger predictor of influenza spread than adult movement to and from workplaces suggesting that non-routine and leisure travel drive local epidemics. Conclusions: These findings highlight the complex nature of influenza spread across multiple geographic scales. © 2012 Stark et al.

Background: Influenza is a contagious respiratory disease responsible for annual seasonal epidemics in temperate climates. An understanding of how influenza spreads geographically and temporally within regions could result in improved public health prevention programs. The purpose of this study was to summarize the spatial and temporal spread of influenza using data obtained from the Pennsylvania Department of Health's influenza surveillance system. Methodology and Findings: We evaluated the spatial and temporal patterns of laboratory-confirmed influenza cases in Pennsylvania, United States from six influenza seasons (2003-2009). Using a test of spatial autocorrelation, local clusters of elevated risk were identified in the South Central region of the state. Multivariable logistic regression indicated that lower monthly precipitation levels during the influenza season (OR = 0.52, 95% CI: 0.28, 0.94), fewer residents over age 64 (OR = 0.27, 95% CI: 0.10, 0.73) and fewer residents with more than a high school education (OR = 0.76, 95% CI: 0.61, 0.95) were significantly associated with membership in this cluster. In addition, time series analysis revealed a temporal lag in the peak timing of the influenza B epidemic compared to the influenza A epidemic. Conclusions: These findings illustrate a distinct spatial cluster of cases in the South Central region of Pennsylvania. Further examination of the regional transmission dynamics within these clusters may be useful in planning public health influenza prevention programs. © 2012 Stark et al.

Background: Many countries, such as Niger, are considering changing their vaccine vial size presentation and may want to evaluate the subsequent impact on their supply chains, the series of steps required to get vaccines from their manufacturers to patients. The measles vaccine is particularly important in Niger, a country prone to measles outbreaks. Methods. We developed a detailed discrete event simulation model of the vaccine supply chain representing every vaccine, storage location, refrigerator, freezer, and transport device (e.g., cold trucks, 4 × 4 trucks, and vaccine carriers) in the Niger Expanded Programme on Immunization (EPI). Experiments simulated the impact of replacing the 10-dose measles vial size with 5-dose, 2-dose and 1-dose vial sizes. Results: Switching from the 10-dose to the 5-dose, 2-dose and 1-dose vial sizes decreased the average availability of EPI vaccines for arriving patients from 83% to 82%, 81% and 78%, respectively for a 100% target population size. The switches also changed transport vehicle's utilization from a mean of 58% (range: 4-164%) to means of 59% (range: 4-164%), 62% (range: 4-175%), and 67% (range: 5-192%), respectively, between the regional and district stores, and from a mean of 160% (range: 83-300%) to means of 161% (range: 82-322%), 175% (range: 78-344%), and 198% (range: 88-402%), respectively, between the district to integrated health centres (IHC). The switch also changed district level storage utilization from a mean of 65% to means of 64%, 66% and 68% (range for all scenarios: 3-100%). Finally, accounting for vaccine administration, wastage, and disposal, replacing the 10-dose vial with the 5 or 1-dose vials would increase the cost per immunized patient from $0.47US to $0.71US and $1.26US, respectively. Conclusions: The switch from the 10-dose measles vaccines to smaller vial sizes could overwhelm the capacities of many storage facilities and transport vehicles as well as increase the cost per vaccinated child. ©

Analysis of historical data has strongly shaped our understanding of the epidemiology of pandemic influenza and informs analysis of current and future epidemics. Here, the authors analyzed previously unpublished documents from a large household survey of the "Spanish" H1N1 influenza pandemic, conducted in 1918, for the first time quantifying influenza transmissibility at the person-to-person level during that most lethal of pandemics. The authors estimated a low probability of person-to-person transmission relative to comparable estimates from seasonal influenza and other directly transmitted infections but similar to recent estimates from the 2009 H1N1 pandemic. The authors estimated a very low probability of asymptomatic infection, a previously unknown parameter for this pandemic, consistent with an unusually virulent virus. The authors estimated a high frequency of prior immunity that they attributed to a largely unreported influenza epidemic in the spring of 1918 (or perhaps to cross-reactive immunity). Extrapolating from this finding, the authors hypothesize that prior immunity partially protected some populations from the worst of the fall pandemic and helps explain differences in attack rates between populations. Together, these analyses demonstrate that the 1918 influenza virus, though highly virulent, was only moderately transmissible and thus in a modern context would be considered controllable. © 2011 The Author.

With several candidate dengue vaccines under development, this is an important time to help stakeholders (e.g., policy makers, scientists, clinicians, and manufacturers) better understand the potential economic value (cost-effectiveness) of a dengue vaccine, especially while vaccine characteristics and strategies might be readily altered. We developed a decision analytic Markov simulation model to evaluate the potential health and economic value of administering a dengue vaccine to an individual (≤ 1 year of age) in Thailand from the societal perspective. Sensitivity analyses evaluated the effects of ranging various vaccine (e.g., cost, efficacy, side effect), epidemiological (dengue risk), and disease (treatment-seeking behavior) characteristics. A ≥ 50% efficacious vaccine was highly cost-effective [< 1x per capita gross domestic product (GDP) ($4,289)] up to a total vaccination cost of $60 and cost-effective [< 3x per capita GDP ($12,868)] up to a total vaccination cost of $200. When the total vaccine series was $1.50, many scenarios were cost saving. Copyright © 2011 by The American Society of Tropical Medicine and Hygiene.

Introduced to minimize open vial wastage, single-dose vaccine vials require more storage space and therefore may affect vaccine supply chains (i.e., the series of steps and processes involved in distributing vaccines from manufacturers to patients). We developed a computational model of Thailand's Trang province vaccine supply chain to analyze the effects of switching from a ten-dose measles vaccine presentation to each of the following: a single-dose measles-mumps-rubella vaccine (which Thailand is currently considering) or a single-dose measles vaccine. While the Trang province vaccine supply chain would generally have enough storage and transport capacity to accommodate the switches, the added volume could push some locations' storage and transport space utilization close to their limits. Single-dose vaccines would allow for more precise ordering and decrease open vial waste, but decrease reserves for unanticipated demand. Moreover, the added disposal and administration costs could far outweigh the costs saved from preventing open vial wastage. © 2011 Elsevier Ltd.

We applied social network analyses to determine how hospitals within Orange County, California, are interconnected by patient sharing, a system which may have numerous public health implications. Our analyses considered 2 general patient-sharing networks: uninterrupted patient sharing (UPS; i.e., direct interhospital transfers) and total patient sharing (TPS; i.e., all interhospital patient sharing, including patients with intervening nonhospital stays). We considered these networks at 3 thresholds of patient sharing: at least 1, at least 10, and at least 100 patients shared. Geographically proximate hospitals were somewhat more likely to share patients, but many hospitals shared patients with distant hospitals. Number of patient admissions and percentage of cancer patients were associated with greater connectivity across the system. The TPS network revealed numerous connections not seen in the UPS network, meaning that direct transfers only accounted for a fraction of total patient sharing. Our analysis demonstrated that Orange County's 32 hospitals were highly and heterogeneously interconnected by patient sharing. Different hospital populations had different levels of influence over the patient-sharing network.

African tick-bite fever is an emerging infectious disease caused by the spotted fever group Rickettsia, Rickettsia africae, and is transmitted by ticks of the genus Amblyomma. To determine the seroprevalence of exposure to R. africae and risk factors associated with infection, we conducted a cross-sectional study of persons in seven rural villages in distinct ecological habitats of Cameroon. We examined 903 plasma samples by using an indirect immunofluorescence assay for antibodies to R. africae and analyzed demographic and occupational data collected from questionnaires. Of the 903 persons tested, 243 (26.9%) had IgG/IgM/IgA reactive with R. africae. Persons from four of the seven village sites were significantly more likely to be seropositive (P < 0.05), and lowland forest sites tended to have higher seroprevalences. These results suggest that African tick-bite fever is common in adults in rural areas of Cameroon and that ecological factors may play a role in the acquisition of R. africae infection. Copyright © 2011 by The American Society of Tropical Medicine and Hygiene.

When influenza vaccines are in short supply, allocating vaccines equitably among different jurisdictions can be challenging. But justice is not the only reason to ensure that poorer counties have the same access to influenza vaccines as do wealthier ones. Using a detailed computer simulation model of the Washington, D.C., metropolitan region, we found that limiting or delaying vaccination of residents of poorer counties could raise the total number of influenza infections and the number of new infections per day at the peak of an epidemic throughout the region-even in the wealthier counties that had received more timely and abundant vaccine access. Among other underlying reasons, poorer counties tend to have high-density populations and more children and other higher-risk people per household, resulting in more interactions and both increased transmission of influenza and greater risk for worse influenza outcomes. Thus, policy makers across the country, in poor and wealthy areas alike, have an incentive to ensure that poorer residents have equal access to vaccines. © 2011 Project HOPE-The People-to-People Health Foundation, Inc.

Background: Laboratory-based evidence is lacking regarding the efficacy of nonpharmaceutical interventions (NPIs) such as alcohol-based hand sanitizer and respiratory hygiene to reduce the spread of influenza. Methods: The Pittsburgh Influenza Prevention Project was a cluster-randomized trial conducted in 10 elementary schools in Pittsburgh, PA, during the 2007 to 2008 influenza season. Children in 5 intervention schools received training in hand and respiratory hygiene, and were provided and encouraged to use hand sanitizer regularly. Children in 5 schools acted as controls. Children with influenza-like illness were tested for influenza A and B by reverse-transcriptase polymerase chain reaction. Results: A total of 3360 children participated in this study. Using reverse-transcriptase polymerase chain reaction, 54 cases of influenza A and 50 cases of influenza B were detected. We found no significant effect of the intervention on the primary study outcome of all laboratory-confirmed influenza cases (incidence rate ratio [IRR]: 0.81; 95% confidence interval [CI]: 0.54, 1.23). However, we did find statistically significant differences in protocol-specified ancillary outcomes. Children in intervention schools had significantly fewer laboratory-confirmed influenza A infections than children in control schools, with an adjusted IRR of 0.48 (95% CI: 0.26, 0.87). Total absent episodes were also significantly lower among the intervention group than among the control group; adjusted IRR 0.74 (95% CI: 0.56, 0.97). Conclusions: NPIs (respiratory hygiene education and the regular use of hand sanitizer) did not reduce total laboratory-confirmed influenza. However, the interventions did reduce school total absence episodes by 26% and laboratory-confirmed influenza A infections by 52%. Our results suggest that NPIs can be an important adjunct to influenza vaccination programs to reduce the number of influenza A infections among children. © 2011 by Lippincott Williams & Wilkins.

Background: During the 2009 H1N1 influenza epidemic, policy makers debated over whether, when, and how long to close schools. While closing schools could have reduced influenza transmission thereby preventing cases, deaths, and health care costs, it may also have incurred substantial costs from increased childcare needs and lost productivity by teachers and other school employees. Methods. A combination of agent-based and Monte Carlo economic simulation modeling was used to determine the cost-benefit of closing schools (vs. not closing schools) for different durations (range: 1 to 8 weeks) and symptomatic case incidence triggers (range: 1 to 30) for the state of Pennsylvania during the 2009 H1N1 epidemic. Different scenarios varied the basic reproductive rate (R0) from 1.2, 1.6, to 2.0 and used case-hospitalization and case-fatality rates from the 2009 epidemic. Additional analyses determined the cost per influenza case averted of implementing school closure. Results: For all scenarios explored, closing schools resulted in substantially higher net costs than not closing schools. For R0= 1.2, 1.6, and 2.0 epidemics, closing schools for 8 weeks would have resulted in median net costs of $21.0 billion (95% Range: $8.0-$45.3 billion). The median cost per influenza case averted would have been $14,185 ($5,423-$30,565) for R0= 1.2, $25,253 ($9,501-$53,461) for R0= 1.6, and $23,483 ($8,870-$50,926) for R0= 2.0. Conclusions: Our study suggests that closing schools during the 2009 H1N1 epidemic could have resulted in substantial costs to society as the potential costs of lost productivity and childcare could have far outweighed the cost savings in preventing influenza cases. © 2011 Brown et al; licensee BioMed Central Ltd.

An agent-based model was developed to explore the effectiveness of possible interventions to reduce neighborhood crime and violence. Both offenders and non-offenders (or citizens) were modeled as agents living in neighborhoods, with a set of rules controlling changes in behavior based on individual experience. Offenders may become more or less inclined to actively commit criminal offenses, depending on the behavior of the neighborhood residents and other nearby offenders, and on their arrest experience. In turn, citizens may become more or less inclined to report crimes, based on the observed prevalence of criminal activity within their neighborhood. This paper describes the basic design and dynamics of the model, and how such models might be used to investigate practical crime intervention programs. © 2011 Springer-Verlag Berlin Heidelberg.

Although the substantial burdens of rotavirus and pneumococcal disease have motivated many countries to consider introducing the rotavirus vaccine (RV) and heptavalent pneumococcal conjugate vaccine (PCV-7) to their National Immunization Programs (EPIs), these new vaccines could affect the countries' vaccine supply chains (i.e., the series of steps required to get a vaccine from their manufacturers to patients). We developed detailed computational models of the Trang Province, Thailand, vaccine supply chain to simulate introducing various RV and PCV-7 vaccine presentations and their combinations. Our results showed that the volumes of these new vaccines in addition to current routine vaccines could meet and even exceed (1) the refrigerator space at the provincial district and sub-district levels and (2) the transport cold space at district and sub-district levels preventing other vaccines from being available to patients who arrive to be immunized. Besides the smallest RV presentation (17.1 cm 3/dose), all other vaccine introduction scenarios required added storage capacity at the provincial level (range: 20 L-1151 L per month) for the three largest formulations, and district level (range: 1 L-124 L per month) across all introduction scenarios. Similarly, with the exception of the two smallest RV presentation (17.1 cm 3/dose), added transport capacity was required at both district and sub-district levels. Added transport capacity required across introduction scenarios from the provincial to district levels ranged from 1 L-187 L, and district to sub-district levels ranged from 1 L-13 L per shipment. Finally, only the smallest RV vaccine presentation (17.1 cm 3/dose) had no appreciable effect on vaccine availability at sub-districts. All other RV and PCV-7 vaccines were too large for the current supply chain to handle without modifications such as increasing storage or transport capacity. Introducing these new vaccines to Thailand could have dynamic effects on the ava

Background: Acute care facilities are connected via patient sharing, forming a network. However, patient sharing extends beyond this immediate network to include sharing with long-term care facilities. The extent of long-term care facility patient sharing on the acute care facility network is unknown. The objective of this study was to characterize and determine the extent and pattern of patient transfers to, from, and between long-term care facilities on the network of acute care facilities in a large metropolitan county. Methods/Principal Findings: We applied social network constructs principles, measures, and frameworks to all 2007 annual adult and pediatric patient transfers among the healthcare facilities in Orange County, California, using data from surveys and several datasets. We evaluated general network and centrality measures as well as individual ego measures and further constructed sociograms. Our results show that over the course of a year, 66 of 72 long-term care facilities directly sent and 67 directly received patients from other long-term care facilities. Long-term care facilities added 1,524 ties between the acute care facilities when ties represented at least one patient transfer. Geodesic distance did not closely correlate with the geographic distance among facilities. Conclusions/Significance: This study demonstrates the extent to which long-term care facilities are connected to the acute care facility patient sharing network. Many long-term care facilities were connected by patient transfers and further added many connections to the acute care facility network. This suggests that policy-makers and health officials should account for patient sharing with and among long-term care facilities as well as those among acute care facilities when evaluating policies and interventions. © 2011 Lee et al.

A proposal has been posted on the ICTV website (2011. 001aG. N. v1. binomial_sp_names) to replace virus species names by non-Latinized binomial names consisting of the current italicized species name with the terminal word "virus" replaced by the italicized and non-capitalized genus name to which the species belongs. If implemented, the current italicized species name Measles virus, for instance, would become Measles morbillivirus while the current virus name measles virus and its abbreviation MeV would remain unchanged. The rationale for the proposed change is presented. © 2010 Springer-Verlag.

Single-dose vaccine formats can prevent clinic-level vaccine wastage but may incur higher production, medical waste disposal, and storage costs than multi-dose formats. To help guide vaccine developers, manufacturers, distributors, and purchasers, we developed a computational model to predict the potential economic impact of various single-dose versus multi-dose measles (MEA), hemophilus influenzae type B (Hib), Bacille Calmette-Guérin (BCG), yellow fever (YF), and pentavalent (DTP-HepB-Hib) vaccine formats. Lower patient demand favors fewer dose formats. The mean daily patient arrival thresholds for each vaccine format are as follows: for the MEA vaccine, 2 patients/day (below which the single-dose vial and above which the 10-dose vial are least costly); BCG vaccine, 6 patients/day (below, 10-dose vial; above, 20-dose vial); Hib vaccine, 5 patients/day (below, single-dose vial; above, 10-dose vial); YF vaccine, 33 patients/day (below, 5-dose vials; above 50-dose vial); and DTP-HepB-Hib vaccine, 5 patients/day (below, single-dose vial; above, 10-dose vial). © 2010 Elsevier Ltd.

Background. Currently, the only tests capable of determining the serotype associated with dengue virus (DENV) infection require sampling during the period of acute viremia. No test can accurately detect the serotype associated with past DENV infections. The standard assay for determination of serotype-specific antibody against DENV is the plaque reduction neutralization test (PRNT), although performance of this test continues to be evaluated. Methods. From a cohort study among schoolchildren in Thailand, PRNT values were determined in serum samples collected before and after infection. A multinomial logistic regression model was used to infer the serotype associated with intercurrent DENV infections. Models were validated based on polymerase chain reaction identification of DENV serotypes. Results. The serotype associated with DENV infection inferred by the model corresponded with polymerase chain reaction in 67.6% of cases, and the k statistic was 0.479. A model for 35 cases with primary seroconversion correctly identified the DENV serotypes causing infection in 77.1% of cases, compared with 66.9%, using a model for 169 cases with secondary seroconversion. The best model using only postinfection PRNT values correctly inferred the DENV serotype causing infection in 60.3% of cases. Conclusions. A statistical model based on both pre- and postinfection PRNT values can be used to infer the serotype associated with DENV infections in prospective studies and vaccine trials. © 2010 by the Infectious Diseases Society of America. All rights reserved.

In seasonal influenza epidemics, pathogens such as respiratory syncytial virus (RSV) often cocirculate with influenza and cause influenzalike illness (ILI) in human hosts. However, it is often impractical to test for each potential pathogen or to collect specimens for each observed ILI episode, making inference about influenza transmission difficult. In the setting of infectious diseases, missing outcomes impose a particular challenge because of the dependence among individuals. We propose a Bayesian competing-risk model for multiple cocirculating pathogens for inference on transmissibility and intervention efficacies under the assumption that missingness in the biological confirmation of the pathogen is ignorable. Simulation studies indicate a reasonable performance of the proposed model even if the number of potential pathogens is misspecified. They also show that a moderate amount of missing laboratory test results has only a small impact on inference about key parameters in the setting of close contact groups. Using the proposed model, we found that a nonpharmaceutical intervention is marginally protective against transmission of influenza A in a study conducted in elementary schools. © 2010.

BACKGROUND. Assessments of infectious disease spread in hospitals seldom account for interfacility patient sharing. This is particularly important for pathogens with prolonged incubation periods or carrier states. METHODS. We quantified patient sharing among all 32 hospitals in Orange County (OC), California, using hospital discharge data. Same-day transfers between hospitals were considered "direct" transfers, and events in which patients were shared between hospitals after an intervening stay at home or elsewhere were considered "indirect" patient-sharing events. We assessed the frequency of readmissions to another OC hospital within various time points from discharge and examined interhospital sharing of patients with Clostridium difficile infection. RESULTS. In 2005, OC hospitals had 319,918 admissions. Twenty-nine percent of patients were admitted at least twice, with a median interval between discharge and readmission of 53 days. Of the patients with 2 or more admissions, 75% were admitted to more than 1 hospital. Ninety-four percent of interhospital patient sharing occurred indirectly. When we used 10 shared patients as a measure of potential interhospital exposure, 6 (19%) of 32 hospitals "exposed" more than 50% of all OC hospitals within 6 months, and 17 (53%) exposed more than 50% within 12 months. Hospitals shared 1 or more patient with a median of 28 other hospitals. When we evaluated patients with C. difficile infection, 25% were readmitted within 12 weeks; 41% were readmitted to different hospitals, and less than 30% of these readmissions were direct transfers. CONCLUSIONS. In a large metropolitan county, interhospital patient sharing was a potential avenue for transmission of infectious agents. Indirect sharing with an intervening stay at home or elsewhere composed the bulk of potential exposures and occurred unbeknownst to hospitals. © 2010 by The Society for Healthcare Epidemiology of America. All rights reserved.

Background In December 2009, when the H1N1 influenza pandemic appeared to be subsiding, public health officials and unvaccinated individuals faced the question of whether continued H1N1 immunization was still worthwhile. Purpose To delineate what combinations of possible mechanisms could generate a third pandemic wave and then explore whether vaccinating the population at different rates and times would mitigate the wave. Methods As part of ongoing work with the Office of the Assistant Secretary for Preparedness and Response at the USDHHS during the H1N1 influenza pandemic, the University of Pittsburgh Models of Infectious Disease Agent Study team employed an agent-based computer simulation model of the Washington DC metropolitan region to delineate what mechanisms could generate a "third pandemic wave" and explored whether vaccinating the population at different rates and times would mitigate the wave. This model included explicit representations of the region's individuals, school systems, workplaces/commutes, households, and communities. Results Three mechanisms were identified that could cause a third pandemic wave; substantially increased viral transmissibility from seasonal forcing (changing influenza transmission with changing environmental conditions, i.e., seasons) and progressive viral adaptation; an immune escape variant; and changes in social mixing from holiday school closures. Implementing vaccination for these mechanisms, even during the down-slope of the fall epidemic wave, significantly mitigated the third wave. Scenarios showed the gains from initiating vaccination earlier, increasing the speed of vaccination, and prioritizing population subgroups based on Advisory Committee on Immunization Practices recommendations. Conclusions Additional waves in an epidemic can be mitigated by vaccination even when an epidemic appears to be waning. © 2010 American Journal of Preventive Medicine.