Role of Age in the Spread of Influenza, 2011-2019: Data From the US Influenza Vaccine Effectiveness Network.

Intraseason timing of influenza infection among persons of different ages could reflect relative contributions to propagation of seasonal epidemics and has not been examined among ambulatory patients. Using data from the US Influenza Vaccine Effectiveness Network, we calculated risk ratios derived from comparing weekly numbers of influenza cases prepeak with those postpeak during the 2010-2011 through 2018-2019 influenza seasons. We sought to determine age-specific differences during the ascent versus descent of an influenza season by influenza virus type and subtype. We estimated 95% credible intervals around the risk ratios using Bayesian joint posterior sampling of weekly cases. Our population consisted of ambulatory patients with laboratory-confirmed influenza who enrolled in an influenza vaccine effectiveness study at 5 US sites during 9 influenza seasons after the 2009 influenza A virus subtype H1N1 (H1N1) pandemic. We observed that young children aged <5 years tended to more often be infected with H1N1 during the prepeak period, while adults aged ≥65 years tended to more often be infected with H1N1 during the postpeak period. However, for influenza A virus subtype H3N2, children aged <5 years were more often infected during the postpeak period. These results may reflect a contribution of different age groups to seasonal spread, which may differ by influenza virus type and subtype.

Effects of Prior Season Vaccination on Current Season Vaccine Effectiveness in the United States Flu Vaccine Effectiveness Network, 2012-2013 Through 2017-2018.

BACKGROUND: We compared effects of prior vaccination and added or lost protection from current season vaccination among those previously vaccinated. METHODS: Our analysis included data from the US Flu Vaccine Effectiveness Network among participants ≥9 years old with acute respiratory illness from 2012-2013 through 2017-2018. Vaccine protection was estimated using multivariate logistic regression with an interaction term for effect of prior season vaccination on current season vaccine effectiveness. Models were adjusted for age, calendar time, high-risk status, site, and season for combined estimates. We estimated protection by combinations of current and prior vaccination compared to unvaccinated in both seasons or current vaccination among prior vaccinated. RESULTS: A total of 31 819 participants were included. Vaccine protection against any influenza averaged 42% (95% confidence interval [CI], 38%-47%) among those vaccinated only the current season, 37% (95% CI, 33-40) among those vaccinated both seasons, and 26% (95% CI, 18%-32%) among those vaccinated only the prior season, compared with participants vaccinated neither season. Current season vaccination reduced the odds of any influenza among patients unvaccinated the prior season by 42% (95% CI, 37%-46%), including 57%, 27%, and 55% against A(H1N1), A(H3N2), and influenza B, respectively. Among participants vaccinated the prior season, current season vaccination further reduced the odds of any influenza by 15% (95% CI, 7%-23%), including 29% against A(H1N1) and 26% against B viruses, but not against A(H3N2). CONCLUSIONS: Our findings support Advisory Committee on Immunization Practices recommendations for annual influenza vaccination. Benefits of current season vaccination varied among participants with and without prior season vaccination, by virus type/subtype and season.

Household transmission of influenza A and B within a prospective cohort during the 2013-2014 and 2014-2015 seasons.

People living within the same household as someone ill with influenza are at increased risk of infection. Here, we use Markov chain Monte Carlo methods to partition the hazard of influenza illness within a cohort into the hazard from the community and the hazard from the household. During the 2013-2014 influenza season, 49 (4.7%) of the 1044 people enrolled in a community surveillance cohort had an acute respiratory illness (ARI) attributable to influenza. During the 2014-2015 influenza season, 50 (4.7%) of the 1063 people in the cohort had an ARI attributable to influenza. The secondary attack rate from a household member was 2.3% for influenza A (H1) during 2013-2014, 5.3% for influenza B during 2013-2014, and 7.6% for influenza A (H3) during 2014-2015. Living in a household with a person ill with influenza increased the risk of an ARI attributable to influenza up to 350%, depending on the season and the influenza virus circulating within the household.

Waning of Measured Influenza Vaccine Effectiveness Over Time: The Potential Contribution of Leaky Vaccine Effect.

BACKGROUND: Several observational studies have shown decreases in measured influenza vaccine effectiveness (mVE) during influenza seasons. One study found decreases of 6-11%/month during the 2011-2012 to 2014-2015 seasons. These findings could indicate waning immunity but could also occur if vaccine effectiveness is stable and vaccine provides partial protection in all vaccinees ("leaky") rather than complete protection in a subset of vaccinees. Since it is unknown whether influenza vaccine is leaky, we simulated the 2011-2012 to 2014-2015 influenza seasons to estimate the potential contribution of leaky vaccine effect to the observed decline in mVE. METHODS: We used available data to estimate daily numbers of vaccinations and infections with A/H1N1, A/H3N2, and B viruses. We assumed that vaccine effect was leaky, calculated mVE as 1 minus the Mantel-Haenszel relative risk of vaccine on incident cases, and determined the mean mVE change per 30 days since vaccination. Because change in mVE was highly dependent on infection rates, we performed simulations using low (15%) and high (31%) total (including symptomatic and asymptomatic) seasonal infection rates. RESULTS: For the low infection rate, decreases (absolute) in mVE per 30 days after vaccination were 2% for A/H1N1 and 1% for A/H3N2and B viruses. For the high infection rate, decreases were 5% for A/H1N1, 4% for A/H3, and 3% for B viruses. CONCLUSIONS: The leaky vaccine bias could account for some, but probably not all, of the observed intraseasonal decreases in mVE. These results underscore the need for strategies to deal with intraseasonal vaccine effectiveness decline.

A review of the cost-effectiveness of adult influenza vaccination and other preventive services.

The Centers for Disease Control and Prevention recommend annual influenza vaccination of persons ≥6 months old. However, in 2016-17, only 43.3% of U.S. adults reported receiving an influenza vaccination. Limited awareness about the cost-effectiveness (CE) or the economic value of influenza vaccination may contribute to low vaccination coverage. In 2017, we conducted a literature review to survey estimates of the CE of influenza vaccination of adults compared to no vaccination. We also summarized CE estimates of other common preventive interventions that are recommended for adults by the U.S. Preventive Services Task Force. Results are presented as costs in US$2015 per quality-adjusted life-year (QALY) saved. Among adults aged 18-64, the CE of influenza vaccination ranged from $8000 to $39,000 per QALY. Assessments for adults aged ≥65 yielded lower CE ratios, ranging from being cost-saving to $15,300 per QALY. Influenza vaccination was cost-saving to $85,000 per QALY for pregnant women in moderate or severe influenza seasons and $260,000 per QALY in low-incidence seasons. For other preventive interventions, CE estimates ranged from cost-saving to $170,000 per QALY saved for breast cancer screening among women aged 50-74, from cost-saving to $16,000 per QALY for colorectal cancer screening, and from $27,000 to $600,000 per QALY for hypertension screening and treatment. Influenza vaccination in adults appears to have a similar CE profile as other commonly utilized preventive services for adults. Efforts to improve adult vaccination should be considered by adult-patient providers, healthcare systems and payers given the health and economic benefits of influenza vaccination.

Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among US Medicare Beneficiaries in Preventing Postinfluenza Deaths During 2012-2013 and 2013-2014.

Background: Recipients of high-dose vs standard-dose influenza vaccines have fewer influenza illnesses. We evaluated the comparative effectiveness of high-dose vaccine in preventing postinfluenza deaths during 2012-2013 and 2013-2014, when influenza viruses and vaccines were similar. Methods: We identified Medicare beneficiaries aged ≥65 years who received high-dose or standard-dose vaccines in community-located pharmacies offering both vaccines. The primary outcome was death in the 30 days following an inpatient or emergency department encounter listing an influenza International of Classification of Diseases, Ninth Revision, Clinical Modification code. Effectiveness was estimated by using multivariate Poisson regression models; effectiveness was allowed to vary by season. Results: We studied 1039645 recipients of high-dose and 1683264 recipients of standard-dose vaccines during 2012-2013, and 1508176 high-dose and 1877327 standard-dose recipients during 2013-2014. Vaccinees were well-balanced for medical conditions and indicators of frail health. Rates of postinfluenza death were 0.028 and 0.038/10000 person-weeks in high-dose and standard-dose recipients, respectively. Comparative effectiveness was 24.0% (95% confidence interval [CI], .6%-42%); there was evidence of variation by season (P = .12). In 2012-2013, high-dose was 36.4% (95% CI, 9.0%-56%) more effective in reducing mortality; in 2013-2014, it was 2.5% (95% CI, -47% to 35%). Conclusions: High-dose vaccine was significantly more effective in preventing postinfluenza deaths in 2012-2013, when A(H3N2) circulation was common, but not in 2013-2014.

Estimating Direct and Indirect Protective Effect of Influenza Vaccination in the United States.

With influenza vaccination rates in the United States recently exceeding 45% of the population, it is important to understand the impact that vaccination is having on influenza transmission. In this study, we used a Bayesian modeling approach, combined with a simple dynamical model of influenza transmission, to estimate this impact. The combined framework synthesized evidence from a range of data sources relating to influenza transmission and vaccination in the United States. We found that, for seasonal epidemics, the number of infections averted ranged from 9.6 million in the 2006-2007 season (95% credible interval (CI): 8.7, 10.9) to 37.2 million (95% CI: 34.1, 39.6) in the 2012-2013 season. Expressed in relative terms, the proportion averted ranged from 20.8% (95% CI: 16.8, 24.3) of potential infections in the 2011-2012 season to 47.5% (95% CI: 43.7, 50.8) in the 2008-2009 season. The percentage averted was only 1.04% (95% CI: 0.15, 3.2) for the 2009 H1N1 pandemic, owing to the late timing of the vaccination program in relation to the pandemic in the Northern hemisphere. In the future, further vaccination coverage, as well as improved influenza vaccines (especially those offering better protection in the elderly), could have an even stronger effect on annual influenza epidemics.

Association Between Hospitalization With Community-Acquired Laboratory-Confirmed Influenza Pneumonia and Prior Receipt of Influenza Vaccination.

IMPORTANCE: Few studies have evaluated the relationship between influenza vaccination and pneumonia, a serious complication of influenza infection. OBJECTIVE: To assess the association between influenza vaccination status and hospitalization for community-acquired laboratory-confirmed influenza pneumonia. DESIGN, SETTING, AND PARTICIPANTS: The Etiology of Pneumonia in the Community (EPIC) study was a prospective observational multicenter study of hospitalizations for community-acquired pneumonia conducted from January 2010 through June 2012 at 4 US sites. In this case-control study, we used EPIC data from patients 6 months or older with laboratory-confirmed influenza infection and verified vaccination status during the influenza seasons and excluded patients with recent hospitalization, from chronic care residential facilities, and with severe immunosuppression. Logistic regression was used to calculate odds ratios, comparing the odds of vaccination between influenza-positive (case) and influenza-negative (control) patients with pneumonia, controlling for demographics, comorbidities, season, study site, and timing of disease onset. Vaccine effectiveness was estimated as (1 - adjusted odds ratio) × 100%. EXPOSURE: Influenza vaccination, verified through record review. MAIN OUTCOMES AND MEASURES: Influenza pneumonia, confirmed by real-time reverse-transcription polymerase chain reaction performed on nasal/oropharyngeal swabs. RESULTS: Overall, 2767 patients hospitalized for pneumonia were eligible for the study; 162 (5.9%) had laboratory-confirmed influenza. Twenty-eight of 162 cases (17%) with influenza-associated pneumonia and 766 of 2605 controls (29%) with influenza-negative pneumonia had been vaccinated. The adjusted odds ratio of prior influenza vaccination between cases and controls was 0.43 (95% CI, 0.28-0.68; estimated vaccine effectiveness, 56.7%; 95% CI, 31.9%-72.5%). CONCLUSIONS AND RELEVANCE: Among children and adults hospitalized with community-acquired pneumonia, those with laboratory-confirmed influenza-associated pneumonia, compared with those with pneumonia not associated with influenza, had lower odds of having received influenza vaccination.

Factors associated with peridomestic Triatoma sanguisuga (Hemiptera: Reduviidae) presence in southeastern Louisiana.

Although rare, there have been isolated reports of autochthonous transmission of Trypanosoma cruzi Chagas in the United States. In June 2006, a human case of domestically transmitted T. cruzi was identified in southern Louisiana. To examine the localized risk of human T. cruzi infection in the area surrounding the initial human case, environmental surveys of households in the area and a serological survey of the residents were performed between September 2008 and November 2009. Human T. cruzi infection was determined using a rapid antigen field test, followed by confirmatory enzyme-linked immunosorbent assay testing in the laboratory. A perimeter search of each participating residence for Triatoma sanguisuga (LeConte), the predominant local triatomine species, was also performed. No participating individuals were positive for antibodies against T. cruzi; however, high levels of T. cruzi infection (62.4%) were detected in collected T. sanguisuga. Households with T. sanguisuga presence were less likely to use air conditioning, and more likely to have either chickens or cats on the property. While the human risk for T cruzi infection in southeastern Louisiana is low, a high prevalence of infected T. sanguisuga does indicate a substantial latent risk for T. cruzi peridomestic transmission. Further examination of the behavior and ecology of T. sanguisuga in the region will assist in refining local T. cruzi risk associations.

A spatial model of mosquito host-seeking behavior.

Mosquito host-seeking behavior and heterogeneity in host distribution are important factors in predicting the transmission dynamics of mosquito-borne infections such as dengue fever, malaria, chikungunya, and West Nile virus. We develop and analyze a new mathematical model to describe the effect of spatial heterogeneity on the contact rate between mosquito vectors and hosts. The model includes odor plumes generated by spatially distributed hosts, wind velocity, and mosquito behavior based on both the prevailing wind and the odor plume. On a spatial scale of meters and a time scale of minutes, we compare the effectiveness of different plume-finding and plume-tracking strategies that mosquitoes could use to locate a host. The results show that two different models of chemotaxis are capable of producing comparable results given appropriate parameter choices and that host finding is optimized by a strategy of flying across the wind until the odor plume is intercepted. We also assess the impact of changing the level of host aggregation on mosquito host-finding success near the end of the host-seeking flight. When clusters of hosts are more tightly associated on smaller patches, the odor plume is narrower and the biting rate per host is decreased. For two host groups of unequal number but equal spatial density, the biting rate per host is lower in the group with more individuals, indicative of an attack abatement effect of host aggregation. We discuss how this approach could assist parameter choices in compartmental models that do not explicitly model the spatial arrangement of individuals and how the model could address larger spatial scales and other probability models for mosquito behavior, such as Lévy distributions.

Disproportionate mosquito feeding on aggregated hosts.

Despite the importance of per-capita feeding rates for mosquito-borne transmission dynamics, the relationship between host aggregation and per-capita feeding rates remains poorly characterized. We conducted indoor experiments to investigate how Culex quinquefasciatus (Say) mosquitoes distribute their blood feeding on variably aggregated domestic chickens (Callus gallus domesticus L.) (one chicken vs. a flock of seven to nine birds). Mosquitoes were always more likely to feed on the larger chicken group; yet, the single chicken tended to be fed on at a higher per-capita rate. When 10 chickens were available the feeding intensity was 4.5 times higher for the single chicken compared with the flock. We conclude that more highly aggregated hosts may experience lower exposure to mosquito bites than less aggregated hosts.

The impact of West Nile virus on the abundance of selected North American birds.

BACKGROUND: The emergence of West Nile virus (WNV) in North America has been associated with high mortality in the native avifauna and has raised concerns about the long-term impact of WNV on bird populations. Here, we present results from a longitudinal analysis of annual counts of six bird species, using North American Breeding Bird Survey data from ten states (1994 to 2010). We fit overdispersed Poisson models to annual counts. Counts from successive years were linked by an autoregressive process that depended on WNV transmission intensity (annual West Nile neuroinvasive disease reports) and was adjusted by El Niño Southern Oscillation events. These models were fit using a Markov chain Monte Carlo algorithm. RESULTS: Model fit was mostly excellent, especially for American Crows, for which our models explained between 26% and 81% of the observed variance. The impact of WNV on bird populations was quantitatively evaluated by contrasting hypothetical count trajectories (omission of WNV) with observed counts. Populations of American crows were most consistently affected with a substantial cumulative impact in six of ten states. The largest negative impact, almost 60%, was found in Illinois. A regionally substantial decline was also seen for American Robins and House Sparrows, while the other species appeared unaffected. CONCLUSIONS: Our results confirm findings from previous studies that single out American Crows as the species most vulnerable to WNV infection. We discuss strengths and limitations of this and other methods for quantifying the impact of WNV on bird populations.

Potential and actual terrestrial rabies exposures in people and domestic animals, upstate South Carolina, 1994-2004: a surveillance study.

BACKGROUND: Although there has been a reduction of rabies in pets and domestic animals during recent decades in the United States, rabies remains enzootic among bats and several species of terrestrial wildlife. Spillover transmission of wildlife rabies to domestic animals therefore remains a public health threat METHODS: Retrospective analysis of surveillance data of reported animal incidents (bites, scratches, mucous membrane contacts) from South Carolina, 1995 to 2003, was performed to assess risk factors of potential rabies exposures among human and animal victims. RESULTS: Dogs and cats contributed the majority (66.7% and 26.4%, respectively) of all reported incidents, with stray dogs and cats contributing 9.0% and 15.1 respectively. Current rabies vaccination status of dogs and cats (40.2% and 13.8%, respectively) were below World Health Organization recommended levels. Owned cats were half as likely to be vaccinated for rabies as dogs (OR 0.53, 95% CI 0.48, 0.58). Animal victims were primarily exposed to wildlife (83.0%), of which 27.5% were rabid. Almost 90% of confirmed rabies exposures were due to wildlife. Skunks had the highest prevalence of rabies among species of exposure animals (63.2%). Among rabid domestic animals, stray cats were the most commonly reported (47.4%). CONCLUSION: While the majority of reported potential rabies exposures are associated with dog and cat incidents, most rabies exposures derive from rabid wildlife. Stray cats were most frequently rabid among domestic animals. Our results underscore the need for improvement of wildlife rabies control and the reduction of interactions of domestic animals, including cats, with wildlife.

Vaccination history as a confounder of studies of influenza vaccine effectiveness.

BACKGROUND: Vaccination history may confound estimates of influenza vaccine effectiveness (VE) when two conditions are present: (1) Influenza vaccination is associated with vaccination history and (2) vaccination modifies the risk of natural infection in the following seasons, either due to persisting vaccination immunity or due to lower previous risk of natural infection. METHODS: Analytic arguments are used to define conditions for confounding of VE estimates by vaccination history. Simulation studies, both with accurate and inaccurate assessment of current and previous vaccination status, are used to explore the potential magnitude of these biases when using different statistical models to address confounding by vaccination history. RESULTS: We found a potential for substantial bias of VE estimates by vaccination history if infection- and/or vaccination-derived immunity persisted from one season to the next and if vaccination uptake in individuals was seasonally correlated. Full adjustment by vaccination history, which is usually not feasible, resulted in unbiased VE estimates. Partial adjustment, i.e. only by prior season's vaccination status, significantly reduced confounding bias. Misclassification of vaccination status, which can also lead to substantial bias, interferes with the adjustment of VE estimates for vaccination history. CONCLUSIONS: Confounding by vaccination history may bias VE estimates, but even partial adjustment by only the prior season's vaccination status substantially reduces confounding bias. Misclassification of vaccination status may compromise VE estimates and efforts to adjust for vaccination history.

Persistent and relapsing babesiosis in immunocompromised patients.

BACKGROUND: Human babesiosis is a tickborne malaria-like illness that generally resolves without complication after administration of atovaquone and azithromycin or clindamycin and quinine. Although patients experiencing babesiosis that is unresponsive to standard antimicrobial therapy have been described, the pathogenesis, clinical course, and optimal treatment regimen of such cases remain uncertain. METHODS: We compared the immunologic status, clinical course, and treatment of 14 case patients who experienced morbidity or death after persistence of Babesia microti infection, despite repeated courses of antibabesial treatment, with those of 46 control subjects whose infection resolved after a single course of standard therapy. This retrospective case-control study was performed in southern New England, New York, and Wisconsin. RESULTS: All case patients were immunosuppressed at the time of acute babesiosis, compared with <10% of the control subjects. Most case patients experienced B cell lymphoma and were asplenic or had received rituximab before babesial illness. The case patients were more likely than control subjects to experience complications, and 3 died. Resolution of persistent infection occurred in 11 patients after 2-10 courses of therapy, including administration of a final antimicrobial regimen for at least 2 weeks after babesia were no longer seen on blood smear. CONCLUSIONS: Immunocompromised people who are infected by B. microti are at risk of persistent relapsing illness. Such patients generally require antibabesial treatment for >or=6 weeks to achieve cure, including 2 weeks after parasites are no longer detected on blood smear.

Revised estimates of influenza-associated excess mortality, United States, 1995 through 2005.

BACKGROUND: Excess mortality due to seasonal influenza is thought to be substantial. However, influenza may often not be recognized as cause of death. Imputation methods are therefore required to assess the public health impact of influenza. The purpose of this study was to obtain estimates of monthly excess mortality due to influenza that are based on an epidemiologically meaningful model. METHODS AND RESULTS: U.S. monthly all-cause mortality, 1995 through 2005, was hierarchically modeled as Poisson variable with a mean that linearly depends both on seasonal covariates and on influenza-certified mortality. It also allowed for overdispersion to account for extra variation that is not captured by the Poisson error. The coefficient associated with influenza-certified mortality was interpreted as ratio of total influenza mortality to influenza-certified mortality. Separate models were fitted for four age categories (< 18, 18-49, 50-64, 65+). Bayesian parameter estimation was performed using Markov Chain Monte Carlo methods. For the eleven year study period, a total of 260,814 (95% CI: 201,011-290,556) deaths was attributed to influenza, corresponding to an annual average of 23,710, or 0.91% of all deaths. CONCLUSION: Annual estimates for influenza mortality were highly variable from year to year, but they were systematically lower than previously published estimates. The excellent fit of our model with the data suggest validity of our estimates.

An evaluation and update of methods for estimating the number of influenza cases averted by vaccination in the United States.

INTRODUCTION: To evaluate the public health benefit of yearly influenza vaccinations, CDC estimates the number of influenza cases and hospitalizations averted by vaccine. Available input data on cases and vaccinations is aggregated by month and the estimation model is intentionally simple, raising concerns about the accuracy of estimates. METHODS: We created a synthetic dataset with daily counts of influenza cases and vaccinations, calculated "true" averted cases using a reference model applied to the daily data, aggregated the data by month to simulate data that would actually be available, and evaluated the month-level data with seven test methods (including the current method). Methods with averted case estimates closest to the reference model were considered most accurate. To examine their performance under varying conditions, we re-evaluated the test methods when synthetic data parameters (timing of vaccination relative to cases, vaccination coverage, infection rate, and vaccine effectiveness) were varied over wide ranges. Finally, we analyzed real (i.e., collected by surveillance) data from 2010 to 2017 comparing the current method used by CDC with the best-performing test methods. RESULTS: In the synthetic dataset (population 1 million persons, vaccination uptake 55%, seasonal infection risk without vaccination 12%, vaccine effectiveness 48%) the reference model estimated 28,768 averted cases. The current method underestimated averted cases by 9%. The two best test methods estimated averted cases with <1% error. These two methods also worked well when synthetic data parameters were varied over wide ranges (≤6.2% error). With the real data, these two methods estimated numbers of averted cases that are a median 8% higher than the currently-used method. CONCLUSIONS: We identified two methods for estimating numbers of influenza cases averted by vaccine that are more accurate than the currently-used algorithm. These methods will help us to better assess the benefits of influenza vaccination.

Annual estimates of the burden of seasonal influenza in the United States: A tool for strengthening influenza surveillance and preparedness.

BACKGROUND: Estimates of influenza disease burden are broadly useful for public health, helping national and local authorities monitor epidemiologic trends, plan and allocate resources, and promote influenza vaccination. Historically, estimates of the burden of seasonal influenza in the United States, focused mainly on influenza-related mortality and hospitalization, were generated every few years. Since the 2010-2011 influenza season, annual US influenza burden estimates have been generated and expanded to include estimates of influenza-related outpatient medical visits and symptomatic illness in the community. METHODS: We used routinely collected surveillance data, outbreak field investigations, and proportions of people seeking health care from survey results to estimate the number of illnesses, medical visits, hospitalizations, and deaths due to influenza during six influenza seasons (2010-2011 through 2015-2016). RESULTS: We estimate that the number of influenza-related illnesses that have occurred during influenza season has ranged from 9.2 million to 35.6 million, including 140 000 to 710 000 influenza-related hospitalizations. DISCUSSION: These annual efforts have strengthened public health communications products and supported timely assessment of the impact of vaccination through estimates of illness and hospitalizations averted. Additionally, annual estimates of influenza burden have highlighted areas where disease surveillance needs improvement to better support public health decision making for seasonal influenza epidemics as well as future pandemics.