Multimodeling approach to evaluating the efficacy of layering pharmaceutical and nonpharmaceutical interventions for influenza pandemics.

When an influenza pandemic emerges, temporary school closures and antiviral treatment may slow virus spread, reduce the overall disease burden, and provide time for vaccine development, distribution, and administration while keeping a larger portion of the general population infection free. The impact of such measures will depend on the transmissibility and severity of the virus and the timing and extent of their implementation. To provide robust assessments of layered pandemic intervention strategies, the Centers for Disease Control and Prevention (CDC) funded a network of academic groups to build a framework for the development and comparison of multiple pandemic influenza models. Research teams from Columbia University, Imperial College London/Princeton University, Northeastern University, the University of Texas at Austin/Yale University, and the University of Virginia independently modeled three prescribed sets of pandemic influenza scenarios developed collaboratively by the CDC and network members. Results provided by the groups were aggregated into a mean-based ensemble. The ensemble and most component models agreed on the ranking of the most and least effective intervention strategies by impact but not on the magnitude of those impacts. In the scenarios evaluated, vaccination alone, due to the time needed for development, approval, and deployment, would not be expected to substantially reduce the numbers of illnesses, hospitalizations, and deaths that would occur. Only strategies that included early implementation of school closure were found to substantially mitigate early spread and allow time for vaccines to be developed and administered, especially under a highly transmissible pandemic scenario.

Estimating community-wide indirect effects of influenza vaccination: triangulation using mathematical models and bias analysis.

Understanding whether influenza vaccine promotion strategies produce community-wide indirect effects is important for establishing vaccine coverage targets and optimizing vaccine delivery. Empirical epidemiologic studies and mathematical models have been used to estimate indirect effects of vaccines but rarely for the same estimand in the same dataset. Using these approaches together could be a powerful tool for triangulation in infectious disease epidemiology because each approach is subject to distinct sources of bias. We triangulated evidence about indirect effects from a school-located influenza vaccination program using two approaches: a difference-in-difference (DID) analysis, and an age-structured, deterministic, compartmental model. The estimated indirect effect was substantially lower in the mathematical model than in the DID analysis (2.1% (95% Bayesian credible intervals 0.4 - 4.4%) vs. 22.3% (95% CI 7.6% - 37.1%)). To explore reasons for differing estimates, we used sensitivity analyses and probabilistic bias analyses. When we constrained model parameters such that projections matched the DID analysis, results only aligned with the DID analysis with substantially lower pre-existing immunity among school-age children and older adults. Conversely, DID estimates corrected for potential bias only aligned with mathematical model estimates under differential outcome misclassification. We discuss how triangulation using empirical and mathematical modelling approaches could strengthen future studies.

Wastewater Surveillance for Influenza A Virus and H5 Subtype Concurrent with the Highly Pathogenic Avian Influenza A(H5N1) Virus Outbreak in Cattle and Poultry and Associated Human Cases - United States, May 12-July 13, 2024.

As part of the response to the highly pathogenic avian influenza A(H5N1) virus outbreak in U.S. cattle and poultry and the associated human cases, CDC and partners are monitoring influenza A virus levels and detection of the H5 subtype in wastewater. Among 48 states and the District of Columbia that performed influenza A testing of wastewater during May 12-July 13, 2024, a weekly average of 309 sites in 38 states had sufficient data for analysis, and 11 sites in four states reported high levels of influenza A virus. H5 subtype testing was conducted at 203 sites in 41 states, with H5 detections at 24 sites in nine states. For each detection or high level, CDC and state and local health departments evaluated data from other influenza surveillance systems and partnered with wastewater utilities and agriculture departments to investigate potential sources. Among the four states with high influenza A virus levels detected in wastewater, three states had corresponding evidence of human influenza activity from other influenza surveillance systems. Among the 24 sites with H5 detections, 15 identified animal sources within the sewershed or adjacent county, including eight milk-processing inputs. Data from these early investigations can help health officials optimize the use of wastewater surveillance during the upcoming respiratory illness season.

Using real-time data to guide decision-making during an influenza pandemic: A modelling analysis.

Influenza pandemics typically occur in multiple waves of infection, often associated with initial emergence of a novel virus, followed (in temperate regions) by a resurgence accompanying the onset of the annual influenza season. Here, we examined whether data collected from an initial pandemic wave could be informative, for the need to implement non-pharmaceutical measures in any resurgent wave. Drawing from the 2009 H1N1 pandemic in 10 states in the USA, we calibrated simple mathematical models of influenza transmission dynamics to data for laboratory confirmed hospitalisations during the initial 'spring' wave. We then projected pandemic outcomes (cumulative hospitalisations) during the fall wave, and compared these projections with data. Model results showed reasonable agreement for all states that reported a substantial number of cases in the spring wave. Using this model we propose a probabilistic decision framework that can be used to determine the need for preemptive measures such as postponing school openings, in advance of a fall wave. This work illustrates how model-based evidence synthesis, in real-time during an early pandemic wave, could be used to inform timely decisions for pandemic response.

Modeling the impacts of antiviral prophylaxis strategies in mitigating seasonal influenza outbreaks in nursing homes.

BACKGROUND: Antiviral chemoprophylaxis is recommended for use during influenza outbreaks in nursing homes to prevent transmission and severe disease among non-ill residents. Centers for Disease Control and Prevention (CDC) guidance recommends prophylaxis be initiated for all non-ill residents once an influenza outbreak is detected and be continued for at least 14 days and until seven days after the last laboratory-confirmed influenza case is identified. However, not all facilities strictly adhere to this guidance and the impact of such partial adherence is not fully understood. METHODS: We developed a stochastic compartmental framework to model influenza transmission within an average-sized U.S. nursing home. We compared the number of symptomatic illnesses and hospitalizations under varying prophylaxis implementation strategies, in addition to different levels of prophylaxis uptake and adherence by residents and healthcare personnel (HCP). RESULTS: Prophylaxis implemented according to current guidance reduced total symptomatic illnesses and hospitalizations among residents by an average of 12% and 36%, respectively, compared with no prophylaxis. We did not find evidence that alternative implementations of prophylaxis were more effective: compared to full adoption of current guidance, partial adoption resulted in increased symptomatic illnesses and/or hospitalizations, and longer or earlier adoption offered no additional improvements. In addition, increasing uptake and adherence among nursing home residents was effective in reducing resident illnesses and hospitalizations, but increasing HCP uptake had minimal indirect impacts for residents. CONCLUSIONS: The greatest benefits of influenza prophylaxis during nursing home outbreaks will likely be achieved through increasing uptake and adherence among residents and following current CDC guidance.

Correction: Recommended reporting items for epidemic forecasting and prediction research: The EPIFORGE 2020 guidelines.

[This corrects the article DOI: 10.1371/journal.pmed.1003793.].

Evaluating Potential Impacts of a Preferential Vaccine Recommendation for Adults 65 Years of Age and Older on US Influenza Burden.

BACKGROUND: High-dose, adjuvanted, and recombinant influenza vaccines may offer improved effectiveness among older adults compared with standard-dose, unadjuvanted, inactivated vaccines. However, the Advisory Committee on Immunization Practices (ACIP) only recently recommended preferential use of these "higher-dose or adjuvanted" vaccines. One concern was that individuals might delay or decline vaccination if a preferred vaccine is not readily available. METHODS: We mathematically model how a recommendation for preferential use of higher-dose or adjuvanted vaccines in adults ≥65 years might impact influenza burden in the United States during exemplar "high-" and "low-"severity seasons. We assume higher-dose or adjuvanted vaccines are more effective than standard vaccines and that such a recommendation would increase uptake of the former but could cause (i) delays in administration of additional higher-dose or adjuvanted vaccines relative to standard vaccines and/or (ii) reductions in overall coverage if individuals only offered standard vaccines forego vaccination. RESULTS: In a best-case scenario, assuming no delay or coverage reduction, a new recommendation could decrease hospitalizations and deaths in adults ≥65 years by 0%-4% compared with current uptake. However, intermediate and worst-case scenarios, with assumed delays of 3 or 6 weeks and/or 10% or 20% reductions in coverage, included projections in which hospitalizations and deaths increased by over 7%. CONCLUSIONS: We estimate that increased use of higher-dose or adjuvanted vaccines could decrease influenza burden in adults ≥65 in the United States provided there is timely and adequate access to these vaccines, and that standard vaccines are administered when they are unavailable.

High Influenza Incidence and Disease Severity Among Children and Adolescents Aged <18 Years - United States, 2022-23 Season.

During the 2022-23 influenza season, early increases in influenza activity, co-circulation of influenza with other respiratory viruses, and high influenza-associated hospitalization rates, particularly among children and adolescents, were observed. This report describes the 2022-23 influenza season among children and adolescents aged <18 years, including the seasonal severity assessment; estimates of U.S. influenza-associated medical visits, hospitalizations, and deaths; and characteristics of influenza-associated hospitalizations. The 2022-23 influenza season had high severity among children and adolescents compared with thresholds based on previous seasons' influenza-associated outpatient visits, hospitalization rates, and deaths. Nationally, the incidences of influenza-associated outpatient visits and hospitalization for the 2022-23 season were similar for children aged <5 years and higher for children and adolescents aged 5-17 years compared with previous seasons. Peak influenza-associated outpatient and hospitalization activity occurred in late November and early December. Among children and adolescents hospitalized with influenza during the 2022-23 season in hospitals participating in the Influenza Hospitalization Surveillance Network, a lower proportion were vaccinated (18.3%) compared with previous seasons (35.8%-41.8%). Early influenza circulation, before many children and adolescents had been vaccinated, might have contributed to the high hospitalization rates during the 2022-23 season. Among symptomatic hospitalized patients, receipt of influenza antiviral treatment (64.9%) was lower than during pre-COVID-19 pandemic seasons (80.8%-87.1%). CDC recommends that all persons aged ≥6 months without contraindications should receive the annual influenza vaccine, ideally by the end of October.

Comparing trained and untrained probabilistic ensemble forecasts of COVID-19 cases and deaths in the United States.

The U.S. COVID-19 Forecast Hub aggregates forecasts of the short-term burden of COVID-19 in the United States from many contributing teams. We study methods for building an ensemble that combines forecasts from these teams. These experiments have informed the ensemble methods used by the Hub. To be most useful to policymakers, ensemble forecasts must have stable performance in the presence of two key characteristics of the component forecasts: (1) occasional misalignment with the reported data, and (2) instability in the relative performance of component forecasters over time. Our results indicate that in the presence of these challenges, an untrained and robust approach to ensembling using an equally weighted median of all component forecasts is a good choice to support public health decision-makers. In settings where some contributing forecasters have a stable record of good performance, trained ensembles that give those forecasters higher weight can also be helpful.

Healthcare-Seeking Behavior for Respiratory Illness Among Flu Near You Participants in the United States During the 2015-2016 Through 2018-2019 Influenza Seasons.

BACKGROUND: Flu Near You (FNY) is an online participatory syndromic surveillance system that collects health-related information. In this article, we summarized the healthcare-seeking behavior of FNY participants who reported influenza-like illness (ILI) symptoms. METHODS: We applied inverse probability weighting to calculate age-adjusted estimates of the percentage of FNY participants in the United States who sought health care for ILI symptoms during the 2015-2016 through 2018-2019 influenza season and compared seasonal trends across different demographic and regional subgroups, including age group, sex, census region, and place of care using adjusted χ 2 tests. RESULTS: The overall age-adjusted percentage of FNY participants who sought healthcare for ILI symptoms varied by season and ranged from 22.8% to 35.6%. Across all seasons, healthcare seeking was highest for the <18 and 65+ years age groups, women had a greater percentage compared with men, and the South census region had the largest percentage while the West census region had the smallest percentage. CONCLUSIONS: The percentage of FNY participants who sought healthcare for ILI symptoms varied by season, geographical region, age group, and sex. FNY compliments existing surveillance systems and informs estimates of influenza-associated illness by adding important real-time insights into healthcare-seeking behavior.

Improving Pandemic Response: Employing Mathematical Modeling to Confront Coronavirus Disease 2019.

Modeling complements surveillance data to inform coronavirus disease 2019 (COVID-19) public health decision making and policy development. This includes the use of modeling to improve situational awareness, assess epidemiological characteristics, and inform the evidence base for prevention strategies. To enhance modeling utility in future public health emergencies, the Centers for Disease Control and Prevention (CDC) launched the Infectious Disease Modeling and Analytics Initiative. The initiative objectives are to: (1) strengthen leadership in infectious disease modeling, epidemic forecasting, and advanced analytic work; (2) build and cultivate a community of skilled modeling and analytics practitioners and consumers across CDC; (3) strengthen and support internal and external applied modeling and analytic work; and (4) working with partners, coordinate government-wide advanced data modeling and analytics for infectious diseases. These efforts are critical to help prepare the CDC, the country, and the world to respond effectively to present and future infectious disease threats.

Lessons Learned from CDC's Global COVID-19 Early Warning and Response Surveillance System.

Early warning and response surveillance (EWARS) systems were widely used during the early COVID-19 response. Evaluating the effectiveness of EWARS systems is critical to ensuring global health security. We describe the Centers for Disease Control and Prevention (CDC) global COVID-19 EWARS (CDC EWARS) system and the resources CDC used to gather, manage, and analyze publicly available data during the prepandemic period. We evaluated data quality and validity by measuring reporting completeness and compared these with data from Johns Hopkins University, the European Centre for Disease Prevention and Control, and indicator-based data from the World Health Organization. CDC EWARS was integral in guiding CDC's early COVID-19 response but was labor-intensive and became less informative as case-level data decreased and the pandemic evolved. However, CDC EWARS data were similar to those reported by other organizations, confirming the validity of each system and suggesting collaboration could improve EWARS systems during future pandemics.

A collaborative multiyear, multimodel assessment of seasonal influenza forecasting in the United States.

Influenza infects an estimated 9-35 million individuals each year in the United States and is a contributing cause for between 12,000 and 56,000 deaths annually. Seasonal outbreaks of influenza are common in temperate regions of the world, with highest incidence typically occurring in colder and drier months of the year. Real-time forecasts of influenza transmission can inform public health response to outbreaks. We present the results of a multiinstitution collaborative effort to standardize the collection and evaluation of forecasting models for influenza in the United States for the 2010/2011 through 2016/2017 influenza seasons. For these seven seasons, we assembled weekly real-time forecasts of seven targets of public health interest from 22 different models. We compared forecast accuracy of each model relative to a historical baseline seasonal average. Across all regions of the United States, over half of the models showed consistently better performance than the historical baseline when forecasting incidence of influenza-like illness 1 wk, 2 wk, and 3 wk ahead of available data and when forecasting the timing and magnitude of the seasonal peak. In some regions, delays in data reporting were strongly and negatively associated with forecast accuracy. More timely reporting and an improved overall accessibility to novel and traditional data sources are needed to improve forecasting accuracy and its integration with real-time public health decision making.

Recommended reporting items for epidemic forecasting and prediction research: The EPIFORGE 2020 guidelines.

BACKGROUND: The importance of infectious disease epidemic forecasting and prediction research is underscored by decades of communicable disease outbreaks, including COVID-19. Unlike other fields of medical research, such as clinical trials and systematic reviews, no reporting guidelines exist for reporting epidemic forecasting and prediction research despite their utility. We therefore developed the EPIFORGE checklist, a guideline for standardized reporting of epidemic forecasting research. METHODS AND FINDINGS: We developed this checklist using a best-practice process for development of reporting guidelines, involving a Delphi process and broad consultation with an international panel of infectious disease modelers and model end users. The objectives of these guidelines are to improve the consistency, reproducibility, comparability, and quality of epidemic forecasting reporting. The guidelines are not designed to advise scientists on how to perform epidemic forecasting and prediction research, but rather to serve as a standard for reporting critical methodological details of such studies. CONCLUSIONS: These guidelines have been submitted to the EQUATOR network, in addition to hosting by other dedicated webpages to facilitate feedback and journal endorsement.

Emergence of SARS-CoV-2 B.1.1.7 Lineage - United States, December 29, 2020-January 12, 2021.

On December 14, 2020, the United Kingdom reported a SARS-CoV-2 variant of concern (VOC), lineage B.1.1.7, also referred to as VOC 202012/01 or 20I/501Y.V1.* The B.1.1.7 variant is estimated to have emerged in September 2020 and has quickly become the dominant circulating SARS-CoV-2 variant in England (1). B.1.1.7 has been detected in over 30 countries, including the United States. As of January 13, 2021, approximately 76 cases of B.1.1.7 have been detected in 12 U.S. states.† Multiple lines of evidence indicate that B.1.1.7 is more efficiently transmitted than are other SARS-CoV-2 variants (1-3). The modeled trajectory of this variant in the U.S. exhibits rapid growth in early 2021, becoming the predominant variant in March. Increased SARS-CoV-2 transmission might threaten strained health care resources, require extended and more rigorous implementation of public health strategies (4), and increase the percentage of population immunity required for pandemic control. Taking measures to reduce transmission now can lessen the potential impact of B.1.1.7 and allow critical time to increase vaccination coverage. Collectively, enhanced genomic surveillance combined with continued compliance with effective public health measures, including vaccination, physical distancing, use of masks, hand hygiene, and isolation and quarantine, will be essential to limiting the spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). Strategic testing of persons without symptoms but at higher risk of infection, such as those exposed to SARS-CoV-2 or who have frequent unavoidable contact with the public, provides another opportunity to limit ongoing spread.

Genomic Surveillance for SARS-CoV-2 Variants Circulating in the United States, December 2020-May 2021.

SARS-CoV-2, the virus that causes COVID-19, is constantly mutating, leading to new variants (1). Variants have the potential to affect transmission, disease severity, diagnostics, therapeutics, and natural and vaccine-induced immunity. In November 2020, CDC established national surveillance for SARS-CoV-2 variants using genomic sequencing. As of May 6, 2021, sequences from 177,044 SARS-CoV-2-positive specimens collected during December 20, 2020-May 6, 2021, from 55 U.S. jurisdictions had been generated by or reported to CDC. These included 3,275 sequences for the 2-week period ending January 2, 2021, compared with 25,000 sequences for the 2-week period ending April 24, 2021 (0.1% and 3.1% of reported positive SARS-CoV-2 tests, respectively). Because sequences might be generated by multiple laboratories and sequence availability varies both geographically and over time, CDC developed statistical weighting and variance estimation methods to generate population-based estimates of the proportions of identified variants among SARS-CoV-2 infections circulating nationwide and in each of the 10 U.S. Department of Health and Human Services (HHS) geographic regions.* During the 2-week period ending April 24, 2021, the B.1.1.7 and P.1 variants represented an estimated 66.0% and 5.0% of U.S. SARS-CoV-2 infections, respectively, demonstrating the rise to predominance of the B.1.1.7 variant of concern† (VOC) and emergence of the P.1 VOC in the United States. Using SARS-CoV-2 genomic surveillance methods to analyze surveillance data produces timely population-based estimates of the proportions of variants circulating nationally and regionally. Surveillance findings demonstrate the potential for new variants to emerge and become predominant, and the importance of robust genomic surveillance. Along with efforts to characterize the clinical and public health impact of SARS-CoV-2 variants, surveillance can help guide interventions to control the COVID-19 pandemic in the United States.

Nowcasting (Short-Term Forecasting) of Influenza Epidemics in Local Settings, Sweden, 2008-2019.

The timing of influenza case incidence during epidemics can differ between regions within nations and states. We conducted a prospective 10-year evaluation (January 2008-February 2019) of a local influenza nowcasting (short-term forecasting) method in 3 urban counties in Sweden with independent public health administrations by using routine health information system data. Detection-of-epidemic-start (detection), peak timing, and peak intensity were nowcasted. Detection displayed satisfactory performance in 2 of the 3 counties for all nonpandemic influenza seasons and in 6 of 9 seasons for the third county. Peak-timing prediction showed satisfactory performance from the influenza season 2011-12 onward. Peak-intensity prediction also was satisfactory for influenza seasons in 2 of the counties but poor in 1 county. Local influenza nowcasting was satisfactory for seasonal influenza in 2 of 3 counties. The less satisfactory performance in 1 of the study counties might be attributable to population mixing with a neighboring metropolitan area.

Early Insights from Statistical and Mathematical Modeling of Key Epidemiologic Parameters of COVID-19.

We report key epidemiologic parameter estimates for coronavirus disease identified in peer-reviewed publications, preprint articles, and online reports. Range estimates for incubation period were 1.8-6.9 days, serial interval 4.0-7.5 days, and doubling time 2.3-7.4 days. The effective reproductive number varied widely, with reductions attributable to interventions. Case burden and infection fatality ratios increased with patient age. Implementation of combined interventions could reduce cases and delay epidemic peak up to 1 month. These parameters for transmission, disease severity, and intervention effectiveness are critical for guiding policy decisions. Estimates will likely change as new information becomes available.

Accuracy of real-time multi-model ensemble forecasts for seasonal influenza in the U.S.

Seasonal influenza results in substantial annual morbidity and mortality in the United States and worldwide. Accurate forecasts of key features of influenza epidemics, such as the timing and severity of the peak incidence in a given season, can inform public health response to outbreaks. As part of ongoing efforts to incorporate data and advanced analytical methods into public health decision-making, the United States Centers for Disease Control and Prevention (CDC) has organized seasonal influenza forecasting challenges since the 2013/2014 season. In the 2017/2018 season, 22 teams participated. A subset of four teams created a research consortium called the FluSight Network in early 2017. During the 2017/2018 season they worked together to produce a collaborative multi-model ensemble that combined 21 separate component models into a single model using a machine learning technique called stacking. This approach creates a weighted average of predictive densities where the weight for each component is determined by maximizing overall ensemble accuracy over past seasons. In the 2017/2018 influenza season, one of the largest seasonal outbreaks in the last 15 years, this multi-model ensemble performed better on average than all individual component models and placed second overall in the CDC challenge. It also outperformed the baseline multi-model ensemble created by the CDC that took a simple average of all models submitted to the forecasting challenge. This project shows that collaborative efforts between research teams to develop ensemble forecasting approaches can bring measurable improvements in forecast accuracy and important reductions in the variability of performance from year to year. Efforts such as this, that emphasize real-time testing and evaluation of forecasting models and facilitate the close collaboration between public health officials and modeling researchers, are essential to improving our understanding of how best to use forecasts to improve public health response to seasonal and emerging epidemic threats.

Estimating the Incidence of Influenza at the State Level - Utah, 2016-17 and 2017-18 Influenza Seasons.

The 2017-18 U.S. influenza season was notable for its high severity, with approximately 45 million illnesses and 810,000 influenza-associated hospitalizations throughout the United States (1). The purpose of the investigation reported here was to create a state-level estimate of the number of persons in Utah who became ill with influenza disease during this severe national seasonal influenza epidemic and to create a sustainable system for making timely updates in future influenza seasons. Knowing the extent of influenza-associated illness can help public health officials, policymakers, and clinicians tailor influenza messaging, planning, and responses for seasonal influenza epidemics or during pandemics. Using national methods and existing influenza surveillance and testing data, the influenza burden (number of influenza illnesses, medical visits for influenza, and influenza-associated hospitalizations) in Utah during the 2016-17 and 2017-18 influenza seasons was estimated. During the 2016-17 season, an estimated 265,000 symptomatic illnesses affecting 9% of Utah residents occurred, resulting in 125,000 medically attended illnesses and 2,700 hospitalizations. During the 2017-18 season, an estimated 338,000 symptomatic illnesses affecting 11% of Utah residents occurred, resulting in 160,000 medically attended illnesses and 3,900 hospitalizations. Other state or county health departments could adapt similar methods in their jurisdictions to estimate the burden of influenza locally and support prompt public health activities.