Multiple models for outbreak decision support in the face of uncertainty.

Policymakers must make management decisions despite incomplete knowledge and conflicting model projections. Little guidance exists for the rapid, representative, and unbiased collection of policy-relevant scientific input from independent modeling teams. Integrating approaches from decision analysis, expert judgment, and model aggregation, we convened multiple modeling teams to evaluate COVID-19 reopening strategies for a mid-sized United States county early in the pandemic. Projections from seventeen distinct models were inconsistent in magnitude but highly consistent in ranking interventions. The 6-mo-ahead aggregate projections were well in line with observed outbreaks in mid-sized US counties. The aggregate results showed that up to half the population could be infected with full workplace reopening, while workplace restrictions reduced median cumulative infections by 82%. Rankings of interventions were consistent across public health objectives, but there was a strong trade-off between public health outcomes and duration of workplace closures, and no win-win intermediate reopening strategies were identified. Between-model variation was high; the aggregate results thus provide valuable risk quantification for decision making. This approach can be applied to the evaluation of management interventions in any setting where models are used to inform decision making. This case study demonstrated the utility of our approach and was one of several multimodel efforts that laid the groundwork for the COVID-19 Scenario Modeling Hub, which has provided multiple rounds of real-time scenario projections for situational awareness and decision making to the Centers for Disease Control and Prevention since December 2020.

Potential impact of annual vaccination with reformulated COVID-19 vaccines: Lessons from the US COVID-19 scenario modeling hub.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) continues to cause significant hospitalizations and deaths in the United States. Its continued burden and the impact of annually reformulated vaccines remain unclear. Here, we present projections of COVID-19 hospitalizations and deaths in the United States for the next 2 years under 2 plausible assumptions about immune escape (20% per year and 50% per year) and 3 possible CDC recommendations for the use of annually reformulated vaccines (no recommendation, vaccination for those aged 65 years and over, vaccination for all eligible age groups based on FDA approval). METHODS AND FINDINGS: The COVID-19 Scenario Modeling Hub solicited projections of COVID-19 hospitalization and deaths between April 15, 2023 and April 15, 2025 under 6 scenarios representing the intersection of considered levels of immune escape and vaccination. Annually reformulated vaccines are assumed to be 65% effective against symptomatic infection with strains circulating on June 15 of each year and to become available on September 1. Age- and state-specific coverage in recommended groups was assumed to match that seen for the first (fall 2021) COVID-19 booster. State and national projections from 8 modeling teams were ensembled to produce projections for each scenario and expected reductions in disease outcomes due to vaccination over the projection period. From April 15, 2023 to April 15, 2025, COVID-19 is projected to cause annual epidemics peaking November to January. In the most pessimistic scenario (high immune escape, no vaccination recommendation), we project 2.1 million (90% projection interval (PI) [1,438,000, 4,270,000]) hospitalizations and 209,000 (90% PI [139,000, 461,000]) deaths, exceeding pre-pandemic mortality of influenza and pneumonia. In high immune escape scenarios, vaccination of those aged 65+ results in 230,000 (95% confidence interval (CI) [104,000, 355,000]) fewer hospitalizations and 33,000 (95% CI [12,000, 54,000]) fewer deaths, while vaccination of all eligible individuals results in 431,000 (95% CI: 264,000-598,000) fewer hospitalizations and 49,000 (95% CI [29,000, 69,000]) fewer deaths. CONCLUSIONS: COVID-19 is projected to be a significant public health threat over the coming 2 years. Broad vaccination has the potential to substantially reduce the burden of this disease, saving tens of thousands of lives each year.

Strategic testing approaches for targeted disease monitoring can be used to inform pandemic decision-making.

More than 1.6 million Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) tests were administered daily in the United States at the peak of the epidemic, with a significant focus on individual treatment. Here, we show that objective-driven, strategic sampling designs and analyses can maximize information gain at the population level, which is necessary to increase situational awareness and predict, prepare for, and respond to a pandemic, while also continuing to inform individual treatment. By focusing on specific objectives such as individual treatment or disease prediction and control (e.g., via the collection of population-level statistics to inform lockdown measures or vaccine rollout) and drawing from the literature on capture-recapture methods to deal with nonrandom sampling and testing errors, we illustrate how public health objectives can be achieved even with limited test availability when testing programs are designed a priori to meet those objectives.

Misapplied management makes matters worse: Spatially explicit control leverages biotic interactions to slow invasion.

A wide range of approaches has been used to manage the spread of invasive species, yet invaders continue to be a challenge to control. In some cases, management actions have no effect or may even inadvertently benefit the targeted invader. Here, we use the mid-20th century management of the Red Imported Fire Ant, Solenopsis invicta, in the US as a motivating case study to explore the conditions under which such wasted management effort may occur. Introduced in approximately 1940, the fire ant spread widely through the southeast US and became a problematic pest. Historically, fire ants were managed with broad-spectrum pesticides; unfortunately, these efforts were largely unsuccessful. One hypothesis suggests that, by also killing native ants, mass pesticide application reduced competitive burdens thereby enabling fire ants to invade more quickly than they would in the absence of management. We use a mechanistic competition model to demonstrate the landscape-level effects of such management. We explicitly model the extent and location of pesticide applications, showing that the same pesticide application can have a positive, neutral, or negative effect on the progress of an invasion, depending on where it is applied on the landscape with respect to the invasion front. When designing management, the target species is often considered alone; however, this work suggests that leveraging existing biotic interactions, specifically competition with native species, can increase the efficacy of management. Our model not only highlights the potential unintended consequences of ignoring biotic interactions, but also provides a framework for developing spatially explicit management strategies that take advantage of these biotic interactions to work smarter, not harder.

Benefits of near-universal vaccination and treatment access to manage COVID-19 burden in the United States.

BACKGROUND: As we continue the fourth year of the COVID-19 epidemic, SARS-CoV-2 infections still cause high morbidity and mortality in the United States. During 2020-2022, COVID-19 was one of the leading causes of death in the United States and by far the leading cause among infectious diseases. Vaccination uptake remains low despite this being an effective burden reducing intervention. The development of COVID-19 therapeutics provides hope for mitigating severe clinical outcomes. This modeling study examines combined strategies of vaccination and treatment to reduce the burden of COVID-19 epidemics over the next decade. METHODS: We use a validated mathematical model to evaluate the reduction of incident cases, hospitalized cases, and deaths in the United States through 2033 under various levels of vaccination and treatment coverage. We assume that future seasonal transmission patterns for COVID-19 will be similar to those of influenza virus and account for the waning of infection-induced immunity and vaccine-induced immunity in a future with stable COVID-19 dynamics. Due to uncertainty in the duration of immunity following vaccination or infection, we consider three exponentially distributed waning rates, with means of 365 days (1 year), 548 days (1.5 years), and 730 days (2 years). We also consider treatment failure, including rebound frequency, as a possible treatment outcome. RESULTS: As expected, universal vaccination is projected to eliminate transmission and mortality. Under current treatment coverage (13.7%) and vaccination coverage (49%), averages of 81,000-164,600 annual reported deaths, depending on duration of immunity, are expected by the end of this decade. Annual mortality in the United States can be reduced below 50,000 per year with 52-80% annual vaccination coverage and below 10,000 annual deaths with 59-83% annual vaccination coverage, depending on duration of immunity. Universal treatment reduces hospitalizations by 88.6% and deaths by 93.1% under current vaccination coverage. A reduction in vaccination coverage requires a comparatively larger increase in treatment coverage in order for hospitalization and mortality levels to remain unchanged. CONCLUSIONS: Adopting universal vaccination and universal treatment goals in the United States will likely lead to a COVID-19 mortality burden below 50,000 deaths per year, a burden comparable to that of influenza virus.

The effect of governance structures on optimal control of two-patch epidemic models.

Infectious diseases continue to pose a significant threat to the health of humans globally. While the spread of pathogens transcends geographical boundaries, the management of infectious diseases typically occurs within distinct spatial units, determined by geopolitical boundaries. The allocation of management resources within and across regions (the "governance structure") can affect epidemiological outcomes considerably, and policy-makers are often confronted with a choice between applying control measures uniformly or differentially across regions. Here, we investigate the extent to which uniform and non-uniform governance structures affect the costs of an infectious disease outbreak in two-patch systems using an optimal control framework. A uniform policy implements control measures with the same time varying rate functions across both patches, while these measures are allowed to differ between the patches in a non-uniform policy. We compare results from two systems of differential equations representing transmission of cholera and Ebola, respectively, to understand the interplay between transmission mode, governance structure and the optimal control of outbreaks. In our case studies, the governance structure has a meaningful impact on the allocation of resources and burden of cases, although the difference in total costs is minimal. Understanding how governance structure affects both the optimal control functions and epidemiological outcomes is crucial for the effective management of infectious diseases going forward.

Synergistic interventions to control COVID-19: Mass testing and isolation mitigates reliance on distancing.

Stay-at-home orders and shutdowns of non-essential businesses are powerful, but socially costly, tools to control the pandemic spread of SARS-CoV-2. Mass testing strategies, which rely on widely administered frequent and rapid diagnostics to identify and isolate infected individuals, could be a potentially less disruptive management strategy, particularly where vaccine access is limited. In this paper, we assess the extent to which mass testing and isolation strategies can reduce reliance on socially costly non-pharmaceutical interventions, such as distancing and shutdowns. We develop a multi-compartmental model of SARS-CoV-2 transmission incorporating both preventative non-pharmaceutical interventions (NPIs) and testing and isolation to evaluate their combined effect on public health outcomes. Our model is designed to be a policy-guiding tool that captures important realities of the testing system, including constraints on test administration and non-random testing allocation. We show how strategic changes in the characteristics of the testing system, including test administration, test delays, and test sensitivity, can reduce reliance on preventative NPIs without compromising public health outcomes in the future. The lowest NPI levels are possible only when many tests are administered and test delays are short, given limited immunity in the population. Reducing reliance on NPIs is highly dependent on the ability of a testing program to identify and isolate unreported, asymptomatic infections. Changes in NPIs, including the intensity of lockdowns and stay at home orders, should be coordinated with increases in testing to ensure epidemic control; otherwise small additional lifting of these NPIs can lead to dramatic increases in infections, hospitalizations and deaths. Importantly, our results can be used to guide ramp-up of testing capacity in outbreak settings, allow for the flexible design of combined interventions based on social context, and inform future cost-benefit analyses to identify efficient pandemic management strategies.

Modeling of Future COVID-19 Cases, Hospitalizations, and Deaths, by Vaccination Rates and Nonpharmaceutical Intervention Scenarios - United States, April-September 2021.

After a period of rapidly declining U.S. COVID-19 incidence during January-March 2021, increases occurred in several jurisdictions (1,2) despite the rapid rollout of a large-scale vaccination program. This increase coincided with the spread of more transmissible variants of SARS-CoV-2, the virus that causes COVID-19, including B.1.1.7 (1,3) and relaxation of COVID-19 prevention strategies such as those for businesses, large-scale gatherings, and educational activities. To provide long-term projections of potential trends in COVID-19 cases, hospitalizations, and deaths, COVID-19 Scenario Modeling Hub teams used a multiple-model approach comprising six models to assess the potential course of COVID-19 in the United States across four scenarios with different vaccination coverage rates and effectiveness estimates and strength and implementation of nonpharmaceutical interventions (NPIs) (public health policies, such as physical distancing and masking) over a 6-month period (April-September 2021) using data available through March 27, 2021 (4). Among the four scenarios, an accelerated decline in NPI adherence (which encapsulates NPI mandates and population behavior) was shown to undermine vaccination-related gains over the subsequent 2-3 months and, in combination with increased transmissibility of new variants, could lead to surges in cases, hospitalizations, and deaths. A sharp decline in cases was projected by July 2021, with a faster decline in the high-vaccination scenarios. High vaccination rates and compliance with public health prevention measures are essential to control the COVID-19 pandemic and to prevent surges in hospitalizations and deaths in the coming months.

When do we need multiple infectious disease models? Agreement between projection rank and magnitude in a multi-model setting.

Mathematical models are useful for public health planning and response to infectious disease threats. However, different models can provide differing results, which can hamper decision making if not synthesized appropriately. To address this challenge, multi-model hubs convene independent modeling groups to generate ensembles, known to provide more accurate predictions of future outcomes. Yet, these hubs are resource intensive, and how many models are sufficient in a hub is not known. Here, we compare the benefit of predictions from multiple models in different contexts: (1) decision settings that depend on predictions of quantitative outcomes (e.g., hospital capacity planning), where assessments of the benefits of multi-model ensembles have largely focused; and (2) decisions settings that require the ranking of alternative epidemic scenarios (e.g., comparing outcomes under multiple possible interventions and biological uncertainties). We develop a mathematical framework to mimic a multi-model prediction setting, and use this framework to quantify how frequently predictions from different models agree. We further explore multi-model agreement using real-world, empirical data from 14 rounds of U.S. COVID-19 Scenario Modeling Hub projections. Our results suggest that the value of multiple models could be different in different decision contexts, and if only a few models are available, focusing on the rank of alternative epidemic scenarios could be more robust than focusing on quantitative outcomes. Although additional exploration of the sufficient number of models for different contexts is still needed, our results indicate that it may be possible to identify decision contexts where it is robust to rely on fewer models, a finding that can inform the use of modeling resources during future public health crises.

Ensemble2: Scenarios ensembling for communication and performance analysis.

Throughout the COVID-19 pandemic, scenario modeling played a crucial role in shaping the decision-making process of public health policies. Unlike forecasts, scenario projections rely on specific assumptions about the future that consider different plausible states-of-the-world that may or may not be realized and that depend on policy interventions, unpredictable changes in the epidemic outlook, etc. As a consequence, long-term scenario projections require different evaluation criteria than the ones used for traditional short-term epidemic forecasts. Here, we propose a novel ensemble procedure for assessing pandemic scenario projections using the results of the Scenario Modeling Hub (SMH) for COVID-19 in the United States (US). By defining a "scenario ensemble" for each model and the ensemble of models, termed "Ensemble2", we provide a synthesis of potential epidemic outcomes, which we use to assess projections' performance, bypassing the identification of the most plausible scenario. We find that overall the Ensemble2 models are well-calibrated and provide better performance than the scenario ensemble of individual models. The ensemble procedure accounts for the full range of plausible outcomes and highlights the importance of scenario design and effective communication. The scenario ensembling approach can be extended to any scenario design strategy, with potential refinements including weighting scenarios and allowing the ensembling process to evolve over time.

Scenario design for infectious disease projections: Integrating concepts from decision analysis and experimental design.

Across many fields, scenario modeling has become an important tool for exploring long-term projections and how they might depend on potential interventions and critical uncertainties, with relevance to both decision makers and scientists. In the past decade, and especially during the COVID-19 pandemic, the field of epidemiology has seen substantial growth in the use of scenario projections. Multiple scenarios are often projected at the same time, allowing important comparisons that can guide the choice of intervention, the prioritization of research topics, or public communication. The design of the scenarios is central to their ability to inform important questions. In this paper, we draw on the fields of decision analysis and statistical design of experiments to propose a framework for scenario design in epidemiology, with relevance also to other fields. We identify six different fundamental purposes for scenario designs (decision making, sensitivity analysis, situational awareness, horizon scanning, forecasting, and value of information) and discuss how those purposes guide the structure of scenarios. We discuss other aspects of the content and process of scenario design, broadly for all settings and specifically for multi-model ensemble projections. As an illustrative case study, we examine the first 17 rounds of scenarios from the U.S. COVID-19 Scenario Modeling Hub, then reflect on future advancements that could improve the design of scenarios in epidemiological settings.

The US COVID-19 and Influenza Scenario Modeling Hubs: Delivering long-term projections to guide policy.

Between December 2020 and April 2023, the COVID-19 Scenario Modeling Hub (SMH) generated operational multi-month projections of COVID-19 burden in the US to guide pandemic planning and decision-making in the context of high uncertainty. This effort was born out of an attempt to coordinate, synthesize and effectively use the unprecedented amount of predictive modeling that emerged throughout the COVID-19 pandemic. Here we describe the history of this massive collective research effort, the process of convening and maintaining an open modeling hub active over multiple years, and attempt to provide a blueprint for future efforts. We detail the process of generating 17 rounds of scenarios and projections at different stages of the COVID-19 pandemic, and disseminating results to the public health community and lay public. We also highlight how SMH was expanded to generate influenza projections during the 2022-23 season. We identify key impacts of SMH results on public health and draw lessons to improve future collaborative modeling efforts, research on scenario projections, and the interface between models and policy.

Benefits of near-universal vaccination and treatment access to manage COVID-19 burden in the United States.

Background: As we enter the fourth year of the COVID-19 pandemic, SARS-CoV-2 infections still cause high morbidity and mortality in the United States. During 2020-2022, COVID-19 was one of the leading causes of death in the United States and by far the leading cause among infectious diseases. Vaccination uptake remains low despite this being an effective burden reducing intervention. The development of COVID-19 therapeutics provides hope for mitigating severe clinical outcomes. This modeling study examines combined strategies of vaccination and treatment to reduce the burden of COVID-19 epidemics over the next decade. Methods: We use a validated mathematical model to evaluate the reduction of incident cases, hospitalized cases, and deaths in the United States through 2033 under various levels of vaccination and treatment coverage. We assume that future seasonal transmission patterns for COVID-19 will be similar to those of influenza virus. We account for the waning of infection-induced immunity and vaccine-induced immunity in a future with stable COVID-19 dynamics. Due to uncertainty in the duration of immunity following vaccination or infection, we consider two exponentially-distributed waning rates, with means of 365 days (one year) and 548 days (1.5 years). We also consider treatment failure, including rebound frequency, as a possible treatment outcome. Results: As expected, universal vaccination is projected to eliminate transmission and mortality. Under current treatment coverage (13.7%) and vaccination coverage (49%), averages of 89,000 annual deaths (548-day waning) and 120,000 annual deaths (365-day waning) are expected by the end of this decade. Annual mortality in the United States can be reduced below 50,000 per year with >81% annual vaccination coverage, and below 10,000 annual deaths with >84% annual vaccination coverage. Universal treatment reduces hospitalizations by 88% and deaths by 93% under current vaccination coverage. A reduction in vaccination coverage requires a comparatively larger increase in treatment coverage in order for hospitalization and mortality levels to remain unchanged. Conclusions: Adopting universal vaccination and universal treatment goals in the United States will likely lead to a COVID-19 mortality burden below 50,000 deaths per year, a burden comparable to that of influenza virus.

Optimal spatial evaluation of a pro rata vaccine distribution rule for COVID-19.

The COVID-19 Vaccines Global Access (COVAX) is a World Health Organization (WHO) initiative that aims for an equitable access of COVID-19 vaccines. Despite potential heterogeneous infection levels across a country, countries receiving allotments of vaccines may follow WHO's allocation guidelines and distribute vaccines based on a jurisdictions' relative population size. Utilizing economic-epidemiological modeling, we benchmark the performance of this pro rata allocation rule by comparing it to an optimal one that minimizes the economic damages and expenditures over time, including a penalty representing the social costs of deviating from the pro rata strategy. The pro rata rule performs better when the duration of naturally- and vaccine-acquired immunity is short, when there is population mixing, when the supply of vaccine is high, and when there is minimal heterogeneity in demographics. Despite behavioral and epidemiological uncertainty diminishing the performance of the optimal allocation, it generally outperforms the pro rata vaccine distribution rule.

Context-dependent representation of within- and between-model uncertainty: aggregating probabilistic predictions in infectious disease epidemiology.

Probabilistic predictions support public health planning and decision making, especially in infectious disease emergencies. Aggregating outputs from multiple models yields more robust predictions of outcomes and associated uncertainty. While the selection of an aggregation method can be guided by retrospective performance evaluations, this is not always possible. For example, if predictions are conditional on assumptions about how the future will unfold (e.g. possible interventions), these assumptions may never materialize, precluding any direct comparison between predictions and observations. Here, we summarize literature on aggregating probabilistic predictions, illustrate various methods for infectious disease predictions via simulation, and present a strategy for choosing an aggregation method when empirical validation cannot be used. We focus on the linear opinion pool (LOP) and Vincent average, common methods that make different assumptions about between-prediction uncertainty. We contend that assumptions of the aggregation method should align with a hypothesis about how uncertainty is expressed within and between predictions from different sources. The LOP assumes that between-prediction uncertainty is meaningful and should be retained, while the Vincent average assumes that between-prediction uncertainty is akin to sampling error and should not be preserved. We provide an R package for implementation. Given the rising importance of multi-model infectious disease hubs, our work provides useful guidance on aggregation and a deeper understanding of the benefits and risks of different approaches.

Scenario Design for Infectious Disease Projections: Integrating Concepts from Decision Analysis and Experimental Design.

Across many fields, scenario modeling has become an important tool for exploring long-term projections and how they might depend on potential interventions and critical uncertainties, with relevance to both decision makers and scientists. In the past decade, and especially during the COVID-19 pandemic, the field of epidemiology has seen substantial growth in the use of scenario projections. Multiple scenarios are often projected at the same time, allowing important comparisons that can guide the choice of intervention, the prioritization of research topics, or public communication. The design of the scenarios is central to their ability to inform important questions. In this paper, we draw on the fields of decision analysis and statistical design of experiments to propose a framework for scenario design in epidemiology, with relevance also to other fields. We identify six different fundamental purposes for scenario designs (decision making, sensitivity analysis, value of information, situational awareness, horizon scanning, and forecasting) and discuss how those purposes guide the structure of scenarios. We discuss other aspects of the content and process of scenario design, broadly for all settings and specifically for multi-model ensemble projections. As an illustrative case study, we examine the first 17 rounds of scenarios from the U.S. COVID-19 Scenario Modeling Hub, then reflect on future advancements that could improve the design of scenarios in epidemiological settings.

Impact of SARS-CoV-2 vaccination of children ages 5-11 years on COVID-19 disease burden and resilience to new variants in the United States, November 2021-March 2022: A multi-model study.

Background: The COVID-19 Scenario Modeling Hub convened nine modeling teams to project the impact of expanding SARS-CoV-2 vaccination to children aged 5-11 years on COVID-19 burden and resilience against variant strains. Methods: Teams contributed state- and national-level weekly projections of cases, hospitalizations, and deaths in the United States from September 12, 2021 to March 12, 2022. Four scenarios covered all combinations of 1) vaccination (or not) of children aged 5-11 years (starting November 1, 2021), and 2) emergence (or not) of a variant more transmissible than the Delta variant (emerging November 15, 2021). Individual team projections were linearly pooled. The effect of childhood vaccination on overall and age-specific outcomes was estimated using meta-analyses. Findings: Assuming that a new variant would not emerge, all-age COVID-19 outcomes were projected to decrease nationally through mid-March 2022. In this setting, vaccination of children 5-11 years old was associated with reductions in projections for all-age cumulative cases (7.2%, mean incidence ratio [IR] 0.928, 95% confidence interval [CI] 0.880-0.977), hospitalizations (8.7%, mean IR 0.913, 95% CI 0.834-0.992), and deaths (9.2%, mean IR 0.908, 95% CI 0.797-1.020) compared with scenarios without childhood vaccination. Vaccine benefits increased for scenarios including a hypothesized more transmissible variant, assuming similar vaccine effectiveness. Projected relative reductions in cumulative outcomes were larger for children than for the entire population. State-level variation was observed. Interpretation: Given the scenario assumptions (defined before the emergence of Omicron), expanding vaccination to children 5-11 years old would provide measurable direct benefits, as well as indirect benefits to the all-age U.S. population, including resilience to more transmissible variants. Funding: Various (see acknowledgments).

Informing pandemic response in the face of uncertainty. An evaluation of the U.S. COVID-19 Scenario Modeling Hub.

Our ability to forecast epidemics more than a few weeks into the future is constrained by the complexity of disease systems, our limited ability to measure the current state of an epidemic, and uncertainties in how human action will affect transmission. Realistic longer-term projections (spanning more than a few weeks) may, however, be possible under defined scenarios that specify the future state of critical epidemic drivers, with the additional benefit that such scenarios can be used to anticipate the comparative effect of control measures. Since December 2020, the U.S. COVID-19 Scenario Modeling Hub (SMH) has convened multiple modeling teams to make 6-month ahead projections of the number of SARS-CoV-2 cases, hospitalizations and deaths. The SMH released nearly 1.8 million national and state-level projections between February 2021 and November 2022. SMH performance varied widely as a function of both scenario validity and model calibration. Scenario assumptions were periodically invalidated by the arrival of unanticipated SARS-CoV-2 variants, but SMH still provided projections on average 22 weeks before changes in assumptions (such as virus transmissibility) invalidated scenarios and their corresponding projections. During these periods, before emergence of a novel variant, a linear opinion pool ensemble of contributed models was consistently more reliable than any single model, and projection interval coverage was near target levels for the most plausible scenarios (e.g., 79% coverage for 95% projection interval). SMH projections were used operationally to guide planning and policy at different stages of the pandemic, illustrating the value of the hub approach for long-term scenario projections.

Potential impact of annual vaccination with reformulated COVID-19 vaccines: lessons from the U.S. COVID-19 Scenario Modeling Hub.

Importance: COVID-19 continues to cause significant hospitalizations and deaths in the United States. Its continued burden and the impact of annually reformulated vaccines remain unclear. Objective: To project COVID-19 hospitalizations and deaths from April 2023-April 2025 under two plausible assumptions about immune escape (20% per year and 50% per year) and three possible CDC recommendations for the use of annually reformulated vaccines (no vaccine recommendation, vaccination for those aged 65+, vaccination for all eligible groups). Design: The COVID-19 Scenario Modeling Hub solicited projections of COVID-19 hospitalization and deaths between April 15, 2023-April 15, 2025 under six scenarios representing the intersection of considered levels of immune escape and vaccination. State and national projections from eight modeling teams were ensembled to produce projections for each scenario. Setting: The entire United States. Participants: None. Exposure: Annually reformulated vaccines assumed to be 65% effective against strains circulating on June 15 of each year and to become available on September 1. Age and state specific coverage in recommended groups was assumed to match that seen for the first (fall 2021) COVID-19 booster. Main outcomes and measures: Ensemble estimates of weekly and cumulative COVID-19 hospitalizations and deaths. Expected relative and absolute reductions in hospitalizations and deaths due to vaccination over the projection period. Results: From April 15, 2023-April 15, 2025, COVID-19 is projected to cause annual epidemics peaking November-January. In the most pessimistic scenario (high immune escape, no vaccination recommendation), we project 2.1 million (90% PI: 1,438,000-4,270,000) hospitalizations and 209,000 (90% PI: 139,000-461,000) deaths, exceeding pre-pandemic mortality of influenza and pneumonia. In high immune escape scenarios, vaccination of those aged 65+ results in 230,000 (95% CI: 104,000-355,000) fewer hospitalizations and 33,000 (95% CI: 12,000-54,000) fewer deaths, while vaccination of all eligible individuals results in 431,000 (95% CI: 264,000-598,000) fewer hospitalizations and 49,000 (95% CI: 29,000-69,000) fewer deaths. Conclusion and Relevance: COVID-19 is projected to be a significant public health threat over the coming two years. Broad vaccination has the potential to substantially reduce the burden of this disease.

Evaluation of the US COVID-19 Scenario Modeling Hub for informing pandemic response under uncertainty.

Our ability to forecast epidemics far into the future is constrained by the many complexities of disease systems. Realistic longer-term projections may, however, be possible under well-defined scenarios that specify the future state of critical epidemic drivers. Since December 2020, the U.S. COVID-19 Scenario Modeling Hub (SMH) has convened multiple modeling teams to make months ahead projections of SARS-CoV-2 burden, totaling nearly 1.8 million national and state-level projections. Here, we find SMH performance varied widely as a function of both scenario validity and model calibration. We show scenarios remained close to reality for 22 weeks on average before the arrival of unanticipated SARS-CoV-2 variants invalidated key assumptions. An ensemble of participating models that preserved variation between models (using the linear opinion pool method) was consistently more reliable than any single model in periods of valid scenario assumptions, while projection interval coverage was near target levels. SMH projections were used to guide pandemic response, illustrating the value of collaborative hubs for longer-term scenario projections.