serosim: An R package for simulating serological data arising from vaccination, epidemiological and antibody kinetics processes.

serosim is an open-source R package designed to aid inference from serological studies, by simulating data arising from user-specified vaccine and antibody kinetics processes using a random effects model. Serological data are used to assess population immunity by directly measuring individuals' antibody titers. They uncover locations and/or populations which are susceptible and provide evidence of past infection or vaccination to help inform public health measures and surveillance. Both serological data and new analytical techniques used to interpret them are increasingly widespread. This creates a need for tools to simulate serological studies and the processes underlying observed titer values, as this will enable researchers to identify best practices for serological study design, and provide a standardized framework to evaluate the performance of different inference methods. serosim allows users to specify and adjust model inputs representing underlying processes responsible for generating the observed titer values like time-varying patterns of infection and vaccination, population demography, immunity and antibody kinetics, and serological sampling design in order to best represent the population and disease system(s) of interest. This package will be useful for planning sampling design of future serological studies, understanding determinants of observed serological data, and validating the accuracy and power of new statistical methods.

Near real-time surveillance of the SARS-CoV-2 epidemic with incomplete data.

When responding to infectious disease outbreaks, rapid and accurate estimation of the epidemic trajectory is critical. However, two common data collection problems affect the reliability of the epidemiological data in real time: missing information on the time of first symptoms, and retrospective revision of historical information, including right censoring. Here, we propose an approach to construct epidemic curves in near real time that addresses these two challenges by 1) imputation of dates of symptom onset for reported cases using a dynamically-estimated "backward" reporting delay conditional distribution, and 2) adjustment for right censoring using the NobBS software package to nowcast cases by date of symptom onset. This process allows us to obtain an approximation of the time-varying reproduction number (Rt) in real time. We apply this approach to characterize the early SARS-CoV-2 outbreak in two Spanish regions between March and April 2020. We evaluate how these real-time estimates compare with more complete epidemiological data that became available later. We explore the impact of the different assumptions on the estimates, and compare our estimates with those obtained from commonly used surveillance approaches. Our framework can help improve accuracy, quantify uncertainty, and evaluate frequently unstated assumptions when recovering the epidemic curves from limited data obtained from public health systems in other locations.

Estimation of Seasonal Influenza Attack Rates and Antibody Dynamics in Children Using Cross-Sectional Serological Data.

Directly measuring evidence of influenza infections is difficult, especially in low-surveillance settings such as sub-Saharan Africa. Using a Bayesian model, we estimated unobserved infection times and underlying antibody responses to influenza A/H3N2, using cross-sectional serum antibody responses to 4 strains in children aged 24-60 months. Among the 242 individuals, we estimated a variable seasonal attack rate and found that most children had ≥1 infection before 2 years of age. Our results are consistent with previously published high attack rates in children. The modeling approach highlights how cross-sectional serological data can be used to estimate epidemiological dynamics.

Life course exposures continually shape antibody profiles and risk of seroconversion to influenza.

Complex exposure histories and immune mediated interactions between influenza strains contribute to the life course of human immunity to influenza. Antibody profiles can be generated by characterizing immune responses to multiple antigenically variant strains, but how these profiles vary across individuals and determine future responses is unclear. We used hemagglutination inhibition titers from 21 H3N2 strains to construct 777 paired antibody profiles from people aged 2 to 86, and developed novel metrics to capture features of these profiles. Total antibody titer per potential influenza exposure increases in early life, then decreases in middle age. Increased titers to one or more strains were seen in 97.8% of participants during a roughly four-year interval, suggesting widespread influenza exposure. While titer changes were seen to all strains, recently circulating strains exhibited the greatest titer rise. Higher pre-existing, homologous titers at baseline reduced the risk of seroconversion to recent strains. After adjusting for homologous titer, we also found an increased frequency of seroconversion against recent strains among those with higher immunity to older previously exposed strains. Including immunity to previously exposures also improved the deviance explained by the models. Our results suggest that a comprehensive quantitative description of immunity encompassing past exposures could lead to improved correlates of risk of influenza infection.

Correction: Practical considerations for measuring the effective reproductive number, Rt.

[This corrects the article DOI: 10.1371/journal.pcbi.1008409.].

An open source tool to infer epidemiological and immunological dynamics from serological data: serosolver.

We present a flexible, open source R package designed to obtain biological and epidemiological insights from serological datasets. Characterising past exposures for multi-strain pathogens poses a specific statistical challenge: observed antibody responses measured in serological assays depend on multiple unobserved prior infections that produce cross-reactive antibody responses. We provide a general modelling framework to jointly infer infection histories and describe immune responses generated by these infections using antibody titres against current and historical strains. We do this by linking latent infection dynamics with a mechanistic model of antibody kinetics that generates expected antibody titres over time. Our aim is to provide a flexible package to identify infection histories that can be applied to a range of pathogens. We present two case studies to illustrate how our model can infer key immunological parameters, such as antibody titre boosting, waning and cross-reaction, as well as latent epidemiological processes such as attack rates and age-stratified infection risk.

Practical considerations for measuring the effective reproductive number, Rt.

Estimation of the effective reproductive number Rt is important for detecting changes in disease transmission over time. During the Coronavirus Disease 2019 (COVID-19) pandemic, policy makers and public health officials are using Rt to assess the effectiveness of interventions and to inform policy. However, estimation of Rt from available data presents several challenges, with critical implications for the interpretation of the course of the pandemic. The purpose of this document is to summarize these challenges, illustrate them with examples from synthetic data, and, where possible, make recommendations. For near real-time estimation of Rt, we recommend the approach of Cori and colleagues, which uses data from before time t and empirical estimates of the distribution of time between infections. Methods that require data from after time t, such as Wallinga and Teunis, are conceptually and methodologically less suited for near real-time estimation, but may be appropriate for retrospective analyses of how individuals infected at different time points contributed to the spread. We advise caution when using methods derived from the approach of Bettencourt and Ribeiro, as the resulting Rt estimates may be biased if the underlying structural assumptions are not met. Two key challenges common to all approaches are accurate specification of the generation interval and reconstruction of the time series of new infections from observations occurring long after the moment of transmission. Naive approaches for dealing with observation delays, such as subtracting delays sampled from a distribution, can introduce bias. We provide suggestions for how to mitigate this and other technical challenges and highlight open problems in Rt estimation.

When intuition falters: repeated testing accuracy during an epidemic.

Widespread, repeated testing using rapid antigen tests to proactively detect asymptomatic SARS-CoV-2 infections has been a promising yet controversial topic during the COVID-19 pandemic. Concerns have been raised over whether currently authorized lateral flow tests are sufficiently sensitive and specific to detect enough infections to impact transmission whilst minimizing unnecessary isolation of false positives. These concerns have often been illustrated using simple, textbook calculations of positivity rates and positive predictive value assuming fixed values for sensitivity, specificity and prevalence. However, we argue that evaluating repeated testing strategies requires the consideration of three additional factors: new infections continue to arise depending on the incidence rate, isolating positive individuals reduces prevalence in the tested population, and each infected individual is tested multiple times during their infection course. We provide a simple mathematical model with an online interface to illustrate how these three factors impact test positivity rates and the number of isolating individuals over time. These results highlight the potential pitfalls of using inappropriate textbook-style calculations to evaluate statistics arising from repeated testing strategies during an epidemic.

Seroepidemiologic Study Designs for Determining SARS-COV-2 Transmission and Immunity.

Serologic studies are crucial for clarifying dynamics of the coronavirus disease pandemic. Past work on serologic studies (e.g., during influenza pandemics) has made relevant contributions, but specific conditions of the current situation require adaptation. Although detection of antibodies to measure exposure, immunity, or both seems straightforward conceptually, numerous challenges exist in terms of sample collection, what the presence of antibodies actually means, and appropriate analysis and interpretation to account for test accuracy and sampling biases. Successful deployment of serologic studies depends on type and performance of serologic tests, population studied, use of adequate study designs, and appropriate analysis and interpretation of data. We highlight key questions that serologic studies can help answer at different times, review strengths and limitations of different assay types and study designs, and discuss methods for rapid sharing and analysis of serologic data to determine global transmission of severe acute respiratory syndrome coronavirus 2.

Characterising antibody kinetics from multiple influenza infection and vaccination events in ferrets.

The strength and breadth of an individual's antibody repertoire is an important predictor of their response to influenza infection or vaccination. Although progress has been made in understanding qualitatively how repeated exposures shape the antibody mediated immune response, quantitative understanding remains limited. We developed a set of mathematical models describing short-term antibody kinetics following influenza infection or vaccination and fit them to haemagglutination inhibition (HI) titres from 5 groups of ferrets which were exposed to different combinations of trivalent inactivated influenza vaccine (TIV with or without adjuvant), A/H3N2 priming inoculation and post-vaccination A/H1N1 inoculation. We fit models with various immunological mechanisms that have been empirically observed but have not previously been included in mathematical models of antibody landscapes, including: titre ceiling effects, antigenic seniority and exposure-type specific cross reactivity. Based on the parameter estimates of the best supported models, we describe a number of key immunological features. We found quantifiable differences in the degree of homologous and cross-reactive antibody boosting elicited by different exposure types. Infection and adjuvanted vaccination generally resulted in strong, broadly reactive responses whereas unadjuvanted vaccination resulted in a weak, narrow response. We found that the order of exposure mattered: priming with A/H3N2 improved subsequent vaccine response, and the second dose of adjuvanted vaccination resulted in substantially greater antibody boosting than the first. Either antigenic seniority or a titre ceiling effect were included in the two best fitting models, suggesting a role for a mechanism describing diminishing antibody boosting with repeated exposures. Although there was considerable uncertainty in our estimates of antibody waning parameters, our results suggest that both short and long term waning were present and would be identifiable with a larger set of experiments. These results highlight the potential use of repeat exposure animal models in revealing short-term, strain-specific immune dynamics of influenza.

Changing Practice in Gastrointestinal Endoscopy: Reducing Distractions for Patient Safety.

Failure in communication during the process of delivering healthcare can have dangerous repercussions. Specifically, failure in interdisciplinary team communication contributes to lapses in patient care. Distractions in procedural areas disrupt team communication. Application of a structured communication algorithm creates agreed-upon cues that promote team communication and facilitate clinical decision making. Frequent disruptions before, during, and after gastro-intestinal endoscopy procedures place veterans at risk for an error. A hierarchical culture promotes intimidation and reduces the likelihood that staff will speak up for patient safety. An endoscopy procedure area implemented a "sterile cockpit" methodology to reduce the number of distractions during procedures. Data collected from a self-reported safety awareness were measured by two different questionnaires and collected through observation of actual practice. Improved awareness of distraction and the impact on patient safety was reported, with a reduction from 24 observed interruptions to zero in 9 months. After reducing distractions in the procedural area, there is a perception of improved nursing quality of care. Additional support is required to consistently remove electronic distractions during a procedure.

Reconstructed influenza A/H3N2 infection histories reveal variation in incidence and antibody dynamics over the life course.

Humans experience many influenza infections over their lives, resulting in complex and varied immunological histories. Although experimental and quantitative analyses have improved our understanding of the immunological processes defining an individual's antibody repertoire, how these within-host processes are linked to population-level influenza epidemiology remains unclear. Here, we used a multi-level mathematical model to jointly infer antibody dynamics and individual-level lifetime influenza A/H3N2 infection histories for 1,130 individuals in Guangzhou, China, using 67,683 haemagglutination inhibition (HI) assay measurements against 20 A/H3N2 strains from repeat serum samples collected between 2009 and 2015. These estimated infection histories allowed us to reconstruct historical seasonal influenza patterns and to investigate how influenza incidence varies over time, space and age in this population. We estimated median annual influenza infection rates to be approximately 18% from 1968 to 2015, but with substantial variation between years. 88% of individuals were estimated to have been infected at least once during the study period (2009-2015), and 20% were estimated to have three or more infections in that time. We inferred decreasing infection rates with increasing age, and found that annual attack rates were highly correlated across all locations, regardless of their distance, suggesting that age has a stronger impact than fine-scale spatial effects in determining an individual's antibody profile. Finally, we reconstructed each individual's expected antibody profile over their lifetime and inferred an age-stratified relationship between probability of infection and HI titre. Our analyses show how multi-strain serological panels provide rich information on long term, epidemiological trends, within-host processes and immunity when analyzed using appropriate inference methods, and adds to our understanding of the life course epidemiology of influenza A/H3N2.

COVID-19 testing and reporting behaviours in England across different sociodemographic groups: a population-based study using testing data and data from community prevalence surveillance surveys.

BACKGROUND: Understanding underlying mechanisms of heterogeneity in test-seeking and reporting behaviour during an infectious disease outbreak can help to protect vulnerable populations and guide equity-driven interventions. The COVID-19 pandemic probably exerted different stresses on individuals in different sociodemographic groups and ensuring fair access to and usage of COVID-19 tests was a crucial element of England's testing programme. We aimed to investigate the relationship between sociodemographic factors and COVID-19 testing behaviours in England during the COVID-19 pandemic. METHODS: We did a population-based study of COVID-19 testing behaviours with mass COVID-19 testing data for England and data from community prevalence surveillance surveys (REACT-1 and ONS-CIS) from Oct 1, 2020, to March 30, 2022. We used mass testing data for lateral flow device (LFD; data for approximately 290 million tests performed and reported) and PCR (data for approximately 107 million tests performed and returned from the laboratory) tests made available for the general public and provided by date and self-reported age and ethnicity at the lower tier local authority (LTLA) level. We also used publicly available data on mean population size estimates for individual LTLAs, and data on ethnic groups, age groups, and deprivation indices for LTLAs. We did not have access to REACT-1 or ONS-CIS prevalence data disaggregated by sex or gender. Using a mechanistic causal model to debias the PCR testing data, we obtained estimates of weekly SARS-CoV-2 prevalence by both self-reported ethnic groups and age groups for LTLAs in England. This approach to debiasing the PCR (or LFD) testing data also estimated a testing bias parameter defined as the odds of testing in infected versus not infected individuals, which would be close to zero if the likelihood of test seeking (or seeking and reporting) was the same regardless of infection status. With confirmatory PCR data, we estimated false positivity rates, sensitivity, specificity, and the rate of decline in detection probability subsequent to reporting a positive LFD for PCR tests by sociodemographic groups. We also estimated the daily incidence, allowing us to calculate the fraction of cases captured by the testing programme. FINDINGS: From March, 2021 onwards, individuals in the most deprived regions reported approximately half as many LFD tests per capita as individuals in the least deprived areas (median ratio 0·50 [IQR 0·44-0·54]). During the period October, 2020, to June, 2021, PCR testing patterns showed the opposite trend, with individuals in the most deprived areas performing almost double the number of PCR tests per capita than those in the least deprived areas (1·8 [1·7-1·9]). Infection prevalences in Asian or Asian British individuals were considerably higher than those of other ethnic groups during the alpha (B.1.1.7) and omicron (B.1.1.529) BA.1 waves. Our estimates indicate that the England Pillar 2 COVID-19 testing programme detected 26-40% of all cases (including asymptomatic cases) over the study period with no consistent differences by deprivation levels or ethnic groups. Testing biases for PCR were generally higher than those for LFDs, in line with the general policy of symptomatic and asymptomatic use of these tests. Deprivation and age were associated with testing biases on average; however, the uncertainty intervals overlapped across deprivation levels, although the age-specific patterns were more distinct. We also found that ethnic minorities and older individuals were less likely to use confirmatory PCR tests through most of the pandemic and that delays in reporting a positive LFD test were possibly longer in populations self-reporting as "Black; African; Black British or Caribbean". INTERPRETATION: Differences in testing behaviours across sociodemographic groups might be reflective of the higher costs of self-isolation to vulnerable populations, differences in test accessibility, differences in digital literacy, and differing perceptions about the utility of tests and risks posed by infection. This study shows how mass testing data can be used in conjunction with surveillance surveys to identify gaps in the uptake of public health interventions both at fine-scale levels and across sociodemographic groups. It provides a framework for monitoring local interventions and yields valuable lessons for policy makers in ensuring an equitable response to future pandemics. FUNDING: UK Health Security Agency.

Infectious disease surveillance needs for the United States: lessons from Covid-19.

The COVID-19 pandemic has highlighted the need to upgrade systems for infectious disease surveillance and forecasting and modeling of the spread of infection, both of which inform evidence-based public health guidance and policies. Here, we discuss requirements for an effective surveillance system to support decision making during a pandemic, drawing on the lessons of COVID-19 in the U.S., while looking to jurisdictions in the U.S. and beyond to learn lessons about the value of specific data types. In this report, we define the range of decisions for which surveillance data are required, the data elements needed to inform these decisions and to calibrate inputs and outputs of transmission-dynamic models, and the types of data needed to inform decisions by state, territorial, local, and tribal health authorities. We define actions needed to ensure that such data will be available and consider the contribution of such efforts to improving health equity.

Viral kinetics of sequential SARS-CoV-2 infections.

The impact of a prior SARS-CoV-2 infection on the progression of subsequent infections has been unclear. Using a convenience sample of 94,812 longitudinal RT-qPCR measurements from anterior nares and oropharyngeal swabs, we identified 71 individuals with two well-sampled SARS-CoV-2 infections between March 11th, 2020, and July 28th, 2022. We compared the SARS-CoV-2 viral kinetics of first vs. second infections in this group, adjusting for viral variant, vaccination status, and age. Relative to first infections, second infections usually featured a faster clearance time. Furthermore, a person's relative (rank-order) viral clearance time, compared to others infected with the same variant, was roughly conserved across first and second infections, so that individuals who had a relatively fast clearance time in their first infection also tended to have a relatively fast clearance time in their second infection (Spearman correlation coefficient: 0.30, 95% credible interval (0.12, 0.46)). These findings provide evidence that, like vaccination, immunity from a prior SARS-CoV-2 infection shortens the duration of subsequent acute SARS-CoV-2 infections principally by reducing viral clearance time. Additionally, there appears to be an inherent element of the immune response, or some other host factor, that shapes a person's relative ability to clear SARS-CoV-2 infection that persists across sequential infections.

Alternative epidemic indicators for COVID-19 in three settings with incomplete death registration systems.

Not all COVID-19 deaths are officially reported, and particularly in low-income and humanitarian settings, the magnitude of reporting gaps remains sparsely characterized. Alternative data sources, including burial site worker reports, satellite imagery of cemeteries, and social media-conducted surveys of infection may offer solutions. By merging these data with independently conducted, representative serological studies within a mathematical modeling framework, we aim to better understand the range of underreporting using examples from three major cities: Addis Ababa (Ethiopia), Aden (Yemen), and Khartoum (Sudan) during 2020. We estimate that 69 to 100%, 0.8 to 8.0%, and 3.0 to 6.0% of COVID-19 deaths were reported in each setting, respectively. In future epidemics, and in settings where vital registration systems are limited, using multiple alternative data sources could provide critically needed, improved estimates of epidemic impact. However, ultimately, these systems are needed to ensure that, in contrast to COVID-19, the impact of future pandemics or other drivers of mortality is reported and understood worldwide.

Nonlinear bifurcations of psychological stress negotiation: new properties of a formal dynamical model.

Dynamical systems analysis is applied to a nonlinear model of stress and coping (Neufeld, 1999). The model is composed of 6 order parameters and 11 control parameters, and integrates core constructs of the topic domain, including variants of cognitive appraisal, differential stress susceptibility, stress activation, and coping propensity. In part owing to recent advances in Competitive Modes Theory (Yao, Yu & Essex, 2002), previously intractable but substantively significant dynamical properties of the 6-dimensional model are identified. They include stable and unstable fixed-point equilibria (higher-dimensional saddle-node bifurcation), oscillatory patterns attending fixed-point de-stabilization, and chaotic behaviors. Examination of the nature of system fixed-point de-stabilization, in relation to its control parameters, unveils mechanisms of re-stabilization, and dynamic stability control. All identified dynamics emerge naturally from a system whose construction guideposts are lodged in the addressed content domain. Dynamical complexities therefore may be intrinsic to the present content domain, possibly no less so than in other disciplines where the presence of such attributes has been established.

Long term intrinsic cycling in human life course antibody responses to influenza A(H3N2): an observational and modeling study.

Background: Over a life course, human adaptive immunity to antigenically mutable pathogens exhibits competitive and facilitative interactions. We hypothesize that such interactions may lead to cyclic dynamics in immune responses over a lifetime. Methods: To investigate the cyclic behavior, we analyzed hemagglutination inhibition titers against 21 historical influenza A(H3N2) strains spanning 47 years from a cohort in Guangzhou, China, and applied Fourier spectrum analysis. To investigate possible biological mechanisms, we simulated individual antibody profiles encompassing known feedbacks and interactions due to generally recognized immunological mechanisms. Results: We demonstrated a long-term periodicity (about 24 years) in individual antibody responses. The reported cycles were robust to analytic and sampling approaches. Simulations suggested that individual-level cross-reaction between antigenically similar strains likely explains the reported cycle. We showed that the reported cycles are predictable at both individual and birth cohort level and that cohorts show a diversity of phases of these cycles. Phase of cycle was associated with the risk of seroconversion to circulating strains, after accounting for age and pre-existing titers of the circulating strains. Conclusions: Our findings reveal the existence of long-term periodicities in individual antibody responses to A(H3N2). We hypothesize that these cycles are driven by preexisting antibody responses blunting responses to antigenically similar pathogens (by preventing infection and/or robust antibody responses upon infection), leading to reductions in antigen-specific responses over time until individual's increasing risk leads to an infection with an antigenically distant enough virus to generate a robust immune response. These findings could help disentangle cohort effects from individual-level exposure histories, improve our understanding of observed heterogeneous antibody responses to immunizations, and inform targeted vaccine strategy. Funding: This study was supported by grants from the NIH R56AG048075 (DATC, JL), NIH R01AI114703 (DATC, BY), the Wellcome Trust 200861/Z/16/Z (SR), and 200187/Z/15/Z (SR). This work was also supported by research grants from Guangdong Government HZQB-KCZYZ-2021014 and 2019B121205009 (YG and HZ). DATC, JMR and SR acknowledge support from the National Institutes of Health Fogarty Institute (R01TW0008246). JMR acknowledges support from the Medical Research Council (MR/S004793/1) and the Engineering and Physical Sciences Research Council (EP/N014499/1). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Quantifying the impact of immune history and variant on SARS-CoV-2 viral kinetics and infection rebound: A retrospective cohort study.

Background: The combined impact of immunity and SARS-CoV-2 variants on viral kinetics during infections has been unclear. Methods: We characterized 1,280 infections from the National Basketball Association occupational health cohort identified between June 2020 and January 2022 using serial RT-qPCR testing. Logistic regression and semi-mechanistic viral RNA kinetics models were used to quantify the effect of age, variant, symptom status, infection history, vaccination status and antibody titer to the founder SARS-CoV-2 strain on the duration of potential infectiousness and overall viral kinetics. The frequency of viral rebounds was quantified under multiple cycle threshold (Ct) value-based definitions. Results: Among individuals detected partway through their infection, 51.0% (95% credible interval [CrI]: 48.3-53.6%) remained potentially infectious (Ct <30) 5 days post detection, with small differences across variants and vaccination status. Only seven viral rebounds (0.7%; N=999) were observed, with rebound defined as 3+days with Ct <30 following an initial clearance of 3+days with Ct ≥30. High antibody titers against the founder SARS-CoV-2 strain predicted lower peak viral loads and shorter durations of infection. Among Omicron BA.1 infections, boosted individuals had lower pre-booster antibody titers and longer clearance times than non-boosted individuals. Conclusions: SARS-CoV-2 viral kinetics are partly determined by immunity and variant but dominated by individual-level variation. Since booster vaccination protects against infection, longer clearance times for BA.1-infected, boosted individuals may reflect a less effective immune response, more common in older individuals, that increases infection risk and reduces viral RNA clearance rate. The shifting landscape of viral kinetics underscores the need for continued monitoring to optimize isolation policies and to contextualize the health impacts of therapeutics and vaccines. Funding: Supported in part by CDC contract #200-2016-91779, a sponsored research agreement to Yale University from the National Basketball Association contract #21-003529, and the National Basketball Players Association.

Estimation of Transmission of COVID-19 in Simulated Nursing Homes With Frequent Testing and Immunity-Based Staffing.

Importance: Nursing homes and other long-term care facilities have been disproportionately impacted by the COVID-19 pandemic. Strategies are urgently needed to reduce transmission in these high-risk populations. Objective: To evaluate COVID-19 transmission in nursing homes associated with contact-targeted interventions and testing. Design, Setting, and Participants: This decision analytical modeling study developed an agent-based susceptible-exposed-infectious (asymptomatic/symptomatic)-recovered model between July and September 2020 to examine SARS-CoV-2 transmission in nursing homes. Residents and staff of a simulated nursing home with 100 residents and 100 staff split among 3 shifts were modeled individually; residents were split into 2 cohorts based on COVID-19 diagnosis. Data were analyzed from September to October 2020. Exposures: In the resident cohorting intervention, residents who had recovered from COVID-19 were moved back from the COVID-19 (ie, infected with SARS-CoV-2) cohort to the non-COVID-19 (ie, susceptible and uninfected with SARS-CoV-2) cohort. In the immunity-based staffing intervention, staff who had recovered from COVID-19 were assumed to have protective immunity and were assigned to work in the non-COVID-19 cohort, while susceptible staff worked in the COVID-19 cohort and were assumed to have high levels of protection from personal protective equipment. These interventions aimed to reduce the fraction of people's contacts that were presumed susceptible (and therefore potentially infected) and replaced them with recovered (immune) contacts. A secondary aim of was to evaluate cumulative incidence of SARS-CoV-2 infections associated with 2 types of screening tests (ie, rapid antigen testing and polymerase chain reaction [PCR] testing) conducted with varying frequency. Main Outcomes and Measures: Estimated cumulative incidence proportion of SARS-CoV-2 infection after 3 months. Results: Among the simulated cohort of 100 residents and 100 staff members, frequency and type of testing were associated with smaller outbreaks than the cohorting and staffing interventions. The testing strategy associated with the greatest estimated reduction in infections was daily antigen testing, which reduced the mean cumulative incidence proportion by 49% in absence of contact-targeted interventions. Under all screening testing strategies, the resident cohorting intervention and the immunity-based staffing intervention were associated with reducing the final estimated size of the outbreak among residents, with the immunity-based staffing intervention reducing it more (eg, by 19% in the absence of testing) than the resident cohorting intervention (eg, by 8% in the absence of testing). The estimated reduction in transmission associated with these interventions among staff varied by testing strategy and community prevalence. Conclusions and Relevance: These findings suggest that increasing the frequency of screening testing of all residents and staff, or even staff alone, in nursing homes may reduce outbreaks in this high-risk setting. Immunity-based staffing may further reduce spread at little or no additional cost and becomes particularly important when daily testing is not feasible.