Host adaptive immune responses may protect against infection or disease when a pathogen is repeatedly encountered. The hazard ratio of infection or disease, given previous infection, is typically sought to estimate the strength of protective immunity. However, variation in individual exposure or susceptibility to infection may introduce frailty bias, whereby a tendency for infections to recur among individuals with greater risk confounds the causal association between previous infection and susceptibility. We introduce a self-matched "case-only" inference method to control for unmeasured individual heterogeneity, making use of negative-control endpoints not attributable to the pathogen of interest. To control for confounding, this method compares event times for endpoints due to the pathogen of interest and negative-control endpoints during counterfactual risk periods, defined according to individuals' infection history. We derive a standard Mantel-Haenszel (matched) odds ratio conveying the effect of prior infection on time to recurrence. We compare performance of this approach to several proportional hazards modeling frameworks and estimate statistical power of the proposed strategy under various conditions. In an example application, we use the proposed method to reestimate naturally acquired protection against rotavirus gastroenteritis using data from previously published cohort studies. This self-matched negative-control design may present a flexible alternative to existing approaches for analyzing naturally acquired immunity, as well as other exposures affecting the distribution of recurrent event times.

The high proportion of transmission events derived from asymptomatic or presymptomatic infections make SARS-CoV-2, the causative agent in COVID-19, difficult to control through the traditional non-pharmaceutical interventions (NPIs) of symptom-based isolation and contact tracing. As a consequence, many US universities developed asymptomatic surveillance testing labs, to augment NPIs and control outbreaks on campus throughout the 2020-2021 academic year (AY); several of those labs continue to support asymptomatic surveillance efforts on campus in AY2021-2022. At the height of the pandemic, we built a stochastic branching process model of COVID-19 dynamics at UC Berkeley to advise optimal control strategies in a university environment. Our model combines behavioral interventions in the form of group size limits to deter superspreading, symptom-based isolation, and contact tracing, with asymptomatic surveillance testing. We found that behavioral interventions offer a cost-effective means of epidemic control: group size limits of six or fewer greatly reduce superspreading, and rapid isolation of symptomatic infections can halt rising epidemics, depending on the frequency of asymptomatic transmission in the population. Surveillance testing can overcome uncertainty surrounding asymptomatic infections, with the most effective approaches prioritizing frequent testing with rapid turnaround time to isolation over test sensitivity. Importantly, contact tracing amplifies population-level impacts of all infection isolations, making even delayed interventions effective. Combination of behavior-based NPIs and asymptomatic surveillance also reduces variation in daily case counts to produce more predictable epidemics. Furthermore, targeted, intensive testing of a minority of high transmission risk individuals can effectively control the COVID-19 epidemic for the surrounding population. Even in some highly vaccinated university settings in AY2021-2022, asymptomatic surveillance testing offers an effective means of identifying breakthrough infections, halting onward transmission, and reducing total caseload. We offer this blueprint and easy-to-implement modeling tool to other academic or professional communities navigating optimal return-to-work strategies.

School closures may reduce the size of social networks among children, potentially limiting infectious disease transmission. To estimate the impact of K-12 closures and reopening policies on children's social interactions and COVID-19 incidence in California's Bay Area, we collected data on children's social contacts and assessed implications for transmission using an individual-based model. Elementary and Hispanic children had more contacts during closures than high school and non-Hispanic children, respectively. We estimated that spring 2020 closures of elementary schools averted 2167 cases in the Bay Area (95% CI: -985, 5572), fewer than middle (5884; 95% CI: 1478, 11.550), high school (8650; 95% CI: 3054, 15 940) and workplace (15 813; 95% CI: 9963, 22 617) closures. Under assumptions of moderate community transmission, we estimated that reopening for a four-month semester without any precautions will increase symptomatic illness among high school teachers (an additional 40.7% expected to experience symptomatic infection, 95% CI: 1.9, 61.1), middle school teachers (37.2%, 95% CI: 4.6, 58.1) and elementary school teachers (4.1%, 95% CI: -1.7, 12.0). However, we found that reopening policies for elementary schools that combine universal masking with classroom cohorts could result in few within-school transmissions, while high schools may require masking plus a staggered hybrid schedule. Stronger community interventions (e.g. remote work, social distancing) decreased the risk of within-school transmission across all measures studied, with the influence of community transmission minimized as the effectiveness of the within-school measures increased.

Background Large-scale school closures have been implemented worldwide to curb the spread of COVID-19. However, the impact of school closures and re-opening on epidemic dynamics remains unclear. Methods We simulated COVID-19 transmission dynamics using an individual-based stochastic model, incorporating social-contact data of school-aged children during shelter-in-place orders derived from Bay Area (California) household surveys. We simulated transmission under observed conditions and counterfactual intervention scenarios between March 17-June 1, and evaluated various fall 2020 K-12 reopening strategies. Findings Between March 17-June 1, assuming children <10 were half as susceptible to infection as older children and adults, we estimated school closures averted a similar number of infections (13,842 cases; 95% CI: 6,290, 23,040) as workplace closures (15,813; 95% CI: 9,963, 22,617) and social distancing measures (7,030; 95% CI: 3,118, 11,676). School closure effects were driven by high school and middle school closures. Under assumptions of moderate community transmission, we estimate that fall 2020 school reopenings will increase symptomatic illness among high school teachers (an additional 40.7% expected to experience symptomatic infection, 95% CI: 1.9, 61.1), middle school teachers (37.2%, 95% CI: 4.6, 58.1), and elementary school teachers (4.1%, 95% CI: -1.7, 12.0). Results are highly dependent on uncertain parameters, notably the relative susceptibility and infectiousness of children, and extent of community transmission amid re-opening. The school-based interventions needed to reduce the risk to fewer than an additional 1% of teachers infected varies by grade level. A hybrid-learning approach with halved class sizes of 10 students may be needed in high schools, while maintaining small cohorts of 20 students may be needed for elementary schools. Interpretation Multiple in-school intervention strategies and community transmission reductions, beyond the extent achieved to date, will be necessary to avoid undue excess risk associated with school reopening. Policymakers must urgently enact policies that curb community transmission and implement within-school control measures to simultaneously address the tandem health crises posed by COVID-19 and adverse child health and development consequences of long-term school closures.