Optimizing COVID-19 testing strategies on college campuses: evaluation of the health and economic costs (preprint)

Colleges and universities in the US struggled to provide safe in-person education throughout the COVID-19 pandemic. Testing coupled with isolation is a nimble intervention strategy that can be tailored to mitigate health and economic costs, as the virus and our arsenal of medical countermeasures continue to evolve. We developed a decision-support tool to aid in the design of university-based testing strategies using a mathematical model of SARS-CoV-2 transmission. Applying this framework to a large public university reopening in the fall of 2021 with a 60% student vaccination rate, we find that the optimal strategy, in terms of health and economic costs, is twice weekly antigen testing of all students. This strategy provides a 95% guarantee that, throughout the fall semester, case counts would not exceed the CDCs original high transmission threshold of 100 cases per 100k persons over 7 days. As the virus and our medical armament continue to evolve, testing will remain a flexible tool for managing risks and keeping campuses open. We have implemented this model as an online tool to facilitate the design of testing strategies that adjust for COVID-19 conditions, university-specific parameters, and institutional goals.

Disproportionate impacts of COVID-19 in a large US city (preprint)

COVID-19 has disproportionately impacted individuals depending on where they live and work, and based on their race, ethnicity, and socioeconomic status. Studies have documented catastrophic disparities at critical points throughout the pandemic, but have not yet systematically tracked their severity through time. Using anonymized hospitalization data from March 11, 2020 to June 1, 2021, we estimate the time-varying burden of COVID-19 by age group and ZIP code in Austin, Texas. During this 15-month period, we estimate an overall 16.9% (95% CrI: 16.1-17.8%) infection rate and 34.1% (95% CrI: 32.4-35.8%) case reporting rate. Individuals over 65 were less likely to be infected than younger age groups (8.0% [95% CrI: 7.5-8.6%] vs 18.1% [95% CrI: 17.2-19.2%]), but more likely to be hospitalized (1,381 per 100,000 vs 319 per 100,000) and have their infections reported (51% [95% CrI: 48-55%] vs 33% [95% CrI: 31-35%]). Children under 18, who make up 20.3% of the local population, accounted for only 5.5% (95% CrI: 3.8-7.7%) of all infections between March 1 and May 1, 2020 compared with 20.4% (95% CrI: 17.3-23.9%) between December 1, 2020 and February 1, 2021. We compared ZIP codes ranking in the 75th percentile of vulnerability to those in the 25th percentile, and found that the more vulnerable communities had 2.5 (95% CrI: 2.0-3.0) times the infection rate and only 70% (95% CrI: 61%-82%) the reporting rate compared to the less vulnerable communities. Inequality persisted but declined significantly over the 15-month study period. For example, the ratio in infection rates between the more and less vulnerable communities declined from 12.3 (95% CrI: 8.8-17.1) to 4.0 (95% CrI: 3.0-5.3) to 2.7 (95% CrI: 2.0-3.6), from April to August to December of 2020, respectively. Our results suggest that public health efforts to mitigate COVID-19 disparities were only partially effective and that the CDC's social vulnerability index may serve as a reliable predictor of risk on a local scale when surveillance data are limited.

Detecting in-school transmission of SARS-CoV-2 from case ratios and documented clusters (preprint)

Claims that in-person schooling has not amplified SARS-CoV-2 transmission are based on similar infection rates in schools and their surrounding communities and limited numbers of documented in-school transmission events. Simulations assuming high in-school transmission suggest that these metrics cannot exclude the possibility that transmission in schools exacerbated overall pandemic risks.

Design of COVID-19 Staged Alert Systems to Ensure Healthcare Capacity with Minimal Closures (preprint)

Community mitigation strategies to combat COVID-19, ranging from healthy hygiene to shelter-in-place orders, exact substantial socioeconomic costs. Judicious implementation and relaxation of restrictions amplify their public health benefits while reducing costs. We derive optimal strategies for toggling between mitigation stages using daily COVID-19 hospital admissions. With public compliance, the policy triggers ensure adequate intensive care unit capacity with high probability while minimizing the duration of strict mitigation measures. In comparison, we show that other sensible COVID-19 staging policies, including Frances ICU-based thresholds and a widely adopted indicator for reopening schools and businesses, require overly restrictive measures or trigger strict stages too late to avert catastrophic surges. As cities worldwide face future pandemic waves, our findings provide a robust strategy for tracking COVID-19 hospital admissions as an early indicator of hospital surges and enacting staged measures to ensure integrity of the health system, safety of the health workforce, and public confidence.

COVID-19 reopening strategies at the county level in the face of uncertainty: Multiple Models for Outbreak Decision Support (preprint)

Policymakers make decisions about COVID-19 management in the face of considerable uncertainty. We convened multiple modeling teams to evaluate reopening strategies for a mid-sized county in the United States, in a novel process designed to fully express scientific uncertainty while reducing linguistic uncertainty and cognitive biases. For the scenarios considered, the consensus from 17 distinct models was that a second outbreak will occur within 6 months of reopening, unless schools and non-essential workplaces remain closed. Up to half the population could be infected with full workplace reopening; non-essential business closures reduced median cumulative infections by 82%. Intermediate reopening interventions identified no win-win situations; there was a trade-off between public health outcomes and duration of workplace closures. Aggregate results captured twice the uncertainty of individual models, providing a more complete expression of risk for decision-making purposes.

The N-terminal domain of spike glycoprotein mediates SARS-CoV-2 infection by associating with L-SIGN and DC-SIGN (preprint)

The widespread occurrence of SARS-CoV-2 has had a profound effect on society and a vaccine is currently being developed. Angiotensin-converting enzyme 2 (ACE2) is the primary host cell receptor that interacts with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Although pneumonia is the main symptom in severe cases of SARS-CoV-2 infection, the expression levels of ACE2 in the lung is low, suggesting the presence of another receptor for the spike protein. In order to identify the additional receptors for the spike protein, we screened a receptor for the SARS-CoV-2 spike protein from the lung cDNA library. We cloned L-SIGN as a specific receptor for the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. The RBD of the spike protein did not bind to L-SIGN. In addition, not only L-SIGN but also DC-SIGN, a closely related C-type lectin receptor to L-SIGN, bound to the NTD of the SARS-CoV-2 spike protein. Importantly, cells expressing L-SIGN and DC-SIGN were both infected by SARS-CoV-2. Furthermore, L-SIGN and DC-SIGN induced membrane fusion by associating with the SARS-CoV-2 spike protein. Serum antibodies from infected patients and a patient-derived monoclonal antibody against NTD inhibited SARS-CoV-2 infection of L-SIGN or DC-SIGN expressing cells. Our results highlight the important role of NTD in SARS-CoV-2 dissemination through L-SIGN and DC-SIGN and the significance of having anti-NTD neutralizing antibodies in antibody-based therapeutics.

Comparison of SARS-CoV-2 infection in two non-human primate species: rhesus and cynomolgus macaques (preprint)

SARS-CoV-2 is a coronavirus that sparked the current COVID-19 pandemic. To stop the shattering effect of COVID-19, effective and safe vaccines, and antiviral therapies are urgently needed. To facilitate the preclinical evaluation of intervention approaches, relevant animal models need to be developed and validated. Rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis) are widely used in biomedical research and serve as models for SARS-CoV-2 infection. However, differences in study design make it difficult to compare and understand potential species-related differences. Here, we directly compared the course of SARS-CoV-2 infection in the two genetically closely-related macaque species. After inoculation with a low passage SARS-CoV-2 isolate, clinical, virological, and immunological characteristics were monitored. Both species showed slightly elevated body temperatures in the first days after exposure while a decrease in physical activity was only observed in the rhesus macaques and not in cynomolgus macaques. The virus was quantified in tracheal, nasal, and anal swabs, and in blood samples by qRT-PCR, and showed high similarity between the two species. Immunoglobulins were detected by various enzyme-linked immunosorbent assays (ELISAs) and showed seroconversion in all animals by day 10 post-infection. The cytokine responses were highly comparable between species and computed tomography (CT) imaging revealed pulmonary lesions in all animals. Consequently, we concluded that both rhesus and cynomolgus macaques represent valid models for evaluation of COVID-19 vaccine and antiviral candidates in a preclinical setting.

A Workflow of Integrated Resources to Catalyze Network Pharmacology Driven COVID-19 Research (preprint)

Motivation: In the event of an outbreak due to an emerging pathogen, time is of the essence to contain or to mitigate the spread of the disease. Drug repositioning is one of the strategies that has the potential to deliver therapeutics relatively quickly. The SARS-CoV-2 pandemic has shown that integrating critical data resources to drive drug-repositioning studies, involving host-host, host-pathogen and drug-target interactions, remains a time-consuming effort that translates to a delay in the development and delivery of a life-saving therapy. Results: Here, we describe a workflow we designed for a semi-automated integration of rapidly emerging datasets that can be generally adopted in a broad network pharmacology research setting. The workflow was used to construct a COVID-19 focused multimodal network that integrates 487 host-pathogen, 74,805 host-host protein and 1,265 drug-target interactions. The resultant Neo4j graph database named "Neo4COVID19" is accessible via a web interface and via API calls based on the Bolt protocol. We believe that our Neo4COVID19 database will be a valuable asset to the research community and will catalyze the discovery of therapeutics to fight COVID-19. Availability: https://neo4covid19.ncats.io . Keywords: SARS-CoV-2, COVID-19, network pharmacology, graph database, Neo4j, data integration, drug repositioning

The impact of asymptomatic COVID-19 infections on future pandemic waves (preprint)

The prevalence of asymptomatic COVID-19 infections is largely unknown and may determine the course of future pandemic waves and the effectiveness of interventions. Using an epidemiological model fit to COVID-19 hospitalization counts from New York City, New York and Austin, Texas, we found that the undocumented attack rate in the first pandemic wave depends on the proportion of asymptomatic infections but not on the infectiousness of such individuals. Based on a recent report that 22.7% of New Yorkers are seropositive for SARS-CoV-2, we estimate that 56% (95% CI: 53-59%) of COVID-19 infections are asymptomatic. Given uncertainty in the case hospitalization rate, however, the asymptomatic proportion could be as low as 20% or as high as 80%. We find that at most 1.26% of the Austin population was infected by April 27, 2020 and conclude that immunity from undetected infections is unlikely to slow future pandemic spread in most US cities in the summer of 2020.

Cocooning is essential to relaxing social distancing (preprint)

As the first wave of COVID-19 recedes, policymakers are contemplating the relaxation of shelter-in-place orders. Using a model capturing high-risk populations and transmission rates estimated from hospitalization data, we find that postponing relaxation will only delay a second wave and cocooning vulnerable populations is needed to prevent overwhelming medical surges.

COVID-19: How to Relax Social Distancing If You Must (preprint)

Following the April 16, 2020 release of the Opening Up America Again guidelines for relaxing COVID-19 social distancing policies, local leaders are concerned about future pandemic waves and lack robust strategies for tracking and suppressing transmission. Here, we present a framework for monitoring COVID-19 hospitalization data to project risks and trigger shelter-in-place orders to prevent overwhelming healthcare surges while minimizing the duration of costly lockdowns. Assuming the relaxation of social distancing increases the risk of infection ten-fold, the optimal strategy for Austin, Texas--the fastest-growing large city in the US--will trigger a total of 135 [90% prediction interval: 126-141] days of sheltering, allow schools to open in the fall, and result in an expected 2929 deaths [90% prediction interval: 2837-3026] by September 2021, which is 29% the annual mortality rate. In the months ahead, policy makers are likely to face difficult choices and the extent of public restraint and cocooning of vulnerable populations may save or cost thousands of lives.