Looking under the lamp-post: quantifying the performance of contact tracing in the United States during the SARS-CoV-2 pandemic (preprint)

Contact tracing forms a crucial part of the public-health toolbox in mitigating and understanding emergent pathogens and nascent disease outbreaks. Contact tracing in the United States was conducted during the pre-Omicron phase of the ongoing COVID-19 pandemic. This tracing relied on voluntary reporting and responses, often using rapid antigen tests (with a high false negative rate) due to lack of accessibility to PCR tests. These limitations, combined with SARS-CoV-2’s propensity for asymptomatic transmission, raise the question “how reliable was contact tracing for COVID-19 in the United States”? We answered this question using a Markov model to examine the efficiency with which transmission could be detected based on the design and response rates of contact tracing studies in the United States. Our results suggest that contact tracing protocols in the U.S. are unlikely to have identified more than 1.65% (95% uncertainty interval: 1.62%-1.68%) of transmission events with PCR testing and 0.88% (95% uncertainty interval 0.86%-0.89%) with rapid antigen testing. When considering an optimal scenario, based on compliance rates in East Asia with PCR testing, this increases to 62.7% (95% uncertainty interval: 62.6%-62.8%). These findings highlight the limitations in interpretability for studies of SARS-CoV-2 disease spread based on U.S. contact tracing and underscore the vulnerability of the population to future disease outbreaks, for SARS-CoV-2 and other pathogens.

The impact of vaccination frequency on COVID-19 public health outcomes: A model-based analysis (preprint)

While the rapid deployment of SARS-CoV-2 vaccines had a significant impact on the ongoing COVID-19 pandemic, rapid viral immune evasion and waning neutralizing antibody titers have degraded vaccine efficacy. Nevertheless, vaccine manufacturers and public health authorities have a number of levers at their disposal to maximize the benefits of vaccination. Here, we use an agent-based modeling framework coupled with the outputs of a population pharmacokinetic model to examine the impact of boosting frequency and durability of vaccinal response on vaccine efficacy. Our work suggests that repeated dosing at frequent intervals (multiple times a year) may offset the degradation of vaccine efficacy, preserving their utility in managing the ongoing pandemic. Our work relies on assumptions about antibody accumulation and the tolerability of repeated vaccine doses. Given the practical significance of potential improvements in vaccinal utility, clinical research to better understand the effects of repeated vaccination would be highly impactful. These findings are particularly relevant as public health authorities worldwide seek to reduce the frequency of boosters to once a year or less. Our work suggests practical recommendations for vaccine manufacturers and public health authorities and draws attention to the possibility that better outcomes for SARS-CoV-2 public health remain within reach.

Heterogeneity in vaccinal immunity to SARS-CoV-2 can be addressed by a personalized booster strategy (preprint)

The ongoing COVID-19 pandemic has placed an unprecedented burden on global health. Crucial for managing this burden, the existing SARS-CoV-2 vaccines have substantially reduced the risk of severe disease and death up to this point. The induction of neutralizing antibodies (nAbs) by these vaccines leads to protection against both infection and severe disease. However, pharmacokinetic (PK) waning and rapid viral evolution degrade neutralizing antibody binding titers, leading to a rapid loss of vaccinal protection against infection occurring on the order of months after vaccination. Additionally, inter-individual heterogeneity in the strength and durability of the vaccine-induced neutralizing response to SARS-CoV-2 can create a further public-health risk by placing a subset of the population at risk. Here we incorporate the heterogeneity in inter-individual response into a pharmacokinetic/ pharmacodynamic (PK/PD) model to project the degree of heterogeneity in immune protection. We extend our model-based approach to examine the impact of evolutionary immune evasion on vaccinal protection. Our findings suggest that viral evolution can be expected to impact the effectiveness of vaccinal protection against severe disease, particularly for individuals with a shorter duration of immune response. One possible solution to immune heterogeneity may be more frequent boosting for individuals with a weaker immune response. We demonstrate a model-based approach to targeted boosting that involves the use of the ECLIA RBD assay to identify individuals whose immune response is insufficient for protection against severe disease. Our work suggests that vaccinal protection against severe disease is not assured and provides a path forward to reducing the risk to immunologically vulnerable individuals.

No magic bullet: limiting in-school transmission in the face of variable SARS-CoV-2 viral loads (preprint)

In the face of a long-running pandemic, understanding the drivers of ongoing SARS-CoV-2 transmission is crucial for the rational management of COVID-19 disease burden. Keeping schools open has emerged as a vital societal imperative during the pandemic, but in-school transmission of SARS-CoV-2 can contribute to further prolonging the pandemic. In this context, the role of schools in driving SARS-CoV-2 transmission acquires critical importance. Here we model in-school transmission from first principles to investigate the effectiveness of layered mitigation strategies on limiting in-school spread. We examine the effect of masks and air quality (ventilation, filtration and ionizers) on steady-state viral load in classrooms, as well as on the number of particles inhaled by an uninfected person. The effectiveness of these measures in limiting viral transmission is assessed for variants with different levels of mean viral load (Wuhan, Delta, Omicron). Our results suggest that a layered mitigation strategy can be used effectively to limit in-school transmission, with certain limitations. First, poorly designed strategies (insufficient ventilation, no masks, staying open under high levels of community transmission) will permit in-school spread even if some level of mitigation is ostensibly present. Second, for viral variants that are sufficiently contagious, it may be difficult to construct any set of interventions capable of blocking transmission once an infected individual is present, underscoring the importance of other measures. Our findings provide several practical recommendations: the use of a layered mitigation strategy that is designed to limit transmission, with other measures such as frequent surveillance testing and smaller class sizes (such as by offering remote schooling options to those who prefer it) as needed.

Estimation of heterogeneous instantaneous reproduction numbers with application to characterize SARS-CoV-2 transmission in Massachusetts counties (preprint)

The reproductive number is an important metric that has been widely used to quantify the infectiousness of communicable diseases. The time-varying instantaneous reproductive number is useful for monitoring the real time dynamics of a disease to inform policy making for disease control. Local estimation of this metric, for instance at a county or city level, allows for more targeted interventions to curb transmission. However, simultaneous estimation of local reproductive numbers must account for potential sources of heterogeneity in these time-varying quantities - a key element of which is human mobility. We develop a statistical method that incorporates human mobility between multiple regions for estimating region-specific instantaneous reproductive numbers. The model also can account for exogenous cases imported from outside of the regions of interest. We propose two approaches to estimate the reproductive numbers, with mobility data used to adjust incidence in the first approach and to inform a formal priori distribution in the second (Bayesian) approach. Through a simulation study, we show that region-specific reproductive numbers can be well estimated if human mobility is reasonably well approximated by available data. We use this approach to estimate the instantaneous reproductive numbers of COVID-19 for 14 counties in Massachusetts using CDC case report data and the human mobility data collected by SafeGraph. We found that, accounting for mobility, our method produces estimates of reproductive numbers that are distinct across counties. In contrast, independent estimation of county-level reproductive numbers tends to produce similar values, as trends in county case-counts for the state are fairly concordant. These approaches can also be used to estimate any heterogeneity in transmission, for instance, age-dependent instantaneous reproductive number estimates. As people are more mobile and interact frequently in ways that permit transmission, it is important to account for this in the estimation of the reproductive number. Author summaryTo control the spreading of an infectious disease, it is very important to understand the real-time infectiousness of the pathogen that causes the disease. An existing metric called instantaneous reproductive number is often used to quantify the average number of secondary cases generated by individuals who are infectious at a certain time point, assuming no changes to current conditions. In practice, we might be interested in using the metric to describe the infectiousness in multiple regions. However, this is challenging when there are visitors traveling between these regions, since this could lead to a misclassification of where an individual is actually infected and create biased estimates for the instantaneous reproductive numbers. We developed a method that takes account of human mobility to estimate the instantaneous reproductive numbers for multiple regions simultaneously, which could reveal the heterogeneity of the metric. This method aims to provide helpful information on region-specific infectiousness for disease control measures that focus on the region with higher pathogen infectiousness. This approach is also applicable for estimating the reproductive number in the presence of other sources of heterogeneity, including by age.

Bayesian back-calculation and nowcasting for line list data during the COVID-19 pandemic (preprint)

Surveillance is the key of controling the COVID-19 pandemic, and it typically suffers from reporting delays and thus can be misleading. Previous methods for adjusting reporting delays are not particularly appropriate for line list data, which usually have lots of missing values that are non-ignorable for modeling reporting delays. In this paper, we develop a Bayesian approach that dynamically integrates imputation and estimation for line list data. We show this Bayesian approach lead to accurate estimates of the epidemic curve and time-varying reproductive numbers and is robust to deviations from model assumptions. We apply the Bayesian approach to a COVID-19 line list data in Massachusetts and find the reproductive number estimates correspond more closely to the control measures than the ones based on the reported curve.

Mask Wearing and Control of SARS-CoV-2 Transmission in the United States (preprint)

Introduction: Cloth face coverings and surgical masks have become commonplace across the United States in response to the SARS-CoV-2 epidemic. While evidence suggests masks help curb the spread of respiratory pathogens, research is limited. Face masks have quickly become a topic of public debate as government mandates have started requiring their use. Here we investigate the association between self-reported mask wearing, social distancing and community SARS-CoV-2 transmission in the United States, as well as the effect of statewide mandates on mask uptake. Methods: Serial cross-sectional surveys were administered June 3 through July 31, 2020 via web platform. Surveys queried individuals' likelihood to wear a face mask to the grocery store or with family and friends. Responses (N=378,207) were aggregated by week and state and combined with measures of the instantaneous reproductive number (Rt), social distancing proxies, respondent demographics and other potential sources of confounding. We fit multivariate logistic regression models to estimate the association between mask wearing and community transmission control (Rt <1) for each state and week. Multiple sensitivity analyses were considered to corroborate findings across mask wearing definitions, Rt estimators and data sources. Additionally, mask wearing in 12 states was evaluated two weeks before and after statewide mandates. Results: We find an upward trend in mask usage across the U.S., although uptake varies by geography and demographic groups. A multivariate logistic model controlling for social distancing and other variables found a 10% increase in mask wearing was associated with a 3.53 (95% CI: 2.03, 6.43) odds of transmission control (Rt <1). We also find that communities with high mask wearing and social distancing have the highest predicted probability of a controlled epidemic. These positive associations were maintained across sensitivity analyses. Segmented regression analysis of mask wearing found no statistical change following mandates, however the positive trend of increased mask wearing over time was preserved. Conclusion: Widespread utilization of face masks combined with social distancing increases the odds of SARS-CoV-2 transmission control. Mask wearing rose separately from government mask mandates, suggesting supplemental public health interventions are needed to maximize mask adoption and disrupt the spread of SARS-CoV-2, especially as social distancing measures are relaxed.

Practical considerations for measuring the effective reproductive number, Rt (preprint)

Estimation of the effective reproductive number, Rt, is important for detecting changes in disease transmission over time. During the COVID-19 pandemic, policymakers 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 methodological recommendations. For near real-time estimation of Rt, we recommend the approach of Cori et al. (2013), 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 (2004), are conceptually and methodologically less suited for near real-time estimation, but may be appropriate for some retrospective analyses. We advise against using methods derived from Bettencourt and Ribeiro (2008), as the resulting Rt estimates may be biased if the underlying structural assumptions are not met. A challenge common to all approaches is 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.

Population density and basic reproductive number of COVID-19 across United States counties (preprint)

The basic reproductive number (R0) is a function of contact rates among individuals, transmission probability, and duration of infectiousness. We sought to determine the association between population density and R0 of SARS-CoV-2 across U.S. counties, and whether population density could be used as a proxy for contact rates. We conducted a cross-sectional analysis using linear mixed models with random intercept and fixed slopes to assess the association of population density and R0. We also assessed whether this association was differential across county-level main mode of transportation-to-work percentage. Counties with greater population density have greater rates of transmission of SARS-CoV-2, likely due to increased contact rates in areas with greater density. The effect of population density and R0 was not modified by private transportation use. Differential R0 by population density can assist in more accurate predictions of the rate of spread of SARS-CoV-2 in areas that do not yet have active cases.

Socioeconomic disparities in subway use and COVID-19 outcomes in New York City (preprint)

Background: The United States CDC has reported that racial and ethnic disparities in the COVID-19 pandemic may in part be due to socioeconomic disadvantages that require individuals to continue to work outside their home and a lack of paid sick leave. However, data-driven analyses of the socioeconomic determinants of COVID-19 burden are still needed. Using data from New York City (NYC), we aimed to determine how socioeconomic factors impact human mobility and COVID-19 burden. Methods/Summary: New York City has a large amount of heterogeneity in socioeconomic status (SES) and demographics among neighborhoods. We used this heterogeneity to conduct a cross-sectional spatial analysis of the associations between human mobility (i.e., subway ridership), sociodemographic factors, and COVID-19 incidence as of April 26, 2020. We also conducted a secondary analysis of NYC boroughs (which are equivalent to counties in the city) to assess the relationship between the decline in subway use and the time it took for each borough to end the exponential growth period of COVID-19 cases. Findings: Areas with the lower median income, a greater percentage of individuals who identify as non-white and/or Hispanic/Latino, a greater percentage of essential workers, and a greater percentage of healthcare workers had more subway use during the pandemic. The positive associations between subway use and median income, and between subway use and percent non-white and/or Hispanic/Latino do not remain when adjusted for the percent of essential workers. This suggests essential work is what drives subway use in lower SES zip codes and communities of color. Increased subway use was associated with a higher rate of COVID-19 cases per 100,000 population when adjusted for testing effort (aRR=1.11; 95% CI: 1.03 - 1.19), but this association was weaker once we adjusted for median income (aRR=1.06; 95% CI: 1.00 - 1.12). All sociodemographic variables were significantly associated with the rate of positive cases per 100,000 population when adjusting for testing effort (except percent uninsured) and adjusting for both income and testing effort. The risk factor with the strongest association with COVID-19 was the percent of individuals in essential work (aRR = 1.59, 95% CI: 1.36 - 1.86). We found that subway use declined prior to any executive order, and there was an estimated 28-day lag between the onset of reduced subway use and the end of the exponential growth period of SARS-CoV-2 within New York City boroughs. Interpretation: Our results suggest that the ability to stay home during the pandemic has been constrained by SES and work circumstances. Poorer neighborhoods are not afforded the same reductions in mobility as their richer counterparts. Furthermore, lower SES neighborhoods have higher disease burdens, which may be due to inequities in ability to shelter-in-place, and/or due to the plethora of other existing health disparities that increase vulnerability to COVID-19. Furthermore, the extended lag time between the dramatic fall in subway ridership and the end of the exponential growth phase for COVID-19 cases is important for future policy, because it demonstrates that if there is a resurgence, and stay-at-home orders are re-issued, then cities can expect to wait a month before reported cases will plateau.