Cryptic transmission of SARS-CoV-2 and the first COVID-19 wave.

Considerable uncertainty surrounds the timeline of introductions and onsets of local transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) globally1-7. Although a limited number of SARS-CoV-2 introductions were reported in January and February 2020 (refs.8,9), the narrowness of the initial testing criteria, combined with a slow growth in testing capacity and porous travel screening10, left many countries vulnerable to unmitigated, cryptic transmission. Here we use a global metapopulation epidemic model to provide a mechanistic understanding of the early dispersal of infections and the temporal windows of the introduction of SARS-CoV-2 and onset of local transmission in Europe and the USA. We find that community transmission of SARS-CoV-2 was likely to have been present in several areas of Europe and the USA by January 2020, and estimate that by early March, only 1 to 4 in 100 SARS-CoV-2 infections were detected by surveillance systems. The modelling results highlight international travel as the key driver of the introduction of SARS-CoV-2, with possible introductions and transmission events as early as December 2019 to January 2020. We find a heterogeneous geographic distribution of cumulative infection attack rates by 4 July 2020, ranging from 0.78% to 15.2% across US states and 0.19% to 13.2% in European countries. Our approach complements phylogenetic analyses and other surveillance approaches and provides insights that can be used to design innovative, model-driven surveillance systems that guide enhanced testing and response strategies.

Quantifying the importance and location of SARS-CoV-2 transmission events in large metropolitan areas.

Detailed characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission across different settings can help design less disruptive interventions. We used real-time, privacy-enhanced mobility data in the New York City, NY and Seattle, WA metropolitan areas to build a detailed agent-based model of SARS-CoV-2 infection to estimate the where, when, and magnitude of transmission events during the pandemic's first wave. We estimate that only 18% of individuals produce most infections (80%), with about 10% of events that can be considered superspreading events (SSEs). Although mass gatherings present an important risk for SSEs, we estimate that the bulk of transmission occurred in smaller events in settings like workplaces, grocery stores, or food venues. The places most important for transmission change during the pandemic and are different across cities, signaling the large underlying behavioral component underneath them. Our modeling complements case studies and epidemiological data and indicates that real-time tracking of transmission events could help evaluate and define targeted mitigation policies.

Estimation of the incubation period and generation time of SARS-CoV-2 Alpha and Delta variants from contact tracing data.

Quantitative information on epidemiological quantities such as the incubation period and generation time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is scarce. We analysed a dataset collected during contact tracing activities in the province of Reggio Emilia, Italy, throughout 2021. We determined the distributions of the incubation period for the Alpha and Delta variants using information on negative polymerase chain reaction tests and the date of last exposure from 282 symptomatic cases. We estimated the distributions of the intrinsic generation time using a Bayesian inference approach applied to 9724 SARS-CoV-2 cases clustered in 3545 households where at least one secondary case was recorded. We estimated a mean incubation period of 4.9 days (95% credible intervals, CrI, 4.4-5.4) for Alpha and 4.5 days (95% CrI 4.0-5.0) for Delta. The intrinsic generation time was estimated to have a mean of 7.12 days (95% CrI 6.27-8.44) for Alpha and of 6.52 days (95% CrI 5.54-8.43) for Delta. The household serial interval was 2.43 days (95% CrI 2.29-2.58) for Alpha and 2.74 days (95% CrI 2.62-2.88) for Delta, and the estimated proportion of pre-symptomatic transmission was 48-51% for both variants. These results indicate limited differences in the incubation period and intrinsic generation time of SARS-CoV-2 variants Alpha and Delta compared to ancestral lineages.

Reactive school closure weakens the network of social interactions and reduces the spread of influenza.

School-closure policies are considered one of the most promising nonpharmaceutical interventions for mitigating seasonal and pandemic influenza. However, their effectiveness is still debated, primarily due to the lack of empirical evidence about the behavior of the population during the implementation of the policy. Over the course of the 2015 to 2016 influenza season in Russia, we performed a diary-based contact survey to estimate the patterns of social interactions before and during the implementation of reactive school-closure strategies. We develop an innovative hybrid survey-modeling framework to estimate the time-varying network of human social interactions. By integrating this network with an infection transmission model, we reduce the uncertainty surrounding the impact of school-closure policies in mitigating the spread of influenza. When the school-closure policy is in place, we measure a significant reduction in the number of contacts made by students (14.2 vs. 6.5 contacts per day) and workers (11.2 vs. 8.7 contacts per day). This reduction is not offset by the measured increase in the number of contacts between students and nonhousehold relatives. Model simulations suggest that gradual reactive school-closure policies based on monitoring student absenteeism rates are capable of mitigating influenza spread. We estimate that without the implemented reactive strategies the attack rate of the 2015 to 2016 influenza season would have been 33% larger. Our study sheds light on the social mixing patterns of the population during the implementation of reactive school closures and provides key instruments for future cost-effectiveness analyses of school-closure policies.

Estimating contact patterns relevant to the spread of infectious diseases in Russia.

Understanding human mixing patterns is the key to provide public health decision makers with model-based evaluation of strategies for the control of infectious diseases. Here we conducted a population-based survey in Tomsk, Russia, asking participants to record all their contacts in physical person during the day. We estimated 9.8 contacts per person per day on average, 15.2 when including additional estimated professional contacts. We found that contacts were highly assortative by age, especially for school-age individuals, and the number of contacts negatively correlated with the age of the participant. The network of contacts was quite clustered, with the majority of contacts (about 72%) occurring between family members, students of the same school/university, and work colleagues. School represents the location where the largest number of contacts was recorded - students contacted about 7 individuals per day at school. Our modeling analysis based on the recorded contact patterns supports the importance of modeling age-mixing patterns - we show that, in the case of an epidemic caused by a novel influenza virus, school-age individuals would be the most affected age group, followed by adults aged 35-44 years. In conclusion, this study reveals an age-mixing pattern in general agreement with that estimated for European countries, although with several quantitative differences. The observed differences can be attributable to sociodemographic and cultural differences between countries. The age- and setting-specific contact matrices provided in this study could be instrumental for the design of control measures for airborne infections, specifically targeted on the characteristics of the Russian population.

Evaluating Seasonal Variations in Human Contact Patterns and Their Impact on the Transmission of Respiratory Infectious Diseases.

BACKGROUND: Human contact patterns are a key determinant driving the spread of respiratory infectious diseases. However, the relationship between contact patterns and seasonality as well as their possible association with the seasonality of respiratory diseases is yet to be clarified. METHODS: We investigated the association between temperature and human contact patterns using data collected through a cross-sectional diary-based contact survey in Shanghai, China, between December 24, 2017, and May 30, 2018. We then developed a compartmental model of influenza transmission informed by the derived seasonal trends in the number of contacts and validated it against A(H1N1)pdm09 influenza data collected in Shanghai during the same period. RESULTS: We identified a significant inverse relationship between the number of contacts and the seasonal temperature trend defined as a spline interpolation of temperature data (p = 0.003). We estimated an average of 16.4 (95% PrI: 15.1-17.5) contacts per day in December 2017 that increased to an average of 17.6 contacts (95% PrI: 16.5-19.3) in January 2018 and then declined to an average of 10.3 (95% PrI: 9.4-10.8) in May 2018. Estimates of influenza incidence obtained by the compartmental model comply with the observed epidemiological data. The reproduction number was estimated to increase from 1.24 (95% CI: 1.21-1.27) in December to a peak of 1.34 (95% CI: 1.31-1.37) in January. The estimated median infection attack rate at the end of the season was 27.4% (95% CI: 23.7-30.5%). CONCLUSIONS: Our findings support a relationship between temperature and contact patterns, which can contribute to deepen the understanding of the relationship between social interactions and the epidemiology of respiratory infectious diseases.

Title evaluation of FluSight influenza forecasting in the 2021-22 and 2022-23 seasons with a new target laboratory-confirmed influenza hospitalizations.

Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. For the 2021-22 and 2022-23 influenza seasons, 26 forecasting teams provided national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one-to-four weeks ahead. Forecast skill is evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperform the baseline model across forecast weeks and locations in 2021-22 and 12 out of 18 models in 2022-23. Averaging across all forecast targets, the FluSight ensemble is the 2nd most accurate model measured by WIS in 2021-22 and the 5th most accurate in the 2022-23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degrade over longer forecast horizons. In this work we demonstrate that while the FluSight ensemble was a robust predictor, even ensembles face challenges during periods of rapid change.

Estimating Changes in Contact Patterns in China Over the First Year of the COVID-19 Pandemic: Implications for SARS-CoV-2 Spread - Four Cities, China, 2020.

Introduction: Previous studies have demonstrated significant changes in social contacts during the first-wave coronavirus disease 2019 (COVID-19) in Chinese mainland. The purpose of this study was to quantify the time-varying contact patterns by age in Chinese mainland in 2020 and evaluate their impact on the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: Diary-based contact surveys were performed for four periods: baseline (prior to 2020), outbreak (February 2020), post-lockdown (March-May 2020), and post-epidemic (September-November 2020). We built a Susceptible-Infected-Recovered (SIR) model to evaluate the effect of reducing contacts on transmission. Results: During the post-epidemic period, daily contacts resumed to 26.7%, 14.8%, 46.8%, and 44.2% of the pre-COVID levels in Wuhan, Shanghai, Shenzhen, and Changsha, respectively. This suggests a moderate risk of resurgence in Changsha, Shenzhen, and Wuhan, and a low risk in Shanghai. School closure alone was not enough to interrupt transmission of SARS-CoV-2 Omicron BA.5, but with the addition of a 75% reduction of contacts at the workplace, it could lead to a 16.8% reduction of the attack rate. To control an outbreak, concerted strategies that target schools, workplaces, and community contacts are needed. Discussion: Monitoring contact patterns by age is key to quantifying the risk of COVID-19 outbreaks and evaluating the impact of intervention strategies.

Spatiotemporal distribution of vector mosquito species and areas at risk for arbovirus transmission in Maricopa County, Arizona.

Mosquito-borne diseases are a major global public health concern and mosquito surveillance systems are essential for the implementation of effective mosquito control strategies. The objective of our study is to determine the spatiotemporal distribution of vector mosquito species in Maricopa County, AZ from 2011 to 2021, and to identify the hotspot areas for West Nile virus (WNV) and St. Louis Encephalitis virus (SLEV) transmission in 2021. The Maricopa County Mosquito Control surveillance system utilizes BG-Sentinel and EVS-CDC traps throughout the entire urban and suburban areas of the county. We estimated specific mosquito species relative abundance per unit area using the Kernel density estimator in ArcGIS 10.2. We calculated the distance between all traps in the surveillance system and created a 4 km buffer radius around each trap to calculate the extent to which each trap deviated from the mean number of Culex quinquefasciatus and Culex tarsalis collected in 2021. Our results show that vector mosquito species are widely distributed and abundant in the urban areas of Maricopa County. A total of 691,170Cx. quinquefasciatus, 542,733 Cx. tarsalis, and 292,305 Aedes aegypti were collected from 2011 to 2022. The relative abundance of Ae. aegypti was highly seasonal peaking in the third and fourth quarters of the year. Culex quinquefasciatus, on the other hand, was abundant throughout the year with several regions consistently yielding high numbers of mosquitoes. Culex tarsalis was abundant but it only reached high numbers in well-defined areas near irrigated landscapes. We also detected high levels of heterogeneity in the risk of WNV and SLEV transmission to humans disregarding traps geographical proximity. The well-defined species-specific spatiotemporal and geographical patterns found in this study can be used to inform vector control operations.

Evaluation of FluSight influenza forecasting in the 2021-22 and 2022-23 seasons with a new target laboratory-confirmed influenza hospitalizations.

Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. Forecasting teams were asked to provide national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one through four weeks ahead for the 2021-22 and 2022-23 influenza seasons. Across both seasons, 26 teams submitted forecasts, with the submitting teams varying between seasons. Forecast skill was evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperformed the baseline model across forecast weeks and locations in 2021-22 and 12 out of 18 models in 2022-23. Averaging across all forecast targets, the FluSight ensemble was the 2nd most accurate model measured by WIS in 2021-22 and the 5th most accurate in the 2022-23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degraded over longer forecast horizons and during periods of rapid change. Current influenza forecasting efforts help inform situational awareness, but research is needed to address limitations, including decreased performance during periods of changing epidemic dynamics.

TLRs Gene Polymorphisms Associated with Pneumonia before and during COVID-19 Pandemic.

BACKGROUND: The progression of infectious diseases depends on the characteristics of a patient's innate immunity, and the efficiency of an immune system depends on the patient's genetic factors, including SNPs in the TLR genes. In this pilot study, we determined the frequency of alleles in these SNPs in a subset of patients with pneumonia. METHODS: This study assessed six SNPs from TLR genes: rs5743551 (TLR1), rs5743708, rs3804100 (TLR2), rs4986790 (TLR4), rs5743810 (TLR6), and rs3764880 (TLR8). Three groups of patients participated in this study: patients with pneumonia in 2019 (76 samples), patients with pneumonia caused by SARS-CoV-2 in 2021 (85 samples), and the control group (99 samples). RESULTS: The allele and genotype frequencies obtained for each group were examined using four genetic models. Significant results were obtained when comparing the samples obtained from individuals with pneumonia before the spread of SARS-CoV-2 and from the controls for rs5743551 (TLR1) and rs3764880 (TLR8). Additionally, the comparison of COVID-19-related pneumonia cases and the control group revealed a significant result for rs3804100-G (TLR2). CONCLUSIONS: Determining SNP allele frequencies and searching for their associations with the course of pneumonia are important for personalized patient management. However, our results need to be comprehensively assessed in consideration of other clinical parameters.

A Unique Observation of a Patient with Vulto-van Silfhout-de Vries Syndrome.

Introduction: Vulto-van Silfhout-de Vries Syndrome (VSVS; OMIM#615828) is a rare hereditary disease associated with impaired intellectual development and speech, delayed psychomotor development, and behavioral anomalies, including autistic behavioral traits and poor eye contact. To date, 27 patients with VSVS have been reported in the literature. Materials and Methods: We describe a 23-year-old male patient with autism spectrum disorder (ASD) who was admitted to the gastroenterological hospital with signs of pseudomembranous colitis. ASD was first noted in the patient at the age of 2.5 years. Later, he developed epileptic seizures and important growth retardation. Prior to the hospitalization, chromosomal aberrations, Fragile X syndrome, and aminoacidopathies/aminoacidurias associated with ASD were excluded. Whole-genome sequencing (WGS) was prescribed to the patient at 23 years old. Results: The patient had a heterozygous carrier of "de novo" variant c.662C > T (p.S221L) in exon 4 of the DEAF1 gene. c.662C > T had not been previously described in genomic databases. According to the ACMG criteria, this missense variant was considered to be pathogenic. VSVS was diagnosed in the patient. Conclusions: The phenotype of the patient is very similar to the data presented in the world literature. However, growth retardation and cachexia, which have not been described previously in the articles, are of interest.

Model-based evaluation of alternative reactive class closure strategies against COVID-19.

There are contrasting results concerning the effect of reactive school closure on SARS-CoV-2 transmission. To shed light on this controversy, we developed a data-driven computational model of SARS-CoV-2 transmission. We found that by reactively closing classes based on syndromic surveillance, SARS-CoV-2 infections are reduced by no more than 17.3% (95%CI: 8.0-26.8%), due to the low probability of timely identification of infections in the young population. We thus investigated an alternative triggering mechanism based on repeated screening of students using antigen tests. Depending on the contribution of schools to transmission, this strategy can greatly reduce COVID-19 burden even when school contribution to transmission and immunity in the population is low. Moving forward, the adoption of antigen-based screenings in schools could be instrumental to limit COVID-19 burden while vaccines continue to be rolled out.

Investigating the relationship between interventions, contact patterns, and SARS-CoV-2 transmissibility.

BACKGROUND: After a rapid upsurge of COVID-19 cases in Italy during the fall of 2020, the government introduced a three-tiered restriction system aimed at increasing physical distancing. The Ministry of Health, after periodic epidemiological risk assessments, assigned a tier to each of the 21 Italian regions and autonomous provinces. It is still unclear to what extent these different sets of measures altered the number of daily interactions and the social mixing patterns. METHODS AND FINDINGS: We conducted a survey between July 2020 and March 2021 to monitor changes in social contact patterns among individuals in the metropolitan city of Milan, Italy, which was hardly hit by the second wave of the COVID-19 pandemic. The number of daily contacts during periods characterized by different levels of restrictions was analyzed through negative binomial regression models and age-specific contact matrices were estimated under the different tiers of restrictions. By relying on the empirically estimated mixing patterns, we quantified relative changes in SARS-CoV-2 transmission potential associated with the different tiers. As tighter restrictions were implemented during the fall of 2020, a progressive reduction in the mean number of daily contacts recorded by study participants was observed: from 15.9 % under mild restrictions (yellow tier), to 41.8 % under strong restrictions (red tier). Higher restrictions levels were also found to increase the relative contribution of contacts occurring within the household. The SARS-CoV-2 reproduction number was estimated to decrease by 17.1 % (95 %CI: 1.5-30.1), 25.1 % (95 %CI: 13.0-36.0) and 44.7 % (95 %CI: 33.9-53.0) under the yellow, orange, and red tiers, respectively. CONCLUSIONS: Our results give an important quantification of the expected contribution of different restriction levels in shaping social contacts and decreasing the transmission potential of SARS-CoV-2. These estimates can find an operational use in anticipating the effect that the implementation of these tiered restriction can have on SARS-CoV-2 reproduction number under an evolving epidemiological situation.

Physiological health indexes predict deterioration and mortality in patients with COVID-19: a comparative study.

Old age is a crucial risk factor for severe coronavirus disease 2019 (COVID-19), with serious or fatal outcomes disproportionately affecting older adults compared with the rest of the population. We proposed that the physiological health status and biological age, beyond the chronological age itself, could be the driving trends affecting COVID-19 severity and mortality. A total of 155 participants hospitalized with confirmed COVID-19 aged 26-94 years were recruited for the study. Four different physiological summary indices were calculated: Klemera and Doubal's biological age, PhenoAge, physiological dysregulation (PD; globally and in specific systems), and integrated albunemia. All of these indices significantly predicted the risk of death (p < 0.01) after adjusting for chronological age and sex. In all models, men were 2.4-4.4-times more likely to die than women. The global PD was shown to be a good predictor of deterioration, with the odds of deterioration increasing by 41.7% per 0.5-unit increase in the global PD. As for death, the odds also increased by 68.3% per 0.5-unit increase in the global PD. Our results are partly attributed to common chronic diseases that aggravate COVID-19, but they also suggest that the underlying physiological state could capture vulnerability to severe COVID-19 and serve as a tool for prognosis that would, in turn, help inpatient management.

Intrinsic generation time of the SARS-CoV-2 Omicron variant: An observational study of household transmission.

Background: Starting from the final months of 2021, the SARS-CoV-2 Omicron variant expanded globally, swiftly replacing Delta, the variant that was dominant at the time. Many uncertainties remain about the epidemiology of Omicron; here, we aim to estimate its generation time. Methods: We used a Bayesian approach to analyze 23,122 SARS-CoV-2 infected individuals clustered in 8903 households as determined from contact tracing operations in Reggio Emilia, Italy, throughout January 2022. We estimated the distribution of the intrinsic generation time (the time between the infection dates of an infector and its secondary cases in a fully susceptible population), realized household generation time, realized serial interval (time between symptom onset of an infector and its secondary cases), and contribution of pre-symptomatic transmission. Findings: We estimated a mean intrinsic generation time of 6.84 days (95% credible intervals, CrI, 5.72-8.60), and a mean realized household generation time of 3.59 days (95%CrI: 3.55-3.60). The household serial interval was 2.38 days (95%CrI 2.30-2.47) with about 51% (95%CrI 45-56%) of infections caused by symptomatic individuals being generated before symptom onset. Interpretation: These results indicate that the intrinsic generation time of the SARS-CoV-2 Omicron variant might not have shortened as compared to previous estimates on ancestral lineages, Alpha and Delta, in the same geographic setting. Like for previous lineages, pre-symptomatic transmission appears to play a key role for Omicron transmission. Estimates in this study may be useful to design quarantine, isolation and contact tracing protocols and to support surveillance (e.g., for the accurate computation of reproduction numbers). Funding: The study was partially funded by EU grant 874850 MOOD.

The impact of relaxing interventions on human contact patterns and SARS-CoV-2 transmission in China.

Nonpharmaceutical interventions to control SARS-CoV-2 spread have been implemented with different intensity, timing, and impact on transmission. As a result, post-lockdown COVID-19 dynamics are heterogeneous and difficult to interpret. We describe a set of contact surveys performed in four Chinese cities (Wuhan, Shanghai, Shenzhen, and Changsha) during the pre-pandemic, lockdown and post-lockdown periods to quantify changes in contact patterns. In the post-lockdown period, the mean number of contacts increased by 5 to 17% as compared to the lockdown period. However, it remains three to seven times lower than its pre-pandemic level sufficient to control SARS-CoV-2 transmission. We find that the impact of school interventions depends nonlinearly on the intensity of other activities. When most community activities are halted, school closure leads to a 77% decrease in the reproduction number; in contrast, when social mixing outside of schools is at pre-pandemic level, school closure leads to a 5% reduction in transmission.

Association of CASR, CALCR, and ORAI1 Genes Polymorphisms With the Calcium Urolithiasis Development in Russian Population.

Kidney stone disease is an urgent medical and social problem. Genetic factors play an important role in the disease development. This study aims to establish an association between polymorphisms in genes coding for proteins involved in calcium metabolism and the development of calcium urolithiasis in Russian population. In this case-control study, we investigated 50 patients with calcium urolithiasis (experimental group) and 50 persons lacking signs of kidney stone disease (control group). For molecular genetic analysis we used a previously developed gene panel consisting of 33 polymorphisms in 15 genes involved in calcium metabolism: VDR, CASR, CALCR, OPN, MGP, PLAU, AQP1, DGKH, SLC34A1, CLDN14, TRPV6, KLOTHO, ORAI1, ALPL, and RGS14. High-throughput target sequencing was utilized to study the loci of interest. Odds ratios and 95% confidence intervals were used to estimate the association between each SNP and risk of urolithiasis development. Multifactor dimensionality reduction analysis was also carried out to analyze the gene-gene interaction. We found statistically significant (unadjusted p-value < 0.05) associations between calcium urolithiasis and the polymorphisms in the following genes: CASR rs1042636 (OR = 3.18 for allele A), CALCR rs1801197 (OR = 6.84 for allele A), and ORAI1 rs6486795 (OR = 2.25 for allele C). The maximum OR was shown for AA genotypes in loci rs1042636 (CASR) and rs1801197 (CALCR) (OR = 4.71, OR = 11.8, respectively). After adjustment by Benjamini-Hochberg FDR we found only CALCR (rs1801197) was significantly associated with the risk of calcium urolithiasis development. There was no relationship between recurrent course of the disease and family history of urolithiasis in investigated patients. Thus we found a statistically significant association of polymorphism rs1801197 (gene CALCR) with calcium urolithiasis in Russian population.

Transmission heterogeneities, kinetics, and controllability of SARS-CoV-2.

A long-standing question in infectious disease dynamics concerns the role of transmission heterogeneities, which are driven by demography, behavior, and interventions. On the basis of detailed patient and contact-tracing data in Hunan, China, we find that 80% of secondary infections traced back to 15% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primary infections, which indicates substantial transmission heterogeneities. Transmission risk scales positively with the duration of exposure and the closeness of social interactions and is modulated by demographic and clinical factors. The lockdown period increases transmission risk in the family and households, whereas isolation and quarantine reduce risks across all types of contacts. The reconstructed infectiousness profile of a typical SARS-CoV-2 patient peaks just before symptom presentation. Modeling indicates that SARS-CoV-2 control requires the synergistic efforts of case isolation, contact quarantine, and population-level interventions because of the specific transmission kinetics of this virus.

Cryptic transmission of SARS-CoV-2 and the first COVID-19 wave in Europe and the United States.

Given the narrowness of the initial testing criteria, the SARS-CoV-2 virus spread through cryptic transmission in January and February, setting the stage for the epidemic wave experienced in March and April, 2020. We use a global metapopulation epidemic model to provide a mechanistic understanding of the global dynamic underlying the establishment of the COVID-19 pandemic in Europe and the United States (US). The model is calibrated on international case introductions at the early stage of the pandemic. We find that widespread community transmission of SARS-CoV-2 was likely in several areas of Europe and the US by January 2020, and estimate that by early March, only 1 - 3 in 100 SARS-CoV-2 infections were detected by surveillance systems. Modeling results indicate international travel as the key driver of the introduction of SARS-CoV-2 with possible importation and transmission events as early as December, 2019. We characterize the resulting heterogeneous spatio-temporal spread of SARS-CoV-2 and the burden of the first COVID-19 wave (February-July 2020). We estimate infection attack rates ranging from 0.78%-15.2% in the US and 0.19%-13.2% in Europe. The spatial modeling of SARS-CoV-2 introductions and spreading provides insights into the design of innovative, model-driven surveillance systems and preparedness plans that have a broader initial capacity and indication for testing.