We measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA concentrations in primary sewage sludge in the New Haven, Connecticut, USA, metropolitan area during the Coronavirus Disease 2019 (COVID-19) outbreak in Spring 2020. SARS-CoV-2 RNA was detected throughout the more than 10-week study and, when adjusted for time lags, tracked the rise and fall of cases seen in SARS-CoV-2 clinical test results and local COVID-19 hospital admissions. Relative to these indicators, SARS-CoV-2 RNA concentrations in sludge were 0-2 d ahead of SARS-CoV-2 positive test results by date of specimen collection, 0-2 d ahead of the percentage of positive tests by date of specimen collection, 1-4 d ahead of local hospital admissions and 6-8 d ahead of SARS-CoV-2 positive test results by reporting date. Our data show the utility of viral RNA monitoring in municipal wastewater for SARS-CoV-2 infection surveillance at a population-wide level. In communities facing a delay between specimen collection and the reporting of test results, immediate wastewater results can provide considerable advance notice of infection dynamics. The progression of the COVID-19 pandemic has been monitored primarily by testing symptomatic individuals for the presence of SARS-CoV-2 RNA and counting the number of positive tests over time 1. However, in the United States and other countries, the spread of COVID-19 has commonly exceeded the testing capacity of public health systems. Moreover, test results are a lagging indicator of the pandemic's progression 2,3 , because testing is usually prompted by symptoms, which might take 2 weeks to present after infection 4 , and delays occur between the appearance of symptoms, testing and the reporting of test results. Monitoring sewage in a community's collection or treatment system has been used previously to provide early surveillance of disease prevalence at a population-wide level, notably for polio 5,6 , and might be similarly beneficial for the current COVID-19 pandemic. SARS-CoV-2 RNA is present in the stool of patients with COVID-19 (refs. 7-9) and in raw wastewater 10-12 , and increased RNA concentrations in raw wastewater have been recently associated with increases in reported COVID-19 cases 11. However, the utility of wastewater SARS-CoV-2 concentrations for tracking the progression of COVID-19 infections is poorly understood. In this study, we investigated how viral RNA concentrations in

IMPORTANCE Efforts to track the severity and public health impact of coronavirus disease 2019 (COVID-19) in the United States have been hampered by state-level differences in diagnostic test availability, differing strategies for prioritization of individuals for testing, and delays between testing and reporting. Evaluating unexplained increases in deaths due to all causes or attributed to nonspecific outcomes, such as pneumonia and influenza, can provide a more complete picture of the burden of COVID-19. OBJECTIVE To estimate the burden of all deaths related to COVID-19 in the United States from March to May 2020. DESIGN, SETTING, AND POPULATION This observational study evaluated the numbers of US deaths from any cause and deaths from pneumonia, influenza, and/or COVID-19 from March 1 through May 30, 2020, using public data of the entire US population from the National Center for Health Statistics (NCHS). These numbers were compared with those from the same period of previous years. All data analyzed were accessed on June 12, 2020. MAIN OUTCOMES AND MEASURES Increases in weekly deaths due to any cause or deaths due to pneumonia/influenza/COVID-19 above a baseline, which was adjusted for time of year, influenza activity, and reporting delays. These estimates were compared with reported deaths attributed to COVID-19 and with testing data. RESULTS There were approximately 781 000 total deaths in the United States from March 1 to May 30, 2020, representing 122 300 (95% prediction interval, 116 800-127 000) more deaths than would typically be expected at that time of year. There were 95 235 reported deaths officially attributed to COVID-19 from March 1 to May 30, 2020. The number of excess all-cause deaths was 28% higher than the official tally of COVID-19-reported deaths during that period. In several states, these deaths occurred before increases in the availability of COVID-19 diagnostic tests and were not counted in official COVID-19 death records. There was substantial variability between states in the difference between official COVID-19 deaths and the estimated burden of excess deaths. CONCLUSIONS AND RELEVANCE Excess deaths provide an estimate of the full COVID-19 burden and indicate that official tallies likely undercount deaths due to the virus. The mortality burden and the completeness of the tallies vary markedly between states.

Summary Antibodies to Zika virus (ZIKV) can be protective. To examine the antibody response in individuals that develop high titers of anti-ZIKV antibodies we screened cohorts in Brazil and Mexico for ZIKV envelope domain III (ZEDIII) binding and neutralization. We find that serologic reactivity to dengue 1 virus (DENV1) EDIII before ZIKV exposure is associated with increased ZIKV neutralizing titers after exposure. Antibody cloning shows that donors with high ZIKV neutralizing antibody titers have expanded clones of memory B cells that express the same immunoglobulin VH3-23/VK1-5 genes. These recurring antibodies cross-react with DENV1, but not other flaviviruses, neutralize both DENV1 and ZIKV, and protect mice against ZIKV challenge. Structural analyses reveal the mechanism of recognition of the ZEDIII lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing shows that antibodies to this region correlate with serum neutralizing activity to ZIKV. Thus, high neutralizing responses to ZIKV are associated with preexisting reactivity to DENV1 in humans.

The number of publicly reported deaths from coronavirus disease 2019 (COVID-19) may underestimate the pandemic's death toll. Such estimates rely on provisional data that are often incomplete and may omit undocumented deaths from COVID-19. Moreover, restrictions imposed by the pandemic (eg, stay-at-home orders) could claim lives indirectly through delayed care for acute emergencies, exacerbations of chronic diseases, and psychological distress (eg, drug overdoses). This study estimated excess deaths in the early weeks of the pandemic and the relative contribution of COVID-19 and other causes. Methods | Weekly death data for the 50 US states and the District of Columbia were obtained from the National Center for Health Statistics for January through April 2020 and the preceding 6 years (2014-2019). 1,2 US totals excluded Connecticut and North Carolina because of missing data. The analysis included total deaths and deaths from COVID-19, influenza/pneumonia, heart disease, diabetes, and 10 other grouped causes (Supplement). Mortality rates for causes other than COVID-19 were available only for underlying causes. Death data with any mention of COVID-19 on the death certificate (as an underlying or contributing cause) were used to capture all deaths attributed to the virus. Population counts for calculating mortality rates were obtained from the US Census Bureau. 3,4 Observed deaths for the 8 weeks between March 1, 2020, and April 25, 2020, were taken from provisional data released on June 10, 2020. 2 Expected deaths (and 95% CIs) for these same weeks were estimated by fitting a hierarchical Poisson regression model to the weekly death counts for the period of

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