Closing the health inequity gap during the pandemic: COVID-19 mortality among racial and ethnic groups in Connecticut, March 2020 to December 2021

COVID-19 has disproportionally burdened racial and ethnic minority groups within the United States. Leveraging statewide data, we examined the evolution of racial and ethnic disparities in COVID-19 related deaths among Connecticut residents residing in non-congregate settings over three periods of the COVID-19 pandemic. Despite observing large disparities in the age-adjusted mortality rates between Hispanics, non-Hispanic Blacks, and non-Hispanic Whites during the initial pandemic period (March to August 2020), we observed meaningful reductions in the disparities during the subsequent periods (August 2020 to July 2021; July to mid December 2021). Further, during the third period, we failed to find a significant difference in age-adjusted mortality between non-Hispanic Blacks and non-Hispanic Whites. These findings provide evidence that attenuation of racial and ethnic disparities in COVID-19 related outcomes are achievable.

Use of recently vaccinated individuals to detect bias in test-negative case-control studies of COVID-19 vaccine effectiveness

Post-authorization observational studies play a key role in understanding COVID-19 vaccine effectiveness following the demonstration of efficacy in clinical trials. While bias due to confounding, selection bias, and misclassification can be mitigated through careful study design, unmeasured confounding is likely to remain in these observational studies. Phase III trials of COVID-19 vaccines have shown that protection from vaccination does not occur immediately, meaning that COVID-19 risk should be similar in recently vaccinated and unvaccinated individuals, in the absence of confounding or other bias. Several studies have used the estimated effectiveness among recently vaccinated individuals as a negative control exposure to detect bias in vaccine effectiveness estimates. In this paper we introduce a theoretical framework to describe the interpretation of such a bias-indicator in test-negative studies, and outline assumptions that would allow the use of recently vaccinated individuals to correct bias due to unmeasured confounding.

Performance of Abbott Architect, Ortho Vitros, and Euroimmun Assays in Detecting Prior SARS-CoV-2 Infection

BackgroundSeveral serological assays have been developed to detect anti-SARS-CoV-2 IgG antibodies, but evidence about their comparative performance is limited. We sought to assess the sensitivity of four anti-SARS-CoV-2 IgG enzyme-linked immunosorbent assays (ELISA) in individuals with evidence of prior SARS-CoV-2 infection. MethodsWe obtained sera from 36 individuals with PCR-confirmed SARS-CoV-2 infection between March and May 2020. We evaluated samples collected at around 21 days ({+/-}14 days) after their initial PCR test using 3 commercially available ELISA assays, two anti-spike (Ortho- Clinical Diagnostics Vitros, and Euroimmun) and one anti-nucleocapsid (Abbott Architect), and a Yale-developed anti-spike ELISA test. We determined the sensitivity of the tests and compared their results. The Euroimmun and Yale ELISA had an equivocal and indeterminate category, which were considered as both negative and positive. ResultsAmong the 36 individuals with SARS-CoV-2 infection, mean age was 43 ({+/-}13) years and 19 (53%) were female. The sensitivities of the tests were not significantly different (Abbott Architect, Ortho Vitros, Euroimmmun, and Yale assays: 86% (95% confidence interval [CI], 71- 95), 94% (95% CI, 81-99), 86% (95% CI, 71-95), and 94% (95% CI, 81-99), respectively; p- value=0.464). The sensitivities of the Euroimmun and Yale ELISA tests increased when the equivocal/indeterminate results were considered positive (97% [95% CI, 85-100] and 100% [95% CI, 90-100], respectively), but were not significantly different from other tests (p=0.082). The cross-correlation coefficient ranged from 0.85-0.98 between three anti-spike protein assays (Ortho Vitros, Euroimmun, Yale) and was 0.58-0.71 between the three anti-spike protein assays and the anti-nucleocapsid assay (Abbott). ConclusionThe sensitivities of four anti-SARS-CoV-2 protein assays did not significantly differ, although the sample size was small. Sensitivity also depended on the interpretation of equivocal and indeterminate results. The strongest correlations were present for the three anti- spike proteins assays. These findings suggest that individual test characteristics and the correlation between different tests should be considered when comparing or aggregating data across different populations studies for serologic surveillance of past SARS-CoV-2 infection.

The Sensitivity of Respiratory Tract Specimens for the Detection of SARS-CoV-2: A Protocol for a Living Systematic Review and Meta-Analysis

BackgroundHighly sensitive, non-invasive, and easily accessible diagnostics for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are essential for the control of the Coronavirus Disease 2019 (COVID-19) pandemic. There is a clear need to establish a gold standard diagnostic for SARS-CoV-2 infection in humans using respiratory tract specimens. MethodsSearches will be conducted in the bibliographic databases Medline, Embase, bioRxiv, medRxiv, F1000, ChemRxiv, PeerJ Preprints, Preprints.org, Beilstein Archive, and Research Square. Relevant government documents and grey literature will be sought on the FDAs Emergency Use Authorizations website, the ECDCs website, and the website of the Foundation for Innovative New Diagnostics. Finally, papers categorized as diagnosis papers by the EPPI Centres COVID-19 living systematic map will be added to our screening process; those papers are tagged with the diagnosis topic based on human review, rather than database searches, and thus this set of papers might include ones that have not been captured by our search strategy.

Testing Frequency Matters | An Evaluation of the Diagnostic Performance of a SARS-CoV-2 Rapid Antigen Test in United States Correctional Facilities

BackgroundThe CDC recommends serial rapid antigen assay collection within congregate facilities for screening and outbreak testing. Though modeling and observational studies from community and long-term care facilities have shown serial collection provides adequate sensitivity and specificity, the diagnostic accuracy of this testing strategy within correctional facilities remains unknown. MethodsUsing Connecticut Department of Corrections (DOC) data from November 21st 2020 to June 15th 2021, we estimated the accuracy of a rapid assay, BinaxNOW, under three collection strategies, a single test in isolation and two and three serial tests separated by 1-4 day intervals. Diagnostic accuracy metrics were estimated in relation to RT-PCRs collected within one day before the first or after the last included rapid antigen tests in a series. ResultsOf the 17,669 residents who contributed at least one RT-PCR or rapid antigen during the study period, 3,979 contributed [≥]1 paired rapid antigen test series. In relation to RT-PCR, the three-rapid antigen test strategy had a sensitivity of 89.6% (95% confidence intervals: 86.1-92.6%) and specificity of 97.2% (CI: 95.1-98.3%). The sensitivities for two and one-rapid antigen test strategy were 75.2% and 52.8%, respectively, and the specificities were 98.5% and 99.4%, respectively. The sensitivity was higher among symptomatic residents and when the RT-PCR was collected before the rapid antigen tests. ConclusionsWe found the serial collection of an antigen test resulted in high diagnostic accuracy. These findings support serial testing within correctional facilities for outbreak investigation, screening, and when rapid detection is required (such as intakes or transfers).

SARS-CoV-2 RNA concentrations in primary municipal sewage sludge as a leading indicator of COVID-19 outbreak dynamics

We report a time course of SARS-CoV-2 RNA concentrations in primary sewage sludge during the Spring COVID-19 outbreak in a northeastern U.S. metropolitan area. SARS-CoV-2 RNA was detected in all environmental samples, and when adjusted for the time lag, the virus RNA concentrations tracked the COVID-19 epidemiological curve. SARS-CoV-2 RNA concentrations were a leading indicator of community infection ahead of compiled COVID-19 testing data and local hospital admissions. Decisions to implement or relax public health measures and restrictions require timely information on outbreak dynamics in a community.

Routine Saliva Testing for SARS-CoV-2 in Children: Partnering with Childcare Centers in the Greater New Haven Community

BackgroundWhile considerable attention was placed on SARS-CoV-2 testing and surveillance programs in the K-12 setting, younger age groups in childcare centers were largely overlooked. Childcare facilities are vital to communities, allowing parents/guardians to remain at work and providing safe environments for both children and staff. Therefore, early in the COVID-19 pandemic, we established a PCR-based COVID-19 surveillance program in childcare facilities, testing children and staff with the goal of collecting actionable public health data and aiding communities in the progressive resumption of standard operations and ways of life. In this study we describe the development of a weekly saliva testing program and provide early results from our experience implementing this in childcare centers. MethodsWe enrolled children (aged 6 months to 7 years) and staff at 8 childcare facilities and trained participants in saliva collection using video chat technology. Weekly surveys were sent out to assess exposures, symptoms, and vaccination status changes. Participants submitted weekly saliva samples at school. Samples were transported to a partnering clinical laboratory for RT-PCR testing using SalivaDirect and results were uploaded to each participants online patient portal within 24 hours. ResultsThis study fostered a cooperative partnership with participating childcare centers, parents/guardians, and staff with the goal of mitigating COVID-19 transmission in childcare centers. Age-related challenges in saliva collection were overcome by working with parents/guardians to conceptualize new collection strategies and by offering parents/guardians continued virtual guidance and support. ConclusionSARS-CoV-2 screening and routine testing programs have focused less on the childcare population, resulting in knowledge gaps in this critical age group, especially as many are still ineligible for vaccination. SalivaDirect testing for SARS-CoV-2 provides a feasible method of asymptomatic screening and symptomatic testing for children and childcare center staff. Given the relative aversion to nasal swabs in the childcare age group, especially as a routine surveillance tool, an at-home saliva collection method provides an attractive alternative. Results can be shared rapidly electronically through participants private medical chart portals, and video chat technology allows for discussion and instruction between investigators and participants.

Reliable estimation of SARS-CoV-2 anti-spike protein IgG titers from single dilution optical density values in serologic surveys

BackgroundAs the COVID-19 pandemic evolves, there is a need for reliable and scalable seroepidemiology methods to estimate incidence, monitor the dynamics of population-level immunity, and guide mitigation and immunization policies. Our aim was to evaluate the reliability of normalized ELISA optical density (nOD) at a single dilution as a predictor of SARS-CoV-2 immunoglobulin titers derived from serial dilutions. MethodsWe conducted serial serological surveys of a community-based cohort from the city of Salvador, Brazil after two sequential COVID-19 epidemic waves. Anti-SARS-CoV-2 spike protein immunoglobulin G (anti-S IgG) ELISA (Euroimmun AG) was performed with serial 3-fold dilutions of sera from 54 of the 1101 cohort participants. We estimated interpolated ELISA titers, used parametric models to fit the relationship between nOD at a single 1:100 dilution and interpolated titers, and assessed the correlation between changes in nOD and changes in titers. ResultsThe relationship between nOD at a single 1:100 dilution and interpolated titers fit a log-log curve, with a residual standard error of 0.304. We derived a conversion table of nOD to interpolated titer values. Additionally, there was a high correlation between changes in nOD and changes in interpolated titers between paired serial samples (r = 0.836, {rho} = 0.873). Changes in nOD reliably predicted increases and decreases in titers, with 98.1% agreement ({kappa} = 95.9%). ConclusionSingle nOD measurements can reliably estimate SARS-CoV-2 antibody titers, significantly reducing time, labor, and resource needs when conducting large-scale serological surveys to ascertain population-level changes in exposure and immunity. HighlightsO_LIOptical density at a single dilution reliably estimates SARS-CoV-2 antibody titers C_LIO_LISerial optical density measurements accurately identify changes in serostatus C_LIO_LIUsing single optical density values can significantly reduce resource use in serosurveys C_LI

SARS-CoV-2 Infection Hospitalization Rate and Infection Fatality Rate among the Non-Congregant Population in Connecticut

ImportanceCOVID-19 case fatality and hospitalization rates, calculated using the number of confirmed cases of COVID-19, have been described widely in the literature. However, the number of infections confirmed by testing underestimates the total infections as it is biased based on the availability of testing and because asymptomatic individuals may remain untested. The infection fatality rate (IFR) and infection hospitalization rate (IHR), calculated using the estimated total infections based on a representative sample of a population, is a better metric to assess the actual toll of the disease. ObjectiveTo determine the IHR and IFR for COVID-19 using the statewide SARS-CoV-2 seroprevalence estimates for the non-congregate population in Connecticut. DesignCross-sectional. SettingAdults residing in a non-congregate setting in Connecticut between March 1 and June 1, 2020. ParticipantsIndividuals aged 18 years or above. ExposureEstimated number of adults with SARS-CoV-2 antibodies. Main Outcome and MeasuresCOVID-19-related hospitalizations and deaths among adults residing in a non-congregate setting in Connecticut between March 1 and June 1, 2020. ResultsOf the 2.8 million individuals residing in the non-congregate settings in Connecticut through June 2020, 113,515 (90% CI 56,758-170,273) individuals had SARS-CoV-2 antibodies. There were a total of 9425 COVID-19-related hospitalizations and 4071 COVID-19-related deaths in Connecticut between March 1 and June 1, 2020, of which 7792 hospitalizations and 1079 deaths occurred among the non-congregate population. The overall COVID-19 IHR and IFR was 6.86% (90% CI, 4.58%-13.72%) and 0.95% (90% CI, 0.63%-1.90%) among the non-congregate population. Older individuals, men, non-Hispanic Black individuals and those belonging to New Haven and Litchfield counties had a higher burden of hospitalization and deaths, compared with younger individuals, women, non-Hispanic White or Hispanic individuals, and those belonging to New London county, respectively. Conclusion and RelevanceUsing representative seroprevalence estimates, the overall COVID-19 IHR and IFR were estimated to be 6.86% and 0.95% among the non-congregate population in Connecticut. Accurate estimation of IHR and IFR among community residents is important to guide public health strategies during an infectious disease outbreak.

Tracking Smell Loss to Identify Healthcare Workers with SARS-CoV-2 Infection

BackgroundHealthcare workers (HCW) treating COVID-19 patients are at high risk for infection and may also spread infection through their contact with vulnerable patients. Smell loss has been associated with SARS-CoV-2 infection, but it is unknown whether monitoring for smell loss can be used to identify asymptomatic infection among high risk individuals, like HCW. MethodsWe performed a prospective cohort study, tracking 473 HCW across three months to determine if smell loss could predict SARS-CoV-2 infection in this high-risk group. HCW subjects completed a longitudinal, novel behavioral at-home assessment of smell function with household items, as well as detailed symptom surveys that included a parosmia screening questionnaire, and RT-qPCR testing to identify SARSCoV-2 infection. ResultsSARS-CoV-2 was identified in 17 (3.6%) of 473 HCW. Among the 17 infected HCW, 53% reported smell loss, and were more likely to report smell loss than COVID-negative HCW on both the at-home assessment and the screening questionnaire (P < .01). 67% reported smell loss prior to having a positive SARS-CoV-2 test, and smell loss was reported a median of two days before testing positive. Neurological symptoms were reported more frequently among COVID-positive HCW who reported smell loss (P < .01). ConclusionsIn this prospective study of HCW, self-reported changes in smell using two different measures were predictive of COVID-19 infection. Smell loss frequently preceded a positive test and was associated with neurological symptoms.

Pooling saliva to increase SARS-CoV-2 testing capacity

Expanding testing capabilities is integral to managing the further spread of SARS-CoV-2 and developing reopening strategies, particularly in regards to identifying and isolating asymptomatic and pre-symptomatic individuals. Central to meeting testing demands are specimens that can be easily and reliably collected and laboratory capacity to rapidly ramp up to scale. We and others have demonstrated that high and consistent levels of SARS-CoV-2 RNA can be detected in saliva from COVID-19 inpatients, outpatients, and asymptomatic individuals. As saliva collection is non-invasive, extending this strategy to test pooled saliva samples from multiple individuals could thus provide a simple method to expand testing capacity. However, hesitation towards pooled sample testing arises due to the dilution of positive samples, potentially shifting weakly positive samples below the detection limit for SARS-CoV-2 and thereby decreasing the sensitivity. Here, we investigated the potential of pooling saliva samples by 5, 10, and 20 samples prior to RNA extraction and RT-qPCR detection of SARS-CoV-2. Based on samples tested, we conservatively estimated a reduction of 7.41%, 11.11%, and 14.81% sensitivity, for each of the pool sizes, respectively. Using these estimates we modeled anticipated changes in RT-qPCR cycle threshold to show the practical impact of pooling on results of SARS-CoV-2 testing. In tested populations with greater than 3% prevalence, testing samples in pools of 5 requires the least overall number of tests. Below 1% however, pools of 10 or 20 are more beneficial and likely more supportive of ongoing surveillance strategies.

Seroprevalence of SARS-CoV-2-Specific IgG Antibodies Among Adults Living in Connecticut Between March 1 and June 1, 2020: Post-Infection Prevalence (PIP) Study

BackgroundA seroprevalence study can estimate the percentage of people with SARS-CoV-2 antibodies in the general population, however, most existing reports have used a convenience sample, which may bias their estimates. MethodsWe sought a representative sample of Connecticut residents, aged [≥]18 years and residing in non-congregate settings, who completed a survey between June 4 and June 23, 2020 and underwent serology testing for SARS-CoV-2-specific IgG antibodies between June 10 and July 29, 2020. We also oversampled non-Hispanic Black and Hispanic subpopulations. We estimated the seroprevalence of SARS-CoV-2-specific IgG antibodies and the prevalence of symptomatic illness and self-reported adherence to risk mitigation behaviors among this population. ResultsOf the 567 respondents (mean age 50 [{+/-}17] years; 53% women; 75% non-Hispanic White individuals) included at the state-level, 23 respondents tested positive for SARS-CoV-2-specific antibodies, resulting in weighted seroprevalence of 4.0 (90% confidence interval [CI] 2.0-6.0). The weighted seroprevalence for the oversampled non-Hispanic Black and Hispanic populations was 6.4% (90% CI 0.9-11.9) and 19.9% (90% CI 13.2-26.6), respectively. The majority of respondents at the state-level reported following risk mitigation behaviors: 73% avoided public places, 75% avoided gatherings of families or friends, and 97% wore a facemask, at least part of the time. ConclusionsThese estimates indicate that the vast majority of people in Connecticut lack antibodies against SARS-CoV-2 and there is variation by race/ethnicity. There is a need for continued adherence to risk mitigation behaviors among Connecticut residents to prevent resurgence of COVID-19 in this region.

Effectiveness of an Inactivated Covid-19 Vaccine with Homologous and Heterologous Boosters against the Omicron (B.1.1.529) Variant

The effectiveness of inactivated vaccines (VE) against symptomatic and severe COVID-19 caused by omicron is unknown. We conducted a nationwide, test-negative, case-control study to estimate VE for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac in Brazil in the Omicron context. Analyzing 1,386,544 matched-pairs, VE against symptomatic disease was 8.6% (95% CI, 5.6-11.5) and 56.8% (95% CI, 56.3-57.3) in the period 8-59 days after receiving a homologous and heterologous booster, respectively. During the same interval, VE against severe Covid-19 was 73.6% (95% CI, 63.9-80.7) and 86.0% (95% CI, 84.5-87.4) after receiving a homologous and heterologous booster, respectively. Waning against severe Covid-19 after 120 days was only observed after a homologous booster. Heterologous booster might be preferable to individuals with completed primary series inactivated vaccine.

Structural risk factors for SARS-CoV-2 infection in an urban slum: Age, gender and income

BackgroundThe structural environment of urban slums, including physical, demographic and socioeconomic attributes, renders inhabitants more vulnerable to SARS-CoV-2 infection. Yet, little is known about the specific determinants that contribute to high transmission within these communities. Methods and findingsWe performed a serosurvey of an established cohort of 2,035 urban slum residents from the city of Salvador, Brazil between November 2020 and February 2021, following the first COVID-19 pandemic wave in the country. We identified high SARS-CoV-2 seroprevalence (46.4%, 95% confidence interval [CI] 44.3-48.6%), particularly among female residents (48.7% [95% CI 45.9-51.6%] vs. 43.2% [95% CI 39.8-46.6%] among male residents), and among children (56.5% [95% CI 52.3-60.5%] vs. 42.4% [95% CI 39.9-45.0%] among adults). In multivariable models that accounted for household-level clustering, the odds ratio for SARS-CoV-2 seropositivity among children was 1.96 (95% CI 1.42-2.72) compared to adults aged 30-44 years. Adults residing in households with children were more likely to be seropositive; this effect was particularly prominent among individuals with age 30-44 and 60 years or more. Women living below the poverty threshold (daily per capita household income <$1.25) and those who were unemployed were more likely to be seropositive. ConclusionsDuring a single wave of the COVID-19 pandemic, cumulative incidence as assessed by serology approached 50% in a Brazilian urban slum population. In contrast to observations from industrialized countries, SARS-CoV-2 incidence was highest among children, as well as women living in extreme poverty. These findings emphasize the need for targeted interventions that provide safe environments for children and mitigate the structural risks posed by crowding and poverty for the most vulnerable residents of urban slum communities.

Effectiveness of CoronaVac, ChAdOx1, BNT162b2 and Ad26.COV2.S among individuals with prior SARS-CoV-2 infection in Brazil

BackgroundCOVID-19 vaccines have proven highly effective among SARS-CoV-2 naive individuals, but their effectiveness in preventing symptomatic infection and severe outcomes among individuals with prior infection is less clear. MethodsUtilizing national COVID-19 notification, hospitalization, and vaccination datasets from Brazil, we performed a case-control study using a test-negative design to assess the effectiveness of four vaccines (CoronaVac, ChAdOx1, Ad26.COV2.S and BNT162b2) among individuals with laboratory-confirmed prior SARS-CoV-2 infection. We matched RT-PCR positive, symptomatic COVID-19 cases with RT-PCR-negative controls presenting with symptomatic illnesses, restricting both groups to tests performed at least 90 days after an initial infection. We used multivariable conditional logistic regression to compare the odds of test positivity, and the odds of hospitalization or death due to COVID-19, according to vaccination status and time since first or second dose of vaccines. FindingsAmong individuals with prior SARS-CoV-2 infection, vaccine effectiveness against symptomatic infection [≥] 14 days from vaccine series completion was 39.4% (95% CI 36.1-42.6) for CoronaVac, 56.0% (95% CI 51.4-60.2) for ChAdOx1, 44.0% (95% CI 31.5-54.2) for Ad26.COV2.S, and 64.8% (95% CI 54.9-72.4) for BNT162b2. For the two-dose vaccine series (CoronaVac, ChAdOx1, and BNT162b2), effectiveness against symptomatic infection was significantly greater after the second dose compared with the first dose. Effectiveness against hospitalization or death [≥] 14 days from vaccine series completion was 81.3% (95% CI 75.3-85.8) for CoronaVac, 89.9% (95% CI 83.5-93.8) for ChAdOx1, 57.7% (95% CI -2.6-82.5) for Ad26.COV2.S, and 89.7% (95% CI 54.3-97.7) for BNT162b2. InterpretationAll four vaccines conferred additional protection against symptomatic infections and severe outcomes among individuals with previous SARS-CoV-2 infection. Provision of a full vaccine series to individuals following recovery from COVID-19 may reduce morbidity and mortality. FundingBrazilian National Research Council, Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro, Oswaldo Cruz Foundation, JBS S.A., Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, Generalitat de Catalunya. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed, medRxiv, and SSRN for articles published from January 1, 2020 until December 15, 2021, with no language restrictions, using the search terms "vaccine effectiveness" AND "previous*" AND ("SARS-CoV-2" OR "COVID-19"). We found several studies evaluating ChAdOx1 and BNT162b2, and one additionally reporting on mRNA-1273 and Ad26.COV2.S, which found that previously infected individuals who were vaccinated had lower risk of symptomatic SARS-CoV-2 infection. One study found that risk of hospitalization was lower for previously infected individuals after a full series of BNT162b2 or mRNA-1273. Limited evidence is available comparing effectiveness of one versus two doses among individuals with prior infection. No studies reported effectiveness of inactivated vaccines among previously infected individuals. Added value of this studyWe used national databases of COVID-19 case surveillance, laboratory testing, and vaccination from Brazil to investigate effectiveness of CoronaVac, ChAdOx1, Ad26.COV2.S and BNT162b2 among individuals with a prior, laboratory-confirmed SARS-CoV-2 infection. We matched >22,000 RT-PCR-confirmed re-infections with >145,000 RT-PCR-negative controls using a test-negative design. All four vaccines were effective against symptomatic SARS-CoV-2 infections, with effectiveness from 14 days after series completion ranging from 39-65%. For vaccines with two-dose regimens, the second dose provided significantly increased effectiveness compared with one dose. Effectiveness against COVID-19-associated hospitalization or death from 14 days after series completion was >80% for CoronaVac, ChAdOx1and BNT162b2. Implications of all the available evidenceWe find evidence that four vaccines, using three different platforms, all provide protection to previously infected individuals against symptomatic SARS-CoV-2 infection and severe outcomes, with a second dose conferring significant additional benefits. These results support the provision of a full vaccine series among individuals with prior SARS-CoV-2 infection.

De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a [~]6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

SARS-CoV-2 Omicron-specific mRNA vaccine induces potent and broad antibody responses in vivo

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has high transmissibility and recently swept the globe. Due to the extensive number of mutations, this variant has high level of immune evasion, which drastically reduced the efficacy of existing antibodies and vaccines. Thus, it is important to test an Omicron-specific vaccine, evaluate its immune response against Omicron and other variants, and compare its immunogenicity as boosters with existing vaccine designed against the reference wildtype virus (WT). Here, we generated an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and tested its activity in animals, both alone and as a heterologous booster to existing WT mRNA vaccine. Our Omicron-specific LNP-mRNA vaccine elicited strong and specific antibody response in vaccination-naive mice. Mice that received two-dose WT LNP-mRNA, the one mimicking the commonly used Pfizer/Moderna mRNA vaccine, showed a >40-fold reduction in neutralization potency against Omicron variant than that against WT two weeks post second dose, which further reduced to background level >3 months post second dose. As a booster shot for two-dose WT mRNA vaccinated mice, a single dose of either a homologous booster with WT LNP-mRNA or a heterologous booster with Omicron LNP-mRNA restored the waning antibody response against Omicron, with over 40-fold increase at two weeks post injection as compared to right before booster. Interestingly, the heterologous Omicron LNP-mRNA booster elicited neutralizing titers 10-20 fold higher than the homologous WT booster against the Omicron variant, with comparable titers against the Delta variant. All three types of vaccination, including Omicron mRNA alone, WT mRNA homologous booster, and Omicron heterologous booster, elicited broad binding antibody responses against SARS-CoV-2 WA-1, Beta, and Delta variants, as well as other Betacoronavirus species such as SARS-CoV, but not Middle East respiratory syndrome coronavirus (MERS-CoV). These data provided direct proof-of-concept assessments of an Omicron-specific mRNA vaccination in vivo, both alone and as a heterologous booster to the existing widely-used WT mRNA vaccine form.

Accuracy of Computable Phenotyping Approaches for SARS-CoV-2 Infection and COVID-19 Hospitalizations from the Electronic Health Record

ObjectiveReal-world data have been critical for rapid-knowledge generation throughout the COVID-19 pandemic. To ensure high-quality results are delivered to guide clinical decision making and the public health response, as well as characterize the response to interventions, it is essential to establish the accuracy of COVID-19 case definitions derived from administrative data to identify infections and hospitalizations. MethodsElectronic Health Record (EHR) data were obtained from the clinical data warehouse of the Yale New Haven Health System (Yale, primary site) and 3 hospital systems of the Mayo Clinic (validation site). Detailed characteristics on demographics, diagnoses, and laboratory results were obtained for all patients with either a positive SARS-CoV-2 PCR or antigen test or ICD-10 diagnosis of COVID-19 (U07.1) between April 1, 2020 and March 1, 2021. Various computable phenotype definitions were evaluated for their accuracy to identify SARS-CoV-2 infection and COVID-19 hospitalizations. ResultsOf the 69,423 individuals with either a diagnosis code or a laboratory diagnosis of a SARS-CoV-2 infection at Yale, 61,023 had a principal or a secondary diagnosis code for COVID-19 and 50,355 had a positive SARS-CoV-2 test. Among those with a positive laboratory test, 38,506 (76.5%) and 3449 (6.8%) had a principal and secondary diagnosis code of COVID-19, respectively, while 8400 (16.7%) had no COVID-19 diagnosis. Moreover, of the 61,023 patients with a COVID-19 diagnosis code, 19,068 (31.2%) did not have a positive laboratory test for SARS-CoV-2 in the EHR. Of the 20 cases randomly sampled from this latter group for manual review, all had a COVID-19 diagnosis code related to asymptomatic testing with negative subsequent test results. The positive predictive value (precision) and sensitivity (recall) of a COVID-19 diagnosis in the medical record for a documented positive SARS-CoV-2 test were 68.8% and 83.3%, respectively. Among 5,109 patients who were hospitalized with a principal diagnosis of COVID-19, 4843 (94.8%) had a positive SARS-CoV-2 test within the 2 weeks preceding hospital admission or during hospitalization. In addition, 789 hospitalizations had a secondary diagnosis of COVID-19, of which 446 (56.5%) had a principal diagnosis consistent with severe clinical manifestation of COVID-19 (e.g., sepsis or respiratory failure). Compared with the cohort that had a principal diagnosis of COVID-19, those with a secondary diagnosis had a more than 2-fold higher in-hospital mortality rate (13.2% vs 28.0%, P<0.001). In the validation sample at Mayo Clinic, diagnosis codes more consistently identified SARS-CoV-2 infection (precision of 95%) but had lower recall (63.5%) with substantial variation across the 3 Mayo Clinic sites. Similar to Yale, diagnosis codes consistently identified COVID-19 hospitalizations at Mayo, with hospitalizations defined by secondary diagnosis code with 2-fold higher in-hospital mortality compared to those with a primary diagnosis of COVID-19. ConclusionsCOVID-19 diagnosis codes misclassified the SARS-CoV-2 infection status of many people, with implications for clinical research and epidemiological surveillance. Moreover, the codes had different performance across two academic health systems and identified groups with different risks of mortality. Real-world data from the EHR can be used to in conjunction with diagnosis codes to improve the identification of people infected with SARS-CoV-2.

Simply saliva: stability of SARS-CoV-2 detection negates the need for expensive collection devices

Most currently approved strategies for the collection of saliva for COVID-19 diagnostics require specialized tubes containing buffers promoted for the stabilization of SARS-CoV-2 RNA and virus inactivation. Yet many of these are expensive, in limited supply, and not necessarily validated specifically for viral RNA. While saliva is a promising sample type as it can be reliably self-collected for the sensitive detection of SARS-CoV-2, the expense and availability of these collection tubes are prohibitive to mass testing efforts. Therefore, we investigated the stability of SARS-CoV-2 RNA and infectious virus detection from saliva without supplementation. We tested RNA stability over extended periods of time (2-25 days) and at temperatures representing at-home storage and elevated temperatures which might be experienced when cold chain transport may be unavailable. We found SARS-CoV-2 RNA in saliva from infected individuals is stable at 4{degrees}C, room temperature ([~]19{degrees}C), and 30{degrees}C for prolonged periods and found limited evidence for viral replication in stored saliva samples. This work demonstrates that expensive saliva collection options involving RNA stabilization and virus inactivation buffers are not always needed, permitting the use of cheaper collection options. Affordable testing methods are urgently needed to meet current testing demands and for continued surveillance in reopening strategies.

Clinical Characteristics and Outcomes for 7,995 Patients with SARS-CoV-2 Infection

ObjectiveSevere acute respiratory syndrome virus (SARS-CoV-2) has infected millions of people worldwide. Our goal was to identify risk factors associated with admission and disease severity in patients with SARS-CoV-2. DesignThis was an observational, retrospective study based on real-world data for 7,995 patients with SARS-CoV-2 from a clinical data repository. SettingYale New Haven Health (YNHH) is a five-hospital academic health system serving a diverse patient population with community and teaching facilities in both urban and suburban areas. PopulationsThe study included adult patients who had SARS-CoV-2 testing at YNHH between March 1 and April 30, 2020. Main outcome and performance measuresPrimary outcomes were admission and in-hospital mortality for patients with SARS-CoV-2 infection as determined by RT-PCR testing. We also assessed features associated with the need for respiratory support. ResultsOf the 28605 patients tested for SARS-CoV-2, 7995 patients (27.9%) had an infection (median age 52.3 years) and 2154 (26.9%) of these had an associated admission (median age 66.2 years). Of admitted patients, 1633 (75.8%) had a discharge disposition at the end of the study period. Of these, 192 (11.8%) required invasive mechanical ventilation and 227 (13.5%) expired. Increased age and male sex were positively associated with admission and in-hospital mortality (median age 81.9 years), while comorbidities had a much weaker association with the risk of admission or mortality. Black race (OR 1.43, 95%CI 1.14-1.78) and Hispanic ethnicity (OR 1.81, 95%CI 1.50-2.18) were identified as risk factors for admission, but, among discharged patients, age-adjusted in-hospital mortality was not significantly different among racial and ethnic groups. ConclusionsThis observational study identified, among people testing positive for SARS-CoV-2 infection, older age and male sex as the most strongly associated risks for admission and in-hospital mortality in patients with SARS-CoV-2 infection. While minority racial and ethnic groups had increased burden of disease and risk of admission, age-adjusted in-hospital mortality for discharged patients was not significantly different among racial and ethnic groups. Ongoing studies will be needed to continue to evaluate these risks, particularly in the setting of evolving treatment guidelines.