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BackgroundBetter understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management. MethodsImmunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1,164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed. FindingsThe median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering of ordinal score over time revealed distinct disease course trajectories. Risk factors associated with prolonged hospitalization or death by day 28 included age [≥] 65 years (odds ratio [OR], 2.01; 95% CI 1.28-3.17), Hispanic ethnicity (OR, 1.71; 95% CI 1.13-2.57), elevated baseline creatinine (OR 2.80; 95% CI 1.63-4.80) or troponin (OR 1.89; 95% 1.03-3.47), baseline lymphopenia (OR 2.19; 95% CI 1.61-2.97), presence of infiltrate by chest imaging (OR 3.16; 95% CI 1.96-5.10), and high SARS-CoV2 viral load (OR 1.53; 95% CI 1.17-2.00). Fatal cases had the lowest ratio of SARS-CoV-2 antibody to viral load levels compared to other trajectories over time (p=0.001). 589 survivors (51%) completed at least one survey at follow-up with 305 (52%) having at least one symptom consistent with PASC, most commonly dyspnea (56% among symptomatic patients). Female sex was the only associated risk factor for PASC. InterpretationIntegration of PCR cycle threshold, and antibody values with demographics, comorbidities, and laboratory/radiographic findings identified risk factors for 28-day outcome severity, though only female sex was associated with PASC. Longitudinal clinical phenotyping offers important insights, and provides a framework for immunophenotyping for acute and long COVID-19. FundingNIH RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe did a systematic search of the PubMed database from January 1st, 2020 until April 24th, 2022 using the search terms: "hospitalized" AND "SARS-CoV-2" OR "COVID-19" AND "Pro-spective" AND "Antibody" OR "PCR" OR "long term follow up" and applying the following filters: "Multicenter Study" AND "Observational Study". No language restrictions were applied. While clinical, laboratory, and radiographic features associated with severe COVID-19 in hospitalized adults have been described, description of the kinetics of SARS-CoV-2 specific assays available to clinicians (e.g. PCR and binding antibody) and their integration with other variables is scarce for both short and long term follow up. The current literature is comprised of several studies with small sample size, cross-sectional design with laboratory data typically only recorded at a single point in time (e.g., on admission), limited clinical characteristics, variable duration of follow up, single-center setting, retrospective analyses, kinetics of either PCR or antibody testing but not both, and outcomes such as death or, mechanical ventilation that do not allow delineation of variations in clinical course. Added value of this studyIn our large longitudinal multicenter cohort, the description of outcome severity, was not limited to survival versus death, but encompassed a clinical trajectory approach leveraging longitudinal data based on time in hospital, disease severity by ordinal scale based on degree of respiratory illness, and presence or absence of limitations at discharge. Fatal COVID-19 cases had the lowest ratio of antibody to viral load levels over time as compared to non-fatal cases. Integration of PCR cycle threshold and antibody values with demographics, baseline comorbidities, and laboratory/radiographic findings identified additional risk factors for outcome severity over the first 28 days. However, female sex was the only variable associated with persistence of symptoms over time. Persistence of symptoms was not associated with clinical trajectory over the first 28 days, nor with antibody/viral loads from the acute phase. Implications of all the available evidenceThe described calculated ratio (binding IgG/PCR Ct value) is unique compared to other studies, reflecting host pathogen interactions and representing an accessible approach for patient risk stratification. Integration of SARS-CoV-2 viral load and binding antibody kinetics with other laboratory as well as clinical characteristics in hospitalized COVID-19 patients can identify patients likely to have the most severe short-term outcomes, but is not predictive of symptom persistence at one year post-discharge.
ABSTRACT
BackgroundIn May-July 2020 in the New York City area, up to 16% of pregnant women had reportedly been infected with SARS-CoV-2. Prior studies found associations between SARS-CoV-2 infection during pregnancy and certain adverse outcomes (e.g., preterm birth, cesarean delivery). These studies relied on reverse transcription polymerase chain reaction (RT-PCR) testing to establish SARS-CoV-2 infection. This led to overrepresentation of symptomatic or acutely ill cases in scientific studies. ObjectiveTo expand our understanding of the effects of SARS-CoV-2 infection during pregnancy on pregnancy outcomes, regardless of symptomatology and stage of infection, by using serological tests to measure IgG antibody levels. Study DesignThe Generation C Study is an ongoing prospective cohort study conducted at the Mount Sinai Health System. All pregnant women receiving obstetrical care at the Mount Sinai Hospital and Mount Sinai West Hospital from April 20, 2020 onwards are eligible for participation. For the current analysis, we included participants who had given birth to a liveborn singleton infant on or before August 15, 2020. Blood was drawn as part of routine clinical care; for each woman, we tested the latest sample available to establish seropositivity using a SARS-CoV-2 serologic enzyme-linked immunosorbent assay. Additionally, RT-PCR testing was performed on a nasopharyngeal swab taken during labor and delivery. Pregnancy outcomes of interest (i.e., gestational age at delivery, birth weight, mode of delivery, Apgar score, ICU/NICU admission, and neonatal hospital length of stay) and covariates were extracted from electronic medical records. Among all Generation C participants who had given birth by August 15, 2020 (n=708), we established the SARS-CoV-2 seroprevalence. Excluding women who tested RT-PCR positive at delivery, we conducted crude and adjusted linear and logistic regression models to compare antibody positive women without RT-PCR positivity at delivery with antibody negative women without RT-PCR positivity at delivery. We stratified analyses by race/ethnicity to examine potential effect modification. ResultsThe SARS-CoV-2 seroprevalence based on IgG measurement was 16.4% (n=116, 95% CI 13.7-19.3). Twelve women (1.7%) were SARS-CoV-2 RT-PCR positive at delivery (11 of these women were seropositive). Seropositive women were generally younger, more often Black or Hispanic, and more often had public insurance and higher pre-pregnancy BMI compared with seronegative women. SARS-CoV-2 seropositivity without RT-PCR positivity at delivery was associated with decreased odds of caesarean delivery (aOR 0.48, 95%CI 0.27; 0.84) compared with seronegative women without RT-PCR positivity at delivery. Stratified by race/ethnicity, the association between seropositivity and decreased odds of caesarean delivery remained for non-Hispanic Black/African-American and Hispanic women, but not for non-Hispanic White women. No other pregnancy outcomes differed by seropositivity, overall or stratified by race/ethnicity. ConclusionSeropositivity for SARS-CoV-2 without RT-PCR positivity at delivery, suggesting that infection occurred earlier during pregnancy, was not associated with selected adverse maternal or neonatal outcomes among live births in a cohort sample of women from New York City. While non-Hispanic Black and Latina women in our cohort had a higher rate of SARS-CoV-2 seropositivity compared with non-Hispanic White women, we found no increase in adverse maternal or neonatal outcomes among these groups due to infection.
ABSTRACT
One year in the coronavirus disease 2019 (COVID-19) pandemic, the first vaccines are being rolled out under emergency use authorizations. It is of great concern that newly emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can escape antibody-mediated protection induced by previous infection or vaccination through mutations in the spike protein. The glutamate (E) to Lysine (K) substitution at position 484 (E484K) in the receptor binding domain (RBD) of the spike protein is present in the rapidly spreading variants of concern belonging to the B.1.351 and P.1 lineages. We performed in vitro microneutralization assays with both the USA-WA1/2020 virus and a recombinant (r)SARS-CoV-2 virus that is identical to USA-WA1/2020 except for the E484K mutation introduced in the spike RBD. We selected 34 sera from study participants based on their SARS-CoV-2 spike ELISA antibody titer (negative [N=4] versus weak [N=8], moderate [N=11] or strong positive [N=11]). In addition, we included sera from five individuals who received two doses of the Pfizer SARS-CoV-2 vaccine BNT162b2. Serum neutralization efficiency was lower against the E484K rSARS-CoV-2 (vaccination samples: 3.4 fold; convalescent low IgG: 2.4 fold, moderate IgG: 4.2 fold and high IgG: 2.6 fold) compared to USA-WA1/2020. For some of the convalescent donor sera with low or moderate IgG against the SARS-CoV-2 spike, the drop in neutralization efficiency resulted in neutralization ID50 values similar to negative control samples, with low or even absence of neutralization of the E484K rSARS-CoV-2. However, human sera with high neutralization titers against the USA-WA1/2020 strain were still able to neutralize the E484K rSARS-CoV-2. Therefore, it is important to aim for the highest titers possible induced by vaccination to enhance protection against newly emerging SARS-CoV-2 variants. Two vaccine doses may be needed for induction of high antibody titers against SARS-CoV-2. Postponing the second vaccination is suggested by some public health authorities in order to provide more individuals with a primer vaccination. Our data suggests that this may leave vaccinees less protected against newly emerging variants.
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BackgroundThe risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subsequent infection among seropositive young adults was studied prospectively. MethodsThe study population comprised 3,249 predominantly male, 18-20-year-old Marine recruits. Upon arrival at a Marine-supervised two-week quarantine, participants were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a 1:150 dilution or greater on receptor binding domain and full-length spike protein enzyme-linked immunosorbent (ELISA) assays. SARS-CoV-2 infection was assessed by PCR at initiation, middle and end of the quarantine. After appropriate exclusions, including participants with a positive PCR during quarantine, we performed three biweekly PCR tests in both seropositive and in seronegative groups once recruits left quarantine and entered basic training and baseline neutralizing antibody titers on all subsequently infected seropositive and selected seropositive uninfected participants. FindingsAmong 189 seropositive participants, 19 (10.1%) had at least one positive PCR test for SARS-CoV-2 during the six-week follow-up (1.1 cases per person-year). In contrast, 1,079 (48.0%) of the 2,247 seronegative participants tested positive (6.2 cases per person-year). The incidence rate ratio was 0.18 (95% CI 0.11-0.28, p<0.00001). Among seropositive recruits, infection was associated with lower baseline full-length spike protein IgG titers (p<0.0001). Compared with seronegative recruits, seropositive recruits had about 10-fold lower viral loads (ORF1ab gene, p<0.005), and trended towards shorter duration of PCR positivity (p=0.18) and more frequent asymptomatic infections (p=0.13). Among seropositive participants, baseline neutralizing titers were detected in 45 of 54 (83.3%) uninfected and in 6 of 19 (31.6%) infected participants during the 6 weeks of observation (ID50 difference p<.0001). InterpretationSeropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection. These findings may be relevant for optimization of mass vaccination strategies. FundingDefense Health Agency and Defense Advanced Research Projects Agency
ABSTRACT
The current COVID-19 (coronavirus disease 19) pandemic, caused by SARS-CoV-2, disproportionally affects the elderly and people with comorbidities like obesity and associated type 2 diabetes mellitus. Small animal models are crucial for the successful development and validation of antiviral vaccines, therapies and to study the role that comorbidities have on the outcome of viral infections. The initially available SARS-CoV-2 isolates require adaptation in order to use the mouse angiotensin converting enzyme 2 (mACE-2) entry receptor and to productively infect the cells of the murine respiratory tract. We have "mouse-adapted" SARS-CoV-2 by serial passaging a clinical virus isolate in the lungs of mice. We then used low doses of this virus in mouse models for advanced age, diabetes and obesity. Similar to SARS-CoV-2 infection in humans, the outcome of infection with mouse-adapted SARS-CoV-2 resulted in enhanced morbidity in aged and diabetic obese mice. Mutations associated with mouse adaptation occurred in the S, M, N and ORF8 genes. Interestingly, one mutation in the receptor binding domain of the S protein results in the change of an asparagine to tyrosine residue at position 501 (N501Y). This mutation is also present in the newly emerging SARS-CoV-2 variant viruses reported in the U.K. (20B/501Y.V1, B1.1.7 lineage) that is epidemiologically associated with high human to human transmission. We show that human convalescent and post vaccination sera can neutralize the newly emerging N501Y virus variant with similar efficiency as that of the reference USA-WA1/2020 virus, suggesting that current SARS-CoV-2 vaccines will protect against the 20B/501Y.V1 strain.
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Herein we measured CD4+ T cell responses against common cold corona (CCC) viruses and SARS-CoV-2 in high-risk health care workers (HCW) and community controls. We observed higher levels of CCC reactive T cells in SARS-CoV-2 seronegative HCW compared to community donors, consistent with potential higher occupational exposure of HCW to CCC. We further show that SARS-CoV-2 reactivity of seronegative HCW was higher than community controls and correlation between CCC and SARS-CoV-2 responses is consistent with cross-reactivity and not associated with recent in vivo activation. Surprisingly, CCC reactivity was decreased in SARS-CoV-2 infected HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses, either directly or indirectly. This result was unexpected, but consistently detected in independent cohorts derived from Miami and San Diego.
ABSTRACT
While the current pandemic remains a thread to human health, the polyclonal nature of the antibody response against SARS-CoV-2 is not fully understood. Other than SARS-CoV-2, humans are susceptible to six different coronaviruses, and previous exposure to antigenically related and divergent seasonal coronaviruses is frequent. We longitudinally profiled the early humoral immune response against SARS-CoV-2 on hospitalized COVID-19 patients, and quantify levels of pre-existing immunity to OC43, HKU1 and 223E seasonal coronaviruses. A strong back-boosting effect to conserved, but not variable regions of OC43 and HKU1 betacoronaviruses spike protein was observed. All patients developed antibodies against SARS-CoV-2 spike and nucleoprotein, with peak induction at day 7 post hospitalization. However a negative correlation was found between antibody memory boost to human coronaviruses and induction of IgG and IgM against SARS-CoV-2 spike. Our findings provide evidence of immunological imprinting that determine the antibody profile to COVID-19 patients in an original antigenic sin fashion.
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SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Questions regarding the robustness, functionality and longevity of the antibody response to the virus remain unanswered. Here we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust IgG antibody responses against the viral spike protein, based on a dataset of 19,860 individuals screened at Mount Sinai Health System in New York City. We also show that titers are stable for at least a period approximating three months, and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggests that more than 90% of seroconverters make detectible neutralizing antibody responses and that these titers are stable for at least the near-term future. One Sentence SummaryAntibody responses induced by natural mild-to-moderate SARS-CoV-2 infection are robust, neutralizing and are stable for at least 3 months.
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By conducting a retrospective, cross-sectional analysis of SARS-CoV-2 seroprevalence in a sentinel group (enriched for SARS-CoV-2 infections) and a screening group (representative of the general population) using >5,000 plasma samples from patients at Mount Sinai Hospital in New York City (NYC), we identified seropositive samples as early as in the week ending February 23, 2020. A stark increase in seropositivity in the sentinel group started the week ending March 22 and in the screening group in the week ending March 29. By the week ending April 19, the seroprevalence in the screening group reached 19.3%, which is well below the estimated 67% needed to achieve community immunity to SARS-CoV-2. These data potentially suggest an earlier than previously documented introduction of SARS-CoV-2 into the NYC metropolitan area. One Sentence SummarySeroprevalence of SARS-CoV-2 in cross-sectional samples from New York City rose from 0% to 19.3% from early February to mid-April.
ABSTRACT
SARS-Cov-2 (severe acute respiratory disease coronavirus 2), which causes Coronavirus Disease 2019 (COVID19) was first detected in China in late 2019 and has since then caused a global pandemic. While molecular assays to directly detect the viral genetic material are available for the diagnosis of acute infection, we currently lack serological assays suitable to specifically detect SARS-CoV-2 antibodies. Here we describe serological enzyme-linked immunosorbent assays (ELISA) that we developed using recombinant antigens derived from the spike protein of SARS-CoV-2. Using negative control samples representing pre-COVID 19 background immunity in the general adult population as well as samples from COVID19 patients, we demonstrate that these assays are sensitive and specific, allowing for screening and identification of COVID19 seroconverters using human plasma/serum as early as two days post COVID19 symptoms onset. Importantly, these assays do not require handling of infectious virus, can be adjusted to detect different antibody types and are amendable to scaling. Such serological assays are of critical importance to determine seroprevalence in a given population, define previous exposure and identify highly reactive human donors for the generation of convalescent serum as therapeutic. Sensitive and specific identification of coronavirus SARS-Cov-2 antibody titers may, in the future, also support screening of health care workers to identify those who are already immune and can be deployed to care for infected patients minimizing the risk of viral spread to colleagues and other patients.