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1.
Sci Rep ; 12(1): 889, 2022 01 18.
Article in English | MEDLINE | ID: covidwho-1630723

ABSTRACT

Predicting the severity of COVID-19 remains an unmet medical need. Our objective was to develop a blood-based host-gene-expression classifier for the severity of viral infections and validate it in independent data, including COVID-19. We developed a logistic regression-based classifier for the severity of viral infections and validated it in multiple viral infection settings including COVID-19. We used training data (N = 705) from 21 retrospective transcriptomic clinical studies of influenza and other viral illnesses looking at a preselected panel of host immune response messenger RNAs. We selected 6 host RNAs and trained logistic regression classifier with a cross-validation area under curve of 0.90 for predicting 30-day mortality in viral illnesses. Next, in 1417 samples across 21 independent retrospective cohorts the locked 6-RNA classifier had an area under curve of 0.94 for discriminating patients with severe vs. non-severe infection. Next, in independent cohorts of prospectively (N = 97) and retrospectively (N = 100) enrolled patients with confirmed COVID-19, the classifier had an area under curve of 0.89 and 0.87, respectively, for identifying patients with severe respiratory failure or 30-day mortality. Finally, we developed a loop-mediated isothermal gene expression assay for the 6-messenger-RNA panel to facilitate implementation as a rapid assay. With further study, the classifier could assist in the risk assessment of COVID-19 and other acute viral infections patients to determine severity and level of care, thereby improving patient management and reducing healthcare burden.


Subject(s)
COVID-19 , Gene Expression Regulation , RNA, Messenger/blood , SARS-CoV-2/metabolism , Acute Disease , COVID-19/blood , COVID-19/mortality , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies
2.
Blood ; 138(19):2900-2900, 2021.
Article in English | EuropePMC | ID: covidwho-1601744

ABSTRACT

Introduction: Randomized trials demonstrated ~95% efficacy of SARS-CoV-2 spike messenger RNA (mRNA) vaccines. Patients (pts) after allogeneic hematopoietic cell transplant (HCT) have a variable period of immune deficiency and the impact of diagnosis, treatment regimens, GvHD, and immunosuppression on vaccine (vacc) immunogenicity is unknown. Methods: We performed a retrospective analysis of 149 consecutive pts (Table) who received a SARS-CoV-2 vacc between 12/17/2020, and 5/21/21, and were tested for anti-SARS-CoV-2 S1/S2 antibodies. Serology testing was performed with the Liaison® SARS-CoV-2 S1/S2 IgG assay (DiaSorin) with ≥15 AU/mL defined as a positive result. Pts with prior COVID-19 infection were excluded. Pts received mRNA-1273/Moderna (n= 46), BNT162b2/Pfizer-BioNTech (n= 100) or Jannsen vacc (n= 3). Reactogenicity was not investigated. Demographic and treatment variables were tested for prediction of vaccine response using Chi-square test or Fisher's exact test for categorical variables and two-sample t test for continuous variables. Univariate and multivariable logistic regression analyses with backward selection using Akaike information criterion (AIC) were used to examine interdependence of those variables and odds ratios (OR) with 95% confidence intervals (CI). Results: Pts underwent HCT from a related HLA matched sibling (n=36), related haploidentical (n= 23), or matched/mismatched unrelated donor (n= 89). 93% received fludarabine in the HCT conditioning regimen (data not shown). All pts received a calcineurin inhibitor (CNI) and 76 pts received ATG for GvHD prophylaxis. All pts achieved at least mixed donor lymphoid engraftment (data not shown). Median time from HCT to 1st vaccination was 26 months (range, 3-258 months). Median age at time of vaccination was 61 years (range, 24-78) and 75 (50%) were female. Serology was tested at a median of 37 days (range, 6-119 days) after the second vacc dose. Serology was tested <14 days in 3 pts;all were seropositive. No pt developed COVID-19 during the period of observation. 101 pts (67%) tested positive for anti-SARS-CoV-2 S1/S2 antibodies (vacc responders). Of the responders, the median time from HCT to 1st vacc was 45.5 months (range, 3-258, SD 39.78). Among the 23 pts between 3-9 months after HCT, 26% (n=6) had a positive antibody response, but all were receiving ongoing immunosuppression at time of vaccination. 29% (n=29) vacc responders were receiving prednisone (pred) in the management of cGvHD at the time of vaccination. 48 pts did not mount an antibody response (vacc non-responders). Of the non-responders, 30 pts were receiving cGvHD treatment at the time of vacc, 31 pts were taking pred, and 20 pts were taking CNIs. In univariate analysis, we found a history of prolonged use of pred (>8 weeks) and/or CNIs, on current treatment for cGvHD at time of vacc, and receipt of rituximab in the preceding 12 months predicted for lack of response (Table). Active use of pred and treatment with pred >8 weeks in the preceding 12 months prior to vacc predicted vacc non-response [OR 0.221;95% CI (0.106 - 0.456);p<0.001] and [OR 0.408;95% CI (0.197 - 0.844);p=0.016] in univariate analysis, respectively, however, active use of pred was predictive [OR 0.07;95% CI (0.016-0.304;p<0.001] while pred treatment >8 weeks was not [OR 2.00;95% CI (0.55-7.298;p=0.293] in multivariable analysis. Other significant predictors for non-response in the multivariable analysis include pt use of ruxolitinib [OR, 0.233, 95% CI, (0.067-0.808);p=0.022], and rituximab within 1 year [OR, 0.026, 95% CI, (0.007-0.099);p<0.001]. Discussion: In this study, we found that 67% allogeneic HCT pts developed anti-SARS-CoV-2 S1/S2 antibodies after SARS-CoV-2 vaccination. Predictors of non-response after adjustment for potential confounders, were factors that are expected to suppress immune response including active use of immunosuppressive medications. Consistent with prior studies, anti-CD20 therapy likely impairs humoral response to vaccination. Ruxolitinib also appears to impair response. owever, a proportion of pts being actively treated for cGvHD responded to vaccination and these pts should still be encouraged to receive vaccination in consideration of the COVID-19 mortality risk. Many questions remain including the protective benefit of immune response, the duration of response, and the potential value of booster vaccinations in non-responders. Figure 1 Disclosures Rowley:  ReAlta Life Sciences: Consultancy.

3.
PLoS Pathog ; 17(10): e1010025, 2021 10.
Article in English | MEDLINE | ID: covidwho-1496544

ABSTRACT

The global SARS-CoV-2 coronavirus pandemic continues to be devastating in many areas. Treatment options have been limited and convalescent donor plasma has been used by many centers to transfer passive neutralizing antibodies to patients with respiratory involvement. The results often vary by institution and are complicated by the nature and quality of the donor plasma itself, the timing of administration and the clinical aspects of the recipients. SARS-CoV-2 infection is known to be associated with an increase in the blood concentrations of several inflammatory cytokines/chemokines, as part of the overall immune response to the virus and consequential to mediated lung pathology. Some of these correlates contribute to the cytokine storm syndrome and acute respiratory distress syndrome, often resulting in fatality. A Phase IIa clinical trial at our institution using high neutralizing titer convalescent plasma transfer gave us the unique opportunity to study the elevations of correlates in the first 10 days after infusion. Plasma recipients were divided into hospitalized COVID-19 pneumonia patients who did not (Track 2) or did (Track 3) require mechanical ventilation. Several cytokines were elevated in the patients of each Track and some continued to rise through Day 10, while others initially increased and then subsided. Furthermore, elevations in MIP-1α, MIP-1ß and CRP correlated with disease progression of Track 2 recipients. Overall, our observations serve as a foundation for further study of these correlates and the identification of potential biomarkers to improve upon convalescent plasma therapy and to drive more successful patient outcomes.


Subject(s)
COVID-19/therapy , Chemokines/blood , Cytokines/blood , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , COVID-19/immunology , Female , Humans , Immunization, Passive , Immunoglobulin Isotypes/blood , Male , Middle Aged
4.
Immunity ; 54(4): 753-768.e5, 2021 04 13.
Article in English | MEDLINE | ID: covidwho-1385739

ABSTRACT

Viral infections induce a conserved host response distinct from bacterial infections. We hypothesized that the conserved response is associated with disease severity and is distinct between patients with different outcomes. To test this, we integrated 4,780 blood transcriptome profiles from patients aged 0 to 90 years infected with one of 16 viruses, including SARS-CoV-2, Ebola, chikungunya, and influenza, across 34 cohorts from 18 countries, and single-cell RNA sequencing profiles of 702,970 immune cells from 289 samples across three cohorts. Severe viral infection was associated with increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells. We identified protective and detrimental gene modules that defined distinct trajectories associated with mild versus severe outcomes. The interferon response was decoupled from the protective host response in patients with severe outcomes. These findings were consistent, irrespective of age and virus, and provide insights to accelerate the development of diagnostics and host-directed therapies to improve global pandemic preparedness.


Subject(s)
Immunity/genetics , Virus Diseases/immunology , Antigen Presentation/genetics , Cohort Studies , Hematopoiesis/genetics , Humans , Interferons/blood , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Myeloid Cells/immunology , Myeloid Cells/pathology , Prognosis , Severity of Illness Index , Systems Biology , Transcriptome , Virus Diseases/blood , Virus Diseases/classification , Virus Diseases/genetics , Viruses/classification , Viruses/pathogenicity
5.
Cell ; 184(15): 3915-3935.e21, 2021 Jul 22.
Article in English | MEDLINE | ID: covidwho-1283262

ABSTRACT

Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.

6.
J Extracell Vesicles ; 10(8): e12110, 2021 06.
Article in English | MEDLINE | ID: covidwho-1258076

ABSTRACT

Circulating nucleic acids, encapsulated within small extracellular vesicles (EVs), provide a remote cellular snapshot of biomarkers derived from diseased tissues, however selective isolation is critical. Current laboratory-based purification techniques rely on the physical properties of small-EVs rather than their inherited cellular fingerprints. We established a highly-selective purification assay, termed EV-CATCHER, initially designed for high-throughput analysis of low-abundance small-RNA cargos by next-generation sequencing. We demonstrated its selectivity by specifically isolating and sequencing small-RNAs from mouse small-EVs spiked into human plasma. Western blotting, nanoparticle tracking, and transmission electron microscopy were used to validate and quantify the capture and release of intact small-EVs. As proof-of-principle for sensitive detection of circulating miRNAs, we compared small-RNA sequencing data from a subset of small-EVs serum-purified with EV-CATCHER to data from whole serum, using samples from a small cohort of recently hospitalized Covid-19 patients. We identified and validated, only in small-EVs, hsa-miR-146a and hsa-miR-126-3p to be significantly downregulated with disease severity. Separately, using convalescent sera from recovered Covid-19 patients with high anti-spike IgG titers, we confirmed the neutralizing properties, against SARS-CoV-2 in vitro, of a subset of small-EVs serum-purified by EV-CATCHER, as initially observed with ultracentrifuged small-EVs. Altogether our data highlight the sensitivity and versatility of EV-CATCHER.


Subject(s)
Extracellular Vesicles/chemistry , Immunologic Techniques/methods , Animals , Bodily Secretions/chemistry , COVID-19/blood , COVID-19/physiopathology , Chlorocebus aethiops , Circulating MicroRNA , High-Throughput Nucleotide Sequencing , Humans , MCF-7 Cells , Mice , RAW 264.7 Cells , Severity of Illness Index , Vero Cells
7.
JCI Insight ; 6(6)2021 03 22.
Article in English | MEDLINE | ID: covidwho-1079148

ABSTRACT

Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response.


Subject(s)
Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/therapy , Immunoglobulin G/therapeutic use , Plasma , SARS-CoV-2/immunology , Severity of Illness Index , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Convalescence , Female , Humans , Immunization, Passive , Immunocompromised Host , Immunoglobulin G/blood , Male , Middle Aged , Pneumonia , Respiration, Artificial
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