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1.
Nat Immunol ; 23(4): 543-555, 2022 04.
Article in English | MEDLINE | ID: covidwho-1738613

ABSTRACT

Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.


Subject(s)
CD8-Positive T-Lymphocytes , Vaccines , Adaptive Immunity , Animals , Humans , Immunity, Innate , Mice , Vaccines, Synthetic
2.
Acad Psychiatry ; 2022 Mar 07.
Article in English | MEDLINE | ID: covidwho-1729438

ABSTRACT

OBJECTIVE: The COVID-19 pandemic has severely disrupted all aspects of academic medicine, including post-doctoral research fellowship training. The current survey examined ways in which research fellows across 28 U.S. nationally diverse sites have been impacted. METHODS: Survey participants included 62 M.D. and Ph.D. post-doctoral fellows and 27 local fellowship center directors within the Veterans Affairs (VA) Advanced Fellowship in Mental Illness Research and Treatment (MIRT), a national fellowship program tasked to develop academic clinician researchers within the field of mental health. Survey questions focused on productivity and challenges experienced by fellows during the pandemic. RESULTS: Half of fellows reported working entirely off-site during the COVID-19 pandemic. All fellows reported some level of disruption in productivity during the pandemic; 73% reported a disruption in data collection, 69% reported decreased scholarly output, 41% reported disruption in grant writing, and 73% reported disruption in ability to provide clinical care. Yet, the majority of fellows (66%) reported not having to change their research goals, pivoting to telehealth-based data collection, and employing extant data for research projects and peer-reviewed publications. CONCLUSIONS: The results of the fellow and director surveys highlight the associated disruption of the COVID-19 pandemic on fellowship-related activities and parallel ingenuity of programs to continue conducting research and clinical services in a modified fashion. While many research goals continued unabated, the findings suggest alterations in data collection methodology and a focus on using extant data, which may have a residual influence on future early career research grant applications.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-313371

ABSTRACT

Background: Prolonged symptoms after SARS-CoV-2 infection are well-documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with serologic biomarkers remain elusive. Methods: Adult inpatient and outpatient SARS-CoV-2 RT-PCR positive patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1-3 months for up to one year after diagnosis;they completed symptom surveys and underwent sampling procedures (blood draw and nasal swab) at each visit. Findings: Our cohort (n=617) ranged from asymptomatic to critical COVID-19 infections. 40% of participants reported at least one symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days, median time from diagnosis to sustained symptom resolution with no recurring symptoms for one month or longer was 214 days. Serum anti-nucleocapsid IgG level in the first week of infection was predictive of time to symptom resolution. A prior diagnosis of lung disease was associated with longer time to symptom resolution. COVID-19 disease severity, ethnicity, sex, cytomegalovirus (CMV) seropositivity, and remdesivir use did not affect time to sustained symptom resolution. More than 90% of participants had SARS-CoV-2-specific antibody>1000 AU/mL nine months after diagnosis. Interpretation: Our findings showed that all disease severities had a similar risk of developing post-COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration. Trial Registration: National clinical trial database NCT04664309.Funding: NIH CTSA grant, U54 NIH Grant, R21 NIEHS, Sean N Parker Center for Allergy and Asthma Research at Stanford University, the Sunshine Foundation, the Crown Foundation, and the Parker Foundation.Declaration of Interest: Dr. Boyd received support for the current manuscript from Meso Scale Discovery and NIH;418 received consulting fees by Regeneron for expert testimony, has stocks or stock options in 419 AbCellera Biologics;Dr. Chinthrajah reports grants from NIAID, CoFAR, Aimmune, DBV 420 Technologies, Astellas, Regeneron, Stanford Maternal and Child Health Research Institute 421 (MCHRI), and FARE. She is an Advisory Board Member at Alladapt Therapeutics, Novartis, 422 Genentech, Sanofi, Allergenis, and Nutricia;Dr. Manisha Desai received support from Chan 423 Zuckerberg Foundation;Dr. Maecker received grants or contracts from NIH, Bill & Melinda 424 Gates Foundation, Ionis Corporation, Amgen Corporation;Consulting fees from Magarray Corp;425 payment or honoraria from UCLA, UC Davis;leadership or fiduciary role at Cytek SAB;stocks 426 or stock options at BD Biosciences;Dr. Nadeau reports grants from National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS), and Food Allergy Research & Education (FARE);Director of World Allergy Organization (WAO) , Advisor at Cour Pharma, Consultant for Excellergy, Red tree ventures, and Phylaxis, Co-founder of Before Brands, Alladapt, Latitude, and IgGenix;and National Scientific Committee member at Immune Tolerance Network (ITN), and National Institutes of Health (NIH) clinical research centers, outside the submitted work;patents include, “Mixed allergen composition and methods for using the same”, “Granulocyte-based methods for detecting and monitoring immune system disorders”, “Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders,” and “Methods of isolating allergen-specific antibodies from humans and uses thereof”;Dr. Benjamin Pinsky received grants or contracts for the present manuscript from MesoScale Diagno tics;Dr. Angele Rogers was a Clinical Trials Advisory Board Member for Merck;Dr. Sindher reports support for the present manuscript from the NIH, Regeneron, DBV Technologies, Aimmune, Novartis, CoFAR, FARE, participated on a DSMB for Astra Zeneca, DBV, and received payment or honorarium from FARE;Neera Ahuja, Maja Artandi, Linda Barman, Catherine Blish, Andra Blomkalns, William Collins, MacKenzie Cox, Linda Geng, Xiaolin Jia, Megan Mahoney, Monali Manohar, Ruth O’hara, Rajan Puri, Katharina Roltgen, Laura Vaughan, Samuel Yang, Shu Cao, Iris Chang, Hena Din, Evan Do, Andrea Fernandez, Alexandra Lee, Natasha Purington, Yael Rosenberg-Hasson, Theo Snow, Daniel Solis, Michelle Verghese, and Yingjie Weng have no conflict of interest.Ethical Approval: This study was reviewed and approved by the Stanford Administrative Panel on Human Subjects in Medical Research.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309904

ABSTRACT

Background: It is unclear if asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS-CoV-2.Methods: All patients testing positive for SARS-CoV-2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub-cohort was followed prospectively to evaluate long-term COVID-19 symptoms.Findings: 168,190 patients underwent SARS-CoV-2 testing, and 6,976 (4·15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1·12 [95% CI 0·86, 1·45], p=0·40). Among SARS-CoV-2 positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared to non-allergic asthma (OR 0·52 (0·28, 0·91), p=0·026);there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID-19 disease had lower eosinophil levels during hospitalization compared to patients with mild or asymptomatic disease, independent of asthma status (p=0.0014). In a patient sub-cohort followed longitudinally, asthmatics and non-asthmatics had similar time to resolution of COVID-19 symptoms, particularly lower respiratory symptoms.Interpretation: Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared to non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms three months post-infection.Trial Registration Information: Sub-cohort analysis performed among those enrolled in a prospective, longitudinal study (NCT# 04373148),Funding Statement: The Sean N. Parker Center for Allergy and Asthma Research, Stanford University, Sunshine Foundation, Crown Foundation, Parker Foundation.Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Ethics Approval Statement: This study was reviewed and approved with a waiver of consent by the Stanford Administrative Panel on Human Subjects in Medical Research.

5.
JAMA Netw Open ; 4(9): e2125524, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1414844

ABSTRACT

Importance: As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)-authorized mRNA COVID-19 vaccines have been reported. Objective: To characterize the immunologic mechanisms underlying allergic reactions to these vaccines. Design, Setting, and Participants: This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing. Exposures: FDA-authorized mRNA COVID-19 vaccines. Main Outcomes and Measures: Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms. Results: Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine. Conclusions and Relevance: Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non-IgE-mediated immune responses to PEG may be responsible in most individuals.


Subject(s)
COVID-19 Vaccines/adverse effects , Hypersensitivity/diagnosis , Adolescent , Adult , Aged , COVID-19 Vaccines/therapeutic use , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Hypersensitivity/epidemiology , Male , Middle Aged , Risk Factors , United States/epidemiology , United States Food and Drug Administration/organization & administration , United States Food and Drug Administration/statistics & numerical data , Vaccination/adverse effects
6.
Contemp Clin Trials ; 108: 106509, 2021 09.
Article in English | MEDLINE | ID: covidwho-1312964

ABSTRACT

More than 3000 clinical trials related to COVID-19 have been registered through clinicaltrials.gov. With so many trials, there is a risk that many will be inconclusive due to being underpowered or due to an inability to recruit patients. At academic medical centers, multiple trials are competing for the same resources; the success of one may come at the expense of another. The COVID-19 Outpatient Pragmatic Protocol Study (COPPS) is a flexible phase 2, multi-site, randomized, blinded trial based at Stanford University designed to overcome these issues by simultaneously evaluating multiple COVID-19 treatments in the outpatient setting in one common platform with shared controls. This approach reduces the overall number of patients required for statistical power, while improving the likelihood that any enrolled patient receives active treatment. The platform study has two main domains designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain), measured with self-collected nasal swabs, or improve clinical outcomes (Clinical Domain), measured through self-reported symptomology data. Data are collected on both domains for all participants enrolled. Participants are followed over a 28-day period. COPPS has the advantage of pragmatism created around its workflow that is also appealing to potential participants because of a lower probability of inactive treatment. At the conclusion of this clinical trial we expect to have identified potentially effective therapeutic strategy/ies for treating COVID-19 in the outpatient setting, which will have a transformative impact on medicine and public health.


Subject(s)
COVID-19 , Humans , Outpatients , Research Design , SARS-CoV-2 , Treatment Outcome
7.
J Exp Med ; 218(8)2021 08 02.
Article in English | MEDLINE | ID: covidwho-1269483

ABSTRACT

Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.


Subject(s)
COVID-19/blood , COVID-19/immunology , Immunity, Innate/physiology , Adult , Aged , COVID-19/genetics , COVID-19/mortality , Case-Control Studies , Cytokines/genetics , Epigenesis, Genetic , Female , Hematopoiesis , Humans , Killer Cells, Natural/pathology , Killer Cells, Natural/virology , Male , Middle Aged , Monocytes/pathology , Monocytes/virology , NF-kappa B/metabolism , Neutrophils/pathology , Neutrophils/virology , Proteomics , Severity of Illness Index , Single-Cell Analysis
8.
Allergy ; 77(1): 173-185, 2022 01.
Article in English | MEDLINE | ID: covidwho-1255322

ABSTRACT

BACKGROUND: It is unclear whether asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS-CoV-2. METHODS: All patients over 28 days old testing positive for SARS-CoV-2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub-cohort was followed prospectively to evaluate long-term COVID-19 symptoms. RESULTS: 168,190 patients underwent SARS-CoV-2 testing, and 6,976 (4.15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1.12 [95% CI 0.86, 1.45], p = .40). Among SARS-CoV-2-positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared with non-allergic asthma (OR 0.52 [0.28, 0.91], p = .026); there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID-19 disease had lower eosinophil levels during hospitalization compared with patients with mild or asymptomatic disease, independent of asthma status (p = .0014). In a patient sub-cohort followed longitudinally, asthmatics and non-asthmatics had similar time to resolution of COVID-19 symptoms, particularly lower respiratory symptoms. CONCLUSIONS: Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared with non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with a more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms 3 months post-infection.


Subject(s)
Asthma , COVID-19 , Asthma/diagnosis , Asthma/epidemiology , COVID-19 Testing , Humans , Phenotype , Retrospective Studies , SARS-CoV-2
9.
Clin Infect Dis ; 74(2): 218-226, 2022 01 29.
Article in English | MEDLINE | ID: covidwho-1216637

ABSTRACT

BACKGROUND: The determinants of coronavirus disease 2019 (COVID-19) disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterized relationships between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia and disease severity, clinical deterioration, and specific EPCs. METHODS: We used quantitative and digital polymerase chain reaction (qPCR and dPCR) to quantify SARS-CoV-2 RNA from plasma in 191 patients presenting to the emergency department with COVID-19. We recorded patient symptoms, laboratory markers, and clinical outcomes, with a focus on oxygen requirements over time. We collected longitudinal plasma samples from a subset of patients. We characterized the role of RNAemia in predicting clinical severity and EPCs using elastic net regression. RESULTS: Of SARS-CoV-2-positive patients, 23.0% (44 of 191) had viral RNA detected in plasma by dPCR, compared with 1.4% (2 of 147) by qPCR. Most patients with serial measurements had undetectable RNAemia within 10 days of symptom onset, reached maximum clinical severity within 16 days, and symptom resolution within 33 days. Initially RNAemic patients were more likely to manifest severe disease (odds ratio, 6.72 [95% confidence interval, 2.45-19.79]), worsening of disease severity (2.43 [1.07-5.38]), and EPCs (2.81 [1.26-6.36]). RNA loads were correlated with maximum severity (r = 0.47 [95% confidence interval, .20-.67]). CONCLUSIONS: dPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Because many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.

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