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1.
Cell ; 185(6): 1025-1040.e14, 2022 03 17.
Article in English | MEDLINE | ID: covidwho-1649487

ABSTRACT

During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.


Subject(s)
Antibodies, Viral , BNT162 Vaccine , COVID-19 , Germinal Center , Antigens, Viral , COVID-19/prevention & control , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Vaccination
2.
Archives of Pathology & Laboratory Medicine ; 145(7):785-796, 2021.
Article in English | ProQuest Central | ID: covidwho-1338028

ABSTRACT

* Context.-Small case series have evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection in formalin-fixed, paraffin-embedded tissue using reverse transcription-polymerase chain reaction, immunohistochemistry (IHC), and/or RNA in situ hybridization (RNAish). [...]acute respiratory distress syndrome has been found in 3.4% of patients with COVID-19 and 72% to 93% of patients with COVID-19 who died.1-3 Furthermore, we and others have shown that acute bronchopneumonia, diffuse alveolar damage (DAD), aspiration pneumonia, and thromboemboli are common findings in the lungs of these patients at autopsy.4-9 Although evidence suggests that COVID-19 also impacts other organs such as heart,9 liver,9 and kidneys,9,10 the virus has so far been identified with certainty only in the lungs and rarely the brain, heart, liver, kidney, placenta, and blood by electron microscopy, immunohistochemistry (IHC), in situ hybridization (ISH), and reverse transcription-polymerase chain reaction (RT-PCR).8'9'11-18 Infection with SARS-CoV-2 is usually identified by the detection of viral RNA using RT-PCR on nasopharyngeal or oropharyngeal swabs. Furthermore, viral cytopathic effects and inclusions observed in cytomegalovirus, herpes simplex virus, and adenovirus infections are not evident in SARS-CoV-2 infections. [...]a formalin-fixed, paraffin-embedded (FFPE) tissue-based test is needed to establish the diagnosis of COVID-19 and guide management of the patient. Potential regional or temporal heterogeneity in viral genomic sequence due to genetic selection or drift may play a similar role, impacting the ability of existing targeted PCR assays to detect the virus in specimens from patients with COVID-19. Because formalin fixation can impact the quality and integrity of nucleic acid, sensitivity for the detection of microorganisms by PCR or other techniques may also be limited.

3.
Arch Pathol Lab Med ; 145(7): 785-796, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1134421

ABSTRACT

CONTEXT.­: Small case series have evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection in formalin-fixed, paraffin-embedded tissue using reverse transcription-polymerase chain reaction, immunohistochemistry (IHC), and/or RNA in situ hybridization (RNAish). OBJECTIVE.­: To compare droplet digital polymerase chain reaction, IHC, and RNAish to detect SARS-CoV-2 in formalin-fixed, paraffin-embedded tissue in a large series of lung specimens from coronavirus disease 2019 (COVID-19) patients. DESIGN.­: Droplet digital polymerase chain reaction and RNAish used commercially available probes; IHC used clone 1A9. Twenty-six autopsies of COVID-19 patients with formalin-fixed, paraffin-embedded tissue blocks of 62 lung specimens, 22 heart specimens, 2 brain specimens, and 1 liver, and 1 umbilical cord were included. Control cases included 9 autopsy lungs from patients with other infections/inflammation and virus-infected tissue or cell lines. RESULTS.­: Droplet digital polymerase chain reaction had the highest sensitivity for SARS-CoV-2 (96%) when compared with IHC (31%) and RNAish (36%). All 3 tests had a specificity of 100%. Agreement between droplet digital polymerase chain reaction and IHC or RNAish was fair (κ = 0.23 and κ = 0.35, respectively). Agreement between IHC and in situ hybridization was substantial (κ = 0.75). Interobserver reliability was almost perfect for IHC (κ = 0.91) and fair to moderate for RNAish (κ = 0.38-0.59). Lung tissues from patients who died earlier after onset of symptoms revealed higher copy numbers by droplet digital polymerase chain reaction (P = .03, Pearson correlation = -0.65) and were more likely to be positive by RNAish (P = .02) than lungs from patients who died later. We identified SARS-CoV-2 in hyaline membranes, in pneumocytes, and rarely in respiratory epithelium. Droplet digital polymerase chain reaction showed low copy numbers in 7 autopsy hearts from ProteoGenex Inc. All other extrapulmonary tissues were negative. CONCLUSIONS.­: Droplet digital polymerase chain reaction was the most sensitive and highly specific test to identify SARS-CoV-2 in lung specimens from COVID-19 patients.


Subject(s)
COVID-19 Testing/methods , COVID-19/diagnosis , Immunohistochemistry , In Situ Hybridization/methods , Lung/virology , Reverse Transcriptase Polymerase Chain Reaction/methods , SARS-CoV-2/isolation & purification , Adult , Aged , Aged, 80 and over , COVID-19/virology , Female , Humans , Male , Middle Aged , Observer Variation , Prospective Studies , RNA, Viral/isolation & purification , Reproducibility of Results , SARS-CoV-2/genetics , Sensitivity and Specificity
4.
Nat Commun ; 11(1): 6319, 2020 12 09.
Article in English | MEDLINE | ID: covidwho-966313

ABSTRACT

The relationship of SARS-CoV-2 pulmonary infection and severity of disease is not fully understood. Here we show analysis of autopsy specimens from 24 patients who succumbed to SARS-CoV-2 infection using a combination of different RNA and protein analytical platforms to characterize inter-patient and intra-patient heterogeneity of pulmonary virus infection. There is a spectrum of high and low virus cases associated with duration of disease. High viral cases have high activation of interferon pathway genes and a predominant M1-like macrophage infiltrate. Low viral cases are more heterogeneous likely reflecting inherent patient differences in the evolution of host response, but there is consistent indication of pulmonary epithelial cell recovery based on napsin A immunohistochemistry and RNA expression of surfactant and mucin genes. Using a digital spatial profiling platform, we find the virus corresponds to distinct spatial expression of interferon response genes demonstrating the intra-pulmonary heterogeneity of SARS-CoV-2 infection.


Subject(s)
COVID-19 , Host Microbial Interactions , Interferons/metabolism , Lung , Adult , Aged , Aged, 80 and over , Aspartic Acid Endopeptidases/metabolism , Autopsy , COVID-19/immunology , COVID-19/metabolism , Epithelial Cells/metabolism , Epithelial Cells/pathology , Epithelial Cells/virology , Female , Humans , Immunity , Immunohistochemistry , In Situ Hybridization , Interferons/genetics , Lung/pathology , Lung/virology , Macrophages/immunology , Male , Middle Aged , Mucins/genetics , Mucins/metabolism , Surface-Active Agents/metabolism , Transcriptome , Viral Load
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