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1.
Int J Biol Sci ; 18(15): 5591-5606, 2022.
Article in English | MEDLINE | ID: covidwho-2040345

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic respiratory infectious disease COVID-19. However, clinical manifestations and outcomes differ significantly among COVID-19 patients, ranging from asymptomatic to extremely severe, and it remains unclear what drives these disparities. Here, we studied 159 sequentially enrolled hospitalized patients with COVID-19-associated pneumonia from Brescia, Italy using the VirScan phage-display method to characterize circulating antibodies binding to 96,179 viral peptides encoded by 1,276 strains of human viruses. SARS-CoV-2 infection was associated with a marked increase in immune antibody repertoires against many known pathogenic and non-pathogenic human viruses. This antiviral antibody response was linked to longitudinal trajectories of disease severity and was further confirmed in additional 125 COVID-19 patients from the same geographical region in Northern Italy. By applying a machine-learning-based strategy, a viral exposure signature predictive of COVID-19-related disease severity linked to patient survival was developed and validated. These results provide a basis for understanding the role of memory B-cell repertoire to viral epitopes in COVID-19-related symptoms and suggest that a unique anti-viral antibody repertoire signature may be useful to define COVID-19 clinical severity.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Virome , Antiviral Agents , Epitopes
2.
J Exp Med ; 219(11)2022 11 07.
Article in English | MEDLINE | ID: covidwho-2037304

ABSTRACT

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10-5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10-5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10-10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for ∼5% of cases of life-threatening influenza pneumonia in patients <70 yr old.


Subject(s)
Autoantibodies , Influenza, Human , Interferon Type I , Pneumonia , COVID-19/complications , COVID-19/immunology , Humans , Influenza, Human/complications , Influenza, Human/immunology , Interferon Type I/immunology , Interferon Type I/metabolism , Pneumonia/complications , Pneumonia/immunology , Yellow Fever Vaccine/adverse effects
3.
Physiology (Bethesda) ; 37(6): 0, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-1986424

ABSTRACT

Inborn errors of immunity (IEI) are a heterogeneous group of disorders affecting immune host defense and immunoregulation. Considering the predisposition to develop severe and chronic infections, it is crucial to understand the clinical evolution of COVID-19 in IEI patients. This review analyzes clinical outcomes following SARS-CoV-2 infection, as well as response to COVID-19 vaccines in patients with IEI.


Subject(s)
COVID-19 , COVID-19 Vaccines , Humans , Immunity , SARS-CoV-2
5.
Bastard, Paul, Vazquez, Sara, Liu, Jamin, Laurie, Matthew T.; Wang, Chung Yu, Gervais, Adrian, Le Voyer, Tom, Bizien, Lucy, Zamecnik, Colin, Philippot, Quentin, Rosain, Jérémie, Catherinot, Emilie, Willmore, Andrew, Mitchell, Anthea M.; Bair, Rebecca, Garçon, Pierre, Kenney, Heather, Fekkar, Arnaud, Salagianni, Maria, Poulakou, Garyphallia, Siouti, Eleni, Sahanic, Sabina, Tancevski, Ivan, Weiss, Günter, Nagl, Laurenz, Manry, Jérémy, Duvlis, Sotirija, Arroyo-Sánchez, Daniel, Paz Artal, Estela, Rubio, Luis, Perani, Cristiano, Bezzi, Michela, Sottini, Alessandra, Quaresima, Virginia, Roussel, Lucie, Vinh, Donald C.; Reyes, Luis Felipe, Garzaro, Margaux, Hatipoglu, Nevin, Boutboul, David, Tandjaoui-Lambiotte, Yacine, Borghesi, Alessandro, Aliberti, Anna, Cassaniti, Irene, Venet, Fabienne, Monneret, Guillaume, Halwani, Rabih, Sharif-Askari, Narjes Saheb, Danielson, Jeffrey, Burrel, Sonia, Morbieu, Caroline, Stepanovskyy, Yurii, Bondarenko, Anastasia, Volokha, Alla, Boyarchuk, Oksana, Gagro, Alenka, Neuville, Mathilde, Neven, Bénédicte, Keles, Sevgi, Hernu, Romain, Bal, Antonin, Novelli, Antonio, Novelli, Giuseppe, Saker, Kahina, Ailioaie, Oana, Antolí, Arnau, Jeziorski, Eric, Rocamora-Blanch, Gemma, Teixeira, Carla, Delaunay, Clarisse, Lhuillier, Marine, Le Turnier, Paul, Zhang, Yu, Mahevas, Matthieu, Pan-Hammarström, Qiang, Abolhassani, Hassan, Bompoil, Thierry, Dorgham, Karim, consortium, Covid Hge, French, Covid study group, consortium, Comet, Gorochov, Guy, Laouenan, Cédric, Rodríguez-Gallego, Carlos, Ng, Lisa F. P.; Renia, Laurent, Pujol, Aurora, Belot, Alexandre, Raffi, François, Allende, Luis M.; Martinez-Picado, Javier, Ozcelik, Tayfun, Keles, Sevgi, Imberti, Luisa, Notarangelo, Luigi D.; Troya, Jesus, Solanich, Xavier, Zhang, Shen-Ying, Puel, Anne, Wilson, Michael R.; Trouillet-Assant, Sophie, Abel, Laurent, Jouanguy, Emmanuelle, Ye, Chun Jimmie, Cobat, Aurélie, Thompson, Leslie M.; Andreakos, Evangelos, Zhang, Qian, Anderson, Mark S.; Casanova, Jean-Laurent, DeRisi, Joseph L..
Science immunology ; 2022.
Article in English | EuropePMC | ID: covidwho-1918542

ABSTRACT

Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals;however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population. Type I IFN auto-Abs are found in 20% of hypoxemic, mRNA vaccinated COVID-19 patients despite SARS-CoV-2 neutralizing antibodies. Description

6.
Clin Infect Dis ; 2021 Dec 07.
Article in English | MEDLINE | ID: covidwho-1852986

ABSTRACT

Binding levels and neutralization activity of anti-type 1 interferon (T1IFN) autoantibodies peaked during acute COVID-19 and markedly decreased thereafter. Most patients maintained some ability to neutralize T1IFN into convalescence despite lower levels of binding IgG. Identifying these autoantibodies in healthy individuals before they develop critical viral disease may be challenging.

7.
Pediatr Allergy Immunol ; 33 Suppl 27: 61-64, 2022 01.
Article in English | MEDLINE | ID: covidwho-1840509

ABSTRACT

Inborn errors of immunity (IEI), also referred to as primary immunodeficiencies (PID), are disorders that, for the most part, result from mutations in genes involved in immune host defense and immune regulation. With the increased availability of high-throughput DNA sequencing and improved genomic data interpretation, the number of newly identified genes associated with IEI has exponentially increased over the last decade. Here, we focus on the newly described IEI associated with severe COVID-19 and SASH3 deficiency, the most recently reported IEI with impaired T-cell receptor (TCR) signaling.


Subject(s)
COVID-19 , Primary Immunodeficiency Diseases , High-Throughput Nucleotide Sequencing , Humans , Mutation , SARS-CoV-2
8.
Ann Clin Transl Neurol ; 9(5): 622-632, 2022 05.
Article in English | MEDLINE | ID: covidwho-1825806

ABSTRACT

OBJECTIVE: Given the continued spread of coronavirus 2, the early predictors of coronavirus disease 19 (COVID-19) associated mortality might improve patients' outcomes. Increased levels of circulating neurofilament light chain (NfL), a biomarker of neuronal injury, have been observed in severe COVID-19 patients. We investigated whether NfL provides non-redundant clinical value to previously identified predictors of COVID-19 mortality. METHODS: We measured serum or plasma NfL concentrations in a blinded fashion in 3 cohorts totaling 338 COVID-19 patients. RESULTS: In cohort 1, we found significantly elevated NfL levels only in critically ill COVID-19 patients. Longitudinal cohort 2 data showed that NfL is elevated late in the course of the disease, following the two other prognostic markers of COVID-19: decrease in absolute lymphocyte count (ALC) and increase in lactate dehydrogenase (LDH). Significant correlations between ALC and LDH abnormalities and subsequent rise of NfL implicate that the multi-organ failure is the most likely cause of neuronal injury in severe COVID-19 patients. The addition of NfL to age and gender in cohort 1 significantly improved the accuracy of mortality prediction and these improvements were validated in cohorts 2 and 3. INTERPRETATION: A substantial increase in serum/plasma NfL reproducibly enhanced COVID-19 mortality prediction. Combined with other prognostic markers, such as ALC and LDH that are routinely measured in ICU patients, NfL measurements might be useful to identify the patients at a high risk of COVID-19-associated mortality, who might still benefit from escalated care.


Subject(s)
COVID-19 , Biomarkers , Cohort Studies , Humans , Intermediate Filaments , Prognosis
9.
Front Immunol ; 13: 841126, 2022.
Article in English | MEDLINE | ID: covidwho-1775675

ABSTRACT

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.


Subject(s)
Autoimmune Diseases , COVID-19 , Lupus Erythematosus, Systemic , Adaptor Proteins, Signal Transducing , Adenosine Triphosphatases , Adult , Autoantibodies , Autoantigens , Autoimmunity , COVID-19/complications , Child , Humans , Immunoglobulins, Intravenous , Ribonucleoproteins , Systemic Inflammatory Response Syndrome
11.
J Nephrol ; 35(3): 745-759, 2022 04.
Article in English | MEDLINE | ID: covidwho-1650680

ABSTRACT

BACKGROUND: Dialysis and kidney transplant patients with moderate-severe COVID-19 have a high mortality rate, around 30%, that is similar in the two populations, despite differences in their baseline characteristics. In these groups, the immunology of the disease has been poorly explored. METHODS: Thirty-two patients on dialysis or with kidney transplant and SARS-CoV-2 infection requiring hospitalization (COV group) were included in our study. Lymphocyte subsets, dendritic cell (DC) counts and monocyte activation were studied. SARS-CoV-2 anti-spike/anti-nucleocapsid were monitored, and baseline cytokines and chemokines were measured in 10 patients. RESULTS: The COV group, compared to healthy subjects and uninfected dialysis/kidney transplant controls, showed lower numbers of CD4 + and CD8 + T cells, Natural-Killer (NK), B cells, plasmacytoid and myeloid DCs, while the proportion of terminally differentiated B-cells was increased. IL6, IL10, IFN-α and chemokines involved in monocyte and neutrophil recruitment were higher in the COV group, compared to uninfected dialysis/kidney transplant controls. Patients with severe disease had lower CD4 + , CD8 + and B-cell counts and lower monocyte HLA-DR expression. Of note, when comparing dialysis and kidney transplant patients with COVID-19, the latter group presented lower NK and pDC counts and monocyte HLA-DR expression. Up to 60 days after symptom onset, kidney transplant recipients showed lower levels of anti-spike antibodies compared to dialysis patients. CONCLUSIONS: During SARS-CoV-2 infection, dialysis and kidney transplant patients manifest immunophenotype abnormalities; these are similar in the two groups, however kidney transplant recipients show more profound alterations of the innate immune system and lower anti-spike antibody response.


Subject(s)
COVID-19 , Kidney Transplantation , HLA-DR Antigens , Humans , Kidney Transplantation/adverse effects , Renal Dialysis/adverse effects , SARS-CoV-2 , Transplant Recipients
12.
Open forum infectious diseases ; 8(Suppl 1):S77-S77, 2021.
Article in English | EuropePMC | ID: covidwho-1602523

ABSTRACT

Background T cells are central to the early identification and clearance of viral infections and support antibody generation by B cells, making them desirable for assessing the immune response to SARS-CoV-2 infection and vaccines. We combined 2 high-throughput immune profiling methods to create a quantitative picture of the SARS-CoV-2 T-cell response that is highly sensitive, durable, diagnostic, and discriminatory between natural infection and vaccination. Methods We deeply characterized 116 convalescent COVID-19 subjects by experimentally mapping CD8 and CD4 T-cell responses via antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I and 284 class II viral peptides. We also performed T-cell receptor (TCR) repertoire sequencing on 1815 samples from 1521 PCR-confirmed SARS-CoV-2 cases and 3500 controls to identify shared public TCRs from SARS-CoV-2-associated CD8 and CD4 T cells. Combining these approaches with additional samples from vaccinated individuals, we characterized the response to natural infection as well as vaccination by separating responses to spike protein from other viral targets. Results We find that T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the SARS-CoV-2 T-cell response peaks about 1-2 weeks after infection and is detectable at least several months after recovery. Applying these data, we trained a classifier to diagnose past SARS-CoV-2 infection based solely on TCR sequencing from blood samples and observed, at 99.8% specificity, high sensitivity soon after diagnosis (Day 3–7 = 85.1%;Day 8–14 = 94.8%) that persists after recovery (Day 29+/convalescent = 95.4%). Finally, by evaluating TCRs binding epitopes targeting all non-spike SARS-CoV-2 proteins, we were able to separate natural infection from vaccination with > 99% specificity. Conclusion TCR repertoire sequencing from whole blood reliably measures the adaptive immune response to SARS-CoV-2 soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points, and distinguishes post-infection vs. vaccine immune responses with high specificity. This approach to characterizing the cellular immune response has applications in clinical diagnostics as well as vaccine development and monitoring. Disclosures Thomas M. Snyder, PhD, Adaptive Biotechnologies (Employee, Shareholder) Rachel M. Gittelman, PhD, Adaptive Biotechnologies (Employee, Shareholder) Mark Klinger, PhD, Adaptive Biotechnologies (Employee, Shareholder) Damon H. May, PhD, Adaptive Biotechnologies (Employee, Shareholder) Edward J. Osborne, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ruth Taniguchi, PhD, Adaptive Biotechnologies (Employee, Shareholder) H. Jabran Zahid, PhD, Microsoft Research (Employee, Shareholder) Rebecca Elyanow, PhD, Adaptive Biotechnologies (Employee, Shareholder) Sudeb C. Dalai, MD, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ian M. Kaplan, PhD, Adaptive Biotechnologies (Employee, Shareholder) Jennifer N. Dines, MD, Adaptive Biotechnologies (Employee, Shareholder) Matthew T. Noakes, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ravi Pandya, PhD, Microsoft Research (Employee, Shareholder) Lance Baldo, MD, Adaptive Biotechnologies (Employee, Shareholder, Leadership Interest) James R. Heath, PhD, Merck (Research Grant or Support, Funding (from BARDA) for the ISB INCOV project, but had no role in planning the research or in writing the paper.) Joaquin Martinez-Lopez, MD, PhD, Adaptive Biotechnologies (Consultant) Jonathan M. Carlson, PhD, Microsoft Research (Employee, Shareholder) Harlan S. Robins, PhD, Adaptive Biotechnologies (Board Member, Employee, Shareholder)

13.
Front Immunol ; 12: 779026, 2021.
Article in English | MEDLINE | ID: covidwho-1581330

ABSTRACT

A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.


Subject(s)
COVID-19/complications , Myocarditis/pathology , Myocarditis/virology , Systemic Inflammatory Response Syndrome/pathology , T-Lymphocytes/immunology , Adult , COVID-19/immunology , COVID-19/pathology , Humans , Male , Myocarditis/immunology , RNA, Viral/analysis , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/immunology
14.
[Unspecified Source]; 2020.
Preprint in English | [Unspecified Source] | ID: ppcovidwho-292804

ABSTRACT

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,015 samples (from 827 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 83.8% [95% CI = 77.6-89.4];Day 8-14 = 92.4% [87.6-96.6]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 96.7% [93.0-99.2]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in vaccine development as well as clinical diagnostics and monitoring.

15.
Front Immunol ; 12: 720205, 2021.
Article in English | MEDLINE | ID: covidwho-1403477

ABSTRACT

Patients with the monogenic immune dysregulatory syndrome autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene, uniformly carry neutralizing autoantibodies directed against type-I interferons (IFNs) and many develop autoimmune pneumonitis, both of which place them at high risk for life-threatening COVID-19 pneumonia. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target the SARS-CoV-2 spike protein and block entry of SARS-CoV-2 in host cells. The use of bamlanivimab and etesevimab early during infection was associated with reduced COVID-19-associated hospitalization and death in patients at high risk for progressing to severe disease, which led the US Food and Drug Administration to issue an emergency use authorization for their administration in non-hypoxemic, non-hospitalized high-risk patients. However, the safety and efficacy of these mAbs has not been evaluated in APECED patients. We enrolled two siblings with APECED on an IRB-approved protocol (NCT01386437) and admitted them prophylactically at the NIH Clinical Center for evaluation of mild-to-moderate COVID-19. We assessed the safety and clinical effects of early treatment with bamlanivimab and etesevimab. The administration of bamlanivimab and etesevimab was well tolerated and was associated with amelioration of COVID-19 symptoms and prevention of invasive ventilatory support, admission to the intensive care, and death in both patients without affecting the production of antibodies to the nucleocapsid protein of SARS-CoV-2. If given early in the course of COVID-19 infection, bamlanivimab and etesevimab may be beneficial in APECED and other high-risk patients with neutralizing autoantibodies directed against type-I IFNs.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , Polyendocrinopathies, Autoimmune/drug therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , COVID-19/complications , COVID-19/genetics , COVID-19/immunology , Female , Humans , Interferons/genetics , Interferons/immunology , Male , Mutation , Polyendocrinopathies, Autoimmune/complications , Polyendocrinopathies, Autoimmune/genetics , Polyendocrinopathies, Autoimmune/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Transcription Factors/genetics , Transcription Factors/immunology
17.
J Clin Immunol ; 41(6): 1146-1153, 2021 08.
Article in English | MEDLINE | ID: covidwho-1384523

ABSTRACT

Immunocompromised patients, including those with inborn errors of immunity (IEI), may be at increased risk for severe or prolonged infections with SARS-CoV-2 (Zhu et al. N Engl J Med. 382:727-33, 2020; Guan et al. 2020; Minotti et al. J Infect. 81:e61-6, 2020). While antibody and T cell responses to SARS-CoV-2 structural proteins are well described in healthy convalescent donors, adaptive humoral and cellular immunity has not yet been characterized in patients with antibody deficiency (Grifoni et al. Cell. 181:1489-1501 e1415, 2020; Burbelo et al. 2020; Long et al. Nat Med. 26:845-8, 2020; Braun et al. 2020). Herein, we describe the clinical course, antibody, and T cell responses to SARS-CoV-2 structural proteins in a cohort of adult and pediatric patients with antibody deficiencies (n = 5) and controls (related and unrelated) infected with SARS-CoV-2. Five patients within the same family (3 with antibody deficiency, 2 immunocompetent controls) showed antibody responses to nucleocapsid and spike proteins, as well as SARS-CoV-2 specific T cell immunity at days 65-84 from onset of symptoms. No significant difference was identified between immunocompromised patients and controls. Two additional unrelated, adult patients with common variable immune deficiency were assessed. One did not show antibody response, but both demonstrated SARS-CoV-2-specific T cell immunity when evaluated 33 and 76 days, respectively, following SARS-CoV-2 diagnosis. This report is the first to show robust T cell activity and humoral immunity against SARS-CoV-2 structural proteins in some patients with antibody deficiency. Given the reliance on spike protein in most candidate vaccines (Folegatti et al. Lancet. 396:467-78, 2020; Jackson et al. N Engl J Med. 383:1920-31, 2020), the responses are encouraging. Additional studies will be needed to further define the timing of onset of immunity, longevity of the immune response, and variability of response in immunocompromised patients.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Common Variable Immunodeficiency/immunology , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adolescent , Adult , Carrier State , Cells, Cultured , Child , Female , Humans , Immunity, Humoral , Lymphocyte Activation , Male , Middle Aged , Mutation/genetics , Pedigree , Transmembrane Activator and CAML Interactor Protein/genetics , Whole Exome Sequencing , Young Adult
18.
J Allergy Clin Immunol ; 148(5): 1192-1197, 2021 11.
Article in English | MEDLINE | ID: covidwho-1385788

ABSTRACT

BACKGROUND: SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEIs); however, little is known about immunogenicity and safety in these patients. OBJECTIVE: We sought to evaluate the impact of genetic diagnosis, age, and treatment on antibody response to COVID-19 vaccine and related adverse events in a cohort of patients with IEIs. METHODS: Plasma was collected from 22 health care worker controls, 81 patients with IEIs, and 2 patients with thymoma; the plasma was collected before immunization, 1 to 6 days before the second dose of mRNA vaccine, and at a median of 30 days after completion of the immunization schedule with either mRNA vaccine or a single dose of Johnson & Johnson's Janssen vaccine. Anti-spike (anti-S) and anti-nucleocapsid antibody titers were measured by using a luciferase immunoprecipitation systems method. Information on T- and B-cell counts and use of immunosuppressive drugs was extracted from medical records, and information on vaccine-associated adverse events was collected after each dose. RESULTS: Anti-S antibodies were detected in 27 of 46 patients (58.7%) after 1 dose of mRNA vaccine and in 63 of 74 fully immunized patients (85.1%). A lower rate of seroconversion (7 of 11 [63.6%]) was observed in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Previous use of rituximab and baseline counts of less than 1000 CD3+ T cells/mL and less than 100 CD19+ B cells/mL were associated with lower anti-S IgG levels. No significant adverse events were reported. CONCLUSION: Vaccinating patients with IEIs is safe, but immunogenicity is affected by certain therapies and gene defects. These data may guide the counseling of patients with IEIs regarding prevention of SARS-CoV-2 infection and the need for subsequent boosts.


Subject(s)
Age Factors , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Polyendocrinopathies, Autoimmune/immunology , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adolescent , Adult , Aged , Antibodies, Viral/blood , Antibody Formation , COVID-19/drug therapy , COVID-19/genetics , Cohort Studies , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunization, Secondary , Immunogenicity, Vaccine , Immunoglobulin G/blood , Immunosuppressive Agents/therapeutic use , Lymphocyte Count , Male , Middle Aged , Phosphoproteins/immunology , Polyendocrinopathies, Autoimmune/drug therapy , Polyendocrinopathies, Autoimmune/genetics , Rituximab/therapeutic use , Seroconversion , Spike Glycoprotein, Coronavirus/immunology , Young Adult
19.
Blood ; 136(Supplement 1):4-4, 2020.
Article in English | PMC | ID: covidwho-1339036

ABSTRACT

Introduction. Covid-19 patients (pts) with hematologic malignancies have a severe prognosis with mortality rates around 40%, particularly when on active treatment (Cattaneo et al, Cancer, in press). However, the long-term prognosis and persistence of specific immune responses among those who survive acute infection are unclear.Aim: Pts with hematological diseases were followed longitudinally after the acute phase of COVID-19 according to protocol NP4156 approved by the local EC. Clinical outcome and specific antibody responses to SARS-CoV-2 were monitored during convalescence, and correlated to the diagnosis and treatment of the underlying hematological disease.Pts and Methods. Pts affected by multiple myeloma (MM), follicular (FL) and diffuse large B-cell (DLC) lymphoma (NHL), chronic lymphoproliferative disorders (CLD), myelodysplastic/chronic myeloproliferative syndromes (MDS/MPN) and surviving the acute phase of virologic-proven COVID-19 were eligible. Immune response parameters were evaluated at +1, +3, +6, +9 and +12 months after nasal swab negativization. Antibodies (Ab) to different conformations of COVID-19 virus proteins, nucleocapsid (N) and spike (S), were measured using a highly sensitive luciferase-immunoprecipitation system (LIPS) assay.Results. Of 51 eligible pts, 41 were tested for SARS-CoV-2 Ab at first timepoint (+1m) (6 pts too early, 2 refusal, 2 lost to follow-up). For 9 of them, Ab levels at +3m were also available. Ab levels of 14 controls without hematologic disorders (Ctrls) also surviving COVID-19 were evaluable at +1m and in 9 of them at +3 months as well. Diagnoses included FL (9) and DLC (6) NHL, CLD (7), MM (10), MDS/MPS (9). The status of hematological disease at the time of COVID-19 diagnosis was as follows: diagnosis (n=4;10%), complete or partial remission (n=16;39%), relapse/refractory (n=6;15%;stable (n=15;36%). Twenty-one pts (51%) were on active treatment, including 6 on chemoimmunotherapy;7 pts had received chemoimmunotherapy previously. Median time from SARS-CoV-2 detection to swab negativity was 30d (range 8-63), and was not influenced by sex, age, hematologic diagnosis, disease status, nor treatment received. Two pts, both affected by DLC secondary to FL, remained swab-positive at day 119+ and 123+.At +1m, both N- and S- seropositivity rate was slightly lower in pts [N+ in 30/41 (73%);S+ in 27/41 (66%)] vs 13/14 for both N+ and S+ in Ctrls (93%) (P=0.16 and 0.08, respectively). Discrepancies between N and S seropositivity were observed in 7 (17%) pts, all with lymphoid disorders. Ab levels were similar in hematologic pts and in Ctrls (N+ 894,707 vs 870,541 LU and S+ 907,591 LU vs 724,120 LU, respectively, P=NS) (Fig.1a). Both seroconversion rates and Ab levels were not influenced by age, sex, status of hematologic disease, ongoing treatment, time to swab negativity, severity of pneumonia and steroid treatment during acute COVID-19. However, a diagnosis of NHL negatively impacted on seroconversion for both N and S. In 15 pts with NHL compared to 26 pts with other hematologic cancers, the N-seropositivity rate was 47% vs 92%, and the S-seropositivity rate was 40% vs 85%y (P=0.002 and 0.0053, respectively). N and S Ab levels were also lower than in other hematologic diseases (515,281 LU vs 1105409 LU, P=.002 and 474,309 LU vs 1,148,303 LU, P=.005 respectively) (Fig.1b). Rituximab (RTX) had been used in 13 of 15 NHL (87%), and treatment was ongoing in 6/13. While N-seroconversion and Ab levels were not influenced, no pts on ongoing RTX had S-seroconversion vs 5/7 pts with past RTX use (P=0.021) and mean antibody levels were 17622 LU vs 668548 LU, respectively (P=0.008).At +3m, no significant variations of both anti-N and anti-S antibody levels had occurred compared to timepoint +1m. Seroconversion status was maintained by 9/9 Ctrls and by 8/8 pts;the only pt with Ab levels below the cut-off at +1m did not show seroconversion at+3m.Conclusions: Overall, hematologic pts surviving COVID-19 have N- and S- antibodies levels and seroconversion rates similar to controls witho t hematologic disorders, although time to swab negativity seems more similar to critically ill pts than in the general population. A diagnosis of NHL negatively impacts on seroconversion and Ab levels, and ongoing RTX seems to have a negative role specifically on anti-S Ab production. Ab response persists at 3 months;the study is ongoing and further data will be available at time of meeting.

20.
Blood ; 136(Supplement 1):47-48, 2020.
Article in English | PMC | ID: covidwho-1339032

ABSTRACT

It has been proposed that patients with hematologic malignancy and autoimmune diseases receiving anti-CD20 monoclonal antibody (mAb) therapy are particularly at risk of severe Coronavirus disease (COVID-19) because the profound and long-lasting B-cell depletion induced by anti-CD20 mAb may impair virus clearance and may also contribute to reactivation of latent viruses, especially hepatitis B and JC viruses.As of July 20, 2020, the total number of COVID-19 cases reported by the Italian authorities reached 245,000. The north of the country was mostly hit, and Milan and Brescia were among the Italian provinces that registered the highest number of COVID-19 cases. Consistent with this, a high number of COVID-19 patients affected with multiple types of hematological disorders (n. 137) and with multiple sclerosis (MS, n. 114) were referred to ASST Spedali Civili di Brescia. Antibodies to SARS-CoV-2 were analyzed in 70 patients with hematological disease, and in few patients with MS. Among these, 10 patients (7 with hematologic disease and 3 with MS) had received treatment with rituximab or ocrelizumab, two anti-CD20 mAbs, within 3 months prior to COVID-19 onset. Clinical indication to CD20-depleting treatment for patients with hematological disorders included Diffuse Large B Cell Lymphoma (DLBCL) or Follicular Non Hodgkin Lymphoma (NHL).Anti-spike protein (anti-S) and anti-nucleocapsid (anti-N) antibodies to SARS-CoV-2 were analyzed during the acute phase of infection and up to 3 months since the onset of symptoms by quantitative measurements of plasma or serum antibodies with luciferase immune precipitation assay systems (LIPS). With this technique, production of anti-S and anti-N antibodies has been demonstrated between day 8 and day 14 after onset of symptoms in immunocompetent individuals, whereas specific antibody production was delayed by few days in immunocompromised patients (Burbelo PD et al, medRxiv. 2020 Apr 24:2020.04.20.20071423).All 10 patients remained seronegative to SARS-CoV-2 for the first 20 days since onset of symptoms. One patient with DLBCL secondary to Follicular NHL had detectable anti-S and anti-N antibodies at day +25, and one patient with MS developed anti-N antibodies by day +23. Two patients, one with DLBCL secondary to Follicular NHL and one with Follicular NHL were still seronegative for both anti-S and anti-N antibodies at 133 and 74 days since onset of symptoms. Two MS patients were seronegative at the last examination, and one other MS patient was anti-S seronegative at day +74.Three of the 10 patients have died;all three were SARS-CoV-2 RT-qPCR+ and seronegative at the time of death.While it has been reported that SARS-CoV-2 is cleared without significant problems by the majority of people with MS or other autoimmune diseases on immunotherapy, these data indicate that treatment with anti-CD20 mAb may significantly alter humoral responses to the virus. Until a vaccine to SARS-CoV-2 is available, the risk-benefit ratio of anti-CD20 mAb therapy in areas with high rates of SARS-CoV-2 infection should be carefully weighed. Moreover, for patients with B-cell malignancies or autoimmune diseases, transient discontinuation of this therapy, or use of alternative therapeutic approaches, should be considered once an efficacious vaccine becomes available.This study was performed according to protocol NP-4000 (Comitato Etico Provinciale), and supported by Regione Lombardia and by the Division of Intramural Research, NIAID.Figure 1

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