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1.
J Allergy Clin Immunol ; 149(6): 1949-1957, 2022 06.
Article in English | MEDLINE | ID: covidwho-1783444

ABSTRACT

BACKGROUND: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. OBJECTIVES: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI. METHODS: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination. RESULTS: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response. CONCLUSIONS: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.


Subject(s)
2019-nCoV Vaccine mRNA-1273 , Antibodies, Neutralizing , COVID-19 , Genetic Diseases, Inborn , Immunologic Deficiency Syndromes , 2019-nCoV Vaccine mRNA-1273/blood , 2019-nCoV Vaccine mRNA-1273/immunology , 2019-nCoV Vaccine mRNA-1273/therapeutic use , Adult , Agammaglobulinemia/genetics , Agammaglobulinemia/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/genetics , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Common Variable Immunodeficiency/genetics , Common Variable Immunodeficiency/immunology , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/immunology , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/immunology , Humans , Immunologic Deficiency Syndromes/blood , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Primary Immunodeficiency Diseases/genetics , Primary Immunodeficiency Diseases/immunology , Prospective Studies , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
2.
Am J Med Genet A ; 188(4): 1142-1148, 2022 04.
Article in English | MEDLINE | ID: covidwho-1593959

ABSTRACT

We studied if clinicians could gain sufficient working knowledge of a computer-assisted diagnostic decision support system (DDSS) (SimulConsult), to make differential diagnoses (DDx) of genetic disorders. We hypothesized that virtual training could be convenient, asynchronous, and effective in teaching clinicians how to use a DDSS. We determined the efficacy of virtual, asynchronous teaching for clinicians to gain working knowledge to make computer-assisted DDx. Our study consisted of three surveys (Baseline, Training, and After Use) and a series of case problems sent to clinicians at Vanderbilt University Medical Center. All participants were able to generate computer-assisted DDx that achieved passing scores of the case problems. Between 75% and 92% agreed/completely agreed the DDSS was useful to their work and for clinical decision support and was easy to use. Participants' use of the DDSS resulted in statistically significant time savings in key tasks and in total time spent on clinical tasks. Our results indicate that virtual, asynchronous teaching can be an effective format to gain a working knowledge of a DDSS, and its clinical use could result in significant time savings across multiple tasks as well as facilitate synergistic interaction between clinicians and lab specialists. This approach is especially pertinent and offers value amid the COVID-19 pandemic.


Subject(s)
Diagnosis, Computer-Assisted , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Teaching , User-Computer Interface , Decision Support Systems, Clinical , Diagnosis, Computer-Assisted/methods , Education, Medical , Humans , Physicians , Surveys and Questionnaires
3.
Health Aff (Millwood) ; 40(12): 1972-1975, 2021 12.
Article in English | MEDLINE | ID: covidwho-1566561

ABSTRACT

A genetic counselor uses her own resources to identify the root cause of her mother's changing personality.


Subject(s)
Genetic Diseases, Inborn/diagnosis , Humans
4.
N Engl J Med ; 385(24): 2264-2270, 2021 12 09.
Article in English | MEDLINE | ID: covidwho-1560911

ABSTRACT

Inherited junctional epidermolysis bullosa is a severe genetic skin disease that leads to epidermal loss caused by structural and mechanical fragility of the integuments. There is no established cure for junctional epidermolysis bullosa. We previously reported that genetically corrected autologous epidermal cultures regenerated almost an entire, fully functional epidermis on a child who had a devastating form of junctional epidermolysis bullosa. We now report long-term clinical outcomes in this patient. (Funded by POR FESR 2014-2020 - Regione Emilia-Romagna and others.).


Subject(s)
Epidermis/transplantation , Epidermolysis Bullosa, Junctional/therapy , Keratinocytes/transplantation , Transduction, Genetic , Transgenes , Cell Self Renewal , Cells, Cultured/transplantation , Child , Clone Cells , Epidermis/pathology , Epidermolysis Bullosa, Junctional/genetics , Epidermolysis Bullosa, Junctional/pathology , Follow-Up Studies , Genetic Diseases, Inborn/pathology , Genetic Diseases, Inborn/therapy , Genetic Therapy , Genetic Vectors , Humans , Keratinocytes/cytology , Keratinocytes/physiology , Male , Regeneration , Stem Cells/physiology , Transplantation, Autologous
5.
Acc Chem Res ; 54(23): 4283-4293, 2021 12 07.
Article in English | MEDLINE | ID: covidwho-1521679

ABSTRACT

After decades of extensive fundamental studies and clinical trials, lipid nanoparticles (LNPs) have demonstrated effective mRNA delivery such as the Moderna and Pfizer-BioNTech vaccines fighting against COVID-19. Moreover, researchers and clinicians have been investigating mRNA therapeutics for a variety of therapeutic indications including protein replacement therapy, genome editing, and cancer immunotherapy. To realize these therapeutics in the clinic, there are many formidable challenges. First, novel delivery systems such as LNPs with high delivery efficiency and low toxicity need to be developed for different cell types. Second, mRNA molecules need to be engineered for improved pharmaceutical properties. Lastly, the LNP-mRNA nanoparticle formulations need to match their therapeutic applications.In this Account, we summarize our recent advances in the design and development of various classes of lipids and lipid derivatives, which can be formulated with multiple types of mRNA molecules to treat diverse diseases. For example, we conceived a series of ionizable lipid-like molecules based on the structures of a benzene core, an amide linker, and hydrophobic tails. We identified N1,N3,N5-tris(3-(didodecylamino)propyl)benzene-1,3,5-tricarboxamide (TT3) as a lead compound for mRNA delivery both in vitro and in vivo. Moreover, we tuned the biodegradability of these lipid-like molecules by introducing branched ester or linear ester chains. Meanwhile, inspired by biomimetic compounds, we synthesized vitamin-derived lipids, chemotherapeutic conjugated lipids, phospholipids, and glycolipids. These scaffolds greatly broaden the chemical space of ionizable lipids for mRNA delivery. In another section, we highlight our efforts on the research direction of mRNA engineering. We previously optimized mRNA chemistry using chemically-modified nucleotides to increase the protein expression, such as pseudouridine (ψ), 5-methoxyuridine (5moU), and N1-methylpseudouridine (me1ψ). Also, we engineered the sequences of mRNA 5' untranslated regions (5'-UTRs) and 3' untranslated regions (3'-UTRs), which dramatically enhanced protein expression. With the progress of LNP development and mRNA engineering, we consolidate these technologies and apply them to treat diseases such as genetic disorders, infectious diseases, and cancers. For instance, TT3 and its analog-derived lipid-like nanoparticles can effectively deliver factor IX or VIII mRNA and recover the clotting activity in hemophilia mouse models. Engineered mRNAs encoding SARS-CoV-2 antigens serve well as vaccine candidates against COVID-19. Vitamin-derived lipid nanoparticles loaded with antimicrobial peptide-cathepsin B mRNA enable adoptive macrophage transfer to treat multidrug resistant bacterial sepsis. Biomimetic lipids such as phospholipids formulated with mRNAs encoding costimulatory receptors lead to enhanced cancer immunotherapy.Overall, lipid-mRNA nanoparticle formulations have considerably benefited public health in the COVID-19 pandemic. To expand their applications in clinical use, research work from many disciplines such as chemistry, engineering, materials, pharmaceutical sciences, and medicine need to be integrated. With these collaborative efforts, we believe that more and more lipid-mRNA nanoparticle formulations will enter the clinic in the near future and benefit human health.


Subject(s)
Drug Carriers/chemistry , Liposomes/chemistry , Nanoparticles/chemistry , RNA, Messenger/chemistry , Animals , Benzamides/chemistry , Biomimetic Materials/chemistry , Communicable Diseases/immunology , Communicable Diseases/therapy , Disease Models, Animal , Genetic Diseases, Inborn/immunology , Genetic Diseases, Inborn/therapy , Humans , Mice , Neoplasms/immunology , Neoplasms/therapy , Phospholipids/chemistry , RNA, Messenger/metabolism , RNA, Messenger/therapeutic use , Untranslated Regions , Vitamins/chemistry
7.
J Allergy Clin Immunol ; 148(4): 911-925, 2021 10.
Article in English | MEDLINE | ID: covidwho-1482662

ABSTRACT

Since its discovery, the Janus kinase-signal transduction and activation of transcription (JAK-STAT) pathway has become recognized as a central mediator of widespread and varied human physiological processes. The field of JAK-STAT biology, particularly its clinical relevance, continues to be shaped by 2 important advances. First, the increased use of genomic sequencing has led to the discovery of novel clinical syndromes caused by mutations in JAK and STAT genes. This has provided insights regarding the consequences of aberrant JAK-STAT signaling for immunity, lymphoproliferation, and malignancy. In addition, since the approval of ruxolitinib and tofacitinib, the therapeutic use of JAK inhibitors (jakinibs) has expanded to include a large spectrum of diseases. Efficacy and safety data from over a decade of clinical studies have provided additional mechanistic insights while improving the care of patients with inflammatory and neoplastic conditions. This review discusses major advances in the field, focusing on updates in genetic diseases and in studies of clinical jakinibs in human disease.


Subject(s)
Genetic Diseases, Inborn/drug therapy , Janus Kinase Inhibitors/therapeutic use , Janus Kinases/immunology , STAT Transcription Factors/immunology , Animals , Cytokines/immunology , Genetic Diseases, Inborn/immunology , Humans , Janus Kinases/genetics , Mutation , STAT Transcription Factors/genetics , Signal Transduction
8.
J Allergy Clin Immunol ; 148(6): 1442-1450, 2021 12.
Article in English | MEDLINE | ID: covidwho-1474659

ABSTRACT

Recent advances in the field of inborn errors of immunity (IEIs) have been wide in scope, including progress in mechanisms of disease, diagnosis, and management. New gene defects affecting the immune response continue to be reported, as many as 26 in the year 2020. It was noted that the presentation of IEIs might not include recurrent infections in 9% of cases, and that current diagnostic methods can identify molecular causes in 92% of patients with severe combined immunodeficiency. Progress in immunopathogenesis explained mechanisms leading to symptoms of autosomal-recessive hyper-IgE syndrome. There was an emphasis on research in primary antibody deficiencies. The benefit of antibiotic prophylaxis to reduce the frequency of infections was demonstrated in these patients. The regimen of rituximab and azathioprine or mycophenolate was proven effective for chronic granulocytic interstitial pneumonia. The efficacy and adverse events of hematopoietic stem cell transplant in different IEI conditions were reported, as well as different strategies to improve outcomes, supporting its use in immunodeficiency and immunodysregulatory syndromes. The recent pandemic of coronavirus disease 2019 affected patients with IEIs, in particular those with deficiency in the interferon-mediated activation of the immune response. Initial data suggest that coronavirus disease 2019 vaccines might elicit anti-coronavirus disease 2019-neutralizing antibody responses in some patients with IEI conditions.


Subject(s)
COVID-19 , Genetic Diseases, Inborn , Immunologic Deficiency Syndromes , Primary Immunodeficiency Diseases , Humans , Metabolism, Inborn Errors , SARS-CoV-2
9.
J Clin Immunol ; 41(7): 1446-1456, 2021 10.
Article in English | MEDLINE | ID: covidwho-1453806

ABSTRACT

STAT2 is distinguished from other STAT family members by its exclusive involvement in type I and III interferon (IFN-I/III) signaling pathways, and its unique behavior as both positive and negative regulator of IFN-I signaling. The clinical relevance of these opposing STAT2 functions is exemplified by monogenic diseases of STAT2. Autosomal recessive STAT2 deficiency results in heightened susceptibility to severe and/or recurrent viral disease, whereas homozygous missense substitution of the STAT2-R148 residue is associated with severe type I interferonopathy due to loss of STAT2 negative regulation. Here we review the clinical presentation, pathogenesis, and management of these disorders of STAT2.


Subject(s)
Genetic Diseases, Inborn/genetics , Immune System Diseases/genetics , Interferon Type I/immunology , STAT2 Transcription Factor/genetics , Virus Diseases/genetics , Animals , Gain of Function Mutation , Genetic Diseases, Inborn/immunology , Genetic Predisposition to Disease , Humans , Immune System Diseases/immunology , Loss of Function Mutation , Phenotype , STAT2 Transcription Factor/chemistry , STAT2 Transcription Factor/immunology , Virus Diseases/immunology
11.
Cell ; 181(6): 1194-1199, 2020 06 11.
Article in English | MEDLINE | ID: covidwho-1385209

ABSTRACT

SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease. The role of human genetics in determining clinical response to the virus remains unclear. Studies of outliers-individuals remaining uninfected despite viral exposure and healthy young patients with life-threatening disease-present a unique opportunity to reveal human genetic determinants of infection and disease.


Subject(s)
Coronavirus Infections/genetics , Coronavirus Infections/immunology , Genetic Predisposition to Disease , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , Age Factors , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Disease Resistance , Genetic Association Studies , Genetic Diseases, Inborn/immunology , Genetic Variation , Genome, Human , Host-Pathogen Interactions , Humans , Infections/genetics , Infections/immunology , Infections/physiopathology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , SARS-CoV-2
12.
ESC Heart Fail ; 8(5): 4296-4300, 2021 10.
Article in English | MEDLINE | ID: covidwho-1332964

ABSTRACT

Giant cell myocarditis (GCM) is a rare condition. Its association with SARS-CoV-2 has not been described before. The 46-year-old female patient was admitted to the clinic on September 2020. She had 7 year adrenal insufficiency history and infarct-like debut of myocardial disease in November 2019. After COVID-19 in April 2020, cardiac disease progressed. The examination showed low QRS voltage, QS complexes in V1 -V5 leads, atrial standstill, left ventricular systolic and restrictive dysfunction, elevated anti-heart antibodies, and subepicardial late gadolinium enhancement by magnetic resonance imaging. Endomyocardial biopsy and pacemaker implantation were performed, but the patient died suddenly due to ventricular tachycardia or ventricular fibrillation (the resuscitation was ineffective). The autopsy revealed GCM, SARS-CoV-2, and Parvovirus B19 were detected in the myocardium. The role of SARS-CoV-2 in the pathogenesis of autoimmune myocarditis is discussed.


Subject(s)
COVID-19 , Cardiomyopathies , Contrast Media , Death, Sudden, Cardiac/etiology , Female , Gadolinium , Genetic Diseases, Inborn , Giant Cells , Heart Atria/abnormalities , Heart Block , Humans , Middle Aged , SARS-CoV-2
13.
Nat Biomed Eng ; 5(7): 643-656, 2021 07.
Article in English | MEDLINE | ID: covidwho-1324420

ABSTRACT

The accurate and timely diagnosis of disease is a prerequisite for efficient therapeutic intervention and epidemiological surveillance. Diagnostics based on the detection of nucleic acids are among the most sensitive and specific, yet most such assays require costly equipment and trained personnel. Recent developments in diagnostic technologies, in particular those leveraging clustered regularly interspaced short palindromic repeats (CRISPR), aim to enable accurate testing at home, at the point of care and in the field. In this Review, we provide a rundown of the rapidly expanding toolbox for CRISPR-based diagnostics, in particular the various assays, preamplification strategies and readouts, and highlight their main applications in the sensing of a wide range of molecular targets relevant to human health.


Subject(s)
CRISPR-Cas Systems/genetics , Communicable Diseases/diagnosis , Nucleic Acid Amplification Techniques/methods , Nucleic Acids/analysis , Communicable Diseases/microbiology , Communicable Diseases/virology , Genetic Diseases, Inborn/diagnosis , Humans , Nucleic Acid Amplification Techniques/economics , Nucleic Acids/metabolism , Point-of-Care Systems , Polymorphism, Single Nucleotide , Sequence Analysis, DNA
15.
Int J Mol Sci ; 22(14)2021 Jul 14.
Article in English | MEDLINE | ID: covidwho-1323263

ABSTRACT

Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds of non-viral vector systems as a promising alternative to virus-based gene delivery counterparts. Consequently, the development of non-viral vectors has gained attention, and nowadays, gene delivery mediated by these systems is considered as the cornerstone of modern gene therapy due to relevant advantages such as low toxicity, poor immunogenicity and high packing capacity. However, despite these relevant advantages, non-viral vectors have been poorly translated into clinical success. This review addresses some critical issues that need to be considered for clinical practice application of non-viral vectors in mainstream medicine, such as efficiency, biocompatibility, long-lasting effect, route of administration, design of experimental condition or commercialization process. In addition, potential strategies for overcoming main hurdles are also addressed. Overall, this review aims to raise awareness among the scientific community and help researchers gain knowledge in the design of safe and efficient non-viral gene delivery systems for clinical applications to progress in the gene therapy field.


Subject(s)
Gene Transfer Techniques , Genetic Diseases, Inborn/therapy , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Nanoparticles/administration & dosage , Animals , Genetic Diseases, Inborn/genetics , Genetic Vectors/genetics , Humans
16.
Signal Transduct Target Ther ; 6(1): 177, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1298834

ABSTRACT

Rapid development of vaccines and therapeutics is necessary to tackle the emergence of new pathogens and infectious diseases. To speed up the drug discovery process, the conventional development pipeline can be retooled by introducing advanced in vitro models as alternatives to conventional infectious disease models and by employing advanced technology for the production of medicine and cell/drug delivery systems. In this regard, layer-by-layer construction with a 3D bioprinting system or other technologies provides a beneficial method for developing highly biomimetic and reliable in vitro models for infectious disease research. In addition, the high flexibility and versatility of 3D bioprinting offer advantages in the effective production of vaccines, therapeutics, and relevant delivery systems. Herein, we discuss the potential of 3D bioprinting technologies for the control of infectious diseases. We also suggest that 3D bioprinting in infectious disease research and drug development could be a significant platform technology for the rapid and automated production of tissue/organ models and medicines in the near future.


Subject(s)
Bioprinting/trends , Genetic Diseases, Inborn/therapy , Printing, Three-Dimensional/trends , Biomimetics/trends , Drug Development/trends , Drug Discovery/trends , Humans , Tissue Engineering/trends
18.
Cytokine Growth Factor Rev ; 58: 134-140, 2021 04.
Article in English | MEDLINE | ID: covidwho-1074698

ABSTRACT

Interferons are the best antiviral agents in vitro against SARS-CoV-2 so far and genetic defects in their signaling cascade or neutralization of alfa-interferons by autoantibodies come with more severe COVID-19. However, there is more, as the SARS-CoV-2 dysregulates not only innate immune mechanisms but also T and B cell repertoires. Most genetic, hematological and immunological studies in COVID-19 are at present phenomenological. However, these and antecedent studies contain the seed grains to resolve many unanswered questions and a whole range of testable hypotheses. What are the links, if existing, between genetics and the occurrence of interferon-neutralizing antibodies? Are NAGGED (neutralizing and generated by gene defect) antibodies involved or not? Is the autoimmune process cause or consequence of virus infection? What are the roles played by cytokine posttranslational modifications, such as proteolysis, glycosylation, citrullination and others? How is systemic autoimmunity linked with type 1 interferons? These questions place cytokines and growth factors at pole positions as keys to unlock basic mechanisms of infection and (auto)immunity. Related to cytokine research, (1) COVID-19 patients develop neutralizing autoantibodies, mainly against alpha interferons and it is not yet established whether this is the consequence or cause of virus replication. (2) The glycosylation of recombinant interferon-beta protects against breaking tolerance and the development of neutralizing antibodies. (3) SARS-CoV-2 induces severe inflammation and release of extracellular proteases leading to remnant epitopes, e.g. of cytokines. (4) In the rare event of homozygous cytokine gene segment deletions, observed neutralizing antibodies may be named NAGGED antibodies. (5) Severe cytolysis releases intracellular content into the extracellular milieu and leads to regulated degradation of intracellular proteins and selection of antibody repertoires, similar to those observed in patients with systemic lupus erythematosus. (6) Systematic studies of novel autoimmune diseases on single cytokines will complement the present picture about interferons. (7) Interferon neutralization in COVID-19 constitutes a preamble of more studies about cytokine-regulated proteolysis in the control of autoimmunity. Here we reformulate these seven conjectures into testable questions for future research.


Subject(s)
Autoimmunity , COVID-19/genetics , COVID-19/immunology , Cytokines/physiology , Interferons/physiology , Autoimmune Diseases/complications , Autoimmune Diseases/epidemiology , Autoimmune Diseases/genetics , Autoimmunity/genetics , Autoimmunity/immunology , COVID-19/epidemiology , COVID-19/therapy , Genetic Diseases, Inborn/complications , Genetic Diseases, Inborn/epidemiology , Genetic Diseases, Inborn/immunology , Genetic Predisposition to Disease/genetics , Humans
19.
Cytokine Growth Factor Rev ; 58: 55-65, 2021 04.
Article in English | MEDLINE | ID: covidwho-1071239

ABSTRACT

SARS-CoV-2 is a recently identified coronavirus accountable for the current pandemic disease known as COVID-19. Different patterns of disease progression infer a diverse host immune response, with interferon (IFN) being pivotal. IFN-I and III are produced and released by virus-infected cells during the interplay with SARS-CoV-2, thus establishing an antiviral state in target cells. However, the efficacy of IFN and its role in the possible outcomes of the disease are not yet defined, as it is influenced both by factors inherent to the virus and to the host. The virus exhibits multiple strategies to counteract the innate immune response, including those shared by SARS-CoV and MERS-CoV and other novel ones. Inborn errors in the host may affect IFN-related effector proteins or decrease its levels in plasma upon neutralization by preexistent autoantibodies. This battle between the IFN response triggered upon SARS-CoV-2 infection, its magnitude and timing, and the efficacy of its antiviral tools in dispute against the viral evasion strategies together with the genetic factors of the host, generate a scenario whose fate contributes to defining the severity of COVID-19.


Subject(s)
Host-Pathogen Interactions , Interferon Type I/physiology , Interferons/physiology , SARS-CoV-2/immunology , Viral Proteins/physiology , Animals , Antiviral Agents/metabolism , COVID-19/genetics , COVID-19/immunology , COVID-19/pathology , Genetic Diseases, Inborn/complications , Genetic Diseases, Inborn/immunology , Genetic Predisposition to Disease , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Immunity, Innate/genetics , Interferon Type I/antagonists & inhibitors , Interferons/antagonists & inhibitors , Pandemics , SARS-CoV-2/pathogenicity
20.
J Exp Med ; 218(4)2021 04 05.
Article in English | MEDLINE | ID: covidwho-1066211

ABSTRACT

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.


Subject(s)
Antibodies, Neutralizing/immunology , Autoantibodies/immunology , Autoimmune Diseases , COVID-19 , Genetic Diseases, Inborn , Interferon-alpha , Receptor, Interferon alpha-beta , SARS-CoV-2 , Yellow Fever Vaccine , Yellow fever virus , Adolescent , Adult , Aged , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , COVID-19/genetics , COVID-19/immunology , Female , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/immunology , HEK293 Cells , Humans , Interferon-alpha/genetics , Interferon-alpha/immunology , Male , Middle Aged , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Vaccines, Attenuated/genetics , Vaccines, Attenuated/immunology , Yellow Fever Vaccine/adverse effects , Yellow Fever Vaccine/genetics , Yellow Fever Vaccine/immunology , Yellow fever virus/genetics , Yellow fever virus/immunology
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