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https://www.arca.fiocruz.br/handle/icict/63898
TYPE I INTERFERON INNATE ERRORS CAUSING SEVERE ADVERSE EVENTS FOLLOWING YELLOW FEVER VACCINATION: A FAMILY-BASED CASE STUDY
Vacina contra febre amarela
Sistema de vacinologia
Author
Affilliation
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Todos os Laboratórios. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Todos os Laboratórios. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Todos os Laboratórios. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Todos os Laboratórios. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto de Tecnologia.em imunobiológicos (Bio-manguinhos). Rio de Janeiro, RJ, Brasil.
Abstract
Introduction: Despite being considered the gold standard vaccine, Yellow Fever Virus 17DD (YFV17DD) is associated with rare cases of neurological or viscerotropic adverse events following immunization (YEL-AVD). Although the mechanisms behind YEL-AVD cases remain elusive, its occurrence days after vaccination suggests innate immune errors (IIE). Objectives: Here, we report a family case from a national-base, phase IV study, aiming to clarify the mechanisms behind YEL-AVD pathogenesis and identify biomarkers useful in reducing the incidence of these rare events. Methodology: Blood samples were collected from the case and relatives 1-2 years after YF17DD immunization (CAAE 60575716.2.0000.5262). DNA was extracted followed by Whole Exome Sequence (WES) analysis, and validation of genetic findings using RT-qPCR. For functional investigation, the Peripheral Blood Mononuclear Cells (PBMC) from YEL-AD cases and nine time-matched controls were used to perform in vitro stimulation with attenuated YFV17DD virus, followed by immunophenotyping, luminex assay, and transcriptomics. Results: The family is composed of 11 siblings including three YEL-AVD cases, two deceased, and one surviving brother (proband). Samples from 4 proband’s nephews were also analyzed. Copy number variation analysis from WES demonstrated that the proband present homozygosity for an IFNAR1 allele lacking exons 3, 4, and 5. The same genotype was detected in the daughter of the deceased sister. Three siblings and one nephew are heterozygous without a history of YEL-AVD. Comparing to the YFV17DD- specific response in the healthy group, the proband presented higher secretion of interferons IFN-a, IFN-b, IFN-g, IFNGR1, and the proinflammatory cytokines CXCL10, IL1-b, and CCL3. The proband presented higher frequency of activated non-classical monocytes and NK cells, and naive T cells IFN-g +. Also, the proband presented 240 exclusive upregulated genes, which were related to antiviral response through USP18, a negative regulator of IFN-a, and type II IFN. In addition, the proband demonstrated upregulation of inflammatory events - pyroptosis and IL-1b production. Conclusion: The family investigated is composed of carriers of defective alleles in IFNAR1, the receptor that triggers the main human antiviral response: type I IFN pathway. The homozygosity of the IFNAR1 depleted for exons 3, 4, and 5 led to YEL-AD in three family members. Our functional findings suggest the absence of type I IFN response, exacerbated type II IFN, and hyperinflammation as a repercussion of a defective IFNAR1, which contributes to YEL-AD pathogenesis.
Keywords in Portuguese
Eventos adversos após a imunizaçãoVacina contra febre amarela
Sistema de vacinologia
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