Immunogenicity and safety of primary fractional-dose yellow fever vaccine in autoimmune rheumatic disease patients with low level of immunosupression

O Brasil enfrentou uma epidemia de febre amarela (FA) no período de 2016 a 2018 e a vacinação passou a ser considerada para pacientes com doenças reumáticas autoimunes (DRAI) com baixa imunossupressão em razão da alta mortalidade desta infecção. Objetivo: Avaliar de forma prospectiva a imunogenicidade em 30 dias e segurança da vacina de febre amarela (VFA) fracionada em pacientes com DRAI em uso de baixa imunossupressão. Métodos e Resultados: Um total de 318 participantes (159 DRAI e 159 controles saudáveis pareados por idade e sexo) foram vacinados com a dose fracionada (um quinto) da VFA 17DD. Todos os participantes foram avaliados no dia da vacinação (D0), e nos dias D5, D10, D30 após a mesma para parâmetros clínicos, incluindo avaliação com escores de atividade das respectivas doença reumática, e parâmetros laboratoriais. As taxas de soroconversão 30 dias após a vacinação (83.7%vs.96.6%, p=0.0006) e a média geométrica dos títulos de anticorpos neutralizantes (GMT) [1143.7 (95%CI 1012.3-1292.2) vs.731( 95%CI 593.6-900.2), p 0.05). Conclusão: A dose fracionada da VFA-17DD nos pacientes com DRAI resultou em alta taxa de soroconversão (> 80%), no entanto mais baixa que nos controles. A viremia vacinal foi mais prolongada, porém menos intensa entre pacientes DRAI se comparados aos controles. A vacina foi imunogênica, segura e não desencadeou reativação de doença reumática nos pacientes em uso de baixa imunossupressão e pode ser indicada para situações epidêmicas ou pacientes que vivem ou trabalham em áreas endêmicas (ClinicalTrials.gov, NCT03430388)Background: Brazil faced a yellow fever (YF) outbreak in 2016-2018 and vaccination was considered for autoimmune rheumatic disease patients (ARD) with low immunosuppression due to YF high mortality. Objective: This study aimed to evaluate, prospectively for the first time, the short-term immunogenicity of the fractional YF vaccine (YFV) immunization in ARD patients with low immunosuppression. Methodology and principal findings: A total of 318 participants (159 ARD and 159 ageand sex-matched healthy controls) were vaccinated with the fractional-dose (one fifth) of 17DD-YFV. All subjects were evaluated at entry (D0), D5, D10, and D30 postvaccination for clinical/laboratory and disease activity parameters for ARD patients. Post-vaccination seroconversion rate (83.7%vs.96.6%, p=0.0006) and geometric mean titers (GMT) of neutralizing antibodies [1143.7 (95%CI 1012.3-1292.2) vs.731( 95%CI 593.6-900.2), p 0.05). Conclusion: Fractional-dose 17DD-YF vaccine in ARD patients resulted in a high rate of seroconversion rate ( > 80%) but lower than controls, with a longer but less intense viremia. This vaccine was immunogenic, safe and did not induce flares in ARD under low immunosuppression and may be indicated in YF outbreak situations and for patients who live or travel to endemic areas. (ClinicalTrials.gov, NCT03430388

INFECÇÃO POR MICOBACTÉRIAS NÃO-TUBERCULOSAS (MNT) EM PACIENTES COM DOENÇAS REUMATOLÓGICAS: EXPERIÊNCIA DE UM CENTRO TERCIÁRIO EM 9 ANOS

Introdução: A prevalência mundial de doença por MNT vem aumentando nos últimos anos, com significativa morbimortalidade. A infecção por MNT é mais frequente em pacientes com alteração pulmonar estrutural (fibrose cística) e infecção pelo HIV, mas outras condições imunossupressoras também são fatores de risco para doença por MNT, em especial doença extrapulmonar. Em 2005 criou-se o Grupo de Infecção em Imunodeprimidos ligado à Divisão de Moléstias Infecciosas e Parasitárias do HCFMUSP para atendimento de infecção em pacientes imunossuprimidos. O objetivo deste estudo foi descrever as características de casos de infecção por MNT acompanhados nesse ambulatório. Métodos: Foi realizada análise retrospectiva de casos de infecção por MNT em pacientes com doença reumatológica encaminhados no período de agosto/2015 a julho/2023. O diagnóstico de doença por MNT foi considerado conforme os critérios da ATS no caso de doença pulmonar ou na presença de quadro clínico compatível e isolamento em cultura de sítio estéril ou material de punção/drenagem cirúrgica. Resultados: Foram identificados 16 episódios de infecção por MNT em 14 pacientes no total de 740 indivíduos atendidos, 57% do sexo feminino, mediana de idade de 47 anos. O principal diagnóstico reumatológico dos pacientes foi Artrite reumatoide (7/14), seguido por Lupus Eritematoso Sistêmico (3/14). O principal imunossupressor em uso foi prednisona (7), seguido por metotrexato (3), micofenolato (1) e leflunomida (1). Três pacientes estavam em uso de biológico: etanercept (2) e rituximab (1). Infecção em sítio extra-pulmonar ocorreu em 50% dos episódios, sendo 5 infecções de pele/partes moles e 3 articulares. As espécies de MNT nesses pacientes foram diversas: MAC (2), M. kansasii (2), M. fortuitum (2), M. abscessus (2), M. chelonae (1), M. arupense (1), M. kyorinense (1), M. mucogenicum (1), Espécie não identificada (2). Dos 14 pacientes, 3 ainda estão em tratamento, 9 curaram, 1 perdeu seguimento e 1 evoluiu a óbito durante o tratamento por causa não relacionada à micobacteriose. Conclusão: A infecção por MNT em pacientes com doenças reumatológicas apresenta-se frequentemente de forma extra-pulmonar, no entanto, com desfecho favorável e sem predominância de qualquer espécie. A identificação da mesma é essencial para adequado tratamento. Aventa-se a hipótese de que o tropismo de agentes infecciosos para os tecidos também acometidos pelas doenças reumáticas poderia ser explicado pela alteração inflamatória local

Safety and immunogenicity of influenza A(H3N2) component vaccine in juvenile systemic lupus erythematosus

Abstract Introduction Seasonal influenza A (H3N2) virus is an important cause of morbidity and mortality in the last 50 years in population that is greater than the impact of H1N1. Data assessing immunogenicity and safety of this virus component in juvenile systemic lupus erythematosus (JSLE) is lacking in the literature. Objective To evaluate short-term immunogenicity and safety of influenza A/Singapore (H3N2) vaccine in JSLE. Methods 24 consecutive JSLE patients and 29 healthy controls (HC) were vaccinated with influenza A/Singapore/INFIMH-16-0019/2016(H3N2)-like virus. Influenza A (H3N2) seroprotection (SP), seroconversion (SC), geometric mean titers (GMT), factor increase in GMT (FI-GMT) titers were assessed before and 4 weeks post-vaccination. Disease activity, therapies and adverse events (AE) were also evaluated. Results JSLE patients and controls were comparable in current age [14.5 (10.1–18.3) vs. 14 (9–18.4) years, p = 0.448] and female sex [21 (87.5%) vs. 19 (65.5%), p = 0.108]. Before vaccination, JSLE and HC had comparable SP rates [22 (91.7%) vs. 25 (86.2%), p = 0.678] and GMT titers [102.3 (95% CI 75.0–139.4) vs. 109.6 (95% CI 68.2–176.2), p = 0.231]. At D30, JSLE and HC had similar immune response, since no differences were observed in SP [24 (100%) vs. 28 (96.6%), p = 1.000)], SC [4 (16.7%) vs. 9 (31.0%), p = 0.338), GMT [162.3 (132.9–198.3) vs. 208.1 (150.5–287.8), p = 0.143] and factor increase in GMT [1.6 (1.2–2.1) vs. 1.9 (1.4–2.5), p = 0.574]. SLEDAI-2K scores [2 (0–17) vs. 2 (0–17), p = 0.765] and therapies remained stable throughout the study. Further analysis of possible factors influencing vaccine immune response among JSLE patients demonstrated similar GMT between patients with SLEDAI  0.05). Conclusion This is the first study that identified adequate immune protection against H3N2-influenza strain with additional vaccine-induced increment of immune response and an adequate safety profile in JSLE. ( www.clinicaltrials.gov , NCT03540823)

Neisseria gonorrhoeae arthritis in a patient with Systemic Lupus: resistance and virulence profiles.

In this study, we describe a case report of gonococcal arthritis in a Systemic Lupus Erythematosus patient. Although several mechanisms favor disseminated gonococcal infection (DGI) in patients immunosuppressed by SLE, this association is rarely reported in literature. We performed whole genome sequencing (WGS) of the etiologic agent involved and molecular analysis using a global collection of N. gonorrhoeae strains. Ours is the only sample derived from synovial fluid identified in this collection, the others being from the usual anatomical sites. Antimicrobial susceptibility was determined by disk diffusion and Etest, and WGS was conducted to determine multilocus sequence typing profiles, group isolates based on core genome single nucleotide polymorphisms (SNP), and identify virulence genes and antimicrobial resistance determinants. The N. gonorrhoeae samples in the global collection were highly heterogeneous. The SNP tree had a total 19532 SNPs in 320 samples. Our sample displayed resistance to ciprofloxacin (MIC = 2 μg/mL) and tetracycline (zone diameter = 0 mm) belonged to ST 1588 and was not closely related to any isolate in the global collection of N. gonorrhoeae strains. The isolate had genetic features related to beta-lactam, tetracycline and quinolone resistance. Seventy-one virulence genes were identified in our sample, belonging to the following classes: adherence, efflux pump, immune modulator, invasion, iron uptake, protease and stress adaptation. Moreover, no virulence genes for immune evasion and toxin were identified

MAIT cells are activated in acute Dengue virus infection and after <i>in vitro</i> Zika virus infection

<div><p>Dengue virus (DENV) and Zika virus (ZIKV) are members of the <i>Flaviviridae</i> and are predominantly transmitted via mosquito bites. Both viruses are responsible for a growing number of infections in tropical and subtropical regions. DENV infection can cause lethargy with severe morbidity and dengue shock syndrome leading to death in some cases. ZIKV is now linked with Guillain-Barré syndrome and fetal malformations including microcephaly and developmental disorders (congenital Zika syndrome). The protective and pathogenic roles played by the immune response in these infections is unknown. Mucosal-associated invariant T (MAIT) cells are a population of innate T cells with potent anti-bacterial activity. MAIT cells have also been postulated to play a role in the immune response to viral infections. In this study, we evaluated MAIT cell frequency, phenotype, and function in samples from subjects with acute and convalescent DENV infection. We found that in acute DENV infection, MAIT cells had elevated co-expression of the activation markers CD38 and HLA-DR and had a poor IFNγ response following bacterial stimulation. Furthermore, we found that MAIT cells can produce IFNγ in response to <i>in vitro</i> infection with ZIKV. This MAIT cell response was independent of MR1, but dependent on IL-12 and IL-18. Our results suggest that MAIT cells may play an important role in the immune response to <i>Flavivirus</i> infections.</p></div

MAIT cells have elevated expression of activation markers in acute DENV infection.

<p>Gating strategy and representative flow plots of MAIT cell frequency (A). MAIT cell frequency in acute and convalescent DENV infection (n = 25, B). MAIT cell count, (as determined by multiplying the lymphocyte count by the frequency of MAIT cells in lymphocytes), in acute and convalescent DENV infection (n = 24, C). Co-expression of CD38 and HLA-DR by MAIT cells in acute and convalescent DENV infection (n = 15, D). CD127 expression (MFI) by MAIT cells in acute and convalescent DENV infection (n = 15, E). PD-1 expression by MAIT cells in acute and convalescent DENV infection (n = 15, F). CCR6 expression (MFI) by MAIT cells in acute and convalescent DENV infection (n = 15, G). ** indicates p < 0.01, and *** indicates p < 0.001.</p

Lower IFNγ production following <i>in vitro</i> stimulation with <i>E</i>. <i>coli</i> by MAIT cells in acute DENV infection.

<p>MAIT cells were stimulated with fixed <i>E</i>. <i>coli</i> (multiplicity of exposure 10) for 24h and IFNγ production by MAIT cells was evaluated by flow cytometry. Representative flow plots of IFNγ production by MAIT cells (A). IFNγ production by MAIT cells in response to <i>E</i>. <i>coli</i> stimulation in acute and convalescent DENV infection (n = 15, B). Association between the levels of sCD14 and MAIT cells IFNγ response to <i>E</i>. <i>coli</i> stimulation in acute DENV infection (C). * indicates p < 0.05.</p