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Tal Sigawi, Adir Israeli, Yaron Ilan Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, IsraelCorrespondence: Yaron Ilan, Faculty of Medicine, Hebrew University and Department of Medicine, Hadassah Medical Center, Jerusalem, Israel, Email ilan@hadassah.org.ilAbstract: Lack of response to immunotherapies poses a significant challenge in treating immune-mediated disorders and cancers. While the mechanisms associated with poor responsiveness are not well defined and change between and among subjects, the current methods for overcoming the loss of response are insufficient. The Constrained Disorder Principle (CDP) explains biological systems based on their inherent variability, bounded by dynamic boundaries that change in response to internal and external perturbations. Inter and intra-subject variability characterize the immune system, making it difficult to provide a single therapeutic regimen to all patients and even the same patients over time. The dynamicity of the immune variability is also a significant challenge for personalizing immunotherapies. The CDP-based second-generation artificial intelligence system is an outcome-based dynamic platform that incorporates personalized variability signatures into the therapeutic regimen and may provide methods for improving the response and overcoming the loss of response to treatments. The signatures of immune variability may also offer a method for identifying new biomarkers for early diagnosis, monitoring immune-related disorders, and evaluating the response to treatments.Keywords: immune system, variability, artificial intelligence, immunotherapy

Jiying Xiao,1 Lingyue Liu,1 Kamran Ali,2 Suling Wu,1 Junsong Chen1 1Department of Pulmonology, Hangzhou Children’s Hospital, Hangzhou, Zhejiang, 310015, People’s Republic of China; 2Department of Surgery, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, People’s Republic of ChinaCorrespondence: Junsong Chen, Department of Pulmonology, Hangzhou Children’s Hospital, NO. 195 Wenhui Road, Gongshu Distract, Hangzhou, Zhejiang, 310015, People’s Republic of China, Tel +86-15990067220, Email doctorsong999@126.comObjective: We aimed to observe and analyze the differences in impulse oscillometry (IOS) and fractional expiratory nitric oxide (FeNO) in relation to asthma control among preschool children, and to explore the predictive value of IOS combined with FeNO for uncontrolled asthma.Methods: This study enrolled 171 preschool children with asthma and 30 healthy preschool children between June 2022 and June 2023. We categorized the asthmatic children as having controlled asthma (n=85) and uncontrolled asthma (n=86) after a 3-month follow-up. IOS and FeNO were collected on the first visit at baseline. Differences in metrics were compared between controlled asthma, uncontrolled asthma and healthy control groups. The area under the receiver operating characteristic curve (AUROC) was utilized to explore the discriminative ability of IOS and FeNO, alone or in combination, against uncontrolled asthma.Results: Compared to the controlled asthma group, the IOS values of R5, X5, R5-R20, and Fres were significantly higher in the uncontrolled asthma group, except for R20. R5 and R5-R20 had the highest area under the curve (AUC), which could reach 0.74 (95% CI 0.66– 0.82) and 0.72 (95% CI 0.64– 0.80). R20 had the lowest AUC of 0.59. The AUC for FeNO alone was 0.88 (95% CI 0.84– 0.93) with a cutoff value of 17.50 ppb, sensitivity and specificity of 0.73 and 0.89. The AUCs of all IOS metrics combined with FeNO were significantly higher, with the highest AUC of 0.92 (95% CI 0.87– 0.96) for R5-R20+FeNO, and with a sensitivity and specificity of 0.88 and 0.84.Conclusion: There were significant differences in IOS and FeNO in relation to asthma control among preschooler children. FeNO might be the best predictor of asthma control, and adding any of IOS metrics increased moderately the predictive value.Keywords: asthma control, impulse oscillometry, fractional expiratory nitric oxide, preschool children

In recent years, various myositis-specific and myositis-associated autoantibodies have been identified in idiopathic inflammatory myopathies, including dermatomyositis (DM), anti-synthetase syndrome (ASS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). These autoantibodies exhibit unique characteristics in terms of organ involvement, severity, and treatment response, making their understanding crucial for accurate diagnosis and effective therapy. This review provides a comprehensive overview of the clinical features of recently discovered myositis-specific and associated autoantibodies, while exploring their potential roles in the pathogenesis and exacerbation of myositis. Key findings include the production of anti-TIF1γ antibodies in model mice, the upregulation of Mi2-related genes in anti-Mi2 antibody-positive dermatomyositis muscle tissue, and Jo-1 antigen-induced T cell activation, shedding light on whether disease mechanisms are driven by autoantibodies or autoantigens.

Abstract The COVID-19 pandemic posed a challenge for people living with HIV (PLWH), particularly immune non-responders (INR) with compromised CD4 T-cell reconstitution following antiretroviral therapy (CD4 count

Abstract Nowadays, filovirus vaccine development may be seen as a paradigm for our response capabilities to emerging and re-emerging infectious diseases. Specifically, the West African Ebola virus disease (EVD) epidemic accelerated countermeasure licensure for several vaccine and therapeutic products. Those products have been successfully used to control EVD outbreaks in Central Africa over the past years. This positive development, however, has not yet reached beyond EVD. Therefore, it is pertinent to increase our efforts in the development of countermeasures for other human pathogenic members of the family Filoviridae as they continue to threaten public health in Sub-Saharan Africa. This review article summarizes the current filovirus vaccines in preclinical macaque studies and human clinical trials and discusses the most promising recent advancements.

Abstract Seasonal epidemics of influenza viruses are responsible for a significant global public health burden. Vaccination remains the most effective way to prevent infection; however, due to the persistence of antigenic drift, vaccines must be updated annually. The selection of vaccine strains occurs months in advance of the influenza season to allow adequate time for production in eggs. RNA vaccines offer the potential to accelerate production and improve efficacy of influenza vaccines. We leveraged the nucleoside-modified RNA (modRNA) platform technology and lipid nanoparticle formulation process of the COVID-19 mRNA vaccine (BNT162b2; Comirnaty®) to create modRNA vaccines encoding hemagglutinin (HA) (modRNA-HA) for seasonal human influenza strains and evaluated their preclinical immunogenicity and toxicity. In mice, a monovalent modRNA vaccine encoding an H1 HA demonstrated robust antibody responses, HA-specific Th1-type CD4+ T cell responses, and HA-specific CD8+ T cell responses. In rhesus and cynomolgus macaques, the vaccine exhibited durable functional antibody responses and HA-specific IFN-γ+ CD4+ T cell responses. Immunization of mice with monovalent, trivalent, and quadrivalent modRNA-HA vaccines generated functional antibody responses targeting the seasonal influenza virus(es) encoded in the vaccines that were greater than, or similar to, those of a licensed quadrivalent influenza vaccine. Monovalent and quadrivalent modRNA-HA vaccines were well-tolerated by Wistar Han rats, with no evidence of systemic toxicity. These nonclinical immunogenicity and safety data support further evaluation of the modRNA-HA vaccines in clinical studies.

Abstract The G protein expressed on the surface of respiratory syncytial virus (RSV) is important for adhesion to host cells and as a vaccine target antigen. The corresponding vaccines can effectively eliminate RSV. However, they exacerbate pulmonary immunopathology including eosinophilic infiltration in the lungs after an RSV challenge in animal models, raising concerns about enhanced respiratory disease (ERD); thus, approaches that mitigate these effects are urgently needed. Herein, we aimed to examine the mechanisms of G protein vaccine-induced ERD in mice, using recombinant G protein as a vaccine antigen. After the RSV challenge, G protein-vaccinated mice exhibited lung weight gain, lung tissue damage, and increased infiltration of eosinophils, neutrophils, and CD4+ T cells into the lungs. We set lung weight gain as the endpoint for ERD and examined the impact of each infiltrating cell on lung weight gain. We observed that CD4+ T cells, but not eosinophils or neutrophils, that infiltrate the lungs are responsible for lung weight gain. In addition, T helper 2 cell-mediated IL-13 induced mucin hypersecretion and lung weight gain. Mucin hypersecretion may contribute to weight gain in the lungs. In conclusion, our results indicate a novel mechanism of G protein vaccine-induced ERD via IL-13 and mucin hypersecretion, which could lead to the development of safe G protein vaccines and the elucidation of the causes of ERD associated with other vaccines.

Abstract We previously described a two-component protein nanoparticle vaccine platform that displays 60 copies of the SARS-CoV-2 spike protein RBD (RBD-NP). The vaccine, when adjuvanted with AS03, was shown to elicit robust neutralizing antibody and CD4 T cell responses in Phase I/II clinical trials, met its primary co-endpoints in a Phase III trial, and has been licensed by multiple regulatory authorities under the brand name SKYCovioneTM. Here we characterize the biophysical properties, stability, antigenicity, and immunogenicity of RBD-NP immunogens incorporating mutations from the B.1.351 (β) and P.1 (γ) variants of concern (VOCs) that emerged in 2020. We also show that the RBD-NP platform can be adapted to the Omicron strains BA.5 and XBB.1.5. We compare β and γ variant and E484K point mutant nanoparticle immunogens to the nanoparticle displaying the Wu-1 RBD, as well as to soluble prefusion-stabilized (HexaPro) spike trimers harboring VOC-derived mutations. We find the properties of immunogens based on different SARS-CoV-2 variants can differ substantially, which could affect the viability of variant vaccine development. Introducing stabilizing mutations in the linoleic acid binding site of the RBD-NPs resulted in increased physical stability compared to versions lacking the stabilizing mutations without deleteriously affecting immunogenicity. The RBD-NP immunogens and HexaPro trimers, as well as combinations of VOC-based immunogens, elicited comparable levels of neutralizing antibodies against distinct VOCs. Our results demonstrate that RBD-NP-based vaccines can elicit neutralizing antibody responses against SARS-CoV-2 variants and can be rapidly designed and stabilized, demonstrating the potential of two-component RBD-NPs as a platform for the development of broadly protective coronavirus vaccines.

Abstract Background There is substantial evidence indicating that cytokines play a role in the immune defense against tuberculosis. This study aims to evaluate the levels of various cytokines in pleural effusion to ditinguish between tuberculosis pleurisy and malignant pleurisy. Methods A total of 82 participants with pleural effusion were included in the training cohort, and 76 participants were included in the validation cohort. The individuals were divided into tuberculosis and malignant pleurisy groups. The concentrations of interleukin-1β (IL-1β), IL-4, IL-6, IL-10, IL-17 A, IL-17 F, IL-21, IL-22, IL-25, IL-31, IL-33, interferon-γ (IFN-γ), soluble CD40 ligand (sCD40L) and tumor necrosis factor-α (TNF-α) in pleural effusion were measured using a multiplex cytokine assay. The threshold values were calculated according to the receiver operating characteristic (ROC) curve analysis to aid in diagnosing tuberculosis pleurisy. Furthermore, the combined measure was validated in the validation cohort. Results The levels of all 14 cytokines in pleural effusion were significantly higher in participants with tuberculosis compared to those with malignant pleurisy (all P

Abstract Adherence to antiretroviral therapy (ART) is essential for the effective management of HIV, which includes keeping the HIV viral load undetectable. This study aimed to determine whether certain ART medications are more “forgiving” of poor adherence in achieving viral suppression. We identified subgroups of ART medication usage and determined the extent to which ART adherence is associated with viral suppression across those subgroups. Data came from claims and clinical records (2017–2019) of 3,552 HIV-positive adult members of a Medicaid managed care plan. Pharmacy fill data were examined to characterize ART medications using latent class analysis (LCA), which captures the complexity of real-world ART usage (i.e., multiple medications, ART switching). LCA yielded five ART medication patterns over three years, mostly characterized by recent medications and formulations of ART, though they varied in number of tablets and in medication class. Mixed effects logistic regression models were estimated to determine whether odds of viral suppression differed by ART adherence level. After adjusting for covariates, those with at least 90% adherence (i.e., 90 to

Abstract The uptake of early infant HIV diagnosis services is crucial for preventing mother to child transmission of virus, and timely management. However, the uptake of the services remains a global challenge, despite major advances in HIV testing. This study investigated the uptake of early infant HIV diagnosis and its associated factors among mothersof exposed infants. The results showed that the uptake of early infant HIV diagnosis was 76%. Factors associated with the uptake are caregivers being married, have higher income level and having adequate knowledge on early infant HIV diagnosis.

Abstract In 2022, South Africa (SA) had the second-highest HIV incidence rate among adolescents worldwide. This study’s participants were boys living in SA aged 15–19 years old, in a current dating or sexual relationship, and diagnosed with HIV before the age of 10. Despite the launch of campaigns to spread awareness of Undetectable equals Untransmittable (U = U), our findings showed that a significant number of adolescents living with HIV do not demonstrate an understanding of the concept. This highlights the importance of integrating U = U messaging in ongoing conversations with healthcare workers given the potential positive impact on adolescent wellbeing, transmission risk perception, and safer sexual practices.

Abstract Systemic inflammation significantly increases the risk of short- and long-term mortality in geriatric hospitalized patients. To predict mortality in older patients with various age-related diseases and infections, including COVID-19, inflammatory biomarkers such as the C-reactive protein (CRP) to albumin ratio (CAR), and related scores and indexes, i.e. Glasgow Prognostic Score (GPS), modified GPS (mGPS), and high sensitivity (hs)-mGPS, have been increasingly utilized. Despite their easy affordability and widespread availability, these biomarkers are predominantly assessed for clinical purposes rather than predictive applications, leading to their underutilization in hospitalized older patients. In this study, we investigated the association of CAR, GPS, mGPS, and hs-mGPS with short-term mortality in 3,206 geriatric hospitalized patients admitted for acute conditions, irrespective of admission diagnosis. We observed that unit increases of CAR, and the highest classes of GPS, mGPS, and hs-mGPS were significantly associated with a two- to threefold increased risk of death, even adjusting the risk for different confounding variables. Interestingly, a hs-mGPS of 2 showed the highest effect size. Furthermore, gender analysis indicated a stronger association between all CRP-albumin based parameters and mortality in men, underscoring the gender-specific relevance of inflammation-based circulating parameters in mortality prediction. In conclusion, scores based on serum CRP and albumin levels offer additional guidance for the stratification of in-hospital mortality risk in older patients by providing additional information on the degree of systemic inflammation.

Abstract Background SARS-CoV-2 infection has become a major international issue, not only from a medical point of view, but also social, economic and political. Most of the available information comes from the United States, Europe, and China, where the population and the socioeconomic status are very different from Latin American countries. This study evaluates the effect of regional socioeconomic characteristics on mortality due SARS-CoV-2 infection in patients with immune-mediated rheumatic diseases (IMRD) from Argentina, Mexico and Brazil. Methods Data from three national registries, SAR-COVID (Argentina), CMR-COVID (Mexico) and ReumaCoV-Brasil (Brazil), were combined. Adult IMRD patients with SARS-CoV-2 infection were recruited. National data for each province/state, including population density, number of physicians per inhabitant, income, unemployment, GINI index, Municipal Human Development Index (MHDI), stringency index, vaccination rate and most frequent viral strains per period were assessed as risk factors for mortality due to COVID-19. Results A total of 4744 patients were included, 2534 (53.4%) from SAR-COVID, 1166 (24.6%) from CMRCOVID and 1044 (22.0%) from ReumaCoV-Brasil. Mortality due to COVID-19 was 5.4%. In the multivariable analysis, higher number of physicians per 1000 inhabitants and being infected during the vaccination period of each country were associated with lower mortality. After adjustment for socioeconomic factors, there was no association with country of residence and mortality. Conclusion These findings corroborate the complex interplay between socioeconomic factors, rheumatic disease activity, and regional disparities as determinants of death due to COVID-19 in Argentina, Brazil and Mexico. Thus, this research provides valuable insights for guiding public health policies and clinical practice in the ongoing fight against the COVID-19 pandemic.

Abstract Systemic vasculitis is a group of rare diseases that share an essential characteristic: inflammation of blood vessel walls. This injury occurs during the disease course, but specific features vary for each entity. In this paper, we will address relevant aspects of the newest monogenic mutation vasculitis, such as deficiency of adenosine deaminase 2 (ADA2) and VEXAS syndrome (UBA1), and other relevant vasculitis, such as Cogan syndrome and Susac syndrome that may share some similarities with them.

Ziheng Chen,1 Jinxin Ma,1 Jiahui Lei,1 Yi Li,1 Ruijuan Zhao,1 Limin Zhao2 1Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Limin Zhao, Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, 7 Weiwu Road, Jinshui District, Zhengzhou, Henan, 450003, People’s Republic of China, Email zhaolimin2002@126.comPurpose: This study aimed to identify environmental risk factors associated with asthmatic fixed airflow obstruction (FAO) and assess the relationship between small airway abnormalities defined by forced expiratory flow at 25– 75% (FEF25-75%) and FAO.Patients and Methods: We analyzed data from 312 han Chinese patients with stable asthma on standard treatment. Low FEF25-75% was defined as post-bronchodilator FEF25-75% z-score 10 years (2.01 [1.06– 3.86], P=0.035) and occupational exposure for > 20 years (2.67 [1.24– 5.91], P=0.013) were associated with asthmatic FAO. In cross-sectional analyses, compared with the normal FEF25-75%/ asthmatics without FAO (NON-FAO) group, the low FEF25-75%/ asthmatics with FAO (FAO) group had lower FEV1 z-scores and FEV1/FVC z-scores, more pack-years and years of biomass and occupational exposure, higher Asthma Control Questionnaire-5 and Chronic Obstructive Pulmonary Disease Assessment Test scores, and more frequent exacerbations. The low FEF25-75%/NON-FAO group showed the same trend, but to a lesser extent.Conclusion: Chronic airway inflammation is not the only driver of asthmatic FAO, and management and treatment targeting environmental risk factors (smoking and biomass and occupational exposures) may slow FAO progression in asthmatics. The FEF25-75% determined by the z-score is a reliable marker of small airway abnormalities, and patients with low FEF25-75% are at greater risk for FAO, requiring more frequent follow-up.Keywords: asthma, fixed airflow obstruction, environmental exposures, forced expiratory flow at 25-75%

Glioblastoma (GBM) is the central nervous system tumor with the most aggressive behavior, and no definitive therapy has yet been found. The tumor microenvironment of GBM is immunosuppressive and is considered a ‘cold tumor’ with low lymphocytic infiltration, but is characterized by a high proportion of glioma-associated macrophages/microglia (GAMs). GAMs promote tumor growth and also affect treatment resistance in GBM. In this review, we describe the origin and classification of GAMs in humans and describe the mechanisms of their activation and the cell-cell interactions between tumor cells and GAMs. We also describe the history of GAM detection methods, especially immunohistochemistry, and discusses the merits and limitations of these techniques. In addition, we summarized chemotactic factors for GAMs and the therapies targeting these factors. Recent single-cell RNA analysis and spatial analysis add new insights to our previous knowledge of GAMs. Based on these studies, GBM therapies targeting GAMs are expected to be further developed.

Sumei Chen,1,* Lingrong Yang,2,* Bing Xia,3 Haitao Zhu,4 Zhenghao Piao,5 Youssef Jounaidi6 1Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, People’s Republic of China; 2Department of Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, People’s Republic of China; 3Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, 310002, People’s Republic of China; 4Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550001, People’s Republic of China; 5Department of Basic Medical Science, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People’s Republic of China; 6Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA*These authors contributed equally to this workCorrespondence: Youssef Jounaidi, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA, Email yjounaidi@mgh.harvard.eduBackground: Enhancing NK cells’ antitumor activity requires sustained cytokine signaling. Interleukin-15 (IL-15) is a potent immunostimulatory cytokine used to armor CAR-NK and CAR-T cell immunotherapies. However, strategies to increase IL-15 expression and antitumor effect may trigger systemic toxicity with the potential to promote oncogenesis and autoimmune diseases.Methods: To overcome these limitations, we developed a new platform (IL15RB) whereby IL-15 with IL-2 signal peptide is tethered to its receptor, IL2Rβ.Results: NK92-expressing IL15RB (NK92IL15RB) cells expand indefinitely without exogenous cytokines and have significantly higher anticancer activity than NK-92 stimulated by IL-15, IL-2, or expressing tethered IL-2. NK92IL5RB showed resistance to irradiation and IL-4. However, TGFβ 1 substantially reduced NK92IL5RB killing, suggesting the need to inhibit TGFβ 1 in IL-15-mediated immunotherapies. IL15RB induced strong STAT3 but weaker STAT5 and STAT1 activation compared to IL-2. Chronic exposure of NK92IL15RB cells to cancer cells reduced STAT3 and STAT1 activation irreversibly, suggesting a role in exhaustion. Combination with CAR-CD19 enhanced NK92IL15RB antitumor activity against leukemia and increased its STAT5 activation. NK92IL15RB anti-tumors activity was further enhanced by combination with anti-PD1.Conclusion: Our data suggest that the tethering of IL-15 to its receptor IL2Rβ empowers NK cell cytolytic activity. Additionally, the tethering of IL-15 will prevent any systemic risk of toxicity.Keywords: IL-15, IL2RB receptor, natural killer cells, cancer immunotherapy, IL15RB

Dennis K Ledford,1 Warner W Carr,2 Wendy C Moore,3 Njira L Lugogo,4 Arjun Mohan,4 Bradley Chipps,5 Alexander R Mackie,6 Andrew W Lindsley,7 Joseph Spahn,6 Christopher S Ambrose8 1Division of Allergy and Immunology, University of South Florida, Tampa, FL, USA; 2Allergy & Asthma Associates of Southern California, Mission Viejo, CA, USA; 3Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 4Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA; 5Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 6BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USA; 7US Medical Affairs, Amgen, Thousand Oaks, CA, USA; 8BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USACorrespondence: Christopher S Ambrose, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA, Tel +1 301-398-4454, Email chris.ambrose@astrazeneca.comPurpose: Younger age of asthma onset (AAO) has been associated with an allergic phenotype, whereas eosinophilic phenotypes have been associated with older AAO. In randomized trials, biologic efficacy among adults with severe asthma (SA) has varied by age at asthma onset. To determine whether these associations observed in trials apply to real-world outcomes, this study examined biologic effectiveness by AAO and biologic class in a large, real-world cohort.Patients and methods: CHRONICLE is an ongoing, real-world study of US adults with subspecialist-treated SA receiving biologics, maintenance corticosteroids, or who are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Patients enrolled between February 2018 and February 2022 who initiated a biologic for SA and had complete data for analysis were included. A locally estimated scatterplot smoothing (LOESS) analysis was used to plot the relationship between percentage exacerbation rate reduction and AAO by biologic class.Results: Of 578 patients with complete data, 198, 149, and 231 were diagnosed with asthma at age < 18, 18– 39, and ≥ 40 years, respectively. Across subgroups, patients were predominantly White (72– 78%), female (67– 73%), and commercially insured (54– 71%). In the LOESS analysis, exacerbation rate reductions were similar for anti-IgE and anti–IL-5/5R and anti–IL-4R subgroups with younger AAO, but the exacerbation rate reduction diminished for patients with older AAO receiving anti-IgE therapy, particularly with asthma onset age ≥ 40 years.Conclusion: Clinicians should consider age of onset in biologic treatment decisions, given reduced effectiveness of omalizumab in patients with asthma onset at age ≥ 40 years.Clinicaltrials.gov Identifier: NCT03373045.Keywords: Biologics, severe asthma, anti-interleukin therapy, anti-immunoglobulin E therapy, effectiveness, age of asthma onset

Monique da Silva Pinto,1 Caroline de Oliveira Ribeiro,1 Paula Morisco de Sá,2 Hermano Albuquerque Castro,3 Thiago Prudente Bártholo,4 Agnaldo José Lopes,4 Pedro Lopes Melo1,5 1Biomedical Instrumentation Laboratory, Institute of Biology and Faculty of Engineering, State University of Rio de Janeiro, Rio de Janeiro, Brazil; 2University of the Brazilian Air Force, Postgraduate Program in Operational Human Performance, Rio de Janeiro, Brazil; 3National School of Public Health, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 4Pedro Ernesto University Hospital, Pulmonary Function Laboratory, State University of Rio de Janeiro, Rio de Janeiro, Brazil; 5State University of Rio de Janeiro, Laboratory of Clinical and Experimental Research in Vascular Biology, Rio de Janeiro, BrazilCorrespondence: Pedro Lopes Melo, Department of Physiology, State University of Rio de Janeiro, São Francisco Xavier Street, Maracanã, Rio de Janeiro, Brazil, Tel +55(21)2334-0705, Email plopes@uerj.brBackground: Asthma onset or worsening of the disease in adulthood may be associated with occupational asthma (OA) or work-exacerbated asthma (WEA). Oscillometry and respiratory modeling offer insight into the pathophysiology and contribute to the early diagnosis of respiratory abnormalities.Purpose: This study aims to compare the changes due to OA and WEA and evaluate the diagnostic accuracy of this method.Patients and Methods: Ninety-nine volunteers were evaluated: 33 in the control group, 33 in the OA group, and 33 in the WEA group. The area under the receiver operator characteristic curve (AUC) was used to describe diagnostic accuracy.Results: Oscillometric analysis showed increased resistance at 4 hz (R4, p< 0.001), 20 hz (R20, p< 0.05), R4-R20 (p< 0.0001), and respiratory work (p< 0.001). Similar analysis showed reductions in dynamic compliance (p< 0.001) and ventilation homogeneity, as evaluated by resonance frequency (Fr, p< 0.0001) and reactance area (p< 0.0001). Respiratory modeling showed increased peripheral resistance (p< 0.0001), hysteresivity (p< 0.0001), and damping (p< 0.0001). No significant changes were observed comparing OA with WEA in any parameter. For OA, the diagnostic accuracy analyses showed Fr as the most accurate among oscillometric parameters (AUC=0.938), while the most accurate from respiratory modeling was hysteresivity (AUC=0.991). A similar analysis for WEA also showed that Fr was the most accurate among traditional parameters (AUC=0.972), and hysteresivity was the most accurate from modeling (AUC=0.987). The evaluation of differential diagnosis showed low accuracy.Conclusion: Oscillometry and modeling have advanced our understanding of respiratory abnormalities in OA and WEA. Furthermore, our study presents evidence suggesting that these models could aid in the early diagnosis of these diseases. Respiratory oscillometry examinations necessitate only tidal breathing and are straightforward to conduct. Collectively, these practical considerations, coupled with the findings of our study, indicate that respiratory oscillometry in conjunction with respiratory modeling, may enhance lung function assessments in OA and WEA.Keywords: occupational asthma, work-exacerbated asthma, pulmonary function, forced oscillations, respiratory modeling, fractional order modeling

Background: Despite clinical implications, the pathogenesis of mucus plugging in asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) remains unclear. We hypothesized that distinct airway microbiomes might affect mucus plugging differently among ACO, asthma, and COPD and among different extents of airway eosinophilic inflammation. Methods: The sputum microbiome, sputum cell differential count, and mucus plug score on computed tomography were cross-sectionally evaluated in patients with chronic airflow limitation. Results: Patients with ACO, asthma, or COPD were enrolled (n = 56, 10, and 25). Higher mucus plug scores were associated with a greater relative abundance of the phylum Proteobacteria (rho = 0.29) only in patients with ACO and a greater relative abundance of the phylum Actinobacteria (rho = 0.46) only in patients with COPD. In multivariable models including only patients with ACO, the presence of mucus plugs was associated with a greater relative abundance of the phylum Proteobacteria and the genus Haemophilus, independent of smoking status, airflow limitation, and emphysema severity. Moreover, the mucus score was associated with a greater relative abundance of the genus Streptococcus (rho = 0.46) in patients with a high sputum eosinophil count (n = 22) and with that of the genus Haemophilus (rho = 0.46) in those with a moderate sputum eosinophil count (n = 26). Conclusions: The associations between mucus plugging and the microbiome in ACO differed from those in COPD and asthma. Greater relative abundances of the phylum Proteobacteria and genus Haemophilus may be involved in mucus plugging in patients with ACO and moderate airway eosinophilic inflammation.

Background: Asthma is characterized by phenotypes of different clinical, demographic, and pathological characteristics. Identifying the profile of exhaled volatile organic compounds (VOCs) in asthma phenotypes may facilitate establishing biomarkers and understanding asthma background pathogenesis. This study aimed to identify exhaled VOCs that characterize severe asthma phenotypes among patients with asthma. Methods: This was a multicenter cross-sectional study of patients with severe asthma in Japan. Clinical data were obtained from medical records, and questionnaires were collected. Exhaled breath was sampled and subjected to thermal desorption gas chromatography-mass spectrometry (GC/MS). Results: Using the decision tree established in the previous nationwide asthma cohort study, 245 patients with asthma were divided into five phenotypes and subjected to exhaled VOC analysis with 50 healthy controls (HCs). GC/MS detected 243 VOCs in exhaled breath samples, and 142 frequently detected VOCs (50% of all samples) were used for statistical analyses. Cluster analysis assigning the groups with similar VOC profile patterns showed the highest similarities between phenotypes 3 and 4 (early-onset asthma phenotypes), followed by the similarities between phenotypes 1 and 2 (late-onset asthma phenotypes). Comparisons between phenotypes 1–5 and HC revealed 19 VOCs, in which only methanesulfonic anhydride showed p

Background: Basal cell hyperplasia is commonly observed in nasal polyp epithelium of eosinophilic chronic rhinosinusitis (eCRS). We examined the function and mechanisms of basal cell hyperplasia in the pathophysiology of eCRS. Methods: We found that normal human bronchial epithelial (NHBE) cells obtained basal cell characteristics when cultured with PneumaCult™-Ex Plus Medium. Most of the cells passaged three times expressed basal cell surface markers CD49f and CD271 by flow cytometry, and basal cell nuclear marker p63 by immunohistochemical staining. We named these NHBE cells with basal cell characteristics cultured Basal-like cells (cBC), and NHBE cells cultured with BEGM™ cultured Epithelial cells (cEC). The characteristics of cBC and cEC were examined and compared by RNA sequencing, RT-PCR, ELISA, and cell proliferation studies. Results: RNA sequencing revealed that cBC showed higher gene expression of thymic stromal lymphopoietin (TSLP), IL-8, TLR3, and TLR4, and lower expression of PAR-2 compared with cEC. The mRNA expression of TSLP, IL-8, TLR3, and TLR4 was significantly increased in cBC, and that of PAR-2 was significantly increased in cEC by RT-PCR. Poly(I:C)-induced TSLP production and LPS-induced IL-8 production were significantly increased in cBC. IL-4 and IL-13 stimulated the proliferation of cBC. Finally, the frequency of p63-positive basal cells was increased in nasal polyp epithelium of eCRS, and Ki67-positive proliferating cells were increased in p63-positive basal cells. Conclusions: Type 2 cytokines IL-4 and IL-13 induce basal cell hyperplasia, and basal cells exacerbate type 2 inflammation by producing TSLP in nasal polyp of eCRS.

Background: We investigated the efficacy and safety of dupilumab in Japanese patients aged ≥6 months to

Background: Allergic asthma is largely dominated by Th2 lymphocytes. Micropeptides in Th2 cells and asthma remain unmasked. Here, we aimed to demonstrate a micropeptide, T-cell regulatory micropeptide (TREMP), in Th2 cell differentiation in asthma. Methods: TREMP translated from lincR-PPP2R5C was validated using Western blotting and mass spectrometry. TREMP knockout mice were generated using CRISPR/Cas9. Coimmunoprecipitation revealed that TREMP targeted pyrroline-5-carboxylate reductase 1 (PYCR1), which was further explored in vitro and in vivo. The levels of TREMP and PYCR1 in Th2 cells from clinical samples were determined by flow cytometry. Results: TREMP, encoded by lincR-PPP2R5C, was in the mitochondrion. The lentivirus encoding TREMP promoted Th2 cell differentiation. In contrast, Th2 differentiation was suppressed in TREMP−/− CD4+ T cells. In the HDM-induced model of allergic airway inflammation, TREMP was increased in pulmonary tissues. Allergic airway inflammation was relieved in TREMP−/− mice treated with HDM. Mechanistically, TREMP interacted with PYCR1, which regulated Th2 differentiation via glycolysis. Glycolysis was decreased in Th2 cells from TREMP−/− mice and PYCR1−/− mice. Similar to TREMP−/− mice, allergic airway inflammation was mitigated in HDM-challenged PYCR1−/− mice. Moreover, we measured TREMP and PYCR1 in asthma patients. And we found that, compared with those in healthy controls, the levels of TREMP and PYCR1 in Th2 cells were significantly increased in asthmatic patients. Conclusions: The micropeptide TREMP encoded by lincR-PPP2R5C promoted Th2 differentiation in allergic airway inflammation by interacting with PYCR1 and enhancing glycolysis. Our findings highlight the importance of neglected micropeptides from noncoding RNAs in allergic diseases.

Background: Intestinal bacteria may play a role in the development of food allergies. This study aimed to analyze and compare the gut microbiota of food-allergic children with that of healthy children of the same age. Methods: Stool samples were collected from one-and-a-half-year-old food-allergic (FA group, n = 29) and healthy controls (HC group, n = 19). A questionnaire was provided to examine the children's birth, dietary, medical, and social histories. The gut microbiota was profiled by 16S rRNA sequencing. Differences in taxonomic composition were assessed using linear discriminant analysis effect size (LEfSe), and microbial functional profiles were predicted with Tax4Fun2. Results: No significant difference in the alpha diversity index between the two groups; however, a negative correlation was observed between the Shannon diversity index and the relative abundance of Bacteroides. A significant difference was observed in beta diversity (permutational multivariate analysis of variance) in the bacterial composition between the FA and HC groups (P 2). The FA group showed a predicted increase in the expression levels of genes associated with intestinal pathogenicity compared with that in the HC group. Conclusions: The gut microbiota of food-allergic children has a higher abundance of bacteria involved in intestinal inflammation and a lower abundance of bacteria involved in immune tolerance than that of healthy children. This dysbiosis may also be associated with food allergies.

Background: Diagnosing perioperative anaphylaxis (POA) is often challenging. Although a guideline recommends measuring tryptase rather than histamine, there is little evidence for this. We aimed to examine the diagnostic performance and appropriate timing of tryptase and histamine measurements for diagnosing anaphylaxis, and the association between Hypersensitivity Clinical Scoring Scheme (HCSS) scores and elevated biomarkers. Methods: We measured tryptase and histamine levels thrice: 30 min, 2 h, and at least 24 h after an anaphylactic event for patients with suspected anaphylaxis, and at the induction of general anesthesia and 30 min and 2 h after the start of surgery for control patients without a reaction. Absolute values and the magnitude and rate of change from baseline were evaluated. We determined the thresholds of tryptase and histamine levels with the best diagnostic performance and compared their performance. Results: Forty-five patients with perioperative anaphylaxis were included in this study. The control group included 30 patients with uneventful general anesthesia and 12 patients with a suspected but unconfirmed diagnosis of perioperative anaphylaxis. Comparison at the same measurement timings showed that tryptase generally had better diagnostic performance than histamine. Both showed better diagnostic performance when assessed using multiple measurements rather than a single measurement. The best diagnostic performance was seen with the percentage change in the higher tryptase value, whether measured at 30 min or 2 h after anaphylaxis onset, as compared to baseline. However, neither tryptase nor histamine levels correlated with HCSS scores. Conclusions: Overall, tryptase showed better diagnostic performance than histamine. When multiple tryptase measurements are possible, parameters calculated using two acute phase measurements and the baseline level have better diagnostic performance.

Background: Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs. Methods: A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016–2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019–2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined. Results: The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4–8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3–63.7; P = 0.001). The in vitro BAT showed higher activation of CD63+ basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P

Background: Food protein-induced enterocolitis syndrome caused by solid foods (Solid-FPIES) is a non-immunoglobulin E-mediated allergic disease characterized by delayed gastrointestinal symptoms. An oral food challenge (OFC) test, although necessary, can be inconclusive in cases with mild symptoms. Moreover, limited diagnostic marker availability highlights the need for novel surrogate markers. We aimed to examine the efficacy of fecal hemoglobin (FHb), lactoferrin (FLf), and calprotectin (FCp) over time in evaluating gastrointestinal inflammation degree in Solid-FPIES. Methods: This observational study included 40 patients and 42 episodes at Juntendo University Hospital and affiliated hospitals between October 2020 and March 2024 categorized into FPIES (12 patients with 11 egg yolk, 1 fish, and 1 soybean episodes), control (14 patients with 15 episodes), and remission (14 patients). Fecal tests were performed for 7 days following antigen exposure. The ratios of each value were divided by the baseline value and analyzed over time course. Results: The FPIES group had significantly higher peak ratios of all fecal markers than the control group (p

Background: To avoid complete elimination of hen eggs (HE) from diet, we introduced a very-low-dose (VLD) oral food challenge (OFC) in patients with severe HE allergy in 2019. Herein, we investigated the efficacy of VLD HE OFC for achieving the full dose OFC. Methods: Patients with an overt allergic reaction to LD (1/32 HE [≤100 mg]) or less, egg white (EW) protein within 6 months were included. In the VLD group, patients not achieving full-dose OFC (1/2 HE: 1600 mg EW protein) within 2 years were excluded. We retrospectively compared the rate of passing a full-dose OFC between patients who underwent a LD OFC before 2019 (LD group) and those who underwent a VLD OFC (1/100 HE: 32 mg EW protein) after 2019 (VLD group). The period for passing the full-dose OFC was evaluated using Kaplan–Meier survival analysis. Results: We enrolled 411 and 111 patients in the LD and VLD groups, respectively. The median age at OFC initiation was 2.2 [1.5–3.6] and 2.1 [1.4–3.2] years in the LD and VLD groups, respectively. EW- and ovomucoid-specific IgE levels were 38.3 (12.5–72.9) and 21.0 (8.3–46.2) kUA/L in the LD group and 49.8 [18.8–83.9] and 32.1 [15.6–67.8] kUA/L in the VLD group, respectively. Over 4 years, the LD and VLD groups passed the full-dose OFC at rates of 70 and 95%, respectively, with significant differences (log-rank test, P

Food allergies are an increasing global problem and societal issue. In addition to the potential for severe allergic reactions from accidental ingestion, food allergies impose a significant burden on the quality of life, nutrition, cost of living, and social activities of both those afflicted and their caregivers. Strict avoidance of allergens and use of emergency medications to treat allergic reactions are the traditional management and treatment strategies; however, significant progress has been made in recent years toward better treatment of food allergies. Many clinical trials on food allergen immunotherapy (oral, epicutaneous, and sublingual) have revealed its efficacy in increasing reaction thresholds and desensitization. These positive results led to the first FDA approval of peanut oral immunotherapy (OIT). However, safer and more effective approaches are required, and adjunct treatments and allergen modifications are being considered. More than 100 facilities in Japan conduct OIT, and numerous studies on it have been reported. Unlike in Europe and the US, stepwise oral food challenges with dietary guidance are conducted separately from the OIT. This review describes the current perspectives on allergen immunotherapy for the treatment of food allergies, focusing on evidence from Japan.

In 2004, we started the initial attempt to evaluate the efficacy of SLIT for Japanese cedar pollinosis (JCP) using Japanese cedar (JC) pollen extract solution through a multicenter, placebo-controlled, double-blind comparative study. Based on its success in demonstrating the substantial efficacy of SLIT, we next conducted a larger-scale study by administering JC pollen to all JCP patients recruited. It was because of aiming to ascertain the effectiveness and safety of SLIT and its underlying mechanisms by comparing high- and non-responder patients. Despite limitations posed by liquid medication, significant effectiveness and safety demonstrated by the 2-year treatment served as the foundation for launching the first SLIT medicine for JCP, in 2014. Furthermore, in addition to the clearer Th1/Th2-imbalanced property in the high-responders, the possible involvement of bitter taste receptors in CD4+ T cells, apoptosis pathways in CD4+ T cells and basophils, and inducing a mast cell degranulation inhibitory molecule in the effect of SLIT was demonstrated. To solve the limitations posed by liquid medication, clinical trials evaluating JC pollen sublingual tablets started in 2014. Due to the minimal side effects, ease of administration, and convenient storage, the sublingual tablet medicine was launched in 2018. Giving the ongoing rise in demand for SLIT and considering that more than 1% of JCP patients are currently undergoing SLIT, the practical use of this treatment for multiple allergens is becoming increasingly important.

Allergen immunotherapy (AIT), including SCIT and SLIT, is a treatment that involves the administration of allergens to which patients with allergic diseases have been sensitized. HDM-SCIT for asthma is indicated in cases of HDM-sensitized allergic asthma with normal lung function. HDM-SCIT improves asthma symptoms and AHR, and decreases the medication dose. Importantly, AIT can improve other allergic diseases complicated by asthma, such as allergic rhinitis, which can also contribute to the improvement of asthma symptoms. Several studies have suggested that HDM-SLIT also attenuates the risk of asthma exacerbations, and improves lung function in asthma cases with allergic rhinitis. Furthermore, AIT can modify the natural course of allergic diseases, including asthma. For example, the effects of AIT are maintained for at least several years after treatment discontinuation. AIT can prevent the onset of asthma when introduced in allergic rhinitis, and can also inhibit or reduce new allergen sensitizations. Recent data have suggested that AIT may suppress non-targeted allergen-induced immune responses in addition to targeted allergen-induced responses, and suppress infections of the lower respiratory tract by enhancing IFN responses.

Jing He,1,&ast; Nan Lin,2,&ast; Ting Jin,2 Ming Lin,1 Zuowei Huang,1 Shuxian Li,1 Jinling Liu,1 Lin Su,1 Xian Ye,2 Lei Wu,1 Zhenghong Song,2 Hongzhen Xu,2 Zhimin Chen1 1Department of Pulmonology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China; 2Nursing Department, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhimin Chen, Department of Pulmonology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, People’s Republic of China, Email zmchen@zju.edu.cn Hongzhen Xu, Master of nursing, Nursing Department, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, People’s Republic of China, Email 6184020@zju.edu.cnBackground: Allergic conditions, identified as a significant global health challenge, are profoundly influenced by indoor allergens, especially house dust mites (HDM). Yet the relationship between mite sensitized components and respiratory allergies and asthma control remains poorly understood.Methods: A cohort of 96 children, either with allergic rhinitis (AR) or rhinitis with asthma syndrome (ARAS), was assessed. Protein microarray technology was deployed to quantify sIgE responses to the allergenic components of Der p and Der f.Results: The study cohort comprised 18 AR and 78 ARAS patients; with 43 mild and 53 moderate-to-severe AR; with 28 uncontrolled, 21 partially controlled, and 29 well-controlled asthma. Sensitization prevalence for HDM components was highest with Der p (97.9%), Der f 2 (97.9%), Der p 2 (94.8%), Der f 1(94.8%), Der p 1 (93.8%), Der p 23 (57.3%). Notably, sIgE concentrations for Der f and Der f 2 were significantly greater in the ARAS compared to AR (P < 0.05). While sIgE levels varied between mild and moderate-to-severe AR, the differences were not statistically significant (P > 0.05). However, Der p 23 sIgE levels demonstrated a significant fluctuation across the asthma control strata (P < 0.05), with the well-controlled group exhibiting the lowest readings.Conclusion: The sIgE levels to HDM allergens were higher in ARAS group compared to AR group, especially Der f and Der f 2, indicating an association between sIgE reactivity and the diagnosis of asthma. Reduced Der p 23 sIgE levels were indicative of enhanced asthma control.Keywords: house dust mite, allergic rhinitis, asthma, molecular sensitization, children

This study aimed to identify biomarkers to distinguish adult-onset Still’s disease (AOSD) and to predict disease phenotypes. In total, 49 patients diagnosed with AOSD and 200 patients with common diseases (controls) were included in the analysis. The levels of 69 cytokines were analyzed using a multi-suspension cytokine array. Cytokine cluster analysis was performed to identify specific molecular networks. Furthermore, random forest analysis and logistic regression analysis were used to rank cytokines based on their importance and to determine specific biomarkers for identification of AOSD patients and phenotypes. Patients with AOSD demonstrated significantly higher macrophage migration inhibitory factor (MIF) and interleukin (IL)-12(p40) serum levels than controls and patients with rheumatoid arthritis. Serum levels of chemokine (C-C motif) ligand (CCL) 8 and CCL22 were significantly lower in AOSD patients with a polycyclic systemic disease phenotype and could be differentiated with high accuracy from the other phenotypes (cutoff value for CCL8 = 122.7 pg/mL, CCL22 = 593.3 pg/mL, sensitivity 66.7%, specificity 87.1%, area under the curve 0.843). Combined MIF and IL-12(p40) levels may represent a biomarker for differentiating patients with AOSD from those with other diseases. The chemokine profiles of AOSD with a polycyclic systemic disease phenotype may differ from other phenotypes.

Abstract Nucleoside-modified mRNA-LNP vaccines have revolutionized vaccine development against infectious pathogens due to their ability to elicit potent humoral and cellular immune responses. In this article, we present the results of the first norovirus vaccine candidate employing mRNA-LNP platform technology. The mRNA-LNP bivalent vaccine encoding the major capsid protein VP1 from GI.1 and GII.4 of human norovirus, generated high levels of neutralizing antibodies, robust cellular responses, and effectively protected human enteroids from infection by the most prevalent genotype (GII.4). These results serve as a proof of concept, demonstrating that a modified-nucleoside mRNA-LNP vaccine based on norovirus VP1 sequences can stimulate an immunogenic response in vivo and generates neutralizing antibodies capable of preventing viral infection in models of human gastrointestinal tract infection.

Abstract Multiple myeloma (MM), a hematological malignancy of the bone marrow, remains largely incurable. The orphan G protein-coupled receptor, GPRC5D, which is uniquely expressed in plasma cells and highly expressed in MM, is a compelling candidate for immunotherapy. In this study, we investigated the efficacy of a combination of DNA vaccine encoding mouse GPRC5D and PD-1 blockade in preventing and treating MM using the 5TGM1 murine model of MM. The mouse vaccine alone was effective in preventing myeloma growth but required PD-1 antibodies to inhibit established MM tumors. We next evaluated the prophylactic and therapeutic efficacy of a nanoplasmid vector encoding human GPRC5D in several murine syngeneic tumor models. Similar results for tumor inhibition were observed, as human GPRC5D-specific T cells and antibodies were induced by DNA vaccines. Taken together, these findings underscore the potential of GPRC5D-targeted DNA vaccines as versatile platforms for the treatment and prevention of MM.

Abstract Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic disease associated with its principal tick vector, Hyalomma spp. with increasing fatal incidence worldwide. Accordingly, CCHF is a World Health Organization-prioritized disease with the absence of effective preventive interventions and approved vaccines or effective treatments. This perspective raised from a multidisciplinary gap analysis considering a One Health approach beneficial for human and animal health and the environment exploring international collaborations, gaps and recommendations.

Abstract Background HIV has an effect on lowering CD4 cell count, which lowers the ability to resist contamination. For patients on ART in areas with limited resources, the CD4 cell count assessment is crucial for determining treatment responses and therapeutic decisions. The volatility of CD4 counts following the introduction of ART over time is still largely uncharacterized, and there are few fresh datasets on CD4 cell count progressions. The goal of this study was to identify the key factors that change over time in CD4 cells for HIV/AIDS patients receiving ART follow-up in northern Ethiopia. Methods A total of 216 HIV/AIDS patients who initiated ART in the Mekelle General Hospital between 2013 and 2016 were involved using systematic random selection techniques. An examination of exploratory data was used to describe the individual profiles of HIV patients. A multivariable random intercept and slope linear mixed regression analysis regarded predictor variables to be statistically significant if their p-value was less than 0.05. Results The random intercept and slope linear mixed model result indicated that there were statistically significant predictors of baseline CD4 cell count (β = 0.0125, P-value = 0.001*) and bedridden functional status (β = -2.459, p = 0.02*) on the change of CD4 cell count over time in HIV/AIDS patients at the 5% significance level. Conclusions Changes in CD4 counts were influenced by the baseline CD4 cell count and the functional status of being bedridden. Because their CD4 cell counts were lower at baseline and they had a functional status of bedridden, the majority of HIV/AIDS patients on ART had substantial predictors on the change of CD4 cell count over time. So, public health service providers should give exceptional guidance and attention is also necessary for those patients who have lower baseline CD4 cell count and bedridden functional status.

Abstract Objectives Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We previously demonstrated that CEACAM1 is predominantly expressed on peripheral blood neutrophils in patients with RA. The aim of the present study was to investigate the effects of Janus kinase inhibitors (JAKi) on cytokine-activated human neutrophils and CEACAM1 expression. Methods Peripheral blood neutrophils were obtained from healthy subjects. Isolated neutrophils were stimulated with tumor necrosis factor-alpha (TNF-α) or granulocyte–macrophage colony-stimulating factor (GM-CSF) in the presence or absence of JAKi. The expression of CEACAM1 in peripheral blood neutrophils was analyzed by flow cytometry. Protein phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 was assessed by western blot using phospho-specific antibodies. Results We found that TNF-α-induced CEACAM1 expression was marginally suppressed after pretreatment with pan-JAK inhibitor, tofacitinib. Moreover, TNF-α induced STAT1 and STAT3 phosphorylation at the late stimulation phase (4 to 16 h). The expressions of CEACAM1 on neutrophils were markedly up-regulated by GM-CSF not by interleukin (IL)-6 stimulation. All JAKi inhibited GM-CSF-induced CEACAM1 expressions on neutrophils, however, the inhibitory effects of baricitinib were larger compared to those of tofacitinib or filgotinib. Moreover, CEACAM1 was marginally upregulated in interferon (IFN)-γ stimulated neutrophils. Similarly, JAKi inhibited IFN-γ-induced CEACAM1 expressions on neutrophils. Conclusions We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation.

Abstract Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complicated, heterogeneous condition distinguished by post-exertional neuroimmune exhaustion and multisystem symptoms. Its complexity poses challenges for physicians, researchers and those inflicted by its presence. Due to conflicting evidence and limiting consensus, the association and contribution autoimmunity serves in the pathophysiology or aetiology of ME/CFS is yet to be confirmed. This systematic review synthesises the currently available data to clarify the role autoimmunity has in the pathogenesis of ME/CFS and explore the therapeutic limitations. Methods This systematic review was conducted in accordance with the PRISMA and Cochrane guidelines. Full-text articles containing the primary key terms “Autoimmunity/Autoimmune” and “ME/CFS” were included provided their suitability to the inclusion and exclusion criteria. Results Ten publications investigating the role of autoimmunity in ME/CFS were examined. One investigated the role of cytokine signalling; Three investigated the genetic nature of autoimmunity in ME/CFS patients; One examined the immune lineage of ME/CFS patients; Six investigated the presence and role of autoantibodies in ME/CFS patients. Conclusion The findings generated from this systematic review highlight inconsistent and insufficient evidence to classify ME/CFS as an autoimmune disease. Additionally, it further emphasises the complexity of ME/CFS and highlights the challenges in distinguishing autoreactivity from deregulatory processes. Future research is urgently needed to advance the development of diagnostic and treatment strategies. PROSPERO Registration Code CRD42024533447.

Abstract Primary immunodeficiency diseases (PIDs), also referred to as inborn errors of immunity, constitute a group of genetic conditions that affect the immune system. The current standard of care for patients with PIDs is lifelong immunoglobulin replacement therapy, delivered by intravenous (IVIG) or subcutaneous (SCIG) infusion. Immune globulin subcutaneous (human) 20% solution stabilized with glycine (Ig20Gly) is indicated as a replacement therapy for PIDs in adults and children of any age in Europe and in patients aged 2 years and above in the USA. Typically, Ig20Gly is administered using an infusion pump; however, delivery of Ig20Gly by manual administration has recently been approved in Europe. Practical recommendations on the use of Ig20Gly manual administration are lacking; this review therefore aims to provide guidance for use of this method of administration. Additionally, we summarize the infusion parameters, safety, patient-reported outcomes, and economic benefits associated with Ig20Gly manual administration. Manual administration of Ig20Gly was shown to permit faster rates of infusion than administration via infusion pump. Patients typically infused at two or fewer infusion sites with manual administration of Ig20Gly. Safety and tolerability profiles were similar for Ig20Gly manual administration and administration by infusion pump. Overall, there were comparable levels of patient satisfaction with manual administration and infusion pump, with patient preference deemed to be a key determinator of success for either method of administration. Economic studies identified cost savings for the healthcare system through manual administration compared with IVIG or SCIG infusion by infusion pump because of the reduced equipment costs and nurse support. For infusion of Ig20Gly by manual administration, a syringe and butterfly needle are used; patients are advised to start infusion at 1–2 mL/min to prevent discomfort. Overall, manual administration of Ig20Gly offers an effective and well-tolerated alternative to administration by infusion pump.

Abstract Background Hand osteoarthritis (HOA) is a highly prevalent disease that may be impacted by social inequalities. Few studies in HOA are from underdeveloped regions. We intend to contribute to fill this gap presenting clinical characteristics of our low-income HOA cohort (LIHOA). Methods Data from 119 patients with a HOA diagnosis fulfilling ACR criteria seen between August 2019 and May 2023 in Fortaleza/Brazil. Evaluations included pain (VAS, visual analogue scale), X-ray (KL, Kellgren-Lawrence), grip and pinch strength (KgF), Cochin hand functional scale (CHFS), FIHOA, and SF-12 scores. Social data included monthly (4 IF nodes. OA in other joints: 37 (36.2%) spine, 28 (29.4%) knee, 21 (20.5%) bunions. Functional impairment was mild [8 (5–14) median FIHOA]. Median serum CRP was 0.2 mg/dL (0.1–0.4) with 14 (20%) patients above reference value. Mean total KL score was 27.6 ± 13.6 with 21 (23%), 38 (41.7%), and 33 (36.2%) KL2, KL3, and KL4, respectively; 51 (54.8%) and 42 (45.2%) patients declared 9SY including 37.2% with a university degree. Individuals earning

IgG4-related disease (IgG4-RD) is an immune disorder characterized by organ enlargement and fibrosis leading to functional impairment. Key immune cell subsets contributing to the pathogenesis of IgG4-RD include T follicular helper 2 cells (Tfh2), Tfh1, CX3CR1 + cytotoxic T cells (CX3CR1 + CTLs), Tregs and IgG4 + B cells. Tfh2 and Tregs are commonly involved in inducing IgG4 class-switching in this disease. Importantly, IgG4-RD can be classified into four clinical phenotypes based on the distribution of affected organs, with each phenotype showing different dominant immune cell subsets involved in its pathogenesis. Specifically, the clinical phenotype of retroperitoneal fibrosis/aortitis is characterized by CX3CR1 + CTLs as the dominant key immune cell subset, while Mikulicz disease with systemic involvement is dominated by Tfh2. In addition to classification based on organ distribution, IgG4-RD can also be categorized into phenotypes associated with malignancy or allergy. The malignancy phenotype is characterized by an increase in CXCR5 + CD2-double negative T cells compared to the allergy phenotype, along with a decrease in naive CD8 + T cells. Moreover, several autoantigens have been identified, and the presence of autoimmune phenotype has been revealed. Due to the pathogenicity of IgG1-type autoantibodies, Tfh1 may be important inducing IgG1 class-switching by IFNγ in autoimmune phenotype. In IgG4-RD with hypocomplementemia, activation of the complement pathway is thought to be induced by IgG1 or IgG2 antibodies, suggesting the involvement of Tfh1 in the disease pathogenesis. Therefore, elucidating the immunological features specific to each clinical characteristic is believed to lead to a deeper understanding of the pathogenesis of IgG4-RD and the discovery of novel therapeutic targets. This review provides an overview of the immunological mechanisms common to IgG4-RD as well as those specific to each clinical characteristic.

Abstract The relative conservation of the influenza hemagglutinin (HA) stem compared to that of the immunodominant HA head makes the HA stem an attractive target for broadly protective influenza vaccines. Here we report the first-in-human, dose-escalation, open-label trial (NCT04579250) evaluating an unadjuvanted group 2 stabilized stem ferritin nanoparticle vaccine based on the H10 A/Jiangxi-Donghu/346/2013 influenza HA, H10ssF, in healthy adults. Participants received a single 20 mcg dose (n = 3) or two 60 mcg doses 16 weeks apart (n = 22). Vaccination with H10ssF was safe and well tolerated with only mild systemic and local reactogenicity reported. No serious adverse events occurred. Vaccination significantly increased homologous H10 HA stem binding and neutralizing antibodies at 2 weeks after both first and second vaccinations, and these responses remained above baseline at 40 weeks. Heterologous H3 and H7 binding antibodies also significantly increased after each vaccination and remained elevated throughout the study. These data indicate that the group 2 HA stem nanoparticle vaccine is safe and induces stem-directed binding and neutralizing antibodies.

Abstract Vaccines are the most effective and sustainable intervention to control ticks and tick-borne diseases (TBD). Using a personalized vaccine design based on regional tick genotypes, a Rhipicephalus appendiculatus Subolesin protective antigen was used in a field trial evaluating tick vaccine efficacy, effectiveness, and safety in cattle infested with multiple tick species in different Ugandan agro-ecological zones. Vaccination with SUB was safe with a protective capacity against anemia and infection, and reduced the number of infested cattle, tick fitness (feeding and reproduction) with vaccine effectiveness against multiple tick species between 93.2% at 167-196 days post-vaccination (dpv) and 61.4% at 251–327 dpv. Total integrated vaccine efficacy/effectiveness was estimated as 98.8%. The Subolesin-based vaccine is protective against multiple cattle tick infestations under field conditions in Uganda. These results support registration and commercialization of the vaccine to reduce tick populations and associated risks for human and animal TBD and chemical acaracides in Uganda.

Abstract Vaccine-induced T cells and neutralizing antibodies are essential for protection against SARS-CoV-2. Previously, we demonstrated that an antigen delivery system, pullulan nanogel (PNG), delivers vaccine antigen to lymph node medullary macrophages and thereby enhances the induction of specific CD8+ T cells. In this study, we revealed that medullary macrophage-selective delivery by PNG depends on its binding to a C-type lectin SIGN-R1. In a K18-hACE2 mouse model of SARS-CoV-2 infection, vaccination with a PNG-encapsulated receptor-binding domain of spike protein decreased the viral load and prolonged the survival in the CD8+ T cell- and B cell-dependent manners. T cell receptor repertoire analysis revealed that although the vaccine induced T cells at various frequencies, low-frequency specific T cells mainly promoted virus clearance. Thus, the induction of specific CD8+ T cells that respond quickly to viral infection, even at low frequencies, is important for vaccine efficacy and can be achieved by SIGN-R1+ medullary macrophage-targeted antigen delivery.

Abstract Developing broad-spectrum influenza vaccines is crucial for influenza control and potential pandemic preparedness. Here, we reported a novel vaccine design utilizing circular RNA (circRNA) as a delivery platform for multi-subtype neuraminidases (NA) (influenza A N1, N2, and influenza B Victoria lineage NA) immunogens. Individual NA circRNA lipid nanoparticles (LNP) elicited robust NA-specific antibody responses with neuraminidase inhibition activity (NAI), preventing the virus from egressing and infecting neighboring cells. Additionally, the administration of circRNA LNP induced cellular immunity in mice. To achieve a universal influenza vaccine, we combined all three subtypes of NA circRNA-LNPs to generate a trivalent circRNA vaccine. The trivalent vaccine elicited a balanced antibody response against all three NA subtypes and a Th1-biased immune response in mice. Moreover, it protected mice against the lethal challenge of matched and mismatched H1N1, H3N2, and influenza B viruses, encompassing circulating and ancestral influenza virus strains. This study highlights the potential of delivering multiple NA antigens through circRNA-LNPs as a promising strategy for effectively developing a universal influenza vaccine against diverse influenza viruses.