The Performance of Pulmonary Function Tests in Predicting Systemic Sclerosis-Interstitial Lung Disease in the European Scleroderma Trial and Research Database.

BACKGROUND AND OBJECTIVES: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) delta change (Δ) and baseline values in predicting the development of SSc-ILD. METHODS: Longitudinal data of DLCO, FVC, and ILD on the HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t0) and after 12 (±4) (t1) and 24 (±4) (t2) months. RESULTS: 474/17805 patients were eligible for the study (403 females); 46 (9.7%) developed ILD at t2. Positivity for anti-topoisomerase antibodies (117 patients) showed an association with ILD development at t2 (p = 0.0031). Neither the mean t0 to t1 change (Δ) of DLCO nor the mean t0 to t1 FVCΔ predicted the appearance of ILD at t2. Investigating the possible role of baseline DLCO and FVC values in predicting ILD appearance after 24 (±4) months, we observed a moderate predictive capability of t0 DLCO < 80%, stronger than that of FVC < 80%. CONCLUSIONS: We suggest that an impaired baseline DLCO may be predictive of the appearance of ILD after 2 years of follow-up. This result advances the hypothesis that a reduction in gas exchange may be considered an early sign of lung involvement. However, further rigorous studies are warranted to understand the predictive role of DLCO evaluation in the course of SSc.

Safety and immunogenicity of a synthetic nanoparticle-based, T cell priming peptide vaccine against dengue in healthy adults in Switzerland: a double-blind, randomized, vehicle-controlled, phase 1 study.

BACKGROUND: Vaccines that minimize the risk of vaccine-induced antibody-dependent enhancement and severe dengue are needed to address the global health threat posed by dengue. This study assessed the safety and immunogenicity of a gold nanoparticle (GNP)-based, multi-valent, synthetic peptide dengue vaccine candidate (PepGNP-Dengue), designed to provide protective CD8+ T cell immunity, without inducing antibodies. METHODS: In this randomized, double-blind, vehicle-controlled, phase 1 trial (NCT04935801), healthy naïve individuals aged 18-45 years recruited at the Centre for primary care and public health, Lausanne, Switzerland, were randomly assigned to receive PepGNP-Dengue or comparator (GNP without peptides [vehicle-GNP]). Randomization was stratified into four groups (low dose [LD] and high dose [HD]), allocation was double-blind from participants and investigators. Two doses were administered by intradermal microneedle injection 21 days apart. Primary outcome was safety, secondary outcome immunogenicity. Analysis was by intention-to-treat for safety, intention-to-treat and per protocol for immunogenicity. FINDINGS: 26 participants were enrolled (August-September 2021) to receive PepGNP-Dengue (LD or HD, n = 10 each) or vehicle-GNP (LD or HD, n = 3 each). No vaccine-related serious adverse events occurred. Most (90%) related adverse events were mild; injection site pain and transient discoloration were most frequently reported. Injection site erythema occurred in 58% of participants. As expected, PepGNP-Dengue did not elicit anti-DENV antibodies of significance. Significant increases were observed in specific CD8+ T cells and dengue dextramer+ memory cell subsets in the LD PepGNP-Dengue but not in the HD PepGNP-Dengue or vehicle-GNP groups, specifically PepGNP-activated CD137+CD69+CD8+ T cells (day 90, +0.0318%, 95% CI: 0.0088-0.1723, p = 0.046), differentiated effector memory (TemRA) and central memory (Tcm) CD8+ T cells (day 35, +0.8/105 CD8+, 95% CI: 0.19-5.13, p = 0.014 and +1.34/105 CD8+, 95% CI: 0.1-7.34, p = 0.024, respectively). INTERPRETATION: Results provide proof of concept that a synthetic nanoparticle-based peptide vaccine can successfully induce virus-specific CD8+ T cells. The favourable safety profile and cellular responses observed support further development of PepGNP-Dengue. FUNDING: Emergex Vaccines Holding Limited.

P. falciparum and P. vivax Orthologous Coiled-Coil Candidates for a Potential Cross-Protective Vaccine.

Over the last four decades, significant efforts have been invested to develop vaccines against malaria. Although most efforts are focused on the development of P. falciparum vaccines, the current availability of the parasite genomes, bioinformatics tools, and high throughput systems for both recombinant and synthetic antigen production have helped to accelerate vaccine development against the P. vivax parasite. We have previously in silico identified several P. falciparum and P. vivax proteins containing α-helical coiled-coil motifs that represent novel putative antigens for vaccine development since they are highly immunogenic and have been associated with protection in many in vitro functional assays. Here, we selected five pairs of P. falciparum and P. vivax orthologous peptides to assess their sero-reactivity using plasma samples collected in P. falciparum- endemic African countries. Pf-Pv cross-reactivity was also investigated. The pairs Pf27/Pv27, Pf43/Pv43, and Pf45/Pv45 resulted to be the most promising candidates for a cross-protective vaccine because they showed a high degree of recognition in direct and competition ELISA assays and cross-reactivity with their respective ortholog. The recognition of P. vivax peptides by plasma of P. falciparum infected individuals indicates the existence of a high degree of cross-reactivity between these two Plasmodium species. The design of longer polypeptides combining these epitopes will allow the assessment of their immunogenicity and protective efficacy in animal models.

Designs and Characterization of Subunit Ebola GP Vaccine Candidates: Implications for Immunogenicity.

The humoral responses of Ebola virus (EBOV) survivors mainly target the surface glycoprotein GP, and anti-GP neutralizing antibodies have been associated with protection against EBOV infection. In order to elicit protective neutralizing antibodies through vaccination a native-like conformation of the antigen is required. We therefore engineered and expressed in CHO cells several GP variants from EBOV (species Zaire ebolavirus, Mayinga variant), including a soluble GP ΔTM, a mucin-like domain-deleted GP ΔTM-ΔMUC, as well as two GP ΔTM-ΔMUC variants with C-terminal trimerization motifs in order to favor their native trimeric conformation. Inclusion of the trimerization motifs resulted in proteins mimicking GP metastable trimer and showing increased stability. The mucin-like domain appeared not to be critical for the retention of the native conformation of the GP protein, and its removal unmasked several neutralizing epitopes, especially in the trimers. The soluble GP variants inhibited mAbs neutralizing activity in a pseudotype transduction assay, further confirming the proteins' structural integrity. Interestingly, the trimeric GPs, a native-like GP complex, showed stronger affinity for antibodies raised by natural infection in EBOV disease survivors rather than for antibodies raised in volunteers that received the ChAd3-EBOZ vaccine. These results support our hypothesis that neutralizing antibodies are preferentially induced when using a native-like conformation of the GP antigen. The soluble trimeric recombinant GP proteins we developed represent a novel and promising strategy to develop prophylactic vaccines against EBOV and other filoviruses.

Results of the phase I open label clinical trial SAKK 06/14 assessing safety of intravesical instillation of VPM1002BC, a recombinant mycobacterium Bacillus Calmette Guérin (BCG), in patients with non-muscle invasive bladder cancer and previous failure of conventional BCG therapy.

Background: VPM1002BC is a modified mycobacterium Bacillus Calmette Guérin (BCG) for the treatment of non-muscle invasive bladder cancer (NMIBC). The genetic modifications are expected to result in better immunogenicity and less side effects. We report on patient safety and immunology of the first intravesical application of VPM1002BC in human. Methods: Six patients with BCG failure received a treatment of 6 weekly instillations with VPM1002BC. Patients were monitored for adverse events (AE), excretion of VPM1002BC and cytokines, respectively. Results: No DLT (dose limiting toxicity) occurred during the DLT-period. No grade ≥3 AEs occurred. Excretion of VPM1002BC in the urine was limited to less than 24 hours. Plasma levels of TNFα significantly increased after treatment and blood-derived CD4+ T cells stimulated with PPD demonstrated significantly increased intracellular GM-CSF and IFN expression. Conclusion: The intravesical application of VPM1002BC is safe and well tolerated by patients and results in a potential Th1 weighted immune response.

[Allergy to furry animals: myth and reality]. / Allergies aux animaux à poils†: mythes et réalités.

Allergy to furry animals is a frequent health issue, and should be suspected when investigating any yearlong rhinoconjonctivitis or asthma. A detailed medical history and skin prick tests are usually sufficient for diagnosis, and if necessary, specific IgE testing may be performed. In case of proven hypersensitivity, avoidance of animal allergens is the main therapeutic measure, primarily by removing the animal from the patient's environment, in association with symptomatic treatment. If animal removing is impossible, other measures exist to decrease allergen load, but not with the same -efficacy as removing the animal, particularly for asthma. Immunotherapy is available for cat and dog allergy, but indication is to be carefully discussed.

Les allergies aux mammifères à poils sont une problématique ­répandue, et une hypersensibilité aux phanères d'animaux est à rechercher devant toute rhino-conjonctivite ou tout asthme ­perannuels. Une anamnèse soigneuse associée aux prick-tests permet d'orienter le diagnostic, qui sera en cas de doute complété par des dosages d'immunoglobulines E (IgE) spécifiques. Face à une hypersensibilité avérée, l'éviction est la pierre angulaire de la prise en charge, associée à un traitement symptomatique. En cas d'impossibilité pour le patient de se séparer de son animal, des mesures existent pour diminuer la charge en allergènes, bien qu'elles soient insuffisantes pour prévenir toute ­exacerbation des symptômes, surtout en cas d'asthme. Des ­désensibilisations existent pour l'allergie au chat et au chien, à discuter au cas par cas.

Epitope Mapping and Fine Specificity of Human T and B Cell Responses for Novel Candidate Blood-Stage Malaria Vaccine P27A.

P27A is a novel synthetic malaria vaccine candidate derived from the blood stage Plasmodium falciparum protein Trophozoite Exported Protein 1 (TEX1/PFF0165c). In phase 1a/1b clinical trials in malaria unexposed adults in Switzerland and in malaria pre-exposed adults in Tanzania, P27A formulated with Alhydrogel and GLA-SE adjuvants induced antigen-specific antibodies and T-cell activity. The GLA-SE adjuvant induced significantly stronger humoral responses than the Alhydrogel adjuvant. Groups of pre-exposed and unexposed subjects received identical vaccine formulations, which supported the comparison of the cellular and humoral response to P27A in terms of fine specificity and affinity for populations and adjuvants. Globally, fine specificity of the T and B cell responses exhibited preferred recognized sequences and did not highlight major differences between adjuvants or populations. Affinity of anti-P27A antibodies was around 10-8 M in all groups. Pre-exposed volunteers presented anti-P27A with higher affinity than unexposed volunteers. Increasing the dose of GLA-SE from 2.5 to 5 µg in pre-exposed volunteers improved anti-P27A affinity and decreased the number of recognized epitopes. These results indicate a higher maturation of the humoral response in pre-exposed volunteers, particularly when immunized with P27A formulated with 5 µg GLA-SE.

Management of allergy transfer upon solid organ transplantation.

Allergy transfer upon solid organ transplantation has been reported in the literature, although only few data are available as to the frequency, significance, and management of these cases. Based on a review of 577 consecutive deceased donors from the Swisstransplant Donor-Registry, 3 cases (0.5%) of fatal anaphylaxis were identified, 2 because of peanut and 1 of wasp allergy. The sera of all 3 donors and their 10 paired recipients, prospectively collected before and after transplantation for the Swiss Transplant Cohort Study, were retrospectively processed using a commercial protein microarray fluorescent test. As early as 5 days posttransplantation, newly acquired peanut-specific IgE were transiently detected from 1 donor to 3 recipients, of whom 1 liver and lung recipients developed grade III anaphylaxis. Yet, to define how allergy testing should be performed in transplant recipients and to better understand the impact of immunosuppressive therapy on IgE sensitization, we prospectively studied 5 atopic living-donor kidney recipients. All pollen-specific IgE and >90% of skin prick tests remained positive 7 days and 3 months after transplantation, indicating that early diagnosis of donor-derived IgE sensitization is possible. Importantly, we propose recommendations with respect to safety for recipients undergoing solid-organ transplantation from donors with a history of fatal anaphylaxis.

The adjuvant GLA-SE promotes human Tfh cell expansion and emergence of public TCRß clonotypes.

The generation of protective humoral immunity after vaccination relies on the productive interaction between antigen-specific B cells and T follicular helper (Tfh) cells. Despite the central role of Tfh cells in vaccine responses, there is currently no validated way to enhance their differentiation in humans. From paired human lymph node and blood samples, we identify a population of circulating Tfh cells that are transcriptionally and clonally similar to germinal center Tfh cells. In a clinical trial of vaccine formulations, circulating Tfh cells were expanded in Tanzanian volunteers when an experimental malaria vaccine was adjuvanted in GLA-SE but not when formulated in Alum. The GLA-SE-formulated peptide was associated with an increase in the extrafollicular antibody response, long-lived antibody production, and the emergence of public TCRß clonotypes in circulating Tfh cells. We demonstrate that altering vaccine adjuvants is a rational approach for enhancing Tfh cells in humans, thereby supporting the long-lived humoral immunity that is required for effective vaccines.

Novel Nanofluidic IgE Assay versus a Reference Method: A Real-World Comparison.

BACKGROUND: Clinically meaningful specific IgE determination is an important step in the diagnosis of allergic diseases. While patient's history and skin prick tests are available during the medical visit, most IgE immunoassays require hours to several days to be available. Recent developments in the field of nanofluidic technology open new horizons for point-of-care management of this unmet medical need. OBJECTIVE: This study aimed to compare IgE diagnostic agreement between a nanofluidic assay (abioSCOPE®) and a laboratory reference method (Phadia Laboratory System®) in a real-world clinical setting. METHODS: Sera from 105 patients whose routine allergy diagnostic workup required a blood sampling were used to compare the novel nanofluidic IgE assay to a reference method in a blind manner for a panel of five respiratory allergens. To assess the agreement between methods, patient records were reviewed by four independent experts to establish the final diagnosis. Experts were blinded to the IgE serological method used, but had access to patient history, skin prick tests, and blood test results. RESULTS: Analytic agreement between the two methods was 81% for the tested panel of allergens (ranging from 77 to 89%). The overall agreement in clinical diagnosis decision taken by the expert panel was 94.6% with the nanofluidic IgE assay when compared to the reference method. CONCLUSION: The nanofluidic IgE assay, as determined through an evaluation based on clinical history, skin prick tests, and IgE measurement, is a valuable tool for allergy experts to identify patients' sensitization patterns at the point of care, and for routine IgE diagnostic workup.

Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.

Immune-checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are arguably the most important development in cancer therapy over the past decade. The indications for these agents continue to expand across malignancies and disease settings, thus reshaping many of the previous standard-of-care approaches and bringing new hope to patients. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), which are often distinctly different from the classical chemotherapy-related toxicities. Owing to the growing use of ICIs in oncology, clinicians will increasingly be confronted with common but also rare irAEs; hence, awareness needs to be raised regarding the clinical presentation, diagnosis and management of these toxicities. In this Review, we provide an overview of the various types of irAEs that have emerged to date. We discuss the epidemiology of these events and their kinetics, risk factors, subtypes and pathophysiology, as well as new insights regarding screening and surveillance strategies. We also highlight the most important aspects of the management of irAEs.

New therapeutic perspectives to manage refractory immune checkpoint-related toxicities.

Immune checkpoint inhibitors are reshaping the prognosis of many cancer and are progressively becoming the standard of care in the treatment of many tumour types. Immunotherapy is bringing new hope to patients, but also a whole new spectrum of toxicities for healthcare practitioners to manage. Oncologists and specialists involved in the pluridisciplinary management of patients with cancer are increasingly confronted with the therapeutic challenge of treating patients with severe and refractory immune-related adverse events. In this Personal View, we summarise the therapeutic strategies that have been used to manage such toxicities resulting from immune checkpoint inhibitor treatment. On the basis of current knowledge about their pathogenesis, we discuss the use of new biological and non-biological immunosuppressive drugs to treat severe and steroid refractory immune-related adverse events. Depending on the immune infiltrate type that is predominant, we propose a treatment algorithm for personalised management that goes beyond typical corticosteroid use. We propose a so-called shut-off strategy that aims at inhibiting key inflammatory components involved in the pathophysiological processes of immune-related adverse events, and limits potential adverse effects of drug immunosuppression on tumour response. This approach develops on current guidelines and challenges the step-by-step increase approach to drug immunosuppression.

[Where are we with oral immunotherapy for food allergy ?] / Allergologie-immunologie: Où en est-on avec l'immunothérapie orale dans l'allergie alimentaire ?

In allergology, food allergy is probably the problem to which medicine has brought the least therapeutic response so far. While oral immunotherapy for peanut, egg and milk is reserved for a few special cases and is not routinely recommended, apple desensitization for adult oral syndrome seems to bring some benefits in clinical practice, particularly in patients with restricted diet in fruits.

Dans le domaine de l'allergologie, l'allergie alimentaire est probablement la problématique à laquelle la médecine a apporté le moins de réponses thérapeutiques jusqu'ici. Alors que l'immunothérapie orale pour les cacahouètes, l'œuf et le lait est réservée à quelques cas particuliers et n'est pas recommandée de routine, la désensibilisation à la pomme lors de syndrome oral croisé chez l'adulte semble apporter certains bénéfices en pratique clinique, en particulier pour des patients dont le régime alimentaire en fruits est considérablement réduit.

[Risk of treatment failure and therapeutic novelties in asthma]. / Allergologie-immunologie: Facteurs d'échec du traitement de l'asthme et nouveautés thérapeutiques.

Asthma is a chronic disease that is still frequently poorly controlled, despite recent advances in understanding its pathophysiology. Poor compliance and ineffective inhalation technique remain the main causes of treatment failure. The comorbidities associated with asthma, such as obesity and chronic rhinosinusitis, are other elements to consider in the management of patients. Biological treatments targeting inflammation mediators show encouraging results in recurrent asthma exacerbations despite optimal management. However, their benefit remains limited to certain patients, thus requiring the study of predictive biomarkers to better delineate their indication.

L'asthme est une maladie chronique encore souvent mal contrôlée, et ce, malgré les récents progrès concernant la compréhension de sa physiopathologie. Une mauvaise adhésion aux traitements et une technique d'inhalation inefficace restent les causes principales d'échecs thérapeutiques. Les comorbidités associées à l'asthme, telles que l'obésité et la rhinosinusite chronique, sont d'autres éléments à considérer dans la prise en charge des patients. Lors d'exacerbations asthmatiques récidivantes, malgré une prise en charge optimale, des traitements biologiques ciblant les promoteurs de l'inflammation montrent des résultats encourageants. Leur bénéfice reste toutefois limité à certains patients, ce qui impose à l'avenir l'étude de biomarqueurs prédictifs de réponse à ces traitements ciblés.

Supplemental parenteral nutrition improves immunity with unchanged carbohydrate and protein metabolism in critically ill patients: The SPN2 randomized tracer study.

BACKGROUND & AIMS: Individualized supplemental parenteral nutrition (SPN) providing measured energy expenditure from day 4 reduced infectious complications in a previous study including 305 intensive care (ICU) patients. The study aimed at investigating the metabolic, and immune responses underlying the clinical response of the previous trial. METHODS: Randomized controlled trial enrolling 23 critically ill patients on day 3 (D3) of admission to the ICU who were fed less than 60% of their energy target by the enteral nutrition (EN) alone: allocation to either continued EN or to SPN to a target validated by indirect calorimetry. Protein and glucose metabolism (primary endpoint) were investigated with tracer isotopes on D4 and D9. Secondary endpoints: 1) immune response, investigated in serum and in stimulated peripheral blood mononuclear cells (PMBC), by dosing a panel of cytokines (infectious complications were recorded), and 2) Muscle mass was assessed by ultrasound of the thigh. RESULTS: Comparable at baseline, the SPN group (n = 11) received more energy (median 24.3 versus 17.8 kcal/kg/day: p < 0.001) and proteins (1.11 versus 0.69 g/kg/day: p < 0.001) than the control group during the five days' intervention, resulting in a less negative energy balance by D9 (p = 0.0027). Net protein breakdown and Glucose kinetics on D9 did not differ, within or between groups. In agreement with a decrease in infection rate, immune response in the SPN group showed decreased serum IL-6 (p = 0.024), IL-1ß, IL-10 levels and TNF-α secretion by PBMC (p = 0.018) at D9. Muscle mass loss from D4 to D15 tended to be less in the SPN group (-16% versus -23%: p = 0.06). Clinical course by D28 did not differ. CONCLUSIONS: Feeding patients to cover an individualised measured energy target with SPN from D4 to cover needs, was associated with improved immunity, less systemic inflammation and a trend to less muscle mass loss. CLINICAL TRIAL REGISTRY: NCT02022813 at https://clinicaltrials.gov/.

The Candidate Blood-stage Malaria Vaccine P27A Induces a Robust Humoral Response in a Fast Track to the Field Phase 1 Trial in Exposed and Nonexposed Volunteers.

Background: P27A is an unstructured 104mer synthetic peptide from Plasmodium falciparum trophozoite exported protein 1 (TEX1), the target of human antibodies inhibiting parasite growth. The present project aimed at evaluating the safety and immunogenicity of P27A peptide vaccine in malaria-nonexposed European and malaria-exposed African adults. Methods: This study was designed as a staggered, fast-track, randomized, antigen and adjuvant dose-finding, multicenter phase 1a/1b trial, conducted in Switzerland and Tanzania. P27A antigen (10 or 50 µg), adjuvanted with Alhydrogel or glucopyranosil lipid adjuvant stable emulsion (GLA-SE; 2.5 or 5 µg), or control rabies vaccine (Verorab) were administered intramuscularly to 16 malaria-nonexposed and 40 malaria-exposed subjects on days 0, 28, and 56. Local and systemic adverse events (AEs) as well as humoral and cellular immune responses were assessed after each injection and during the 34-week follow-up. Results: Most AEs were mild to moderate and resolved completely within 48 hours. Systemic AEs were more frequent in the formulation with alum as compared to GLA-SE, whereas local AEs were more frequent after GLA-SE. No serious AEs occurred. Supported by a mixed Th1/Th2 cell-mediated immunity, P27A induced a marked specific antibody response able to recognize TEX1 in infected erythrocytes and to inhibit parasite growth through an antibody-dependent cellular inhibition mechanism. Incidence of AEs and antibody responses were significantly lower in malaria-exposed Tanzanian subjects than in nonexposed European subjects. Conclusions: The candidate vaccine P27A was safe and induced a particularly robust immunogenic response in combination with GLA-SE. This formulation should be considered for future efficacy trials. Clinical Trials Registration: NCT01949909, PACTR201310000683408.