Difference in the cellular response following THP-1 derived phagocytic monocyte cells exposure to commercial aluminum-based adjuvants and aluminum-containing vaccines.

BACKGROUND: Aluminum-based adjuvants (ABAs) enhance the immune response following vaccine injection. Their mechanisms of action are not fully understood, and their bio-persistency have been described associated with long-term adverse effects. METHODS: We evaluated and compared the cellular effects of the two main ABAs and whole vaccines on ATP production, ROS generation and cytokines production (IL-6 and IL-10), using THP-1 cells. RESULTS: ABAs altered the cell energy metabolism by increasing ROS production after 24 h and reducing ATP production after 48 h. In addition, both ABAs and whole vaccines induced different kinetics of IL-6 production, whereas only ABAs induced IL-10 secretion. CONCLUSION: This study showed clearly, for a first time, a difference in cellular response to the ABAs and whole vaccines which should be taken into consideration in future studies focusing on the effect of ABA in vaccines. Future studies on ABAs should also pay attention to mitochondrial function alterations following exposure to ABA-containing vaccines.

TLR-2 agonist Pam3CSK4 has no therapeutic effect on visceral leishmaniasis in BALB/c mice and may enhance the pathogenesis of the disease.

Most of the existing Leishmania-related research about TLR-2 agonists was focusing on their role as adjuvants in the vaccine, few studied its therapeutic effect. This paper aims to explore the therapeutic effect of TLR-2 agonist Pam3CSK4 on Leishmania-infected mice and the underlying immune molecular mechanisms. In L. donovani-infected BALB/c mice, one group was treated with Pam3CSK4 after infection and the other group was not treated. Normal uninfected mice treated with Pam3CSK4 or untreated were used as controls. Parasite load, hepatic pathology and serum antibodies were detected to assess the severity of the infection. The expression of immune-related genes, spleen lymphocyte subsets and liver RNA-seq were employed to reveal possible molecular mechanisms. The results showed that the liver and spleen parasite load of infected mice in Pam3CSK4 treated and untreated groups had no statistical difference, indicating Pam3CSK4 might have no therapeutic effect on visceral leishmaniasis. Infected mice treated with Pam3CSK4 possessed more hepatic inflammation focus, lower IgG and IgG2a antibody titers, and a lower proportion of spleen CD3+CD4+ T cells. Transcriptome analysis revealed that Th1/Th2 differentiation, NK cells, Th17 cell, complement system and calcium signaling pathways were down-regulated post-treatment of Pam3CSK4. In this study, TLR-2 agonist Pam3CSK4 showed no therapeutic effect on visceral leishmaniasis in BALB/c mice and might enhance the pathogenesis of the disease possibly due to the down-regulation of several immune-related pathways, which can improve our understanding of the role of TLR-2 in both treatment and vaccine development.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA), medical treatment of severe systemic compromise: case report.

Case description: A 42-year-old woman with severe pulmonary and mediastinal inflammatory involvement, secondary to infiltration of a silicone-related allogenic material with systemic migration. Clinical findings: The patient developed esophageal and bronchial stenosis, recurrent infections, malnutrition, and respiratory deterioration, making surgical removal of the allogenic material impossible. Treatment and outcome: Clinical and radiological improvement was achieved after treatment with multiple intravenous and oral immunomodulators. Clinical relevance: Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a heterogeneous disease resulting from exposure to allogenic substances in a susceptible subject. These substances cause autoimmune or autoinflammatory phenomena. Since ASIA was described ten years ago, its diagnostic criteria are still under discussion, with an uncertain prognosis. The ideal therapy is based on eliminating the causative substance, but this is not always possible. Therefore, it is necessary to start an immunomodulatory treatment, using it in this patient, a scheme that had not been previously reported in the literature.

Descripción del caso: Mujer de 42 años con compromiso inflamatorio pulmonar y mediastinal severo, secundario a infiltración de un material alogénico relacionado con la silicona con migración sistémica. Hallazgos clínicos: La paciente desarrolló estenosis esofágica y bronquial, infecciones recurrentes, desnutrición y deterioro respiratorio, imposibilitando la extracción quirúrgica del material alogénico. Tratamiento y resultado: Mejoría clínica y radiológica lograda tras un tratamiento con múltiples inmunomoduladores intravenosos y orales. Relevancia clínica: El síndrome autoinmune / inflamatorio inducido por adyuvantes (ASIA) es una enfermedad heterogénea que resulta de la exposición a sustancias alógenas en un sujeto con susceptibilidad genética. Estas sustancias inducen fenómenos autoinmunitarios o autoinflamatorios. Desde que ASIA fue descrito hace 10 años, sus criterios diagnósticos continúan en discusión, con un pronóstico incierto. El tratamiento idóneo se basa en eliminar la sustancia causante, pero no siempre es posible, por lo cual se hace necesario iniciar un tratamiento inmunomodulador, empleándose en esta paciente un esquema que no había sido reportado previamente en la literatura.

[Autoimmune/inflammatory syndrome induced by adjuvants. Case report]. / Síndrome autoinmunitario/inflamatorio inducido por adyuvantes. Reporte de caso.

Background: The indiscriminate application of substances for aesthetic purposes, such as silicone in breast implants, leads to the production of common local signs such as inflammation, skin irregularities, edema, erythema, vascular neoformations, and ulcers, which can evolve into general symptoms such as fever, asthenia, weakness, arthralgia or activate the immune system abnormally, causing the appearance of autoimmune diseases. This set of signs and symptoms is called adjuvant-induced autoimmune/inflammatory syndrome. Clinical case: We present the case of a 50-year-old woman with a history of silicone-based breast implants who spontaneously developed a hemorrhagic coagulopathy, type A acquired hemophilia was documented, that is, autoantibodies against coagulation factor VIII. Thanks to the work of a multidisciplinary team, it is possible to successfully diagnose and treat the patient with bridging agents, implant removal and management of associated symptoms. Conclusion: the importance of knowing the pathology is recognized, which, although it is rare, when it occurs has a high mortality rate if it is not diagnosed and treated on time.

Introducción: la aplicación de sustancias con fines estéticos de forma indiscriminada, como es el caso de la silicona en los implantes mamarios, llevan a la producción de signos locales comunes como: inflamación, irregularidad en la piel, edema, eritema, neoformaciones vasculares y úlceras, que pueden evolucionar a síntomas generales como la fiebre, astenia, adinamia, artralgias o a activar, de manera anómala, el sistema inmunitario, causando la aparición de enfermedades autoinmunitarias. A este conjunto de signos y síntomas se le denomina síndrome autoinmunitario/inflamatorio inducido por adyuvantes. Caso clínico: presentamos el caso de una mujer de 50 años con antecedente de implantes mamarios a base de silicona que desarrolla, de manera espontánea, una coagulopatía hemorrágica, se documenta hemofilia tipo A adquirida, es decir, autoanticuerpos contra el factor VIII de la coagulación. Gracias al trabajo de un equipo multidisciplinario se consigue diagnosticar y tratar de manera exitosa a la paciente con agentes de puente, remoción de los implantes y manejo de los síntomas asociados. Conclusión: se reconoce la importancia de conocer la patología que, si bien es rara, cuando se presenta tiene alta tasa de mortalidad si no se diagnostica y trata a tiempo.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): past, present, and future implications.

Adjuvants, as the name indicates, are adjoined material aimed to assist in functioning as when added to vaccines they are meant to boost the effect and strongly stimulate the immune system. The response of the immune system can be unpredictable, and the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was developed to address possible adverse reactions of an autoimmune and inflammatory type that may be caused by adjuvants. While ASIA, as a syndrome, was coined and defined in 2011; reports describing patients with vague and nonspecific clinical symptoms following vaccinations appeared much earlier. In other words, ASIA came to define, arrange, and unite the variety of symptoms, related to autoimmunity, caused not by the vaccine itself, rather by the adjuvant part of the vaccine such as aluminum, among others. Accordingly, the introduction of ASIA enabled better understanding, proper diagnosis, and early treatment of the disorder. Furthermore, ASIA was shown to be associated with almost all body systems and various rheumatic and autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, and systemic sclerosis. In addition, the correlation between COVID-19 and ASIA was noticed during the pandemic. In this review, we summarized the reported effects of adjuvants and medical literature before and after ASIA was defined, the several ways ASIA can manifest and impact different systems of the body, and the incidences of ASIA during the COVID-19 pandemic. It is important to clarify, that vaccines are among, if not the, most effective means of fighting infectious diseases however, we believe that vaccines manufacturing is not above criticism, particularly when it comes to added substances possessing a risk of side effects.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in 2023.

In 2011, a syndrome entitled ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants; Shoenfeld's syndrome) was first described. ASIA aimed to organize under a single umbrella, the existing evidence regarding certain environmental factors which possess immune stimulatory properties, in order to shed light on a common pathway of autoimmune pathogenesis. Such environmental immune stimulators, or adjuvants, include among others: aluminum salts as in vaccines, various medical implants, as well as various infectious agents. After the launch of the ASIA syndrome, the expansion and recognition of this syndrome by different researchers from different countries began. During the past decades, evidence had been accumulating that (auto)immune symptoms can be triggered by exposure to environmental immune stimulatory factors that act as an adjuvant in genetically susceptible individuals. A panoply of unexplained subjective and autonomic-related symptoms has been reported in patients with ASIA syndrome. The current review summarizes and updates accumulated knowledge from the past decades, describing new adjuvants- (e.g. polypropylene meshes) and vaccine- (e.g. HPV and COVID vaccines) induced ASIA. Furthermore, a direct association between inflammatory/autoimmune diseases with ASIA syndrome, will be discussed. Recent cases will strengthen some of the criteria depicted in ASIA syndrome such as clear improvement of symptoms by the removal of adjuvants (e.g. silicone breast implants) from the body of patients. Finally, we will introduce additional factors to be included in the criteria for ASIA syndrome such as: (1) dysregulated non-classical autoantibodies directed against G-protein coupled receptors (GPCRs) of the autonomic nervous system and (2)) small fiber neuropathy (SFN), both of which might explain, at least in part, the development of 'dysautonomia' reported in many ASIA patients.

Síndrome autoimune induzida por adjuvantes (ASIA) sinais e sintomas experienciados por mulheres / Implementation of an intravenous therapy team based on convergent-assistance research / Síndrome autoinmune inducido por adyuvante (ASIA) signos y síntomas experimentados por mujeres

Objetivo: Identificar sinais e sintomas experienciados por mulheres com síndrome autoimune induzida por adjuvantes (ASIA) devido ao uso de prótese mamária e os tratamentos realizados. Método: Estudo de campo de abordagem qualitativa realizado por meio de entrevistas online utilizan-do-se a técnica bola de neve. Incluíram-se 13 participantes. Resultados: A partir da análise dos dados, foram elencadas quatro categorias: conhecimento acerca da síndrome; sinais e sintomas; tratamento; e cuidados e implicações de Enfermagem. Identificaram-se mais de 120 sinais e sintomas, e o explante foi mencionado como tratamento definitivo por todas as entrevistadas. Os sinais e sintomas apresentados pelas participantes vão ao encontro do que é descrito pela literatura. Conclusão: Antes da descoberta da doença, as participantes realizaram tratamento com foco no alívio dos sintomas. Após o diag-nóstico, todas as mulheres procederam com o explante

Objective: To identify signs and symptoms experienced by women with autoimmune/inflammatory syndrome induced by adjuvants (ASIA) due to the use of breast implants and the treatments performed. Method: Field study with a qualitative approach carried out through online interviews using the snowball technique. 13 participants were included. Results: Based on data analysis, four categories were listed: knowledge about the syndrome; signs and symptoms; treatment; and nursing care and implications. Over 120 signs and symptoms were identified, and the explant was mentioned as a defi-nitive treatment by all interviewees. The signs and symptoms presented by the participants are in line with what is described in the literature. Conclusion:Before discovering the disease, the participants underwent treatment focused on symptom relief. After diagnosis, all women proceeded with the explant.Keywords: Autoimmune diseases. Prothesis implantation. Breast implantation. Silicones. Perioperative nursing

Objetivo: Identificar los signos y síntomas experimentados por mujeres con síndrome autoinmune inducido por adyuvantes (ASIA) debido al uso de implantes mamarios y los tratamientos realizados. Método: Estudio de campo con enfoque cualitativo realizado a través de entrevistas en línea utilizando la técnica de bola de nieve. Se incluyeron 13 participantes. Resultados: Con base en el análisis de los datos, se enumeraron cuatro categorías: conocimiento sobre el síndrome; signos y síntomas; tratamiento; y cuidados e implicaciones de enfermería. Se identificaron más de 120 signos y sínto-mas, y todos los entrevistados mencionaron el explante como tratamiento definitivo. Los signos y síntomas presentados por los participantes están en línea con lo descrito en la literatura. Conclusión: Antes de descubrir la enfermedad, los participantes realizaban un tratamiento enfocado en el alivio de los síntomas. Después del diagnóstico, todas las mujeres procedieron al explante

ASIA syndrome with severe lupus - A case report.

The autoimmune/inflammatory syndrome induced by adjuvants (ASIA), also known as Shoenfeld's syndrome, encompasses several autoimmune conditions/phenomena that are triggered following the exposure to materials with an adjuvant activity known to augment an antigen-driven immune response. In some inherently vulnerable patients, they act as second hits to trigger or unmask an autoimmune disorder which ranges from generalized non-specific constitutional symptoms, and autoantibody production, to a new onset, of a fully-fledged autoimmune syndrome. In this manuscript, we present a case of a 37-year-old lady who developed systemic lupus erythematosus characterized by mucocutaneous, musculoskeletal, hematological neurological, and renal involvement a few years after silicone breast implants.

Autoimmune/autoinflammatory syndrome induced by adjuvants: a focus on silicone.

Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) was first described in 2011 to cover disorders characterized by dysregulation of the immune system after exposure to an adjuvant. In the present review, the authors focus on silicone-induced ASIA. In the last two decades, there has been worldwide increase in the use of silicone breast implant (SBI) as an aesthetic procedure, raising concerns for possible effects on the immune system, especially in people who already have previous immune dysregulation. The authors did a critical review of the most important articles referring to silicone-induced ASIA, including most recent studies regarding physiopathologic mechanism. Despite large-scale epidemiological studies conducted to assess the association between SBI and autoimmune/rheumatic disorders, the results remain inconclusive, and the debate over the safety of SBIs remains heated. The explantation of silicone breast has been indicated for silicone-induced ASIA with improvement of unspecific symptoms in the majority of patients; however, the outcome seems different in patients with definitive autoimmune rheumatic disease (AIRD). There is no prospective study evaluating the risk of flares after SBI in patients who already have an AIRD. Therefore, based on the literature, we cannot contraindicate the procedure; however, we need to advertise about the risk of ASIA to the patients with AIRD. Long-term safety and implant-related outcomes should be discussed with these patients, considering each case individually, assessing genetic and environmental factors, and determining if the autoimmune disease is in remission or not, for shared decision among patient and the physician.

CpG ODN (K3)-toll-like receptor 9 agonist-induces Th1-type immune response and enhances cytotoxic activity in advanced lung cancer patients: a phase I study.

BACKGROUND: Cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) (K3)-a novel synthetic single-stranded DNA immune adjuvant for cancer immunotherapy-induces a potential Th1-type immune response against cancer cells. We conducted a phase I study of CpG ODN (K3) in patients with lung cancer to assess its safety and patients' immune responses. METHODS: The primary endpoint was the proportion of dose-limiting toxicities (DLTs) at each dose level. Secondary endpoints included safety profile, an immune response, including dynamic changes in immune cell and cytokine production, and progression-free survival (PFS). In a 3 + 3 dose-escalation design, the dosage levels for CpG ODN (K3) were 5 or 10 mg/body via subcutaneous injection and 0.2 mg/kg via intravenous administration on days 1, 8, 15, and 29. RESULTS: Nine patients (eight non-small-cell lung cancer; one small-cell lung cancer) were enrolled. We found no DLTs at any dose level and observed no serious treatment-related adverse events. The median observation period after registration was 55 days (range: 46-181 days). Serum IFN-α2 levels, but not inflammatory cytokines, increased in six patients after the third administration of CpG ODN (K3) (mean value: from 2.67 pg/mL to 3.61 pg/mL after 24 hours). Serum IFN-γ (mean value, from 9.07 pg/mL to 12.7 pg/m after 24 hours) and CXCL10 levels (mean value, from 351 pg/mL to 676 pg/mL after 24 hours) also increased in eight patients after the third administration. During the treatment course, the percentage of T-bet-expressing CD8+ T cells gradually increased (mean, 49.8% at baseline and 59.1% at day 29, p = 0.0273). Interestingly, both T-bet-expressing effector memory (mean, 52.7% at baseline and 63.7% at day 29, p = 0.0195) and terminally differentiated effector memory (mean, 82.3% at baseline and 90.0% at day 29, p = 0.0039) CD8+ T cells significantly increased. The median PFS was 398 days. CONCLUSIONS: This is the first clinical study showing that CpG ODN (K3) activated innate immunity and elicited Th1-type adaptive immune response and cytotoxic activity in cancer patients. CpG ODN (K3) was well tolerated at the dose settings tested, although the maximum tolerated dose was not determined. TRIAL REGISTRATION: UMIN-CTR number 000023276. Registered 1 September 2016, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000026649.

Trivalent chromium supplementation ameliorates adjuvant induced rheumatoid arthritis through up-regulation of FOXP3 and decrease in synovial Cathepsin G expression.

BACKGROUND: Rheumatoid arthritis (RA) is a known debilitating autoimmune disease. Immune-suppressants that are used for disease treatment have serious side effects, therefore, trivalent chromium (Cr (III)); which has shown evidence of its influences on some inflammatory pathways and cytokines; was used in this study for the first time to be assessed for its therapeutic effect in RA rat model and was compared to prednisolone in a trial to find a treatment with lesser side effects. METHODS: Adult male albino rats were randomly divided into four groups: normal, untreated RA, prednisolone treated RA (1.25 mg/kg/day) and Cr (III) treated RA groups (80 µg/kg/day), induction of RA was done by subcutaneous complete Freund adjuvant injection. Study duration was 4 weeks throughout which arthritis scoring and weight measurement were pursued. Histopathological examination and immunohistochemical FOXP3 assessment were done for joint biopsies. Serum inflammatory markers (interleukin 17, interleukin 10, CRP) and synovial erosive arthritis marker (Cathepsin G) were measured. HDL and non-HDL cholesterol were estimated as well. RESULTS: Cr (III) treatment showed marked clinical and histopathological improvement, also astonishing anti-inflammatory effects (increase in FOXP3 expression and interleukin 10, with decrease in interleukin 17, CRP and synovial Cathepsin G) to the extent that Cr (III) effects on inflammation abolishment were comparable to that of prednisolone and even better at some aspects. Moreover, Cr (III) was protective from side effects, i.e., weight gain and dyslipidemia that were seen with prednisolone treatment. CONCLUSIONS: Cr (III) is promising in treating RA and it lacks some side effects of accustomed immune-modulatory agents including prednisolone. Further experimental studies and clinical trials should be held to see the efficacy of Cr (III) in different doses and to assess its long term side effects when used for rheumatoid arthritis and other autoimmune diseases treatment.

Risk factors for granulomas in children following immunization with aluminium-adsorbed vaccines: A Danish population-based cohort study.

BACKGROUND: Aluminium-adsorbed vaccines may in some children cause severely itching nodules at the injection site, known as vaccination granulomas. OBJECTIVE: To investigate vaccine-, child- and maternal-level risk factors for the development of vaccination granulomas following immunization with aluminium-adsorbed vaccines. METHODS: A Danish population-based cohort study with 553 932 children born in Denmark from 1 January 2009 to 31 December 2018, vaccinated with an aluminium-adsorbed vaccine during the first year of life, followed until 31 December 2020. Poisson regression was used to estimate granuloma rate ratios according to the type of adjuvant, accumulated dose of aluminium, timing of vaccination appointments, sex, gestational age, having siblings with granulomas, maternal age and maternal ethnicity. RESULTS: We identified 1901 vaccination granuloma cases (absolute risk, 0.34%). Among vaccine level factors, revaccination (third vs. first vaccination appointment, adjusted rate ratio [RR] 1.26, 95% confidence interval [CI] 1.03-1.55), the specific adjuvant used (aluminium phosphate vs. hydroxide, RR 0.58, 95% CI 0.48-0.70) and dosage (≥1.0 mg vs. <1.0 mg, RR 1.34, 95% CI 1.19-1.52) were associated with risk of granulomas; the timing of vaccination appointments was not. Among child-level factors, female sex (vs. males, RR 1.12, 95% CI, 1.02-1.22), prematurity (vs. term birth, RR 0.71, 95% CI, 0.54-0.93) and having sibling(s) with granulomas (vs. no siblings with granulomas, RR 46.15, 95% CI, 33.67-63.26) were associated with risk of granulomas. Among maternal-level factors, non-Danish ethnicity (vs. Danish, RR 0.51, 95% CI, 0.42-0.63) and young maternal age (<20 years vs. 20-39 years, RR 0.46, 95% CI 0.25-0.83) were associated with risk of granulomas. CONCLUSIONS: Several risk factors for vaccination granulomas at the vaccine, child and maternal levels, were identified. Reducing the dose of aluminium or replacing aluminium hydroxide with aluminium phosphate could reduce the risk of granulomas. However, this must be balanced against the potential for reduced immunogenicity.

Safety, immunogenicity, and protection provided by unadjuvanted and adjuvanted formulations of a recombinant plant-derived virus-like particle vaccine candidate for COVID-19 in nonhuman primates.

Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, effective vaccines are essential to control the current coronavirus disease 2019 (COVID-19) pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here, we report the immunogenicity and protection induced in rhesus macaques by intramuscular injections of a VLP bearing a SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytidine-phospho-guanosine (CpG) 1018. Although a single dose of the unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after priming) and adjuvant administration significantly improved both responses, with higher immunogenicity and protection provided by the AS03-adjuvanted CoVLP. Fifteen micrograms of CoVLP adjuvanted with AS03 induced a polyfunctional interleukin-2 (IL-2)-driven response and IL-4 expression in CD4 T cells. Animals were challenged by multiple routes (i.e., intratracheal, intranasal, and ocular) with a total viral dose of 106 plaque-forming units of SARS-CoV-2. Lower viral replication in nasal swabs and bronchoalveolar lavage fluid (BALF) as well as fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of proinflammatory cytokines and chemotactic factors in the BALF were observed in animals immunized with the CoVLP adjuvanted with AS03. No clinical, pathologic, or virologic evidence of vaccine-associated enhanced disease was observed in vaccinated animals. The CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.

Whether Immunostimulants Are Effective in Susceptible Children Suffering From Recurrent Respiratory Tract Infections: A Modeling Analysis Based on Literature Aggregate Data.

Immunostimulants are gradually being used in the prevention and treatment of recurrent respiratory tract infections in susceptible children, but their drug effects have not been quantified. The purpose of this study was to confirm the efficacy of immunostimulants in the prevention and treatment of recurrent respiratory tract infections in susceptible children. A model-based meta-analysis was used to describe the time course of placebo and immunostimulants in the prevention of respiratory tract infections in children. The cumulative number of respiratory tract infections was used as an indicator of efficacy. A meta-analysis was used to analyze the incidence of drug-related adverse events. Fourteen articles with 2400 pediatric subjects were finally included in the analysis. The results showed that the cumulative number of respiratory tract infections increased linearly with time, with the incidence of respiratory tract infections in the placebo group being 0.65 (95% confidence interval [CI], 0.55-0.75) per month. OM-85 BV and pidotimod reduced the incidence of respiratory tract infections by 0.21 (95%CI, 0.16-0.26) and 0.19 (95%CI, 0.17-0.21) compared to placebo per month, respectively. Pidotimod and OM-85 BV can effectively reduce the incidence of respiratory tract infections in susceptible children, with no significant increase in the incidence of drug-related adverse events when compared with placebo (risk ratio values were 1.07 [95%CI, 0.66-1.71] and 1.31 [95%CI, 0.54-3.19], respectively). This study provides quantitative support for the application of immunostimulants for the prevention of recurrent respiratory tract infections in children.

Pentahydroxy flavonoid isolated from Madhuca indica ameliorated adjuvant-induced arthritis via modulation of inflammatory pathways.

Rheumatoid arthritis (RA) is an autoimmune disease associated with advanced joint dysfunction. Madhuca indica J. F. Gmel, from the family Sapotaceae, is an Indian medicinal plant reported to have an array of pharmacological properties. The aim of present investigation was to determine the anti-arthritic potential of an isolated phytoconstituent from methanolic leaf extract of Madhuca indica (MI-ALC) against FCA-induced experimental arthritis. Polyarthritis was induced in female rats (strain: Wistar) via an intradermal injection of FCA (0.1 mL) into the tail. Polyarthritis developed after 32 days of FCA administration. Then rats were treated orally with an isolated phytoconstituent from MI-ALC at doses of 5, 10, and 20 mg/kg. Findings suggested that High-Performance Thin-Layer Chromatography, Fourier-Transform Infrared Spectroscopy, and Liquid Chromatography-Mass Spectrometry spectral analyses of the phytoconstituent isolated from MI-ALC confirmed the structure as 3,5,7,3',4'-Pentahydroxy flavone (i.e., QTN). Treatment with QTN (10 and 20 mg/kg) showed significant (p < 0.05) inhibition of increased joint diameter, paw volume, paw withdrawal threshold, and latency. The elevated synovial oxidative stress (Superoxide dismutase, reduced glutathione, and malondialdehyde) and protein levels of Tumor necrosis factor-α (TNF-α) and Interleukin (ILs) were markedly (p < 0.05) reduced by QTN. It also effectively (p < 0.05) ameliorated cyclooxygenase-2 (COX-2), Nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kß) and its inhibitor-α (Ikßα), and ATP-activated P2 purinergic receptors (P2X7) protein expressions as determined by western blot analysis. In conclusion, QTN ameliorates FCA-induced hyperalgesia through modulation of elevated inflammatory release (NF-kß, Ikßα, P2X7, and COX-2), oxido-nitrosative stress, and pro-inflammatory cytokines (ILs and TNF-α) in experimental rats.

Does COVID-19 Vaccination Warrant the Classical Principle "ofelein i mi vlaptin"?

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic warrants an imperative necessity for effective and safe vaccination, to restrain Coronavirus disease 2019 (COVID-19) including transmissibility, morbidity, and mortality. In this regard, intensive medical and biological research leading to the development of an arsenal of vaccines, albeit incomplete preconditioned evaluation, due to emergency. The subsequent scientific gap raises some concerns in the medical community and the general public. More specifically, the accelerated vaccine development downgraded the value of necessary pre-clinical studies to elicit medium- and long-term beneficial or harmful consequences. Previous experience and pathophysiological background of coronaviruses' infections and vaccine technologies, combined with the global vaccines' application, underlined the obligation of a cautious and qualitative approach, to illuminate potential vaccination-related adverse events. Moreover, the high SARS-CoV-2 mutation potential and the already aggregated genetical alterations provoke a rational vagueness and uncertainty concerning vaccines' efficacy against dominant strains and the respective clinical immunity. This review critically summarizes existing evidence and queries regarding SARS-CoV-2 vaccines, to motivate scientists' and clinicians' interest for an optimal, individualized, and holistic management of this unprecedented pandemic.

A Reduced Dose Whole Virion Aluminum Adjuvanted Seasonal Influenza Vaccine Is Immunogenic, Safe, and Well Tolerated in Pediatric Patients.

BACKGROUND: Data suggest that pediatric patients might react differently to influenza vaccination, both in terms of immunity and side effects. We have recently shown that using a whole virion vaccine with aluminum phosphate adjuvants, reduced dose vaccines containing 6 µg of viral hemagglutinin (HA) per strain are immunogenic, and well tolerated in adult and elderly patients. Here we show the results of a multicenter clinical trial of pediatric patients, using reduced doses of a new, whole virion, aluminum phosphate adjuvanted vaccine (FluArt, Budapest, Hungary). METHODS: A total of 120 healthy volunteers were included in two age groups (3-11 years, receiving 3 µg of HA per strain, and 12-18 years, receiving 6 µg of HA per strain). We used hemagglutination inhibition testing to assess immunogenicity, based on EMA and FDA licensing criteria, including post/pre-vaccination geometric mean titer ratios, seroconversion and seropositivity rates. Safety and tolerability were assessed using CHMP guidelines. RESULTS: All subjects entered the study and were vaccinated (ITT population). All 120 subjects attended the control visit on Day 21 (PP population). All immunogenicity licensing criteria were met in both age groups for all three vaccine virus strains. No serious adverse events were detected and the vaccine was well tolerated by both age groups. DISCUSSION: Using a whole virion vaccine and aluminum phosphate adjuvants, a reduction in the amount of the viral hemmaglutinin is possible while maintaining immunogenicity, safety and tolerability in pediatric and adolescent patients.