A Dual-Adjuvanted Parenteral-Intranasal Subunit Nanovaccine generates Robust Systemic and Mucosal Immunity Against SARS-CoV-2 in Mice.

Existing parenteral SARS-CoV-2 vaccines produce only limited mucosal responses, essential for reducing transmission and achieving sterilizing immunity. Appropriately designed mucosal boosters can overcome the shortcomings of parenteral vaccines and enhance pre-existing systemic immunity. Here, a new protein subunit nanovaccine is developed by utilizing dual-adjuvanted (RIG-I: PUUC RNA and TLR-9: CpG DNA) polysaccharide-amino acid-lipid nanoparticles (PAL-NPs) along with SARS-CoV-2 S1 trimer protein, that can be delivered both intramuscularly (IM) and intranasally (IN) to generate balanced mucosal-systemic SARS-CoV-2 immunity. Mice receiving IM-Prime PUUC+CpG PAL subunit nanovaccine, followed by an IN-Boost, developed high levels of IgA, IgG, and cellular immunity in the lungs and showed robust systemic humoral immunity. Interestingly, as a purely intranasal subunit vaccine (IN-Prime/IN-Boost), PUUC+CpG PAL-NPs induced stronger lung-specific T cell immunity than IM-Prime/IN-Boost, and a comparable IgA and neutralizing antibodies, although with a lower systemic antibody response, indicating that a fully mucosal delivery route for SARS-CoV-2 vaccination may also be feasible. The data suggest that PUUC+CpG PAL subunit nanovaccine is a promising candidate for generating SARS-CoV-2 specific mucosal immunity.

Improvement in pain by using lidocaine combined with esketamine in elderly patients receiving local anaesthesia for percutaneous kyphoplasty: a randomized controlled study.

BACKGROUND: Elderly patients often experience severe pain during percutaneous kyphoplasty under local anaesthesia. The aim of this work was to evaluate the effect of lidocaine combined with esketamine on pain improvement in elderly patients receiving local anaesthesia via percutaneous kyphoplasty. METHODS: This prospective, randomized comparative trial was conducted on 66 elderly patients, aged 60-80 years, with an American Society of Anaesthesiologists (ASA) grade of I-III, I‒III and a BMI of 18.5-25 kg/m2, who underwent single-level lumbar percutaneous kyphoplasty under local anaesthesia. Patients were divided into two equal groups (33 per group). Group LE received 200 mg of 1% lidocaine and 25 mg of esketamine (total volume of 20 ml), and Group L received 200 mg of 1% lidocaine (total volume of 20 ml). Patient characteristics, surgery, VAS scores, MAP, HR, MOAA/S scores, patient satisfaction and related adverse reactions were compared for the groups. The VAS scores during and after surgery were considered the primary outcome. RESULTS: There were statistically significant differences in the VAS score between the two groups at the following time points: channel establishment by the puncture needle, balloon dilation, bone cement injection and postoperative period (P < 0.05). The VAS score decreased in the LE group, but the MAP and HR were more stable, and the difference was statistically significant (P < 0.05). The difference in the MOAA/S score between the two groups was statistically significant (P < 0.05), and the MOAA/S score in the LE group decreased. The patient satisfaction level in the LE group was 100% and 48.48% in the L group (P < 0.05). There were no related complications or adverse reactions in either group. CONCLUSION: The application of lidocaine combined with esketamine in local episcopal percutaneous vertebral kyphoplasty in elderly patients not only provides an effective analgesic effect but also improves surgical safety and patient comfort, which has important clinical value in promoting the optimization of surgical anaesthesia management in elderly patients. TRIAL REGISTRATION: The study was registered at Chictr.org.cn with the number ChiCTR2400083466 on 06/12/2023.

Role of Adjuvants in Enhancing the Efficacy and Duration of Anesthesia Blocks: A Comprehensive Review.

Anesthesia blocks are integral to modern pain management, offering targeted and effective relief for various surgical and procedural interventions. These techniques, including regional and peripheral nerve blocks (PNBs), involve the administration of local anesthetics to specific body areas, either through epidural, spinal, or direct nerve injections. While effective, incorporating adjuvants, substances added to local anesthetics, can significantly enhance their efficacy and prolong their duration. Adjuvants such as opioids, corticosteroids, alpha-2 agonists, and nonsteroidal anti-inflammatory drugs (NSAIDs) are used to amplify analgesic effects, reduce the need for general anesthesia, and improve postoperative outcomes. This review explores the role of adjuvants in optimizing anesthesia blocks, examining their mechanisms of action, clinical benefits, and safety considerations. Adding adjuvants can lead to enhanced pain control, reduced dosage of local anesthetics, and fewer systemic side effects. By integrating adjuvants into anesthesia practice, clinicians can achieve more precise and sustained pain management, tailoring approaches to individual patient needs and specific procedural demands. This comprehensive review highlights current evidence on using adjuvants, their impact on anesthesia block effectiveness, and future research directions. Understanding the role of adjuvants is crucial for improving patient outcomes and advancing pain management techniques in various surgical settings.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): A case of systemic symptoms following breast implants and vaccinations.

INTRODUCTION AND IMPORTANCE: The Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA) is a recently recognized entity characterized by a constellation of nonspecific symptoms that develop after exposure to adjuvants. Adjuvants can include vaccines, silicone, and other foreign substances. Here, we present the case of a 31-year-old woman who developed ASIA syndrome following breast implants and booster vaccinations, emphasizing the diagnostic challenges and treatment considerations. CASE PRESENTATION: A 31-year-old female presented with a history of progressive systemic symptoms including chronic fatigue, myalgia, arthralgia, and headaches, four months after receiving breast implants. Her clinical history was further complicated by multiple vaccinations, including influenza and SARS-CoV-2 boosters. After extensive diagnostic workup and unsuccessful medical management, she was diagnosed with ASIA syndrome. The decision was made to remove the implants, leading to rapid and complete resolution of her symptoms. CLINICAL DISCUSSION: ASIA syndrome is a difficult diagnosis due to its broad symptomatology and its mimicry of other autoimmune and inflammatory conditions. Diagnostic criteria, proposed by Shoenfeld et al., include exposure to adjuvants and the appearance of typical clinical manifestations such as fatigue, myalgias, and arthralgias. In this case, the temporal association with breast implants and vaccinations made the diagnosis more evident. Surgical removal of the implants led to immediate improvement, reinforcing the diagnosis. CONCLUSION: This case highlights the importance of recognizing ASIA syndrome as a potential diagnosis in patients with exposure to adjuvants and unexplained systemic symptoms. Early diagnosis and intervention, such as removal of the triggering adjuvant, are essential for patient recovery. EVIDENCE BASED MEDICINE RANKING: Level IV.

A TLR7 Agonist Conjugated to a Nanofibrous Peptide Hydrogel as a Potent Vaccine Adjuvant.

Toll-like receptors (TLRs) recognize pathogen- and damage-associated molecular patterns and, in turn, trigger the release of cytokines and other immunostimulatory molecules. As a result, TLR agonists are increasingly being investigated as vaccine adjuvants. Many of these agonists are small molecules that quickly diffuse away from the vaccination site, limiting their co-localization with antigens and, thus, their effect. Here, the small-molecule TLR7 agonist 1V209 is conjugated to a positively-charged multidomain peptide (MDP) hydrogel, K2, which was previously shown to act as an adjuvant promoting humoral immunity. Mixing the 1V209-conjugated K2 50:50 with the unfunctionalized K2 produces hydrogels that retain the shear-thinning and self-healing physical properties of the original MDP while improving the solubility of 1V209 more than 200-fold compared to the unconjugated molecule. When co-delivered with ovalbumin as a model antigen, 1V209-functionalized K2 produces a robust Th2 immune response and an antigen-specific Th1 immune response superior to alum, a widely used vaccine adjuvant. Together, these results suggest that K2 MDP hydrogels functionalized with 1V209 are a promising adjuvant for vaccines against infectious diseases, especially those benefiting from a combined Th1 and Th2 immune response.

Continuous Treatment with IncobotulinumtoxinA Despite Presence of BoNT/A Neutralizing Antibodies: Immunological Hypothesis and a Case Report.

Botulinum Neurotoxin A (BoNT/A) is a bacterial protein that has proven to be a valuable pharmaceutical in therapeutic indications and aesthetic medicine. One major concern is the formation of neutralizing antibodies (nAbs) to the core BoNT/A protein. These can interfere with the therapy, resulting in partial or complete antibody (Ab)-mediated secondary non-response (SNR) or immunoresistance. If titers of nAbs reach a level high enough that all injected BoNT/A molecules are neutralized, immunoresistance occurs. Studies have shown that continuation of treatment of neurology patients who had developed Ab-mediated partial SNR against complexing protein-containing (CPC-) BoNT/A was in some cases successful if patients were switched to complexing protein-free (CPF-) incobotulinumtoxinA (INCO). This seems to contradict the layperson's basic immunological understanding that repeated injection with the same antigen BoNT/A should lead to an increase in antigen-specific antibody titers. As such, we strive to explain how immunological memory works in general, and based on this, we propose a working hypothesis for this paradoxical phenomenon observed in some, but not all, neurology patients with immunoresistance. A critical factor is the presence of potentially immune-stimulatory components in CPC-BoNT/A products that can act as immunologic adjuvants and activate not only naïve, but also memory B lymphocyte responses. Furthermore, we propose that continuous injection of a BoN/TA formulation with low immunogenicity, e.g., INCO, may be a viable option for aesthetic patients with existing nAbs. These concepts are supported by a real-world case example of a patient with immunoresistance whose nAb levels declined with corresponding resumption of clinical response despite regular INCO injections.

Comparative Ability of Various Immunosuppressants as Adjuvants on the Activity of T1D Vaccine.

Background: Type 1 diabetes (T1D) is an autoimmune disorder characterised by the destruction of insulin-producing beta cells in the pancreatic islets, resulting from a breakdown in immunological tolerance. Currently, T1D treatment primarily relies on insulin replacement or immunosuppressive therapies. However, these approaches often have significant drawbacks, including adverse effects, high costs, and limited long-term efficacy. Consequently, there is a pressing need for innovative immunotherapeutic strategies capable of inducing antigen-specific tolerance and protecting beta cells from autoimmune destruction. Among the various antigens, ß-cell antigens like 65 kDa glutamic acid decarboxylase (GAD65) have been explored as vaccine candidates for T1D. Despite their potential, their effectiveness in humans remains modest, necessitating the use of appropriate adjuvants to enhance the vaccine's protective effects. Methods: In this study, we evaluated the therapeutic potential of kynurenine (KYN), dexamethasone (DXMS), tacrolimus (FK506), and aluminium hydroxide (Alum) in combination with the GAD65 phage vaccine as adjuvants. Results: Our findings demonstrate that KYN, when used in conjunction with the GAD65 vaccine, significantly enhances the vaccine's immunosuppressive effects. Compared to dexamethasone, FK506, and Alum adjuvants, KYN more effectively reduced the incidence and delayed the onset of T1D, preserved ß-cell function, and promoted the induction of regulatory T cells and antigen-specific tolerance. These results suggest that KYN combined with vaccines could offer superior preventive and therapeutic benefits for T1D compared to existing treatments. Additionally, we investigated the dose-dependent effects of the GAD65 vaccine by including a low-dose group in our study. The results indicated that reducing the vaccine dose below 1010 plaque-forming units (pfu) did not confer any protective advantage or therapeutic benefit in combination with KYN. This finding underscores that 1010 pfu is the minimum effective dose for the GAD65 vaccine in achieving a protective response. In conclusion, KYN shows considerable promise as an adjuvant for the GAD65 vaccine in T1D therapy, potentially offering a more effective and durable treatment option than current immunosuppressive strategies.

ASIA Syndrome: State-of-the-Art and Future Perspectives.

The expression "Autoimmune/inflammatory syndrome induced by adjuvants (ASIA)" was coined by Shoenfeld and colleagues in 2011. It defines a group of immune-mediated disorders that arise in people, with a genetic predisposition, following exposure to adjuvant agents. This syndrome has been reported after contact with silicone implants, medications, infections, metals, vaccines, and other substances. It typically occurs in individuals with a genetic predisposition, particularly involving genes, such as HLA-DRB1 (major histocompatibility complex, class II, DR beta 1) and PTPN22 (protein tyrosine phosphatase non-receptor type 22). Some stimuli lead to an overactivation of the immune system, prompt the production of autoantibodies, and finally cause autoimmune disorders. This narrative review aims to provide an overview of the ASIA syndrome with a special focus on the role of adjuvants in different vaccines, especially after the COVID-19 pandemic, and insights into development of new treatments.

Basic Properties and Development Status of Aluminum Adjuvants Used for Vaccines.

BACKGROUND: Aluminum adjuvants, renowned for their safety and efficacy, act as excellent adsorbents and vaccine immunogen enhancers, significantly contributing to innate, endogenous, and humoral immunity. An ideal adjuvant not only boosts the immune response but also ensures optimal protective immunity. Aluminum adjuvants are the most widely used vaccine adjuvants and have played a crucial role in both the prevention of existing diseases and the development of new vaccines. With the increasing emergence of new vaccines, traditional immune adjuvants are continually being researched and upgraded. The future of vaccine development lies in the exploration and integration of novel adjuvant technologies that surpass the capabilities of traditional aluminum adjuvants. One promising direction is the incorporation of nanoparticles, which offer precise delivery and controlled release of antigens, thereby enhancing the overall immune response. CONCLUSIONS: This review summarizes the types, mechanisms, manufacturers, patents, advantages, disadvantages, and future prospects of aluminum adjuvants. Although aluminum adjuvants have certain limitations, their contribution to enhancing vaccine immunity is significant and cannot be ignored. Future research should continue to explore their mechanisms of action and address potential adverse reactions to achieve improved vaccine efficacy.

Exploring yeast glucans for vaccine enhancement: Sustainable strategies for overcoming adjuvant challenges in a SARS-CoV-2 model.

Vaccine adjuvants are important for enhancing vaccine efficacy, and although aluminium salts (Alum) are the most used, their limited ability to induce specific immune responses has spurred the search for new adjuvants. However, many adjuvants fail during product development due to manufacturability, supply, stability, or safety concerns. This work hypothesizes that protein-free yeast glucans can be used as vaccine adjuvants due to their known immunostimulatory activity and high abundancy. Thus, high molecular weight glucans with over 99% purity, comprising 64-70% ß-glucans and 29-35% α-glucans, were extracted from a wild-type yeast and an engineered yeast to produce a steviol glycoside. These glucans underwent carboxymethylation to enhance solubility. Both water-dispersible and particulate glucans were evaluated as adjuvants, either alone or in combination with Alum or squalene stable emulsion (SE), for a SARS-CoV-2 vaccine. The study demonstrated that glucans triggered a robust immune response and enhanced the effects of Alum and SE when used in combination, both in vitro and in vivo. Water-dispersible glucans combined with Alum, and particulate glucans combined with SE, increased the production of specific antibodies against SARS-CoV-2 spike protein and enhanced serum neutralization titers against SARS-CoV-2 pseudovirus. Furthermore, the results indicated that larger molecular weight glucans from engineered yeast exhibited stronger immunogenic activity in comparison to wild-type yeast glucans. In conclusion, appropriately formulated glucans have the potential to be scalable, low-cost vaccine adjuvants, potentially overcoming the limitations of current adjuvants.

Rational design of adjuvants boosts cancer vaccines.

Cancer vaccines are expected to be next breakthrough in cancer immunotherapy. In cancer vaccines, adjuvants play an important role by enhancing and reshaping tumor antigen-specific immune responses. Failures in previous cancer vaccine clinical trials can be attributed to inappropriate selection and design of tumor antigens and adjuvants. Using basic theories of tumor immunology, the development of sequencing technology and nanotechnology enables the creation of cancer vaccines through appropriate selection of tumor antigens and adjuvants and their nanoscale assembly based on the specific characteristics of each tumor. In this chapter, we begin by discussing the various types of cancer vaccines and categories of tumor antigens. Then, we summarize the classification of adjuvants for cancer vaccines, including immunostimulatory molecules and delivery systems, and clarify the various factors that influence the properties of adjuvants, such as chemical composition, structure, and surface modification. Finally, we provide perspectives and insights on rational design of adjuvants in cancer vaccines to enhance their efficacy.

Efficacy of nonopioid analgesics and adjuvants in multimodal analgesia for reducing postoperative opioid consumption and complications in obesity: a systematic review and network meta-analysis.

BACKGROUND: Managing postoperative pain in patients with obesity is challenging. Although multimodal analgesia has proved effective for pain relief, the specific impacts of different nonopioid i.v. analgesics and adjuvants on these patients are not well-defined. This study aims to assess the effectiveness of nonsteroidal antiinflammatory drugs, paracetamol, ketamine, α-2 adrenergic receptor agonists, lidocaine, magnesium, and oral gabapentinoids in reducing perioperative opioid consumption and, secondarily, in mitigating the occurrence of general and postoperative pulmonary complications (POPCs), nausea, vomiting, PACU length of stay (LOS), and hospital LOS among surgical patients with obesity. METHODS: A systematic review and network meta-analysis was performed. PubMed, Scopus, Web of Science, CINAHL, and EMBASE were searched. Only English-language RCTs investigating the use of nonopioid analgesics and adjuvants in adult surgical patients with obesity were included. The quality of evidence and certainty were assessed using the RoB 2 tool and GRADE framework, respectively. RESULTS: In total, 37 RCTs involving 3602 patients were included in the quantitative analysis. Compared with placebo/no intervention or a comparator, dexmedetomidine, ketamine, lidocaine, magnesium, and gabapentin significantly reduced postoperative opioid consumption after surgery. Ketamine/esketamine also significantly reduced POPCs. Ibuprofen, dexmedetomidine, and lidocaine significantly reduced postoperative nausea, whereas dexmedetomidine, either alone or combined with pregabalin, and lidocaine reduced postoperative vomiting. Dexmedetomidine significantly reduced PACU LOS, whereas both paracetamol and lidocaine reduced hospital LOS. CONCLUSIONS: Intravenous nonopioid analgesics and adjuvants are crucial in multimodal anaesthesia, reducing opioid consumption and enhancing postoperative care in adult surgical patients with obesity. SYSTEMATIC REVIEW PROTOCOL: CRD42023399373 (PROSPERO).

Safety and efficacy of toll-like receptor agonists as therapeutic agents and vaccine adjuvants for infectious diseases in animals: a systematic review.

Introduction: Strengthening global health security relies on adequate protection against infectious diseases through vaccination and treatment. Toll-like receptor (TLR) agonists exhibit properties that can enhance immune responses, making them potential therapeutic agents or vaccine adjuvants. Methods: We conducted an extensive systematic review to assess the efficacy of TLR agonists as therapeutic agents or vaccine adjuvants for infectious diseases and their safety profile in animals, excluding rodents and cold-blooded animals. We collected qualitative and available quantitative data on the efficacy and safety outcomes of TLR agonists and employed descriptive analysis to summarize the outcomes. Results: Among 653 screened studies, 51 met the inclusion criteria. In this review, 82% (42/51) of the studies used TLR agonists as adjuvants, while 18% (9/51) applied TLR agonist as therapeutic agents. The predominant TLR agonists utilized in animals against infectious diseases was CpG ODN, acting as a TLR9 agonist in mammals, and TLR21 agonists in chickens. In 90% (46/51) of the studies, TLR agonists were found effective in stimulating specific and robust humoral and cellular immune responses, thereby enhancing the efficacy of vaccines or therapeutics against infectious diseases in animals. Safety outcomes were assessed in 8% (4/51) of the studies, with one reporting adverse effects. Discussion: Although TLR agonists are efficacious in enhancing immune responses and the protective efficacy of vaccines or therapeutic agents against infectious diseases in animals, a thorough evaluation of their safety is imperative to in-form future clinical applications in animal studies. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=323122.

Protection against influenza hospitalizations from enhanced influenza vaccines among older adults: A systematic review and network meta-analysis.

BACKGROUND: Influenza vaccines are available to help protect persons aged ≥65 years, who experience thousands of influenza hospitalizations annually. Because some influenza vaccines may work better than others, we sought to assess benefit of high-dose (HD), adjuvanted (ADJ), and recombinant (RIV) influenza vaccines ("enhanced influenza vaccines") compared with standard-dose unadjuvanted influenza vaccines (SD) and with one another for prevention of influenza-associated hospitalizations among persons aged ≥65 years. METHODS: We searched MEDLINE, Embase, CINAHL, Scopus, and Cochrane Library to identify randomized or observational studies published between January 1990 and October 2023 and reporting relative vaccine effectiveness (rVE) of HD, ADJ, or RIV for prevention of influenza-associated hospitalizations among adults aged ≥65 years. We extracted study data, assessed risk of bias, and conducted random-effects network meta-analysis and meta-regression. RESULTS: We identified 32 studies with 90 rVE estimates from five randomized and 27 observational studies (71,459,918 vaccinated participants). rVE estimates varied across studies and influenza seasons. Pooled rVE from randomized studies was 20% (95% CI -54 to 59) and 25% (95% CI -19 to 53) for ADJ and HD compared with SD, respectively; rVE was 6% (95% CI -109 to 58) for HD compared with ADJ; these differences were not statistically significant. In observational studies, ADJ, HD, and RIV conferred modestly increased protection compared with SD (rVE ranging from 10% to 19%), with no significant differences between HD, ADJ, and RIV. With enhanced vaccines combined, rVE versus SD was 18% (95% CI 3 to 32) from randomized and 11% (95% CI 8 to 14) from observational evidence. Meta-regression of observational studies suggested that those requiring laboratory confirmation of influenza reported greater benefit of enhanced vaccines. CONCLUSIONS: HD, ADJ, and RIV provided stronger protection than SD against influenza hospitalizations among older adults. No differences in benefit were observed in comparisons of enhanced influenza vaccines with one another.

Complement C5a Receptor Signaling in Macrophages Enhances Trained Immunity Through mTOR Pathway Activation.

Complement C5a receptor (C5aR) signaling in immune cells has various functions, inducing inflammatory or anti-inflammatory responses based on the type of ligand present. The Co1 peptide (SFHQLPARSRPLP) has been reported to activate C5aR signaling in dendritic cells. We investigated the effect of C5aR signaling via the Co1 peptide on macrophages. In peritoneal macrophages, the interaction between C5aR and the Co1 peptide activated the mTOR pathway, resulting in the production of pro-inflammatory cytokines. Considering the close associations of mTOR signaling with IL-6 and TNF-α in macrophage training, our findings indicate that the Co1 peptide amplifies ß-glucan-induced trained immunity. Overall, this research highlights a previously underappreciated aspect of C5aR signaling in trained immunity, and posits that the Co1 peptide is a potentially effective immunomodulator for enhancing trained immunity.

Adjuvant Use of the Invariant-Natural-Killer-T-Cell Agonist α-Galactosylceramide Leads to Vaccine-Associated Enhanced Respiratory Disease in Influenza-Vaccinated Pigs.

Invariant natural killer T (iNKT) cells are glycolipid-reactive T cells with potent immunoregulatory properties. iNKT cells activated with the marine-sponge-derived glycolipid, α-galactosylceramide (αGC), provide a universal source of T-cell help that has shown considerable promise for a wide array of therapeutic applications. This includes harnessing iNKT-cell-mediated immune responses to adjuvant whole inactivated influenza virus (WIV) vaccines. An important concern with WIV vaccines is that under certain circumstances, they are capable of triggering vaccine-associated enhanced respiratory disease (VAERD). This immunopathological phenomenon can arise after immunization with an oil-in-water (OIW) adjuvanted WIV vaccine, followed by infection with a hemagglutinin and neuraminidase mismatched challenge virus. This elicits antibodies (Abs) that bind immunodominant epitopes in the HA2 region of the heterologous virus, which purportedly causes enhanced virus fusion activity to the host cell and increased infection. Here, we show that αGC can induce severe VAERD in pigs. However, instead of stimulating high concentrations of HA2 Abs, αGC elicits high concentrations of interferon (IFN)-γ-secreting cells both in the lungs and systemically. Additionally, we found that VAERD mediated by iNKT cells results in distinct cytokine profiles and altered adaptation of the challenge virus following infection compared to an OIW adjuvant. Overall, these results provide a cautionary note about considering the formulation of WIV vaccines with iNKT-cell agonists as a potential strategy to modulate antigen-specific immunity.

Characterization of the Immune-Modulating Properties of Different ß-Glucans on Myeloid Dendritic Cells.

In allergen-specific immunotherapy, adjuvants are explored for modulating allergen-specific Th2 immune responses to re-establish clinical tolerance. One promising class of adjuvants are ß-glucans, which are naturally derived sugar structures and components of dietary fibers that activate C-type lectin (CLR)-, "Toll"-like receptors (TLRs), and complement receptors (CRs). We characterized the immune-modulating properties of six commercially available ß-glucans, using immunological (receptor activation, cytokine secretion, and T cell modulating potential) as well as metabolic parameters (metabolic state) in mouse bone marrow-derived myeloid dendritic cells (mDCs). All tested ß-glucans activated the CLR Dectin-1a, whereas TLR2 was predominantly activated by Zymosan. Further, the tested ß-glucans differentially induced mDC-derived cytokine secretion and activation of mDC metabolism. Subsequent analyses focusing on Zymosan, Zymosan depleted, ß-1,3 glucan, and ß-1,3 1,6 glucan revealed robust mDC activation with the upregulation of the cluster of differentiation 40 (CD40), CD80, CD86, and MHCII to different extents. ß-glucan-induced cytokine secretion was shown to be, in part, dependent on the activation of the intracellular Dectin-1 adapter molecule Syk. In co-cultures of mDCs with Th2-biased CD4+ T cells isolated from birch allergen Bet v 1 plus aluminum hydroxide (Alum)-sensitized mice, these four ß-glucans suppressed allergen-induced IL-5 secretion, while only Zymosan and ß-1,3 glucan significantly suppressed allergen-induced interferon gamma (IFNγ) secretion, suggesting the tested ß-glucans to have distinct effects on mDC T cell priming capacity. Our experiments indicate that ß-glucans have distinct immune-modulating properties, making them interesting adjuvants for future allergy treatment.

Vaccines and allergy: Back to the right places.

Hypersensitivity reactions represent one of the most common causes of hesitancy for adherence to national vaccination programs. The majority of hypersensitivity reactions after vaccination are mild, and anaphylaxis is reported to be rare, although it remains challenging to estimate the frequency attributed to each single vaccine, either because of the lower number of administered doses of less common vaccines, or the administration of simultaneous vaccine in most of the vaccination programs. Although literature remains scattered, international consensus guides clinicians in identifying patients who might need the administration of vaccines in protected environments due to demonstrated hypersensitivity to vaccine components or adjuvants. Here we provide the current guidance on hypersensitivity reactions to vaccines and on vaccination of children with allergy disorders.

Anticancer agent 5-fluorouracil reverses meropenem resistance in carbapenem-resistant Gram-negative pathogens.

The global increasing incidence of clinical infections caused by carbapenem-resistant Gram-negative pathogens requires urgent and effective treatment strategies. Antibiotic adjuvants represent a promising approach to enhance the efficacy of meropenem against carbapenem-resistant bacteria. This study shows that the anticancer agent 5-fluorouracil (5-FU, 50 µM) significantly reduced the minimum inhibitory concentration of meropenem against blaNDM-5 positive Escherichia coli by 32-fold through cell-based high-throughput screening. Further pharmacological studies indicated that 5-FU exhibited potentiation effects on carbapenem antibiotics against 42 Gram-negative bacteria producing either metallo-ß-lactamases (MBLs), such as NDM and IMP, or serine ß-lactamases (Ser-BLs), like KPC and OXA. These bacteria included E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp., 32 of which were obtained from human clinical samples. Mechanistic investigations revealed that 5-FU inhibited the transcription and expression of the blaNDM-5 gene. In addition, 5-FU combined with meropenem enhanced bacterial metabolism, and stimulated the production of reactive oxygen species (ROS), thereby rendering bacteria more susceptible to meropenem. In a mouse systemic infection model, 5-FU combined with meropenem reduced bacterial loads and effectively elevated the survival rate of 83.3%, compared with 16.7% with meropenem monotherapy. Collectively, these findings indicate the potential of 5-FU as a novel meropenem adjuvant to improve treatment outcomes against infections caused by carbapenem-resistant bacteria.