Antibody-dependent Enhancement Research Articles

Nasally delivered chitosan-coated poly(lactide-co-glycolide) encapsulating honeybee venom enhances T helper 1-related immunity against Salmonella Typhimurium infection in pigs.

Salmonella Typhimurium is a significant zoonotic concern for human food poisoning and a substantial economic burden in the swine industry. We previously reported that nasally delivered chitosan-coated poly(lactide-co-glycolide) (PLGA) encapsulating honeybee venom (CP-HBV) could enhance CD4+ T helper 1 (Th1)-related immune responses in healthy pigs. Building upon these findings, the current study aimed to investigate the protective immune enhancement by nasally delivered CP-HBV in pigs challenged with S Typhimurium. 36 healthy, 4-week-old, female, Landrace X Yorkshire X Duroc pigs. 36 pigs were allocated into 3 groups: CP-HBV (n = 16), control (n = 16), and healthy baseline control (n = 4). CP-HBV and control groups were challenged with S Typhimurium 7 days post-treatment. Pigs from the healthy control group were sacrificed at 0 days postinfection (DPI), and 4 pigs from each of the control and CP-HBV groups were sacrificed at 1, 2, 4, and 7 DPI. Salmonella shedding, immune cell frequencies, cytokines, and transcriptional factor expression levels were measured. The CP-HBV group exhibited lower bacterial shedding and an enhanced Th1-related immune response characterized by an upregulation of CD4+ T cells and CD4+ Interferon-γ+ T cells, accompanied by increased expression of Th1-related cytokines and reduced expression of regulatory T cells and immunosuppressive cytokines compared to the control group. CP-HBV is a promising strategy for controlling Salmonella infections in pigs and improving public health.

Immunostimulatory activity of the aqueous extract from the leaves of Sambucus racemosa subsp. pendula through TLR4‑dependent JNK activation in RAW264.7 cells.

Sambucus racemosa subsp. pendula (SRP) is an endemic plant of Korea, exclusively found on Ulleungdo Island. SRP is widely used as both a traditional medicine and food source. However, there is a lack of research on the pharmacological activities of SRP. Therefore, the present study aimed to explore the potential use of SRP leaves (SRPL) as a natural immunostimulant by analyzing its macrophage activation properties and the underlying mechanisms of action. Among the various extraction conditions, SRPL (AE20-SRPL) extracted with 100% distilled water at 20˚C induced the highest nitric oxide (NO) production in RAW264.7 cells. Thus, the further studies were performed using AE20-SRPL. AE20-SRPL increased the production of immunostimulatory factors such as NO, prostaglandin E2, inducible nitric oxide synthase, cyclooxygenase-2, IL-1β and TNF-α and phagocytosis in a dose-dependent manner in RAW264.7 cells without exhibiting cytotoxicity. Among Toll-like receptor (TLR)2 and TLR4, inhibition of TLR4 significantly reduced AE20-SRPL-mediated increases in the production of immunostimulatory factors and phagocytosis in RAW264.7 cells. Furthermore, in RAW264.7 cells, inhibition of JNK, one of the components of MAPK signaling along with ERK1/2 and p38, attenuated the AE20-SRPL-mediated increases in the production of immunostimulatory factors and phagocytosis. Additionally, AE20-SRPL induced the phosphorylation of JNK and inhibition of TLR4 reduced AE20-SRPL-mediated JNK phosphorylation. These results suggested that AE20-SRPL may enhance the production of immunostimulatory factors and phagocytosis through TLR4-dependent activation of JNK in macrophages. Although the present study is limited to in vitro research using a cell model, AE20-SRPL demonstrated potential as a natural material capable of inducing macrophage activation for immune enhancement.

An In Silico Design of a Vaccine against All Serotypes of the Dengue Virus Based on Virtual Screening of B-Cell and T-Cell Epitopes.

Dengue virus poses a significant global health challenge, particularly in tropical and subtropical regions. Despite the urgent demand for vaccines in the control of the disease, the two approved vaccines, Dengvaxia and TV003/TV005, there are current questions regarding their effectiveness due to an increased risk of antibody-dependent enhancement (ADE) and reduced protection. These challenges have underscored the need for further development of improved vaccines for Dengue Virus. This study presents a new design using an in silico approach to generate a more effective dengue vaccine. Initially, our design process began with the collection of Dengue polyprotein sequences from 10 representative countries worldwide. And then conserved fragments of viral proteins were retrieved as the bases for epitope screening. The selection of epitopes was then carried out with criteria such as antigenicity, immunogenicity, and binding affinity with MHC molecules, while the exclusion criteria were according to their allergenicity, toxicity, and potential for antibody-dependent enhancement. We then constructed a core antigen with the selected epitopes and linked the outcomes with distinct adjuvant proteins, resulting in three candidate vaccines: PSDV-1, PSDV-2, and PSDV-3. Among these, PSDV-2 was selected for further validation due to its superior physicochemical and structural properties. Extensive simulations demonstrated that PSDV-2 exhibited strong binding to pattern recognition receptors, high stability, and robust immune induction, confirming its potential as a high-quality vaccine candidate. For its recombinant expression, a plasmid was subsequently designed. Our new vaccine design offers a promising additional option for Dengue virus protection. Further experimental validations will be conducted to confirm its protective efficacy and safety.

Effect of Selenium and Selenoproteins on Radiation Resistance.

With the advancement of radiological medicine and nuclear industry technology, radiation is increasingly used to diagnose human health disorders. However, large-scale nuclear leakage has heightened concerns about the impact on human organs and tissues. Selenium is an essential trace element that functions in the body mainly in the form of selenoproteins. Selenium and selenoproteins can protect against radiation by stimulating antioxidant actions, DNA repair functions, and immune enhancement. While studies on reducing radiation through antioxidants have been conducted for many years, the underlying mechanisms of selenium and selenoproteins as significant antioxidants in radiation damage mitigation remain incompletely understood. Therefore, this paper aims to provide new insights into developing safe and effective radiation protection agents by summarizing the anti-radiation mechanism of selenium and selenoproteins.

Efficacy of Qi-Gen powder for immunity enhancement and investigation of its therapeutic mechanisms through gene expression profiling

Infection with different viruses threatens the health of animals in the livestock and poultry industry. Immunopotentiators can increase natural immunity and vaccination efficacy; however, most are expensive chemical and biological compounds with questionable safety. Traditional Chinese medicines (TCMs) such as Yupingfeng (YPF), a well-known immunomodulatory remedy, provide healthy alternatives to such agents. The aim of this study was to examine the therapeutic properties of Qi-Gen powder (QG) and compare them with those of YPF. The immune organ index, cytokine levels, and other indicators were utilized to evaluate the effects of QG in an immunosuppression mouse model. QG was further assessed for its ability to enhance vaccine effectiveness in chickens immunized for Newcastle disease virus (NDV). Potential therapeutic mechanisms and targets of QG were examined in the breast cancer cell line MCF-7 using microarray technology combined with the TCM systems pharmacology database of known targets. Compared with model controls, QG improved immunological function, outperforming YPF in mice. QG also enhanced the immunological response to NDV vaccine in immune organs and increased feed intake of chickens. Further research is needed to validate the link between the PI3K/Akt/GSK-3 pathway and the immune-boosting effects of QG.

Tibetan tea extract exerts anti-tumor effects and potentiate paclitaxel-induced cytotoxicity and apoptosis in human hepatocellular carcinoma cells HepG2

Tibetan Tea (TT), traditionally esteemed by indigenous communities on the Qinghai-Tibet Plateau for over thirteen centuries, is a post-fermented tea recognized for its wide spectrum of biological functions. These include antioxidant capabilities, hypocholesterolemic effects, anti-hyperglycemic properties, and immune system enhancement. Nevertheless, additional medicinal potentials of TT, including its anticancer effects, remain to be unveiled in empirical studies. We aimed to evaluate the antiproliferative and chemotherapy-enhancing effects of TT extract on human hepatocellular carcinoma (HCC) cells, thereby initiating an inquiry into the potential molecular mechanisms involved. In this study, it was observed that TT extract suppressed the proliferation of HCC cells and triggered significant apoptosis. This apoptotic induction was facilitated through the activation of caspase-3, caspase-8, and caspase-9, along with decreased expression ratio of Bcl-2/Bax protein in HCC cells. Moreover, the combinational treatment of TT extract and Paclitaxel (Taxol) was found to enhance the anticancer effect. The expression level of P-glycoprotein (P-gp) encoded by the MDR1 (Multiple Drug Resistance) gene was remarkably decreased, revealing that TT extract might have the potential to be utilized as an adjuvant to promote HCC treatment. In conclusion, the Tibetan Tea extract exhibits cytotoxic, anticancer, and chemosensitization properties.

Treating Deep-Seated Tumors with Radiodynamic Therapy: Progress and Perspectives.

Radiodynamic therapy (RDT), as an emerging cancer treatment method, has attracted attention due to its remarkable therapeutic efficacy using low-dose, high-energy radiation (such as X-rays) and has shown significant potential in cancer treatment. The RDT system typically consists of scintillators and photosensitizers (PSs). Scintillators absorb X-rays and convert them to visible light, activating nearby PSs to generate cytotoxic reactive oxygen species (ROS). Challenges faced by the two-component strategy, including low loading capacity and inefficient energy transfer, hinder its final effectiveness. In addition, the tumor microenvironment (TME) with hypoxia and immunosuppression limits the efficacy of RDTs. Recent advances introduce one-component RDT systems based on nanomaterials with high-Z metal elements, which effectively inhibit deep-seated tumors. These novel RDT systems exhibit immune enhancement and immune memory, potentially eliminating both primary and metastatic tumors. This review comprehensively analyzes recent advances in the rational construction of RDTs, exploring their mechanisms and application in the treatment of deep-seated tumors. Aimed at providing a practical resource for oncology researchers and practitioners, the review offers new perspectives for potential future directions in RDT research.

Nonreciprocity in CHIKV and MAYV Vaccine-Elicited Protection.

Chikungunya virus (CHIKV) is a pathogenic arthritogenic alphavirus responsible for large-scale human epidemics for which a vaccine was recently approved for use. Mayaro virus (MAYV) is a related emerging alphavirus with epidemic potential with circulation overlap potential with CHIKV. We previously reported the ability of a non-replicating human adenovirus (AdV)-vectored vaccine expressing the MAYV structural polyprotein to protect against disease in mice following challenge with MAYV, CHIKV and UNAV. Herein, we evaluated mouse immunity and protective efficacy for an AdV-CHIKV full structural polyprotein vaccine in combination with heterologous AdV-MAYV prime/boost regimens versus vaccine coadministration. Heterologous prime/boost regimens skewed immunity toward the prime vaccine antigen but allowed for a boost of cross-neutralizing antibodies, while vaccine co-administration elicited robust, balanced responses capable of boosting. All immunization strategies protected against disease from homologous virus infection, but reciprocal protective immunity differences were revealed upon challenge with heterologous viruses. In vivo passive transfer experiments reproduced the inequity in reciprocal cross-protection after heterologous MAYV challenge. We detected in vitro antibody-dependent enhancement of MAYV replication, suggesting a potential mechanism for the lack of cross-protection. Our findings provide important insights into rational alphavirus vaccine design that may have important implications for the evolving alphavirus vaccine landscape.

A chemometric study comparing nutritional profiles and functional attributes of two botanical forms of Lablab Bean (Lablab purpureus (L.) Sweet)

Growing health awareness has stimulated a focus on natural immune enhancement. Lablab beans {Lablab purpureus (L.) Sweet}, abundant in bioactive compounds, were investigated for protein, mineral, and vitamin profiles. This research specifically conducted a comparative analysis between two distinct botanical forms: Lablab purpureus var. typicus L. and L. purpureus var. lignosus L, focusing on their nutritional profiles. Among L. purpureus var. typicus L. genotypes, RCPD-6 exhibited the highest protein content (25.46 ± 0.29 g/100 g) followed by RCPD-1 (23.74 ± 0.26 g/100 g). In contrast, L. purpureus var. lignosus L., L. purpureus var. lignosus L. particularly genotype RCPD-22, had lower protein content (19 ± 0.15 g/100 g). Significant variations in Fe content were observed within L. purpureus var. typicus L., ranging from 5.97 ± 0.01 to 10.5 ± 0.02 mg/100 g, with RCPD-2 reported the highest. Zn content ranged from 1.7 ± 0.01 to 3.65 ± 0.02 mg/100 g in both forms. The calcium content in L. purpureus var. typicus L. genotypes are found to be high, ranging from 372.72 ± 0.02 mg/100 g to 458.75 ± 0.03 mg/100 g, suggesting that var. typicus holds promise as a significant dietary source of Ca. P content exhibited variability, ranging from 317.12 ± 0.01 to 460.07 ± 0.06 mg/100 g. L. purpureus var. typicus L. shows correlated levels of protein/Zn, vitamins A/C, and antioxidant activities (DPPH/ABTS) suggesting targeted breeding for co-improved health benefits. It is noteworthy that L. purpureus var. typicus L., whose pods are consumed as vegetables, exhibits higher nutritional content in terms of protein, iron, calcium, and vitamin A. This clearly suggests that L. purpureus var. typicus L. surpasses L. purpureus var. lignosus L. in nutritional value. To strengthen findings, chemometric techniques such as principal component analysis (PCA) and agglomerative hierarchical clustering (AHC) were employed for differentiation between the two botanical forms. These methods highlight the disparities in their nutritional profiles and functional characteristics. PCA analysis demonstrated that the first three components encapsulated 80.67 % of the overall variability. Meanwhile, AHC grouped cultivars into two major clusters which can be divided into two sub-groups based on the evaluated parameters. The data obtained provide a significant contribution to the scientific evaluation of the two botanical forms of lablab bean, particularly in terms of their nutritional profiles and functional attributes.

From Diagnosis to Recovery: The Life-Changing Benefits of Exercise for Cancer Patients

Physical activity has emerged as a crucial component in the comprehensive care of oncological patients, offering significant benefits across the cancer continuum—from prevention to treatment, recovery, and survivorship. This article provides an in-depth exploration of the role of exercise in cancer care, highlighting its potential to improve physical function, reduce treatment-related side effects, enhance mental well-being, and improve overall quality of life. Epidemiological evidence supports the protective effect of regular physical activity in reducing the risk of developing certain cancers, such as breast, colorectal, and endometrial cancer, through mechanisms like hormonal regulation, inflammation reduction, and immune function enhancement. During active cancer treatment, exercise helps combat common side effects such as fatigue, muscle wasting, and cardiovascular decline, while also offering psychological benefits like reduced anxiety and depression. Tailored exercise programs, developed in collaboration with healthcare professionals, are essential for addressing the unique needs of cancer patients, considering factors like cancer type, treatment stage, and comorbidities. Post-treatment, physical activity continues to play a vital role in rehabilitation, reducing the risk of recurrence, and supporting long-term survivorship. Despite the clear benefits, barriers such as physical limitations, psychological distress, and lack of access to resources can hinder patients' ability to engage in regular exercise. Addressing these challenges through personalized care plans, patient education, and supportive interventions is crucial. As research in exercise oncology advances, integrating physical activity into routine cancer care holds promise for improving outcomes and enhancing the overall well-being of cancer patients.

Lonicera japonica Fermented by Lactobacillus plantarum Improve Multiple Patterns Driven Osteoporosis.

Osteoporosis (OP) represents a global health challenge. Certain functional food has the potential to mitigate OP. Honeysuckle (Lonicera japonica) solution has medicinal effects, such as anti-inflammatory and immune enhancement, and can be used in functional foods such as health drinks and functional snacks. The composition of honeysuckle changed significantly after fermentation, and 376 metabolites were enriched. In this study, we used dexamethasone to induce OP in the rat model. Research has confirmed the ability of FS (fermented Lonicera japonica solution) to enhance bone mineral density (BMD), repair bone microarchitectural damage, and increase blood calcium levels. Markers such as tartrate-resistant acid phosphatase-5b (TRACP-5b) and pro-inflammatory cytokines (TNF-α and IL-6) were notably decreased, whereas osteocalcin (OCN) levels increased after FS treatment. FS intervention in OP rats restored the abundance of 6 bacterial genera and the contents of 17 serum metabolites. The results of the Spearman correlation analysis showed that FS may alleviate OP by restoring the abundance of 6 bacterial genera and the contents of 17 serum metabolites, reducing osteoclast differentiation, promoting osteoblast differentiation, and reducing the inflammatory response. This study revealed that Lactobacillus plantarum-fermented honeysuckle alleviated OP through intestinal bacteria and serum metabolites and provided a theoretical basis for the development of related functional foods.

Immunologic Crosstalk and Host-Specific Immune Signature Associated with Dengue.

In tropical and subtropical regions, dengue fever is a common febrile illness that is mostly spread by Aedes mosquitoes. Urban population migration, inadequate water storage facilities, and high mosquito density are features associated with this disease. The severity of the illness ranges from mild to deadly dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), often with severe cases causing profound shock from extensive plasma leakage, and may result in demise. The symptoms of the illness include headache, myalgia, retro-orbital pain, and hemorrhagic signs. There may also be an intermittent shift in blood vessel integrity and coagulation, but recovery is typically complete and rapid. In this review, we emphasize the immunological aspects of this illness. The intricate interactions among the virus, host genes, and host immune systems impact the pathophysiology of dengue. Postinfection antibody-dependent enhancement is prominent, which significantly influences the etiology and virulence of the disease. Whereas the severe form only manifests when the host immune system is actively working to eradicate the infection by secreting several inflammatory cytokines, chemokines, and lipid mediators, for example, early dengue virus infection (DVI) resulted in the production of Interleukin 2 (IL-2), IL-6, and later infection, IL-4, IL-5, and IL-10. Higher concentrations of interferons gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage migration inhibitory factor (MIF), IL-1, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, and IL-13 were found in DHF patients. These are significantly more prevalent in severe infections than in mild ones. Numerous immunopathogenic processes involving both virus and host variables influence the severity of dengue. There is growing evidence that a compromised immune system limits viral clearance and causes severe inflammation, which in turn causes dengue hemorrhagic fever and dengue shock syndrome. Furthermore, the capacity of DENV to infect a broad range of immune cells, such as macrophages, dendritic cells, mast cells, T and B cells, and monocytes, further dysregulates these cells' antiviral activities, leading to the spread of the virus. Even though a number of risk factors linked to the advancement of the disease have been suggested, further research and evaluation of novel technologies are necessary to understand the complicated etiology and develop reliable and effective vaccines to fight against this febrile illness.

Regulatory Effects of Alhagi Honey Small-Molecule Sugars on Growth Performance and Intestinal Microbiota of Lambs.

The present study was designed to assess the impact of Alhagi honey small-molecule sugars (AHAS) on Hu lambs. Therefore, in this study, AHAS low-dose (AHAS-L, 200 mg/ kg per day), AHAS medium-dose (AHAS-M, 400 mg/kg per day), and AHAS high-dose (AHAS-H, 800 mg/kg per day) were administered to Hu lambs to investigate the regulatory effects of AHAS on growth performance, oxidation index, immune system enhancement, and intestinal microbiota. The results showed that lambs in the AHAS-H group exhibited significantly increased in average daily weight gain, and growth performance compared to those in the control group (p < 0.05). Moreover, AHAS-H supplementation resulted in increased levels of serum antioxidant enzymes (SOD, GSH-Px, and T-AOC), serum antibodies (IgA, IgG, and IgM), and cytokines (IL-4, 10,17, IFN-γ, and TNF-α) compared with the control group (p < 0.05). Additionally, it increased the quantity and richness of beneficial bacteria at such as Sphingomonas, Ralstonia, and Flavobacterium, activating various metabolic pathways and promoting the production of various short-chain fatty acids. In summary, our findings highlight the potential of AHAS-H treatment in enhancing intestinal health of lambs by improving intestinal function, immunity, and related metabolic pathways. Consequently, these results suggest that AHAS holds promising potential as a valuable intervention for optimizing growth performance and intestinal health in lambs.

Dengue virus: pathogenesis and potential for small molecule inhibitors.

Dengue, caused by dengue virus (DENV), is now endemic in nearly 100 countries and infection incidence is reported in another 30 countries. Yearly an estimated 400 million cases and 2200 deaths are reported. Effective vaccines against DENV are limited and there has been significant focus on the development of effective antiviral against the disease. The World Health Organization has initiated research programs to prioritize the development and optimization of antiviral agents against several viruses including Flaviviridae. A significant effort has been taken by the researchers to develop effective antivirals against DENV. Several potential small-molecule inhibitors like efavirenz, tipranavir and dasabuvir have been tested against envelope and non-structural proteins of DENV, and are in clinical trials around the world. We recently developed one small molecule, namely 7D, targeting the host PF4-CXCR3 axis. 7D inhibited all 4 serotypes of DENV in vitro and specifically DENV2 infection in two different mice models. Although the development of dengue vaccines remains a high priority, antibody cross reactivity among the serotypes and resulting antibody-dependent enhancement (ADE) of infection are major concerns that have limited the development of effective vaccine against DENV. Therefore, there has been a significant emphasis on the development of antiviral drugs against dengue. This review article describes the rescue effects of some of the small molecule inhibitors to viral/host factors associated with DENV pathogenesis.

Dengue Hemorrhagic Fever in Quang Nam Province (Vietnam) from 2020 to 2022-A Study on Serotypes Distribution and Immunology Factors.

Background: Dengue hemorrhagic fever (DHF) is the most prevalent and fastest-growing vector-borne disease globally, with symptoms ranging from mild to severe and, in some cases, fatal. Quang Nam province in Vietnam can serve as a model for dengue epidemiological study, as it is an endemic region for DHF with a tropical climate, which significantly constrains the health system. However, there are very few epidemiological and microbiological reports on Dengue virus (DENV) serotypes in this region due to the limited availability of advanced surveillance infrastructure. Aims of the study: This study aims to (1) assess the PCR positivity rates among hospitalized patients with clinical Dengue presentation; (2) identify the circulating DENV serotypes; and (3) assess the impact of secondary DENV infections on outbreak severity by detecting the presence of DENV-specific IgG antibodies in the plasma of DENV-infected patients. Materials and methods: Blood samples from patients clinically diagnosed with DHF and admitted to Quang Nam General Hospital (2020-2022) were analyzed. RNA extraction was performed using the NKDNA/RNAprep MAGBEAD kit, followed by Multiplex Reverse Transcription real-time Polymerase Chain Reaction (MLP RT-rPCR) for DENV detection and serotype identification. Positive samples were further tested for DENV-specific IgG antibodies using an enzyme-linked immunosorbent assay (ELISA). Results: The PCR positivity rate among hospitalized patients was approximately 68% throughout the study period. A significant shift in DENV serotypes was observed, with DENV-2 initially dominant and later giving way to DENV-1. IgG was detected in nearly half of the MPL RT-rPCR-positive samples, indicating secondary DENV infections. Conclusions: Our study highlights persistent dengue prevalence and dynamic shifts in DENV serotypes in Quang Nam province, emphasizing the need for improved diagnostic strategies and timely sample collection. The significant serotype shifts and the presence of IgG in hospitalized patients suggest potential severe outcomes from recurrent DENV infections, possibly linked to antibody-dependent enhancement (ADE) effect, underscoring the importance of advanced surveillance, vector control, vaccination campaigns, and public education to predict and prevent future DHF epidemics.

The N and C-terminal deleted variant of the dengue virus NS1 protein is a potential candidate for dengue vaccine development

NS1 is an elusive dengue protein, involved in viral replication, assembly, pathogenesis, and immune evasion. Its levels in blood plasm are positively related to disease severity like thrombocytopenia, hemorrhage, and vascular leakage. Despite its pathogenic roles, NS1 is being used in various vaccine formulations due to its sequence conservancy, ability to produce protective antibodies and low risk for inducing antibody-dependent enhancement. In this study, we have used bioinformatics tools and reported literature to develop an NS1 variant (dNS1). Molecular docking studies were performed to evaluate the receptor-binding ability of the NS1 and dNS1 with TLR4. NS1 and dNS1 (153 to 312 amino acid region) genes were cloned, expressed and protein was purified followed by refolding. Docking studies showed the binding of NS1 and dNS1 with the TLR4 receptor which suggests that N and C-terminal sequences of NS1 are not critical for receptor binding. Antibodies against NS1 and dNS1 were raised in rabbits and binding affinity of anti-dNS1 anti-NS1 sera was evaluated against both NS1 and dNS1. Similar results were observed through western blotting which highlight that N and C-terminal deletion of NS1 does not compromise the immunogenic potential of dNS1 hence, supports its use in future vaccine formulations as a substitute for NS1.

Challenges in the Development of Dengue Vaccine

The development of a dengue vaccine presents numerous challenges, largely due to the complexity of the virus and the human immune response. One of the primary hurdles is Antibody-Dependent Enhancement (ADE), where antibodies from a previous dengue infection can facilitate a more severe secondary infection with a different serotype, exacerbating the disease. Cross-reactivity with other flaviviruses, such as Zika, complicates the immune response further. Additionally, the vaccine must elicit a balanced immune response against all four dengue serotypes, which is difficult to achieve. The role of T follicular helper (TFH) cells in enhancing vaccine efficacy has emerged as a critical area of focus. Efficiently targeting and inducing TFH cells through specific adjuvants could enhance neutralizing antibody production and long-lasting immunity, addressing some of the current vaccine limitations. Despite these challenges, ongoing research and trials continue to advance the field towards a more effective dengue vaccine.

Effects of Aureobasidium Pullulans produced β-1,3-1,6-glucan on CA19-9, sCD44, IgA and sCD209 in patients undergoing surgical resection of malignant pancreatic tumors.

96 Background: Pancreatic cancer is a highly refractory tumor with poor prognosis, which aggressively progresses by suppressing the immunity. Surgical procedure related stress further weakens the immunity and aids cancer stem cell metastases, warranting immune enhancement strategies. AFO-202 strain of Aureobasidium Pullulans produced β-1,3-1,6 glucan (Nichi BRITE), having yielded immune enhancement in earlier studies, we evaluated its effects in patients undergoing surgical resection of malignant pancreatic tumors. Methods: 30 subjects in two groups were enrolled; control arm (n=15, "P" group) received a placebo, and treatment arm (n=15, "G" group) received Nichi BRITE 250mg/day, in three divided doses, for 22 days from the pre-operative day. Serum beta glucan specific IgA2 (BG-IgA), total IgA (IgA), sCD209, Serum Amyloid A (SAA), sCD44 and CA19-9 were evaluated at base line and at periodic intervals. Results: sCD44 significantly decreased 48.94% in “G” group and only 4.58% in “P” group (p = &lt; 0.0001) on day 21. sCD209 on day 21 in “G” group increased by 54.68% (p = 0.04) against 15.03% in “P”. BG-IgA at day 10 increased around 150% in “G”, and only by 6% in “P”. Total IgA, increased by 20.60% in “G” and only 5.73% in “P”. SAA increased to 251.32% in “G” on day 21 and in “P” it decreased by 6.11%. Decreased sCD44 when correlated against Neutrophil to Lymphocyte Ratio (NLR), a significant positive correlation was in “G” (r statistic= 0.758; p-value =0.006; 95% CI= 0.2907~0.9335), but a negative correlation in “P”. Pancreatic cancer marker CA19-9 decreased significantly in three months follow up in “G” (-86.02 U/ml) whereas it increased in “P” by +5.91 U/ml. Mean survival of Nichi BRITE group was 25.9 months against 22.3 months in “P” group. Conclusions: Administration of Nichi BRITE glucans to patients undergoing surgical resection of malignant pancreatic tumor was safe and it enhanced biomarkers of innate and adaptive immunity. Nichi BRITE significantly decreased the circulating cancer stem cell marker sCD44 implying a lesser recurrence risk, especially in patients with high NLR ratio who have a poor prognosis, and significantly reduced the CA 19-9 levels implying a better prognosis, making us recommend it as an adjuvant to patients undergoing surgeries for malignant tumors, and be included in the guidelines of clinical nutrition.

Mechanisms of antibody-dependent enhancement of infectious disease.

Antibody-dependent enhancement (ADE) of infectious disease is a phenomenon whereby host antibodies increase the severity of an infection. It is well established in viral infections but ADE also has an underappreciated role during bacterial, fungal and parasitic infections. ADE can occur during both primary infections and re-infections with the same or a related pathogen; therefore, understanding the underlying mechanisms of ADE is critical for understanding the pathogenesis and progression of many infectious diseases. Here, we review the four distinct mechanisms by which antibodies increase disease severity during an infection. We discuss the most established mechanistic explanation for ADE, where cross-reactive, disease-enhancing antibodies bound to pathogens interact with Fc receptors, thereby enhancing pathogen entry or replication, ultimately increasing the total pathogen load. Additionally, we explore how some pathogenic antibodies can shield bacteria from complement-dependent killing, thereby enhancing bacterial survival. We interrogate the molecular mechanisms by which antibodies can amplify inflammation to drive severe disease, even in the absence of increased pathogen replication. We also examine emerging roles for autoantibodies in enhancing the pathogenesis of infectious diseases. Finally, we discuss how we can leverage these insights to improve vaccine design and future treatments for infectious diseases.

An Engineered N-Glycosylated Dengue Envelope Protein Domain III Facilitates Epitope-Directed Selection of Potently Neutralizing and Minimally Enhancing Antibodies.

The envelope protein of dengue virus (DENV) is a primary target of the humoral immune response. The domain III of the DENV envelope protein (EDIII) is known to be the target of multiple potently neutralizing antibodies. One such antibody is 3H5, a mouse antibody that binds strongly to EDIII and potently neutralizes DENV serotype 2 (DENV-2) with unusually minimal antibody-dependent enhancement (ADE). To selectively display the binding epitope of 3H5, we strategically modified DENV-2 EDIII by shielding other known epitopes with engineered N-glycosylation sites. The modifications resulted in a glycosylated EDIII antigen termed "EDIII mutant N". This antigen was successfully used to sift through a dengue-immune scFv-phage library to select for scFv antibodies that bind to or closely surround the 3H5 epitope. The selected scFv antibodies were expressed as full-length human antibodies and showed potent neutralization activity to DENV-2 with low or negligible ADE resembling 3H5. These findings not only demonstrate the capability of the N-glycosylated EDIII mutant N as a tool to drive an epitope-directed antibody selection campaign but also highlight its potential as a dengue immunogen. This glycosylated antigen shows promise in focusing the antibody response toward a potently neutralizing epitope while reducing the risk of antibody-dependent enhancement.