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BACKGROUND: HVTN 120 is a phase 1/2a randomized double-blind placebo-controlled human immunodeficiency virus (HIV) vaccine trial that evaluated the safety and immunogenicity of ALVAC-HIV (vCP2438) and MF59- or AS01B-adjuvanted bivalent subtype C gp120 Env protein at 2 dose levels in healthy HIV-uninfected adults. METHODS: Participants received ALVAC-HIV (vCP2438) alone or placebo at months 0 and 1. At months 3 and 6, participants received either placebo, ALVAC-HIV (vCP2438) with 200 μg of bivalent subtype C gp120 adjuvanted with MF59 or AS01B, or ALVAC-HIV (vCP2438) with 40 μg of bivalent subtype C gp120 adjuvanted with AS01B. Primary outcomes were safety and immune responses. RESULTS: We enrolled 160 participants, 55% women, 18-40 years old (median age 24 years) of whom 150 received vaccine and 10 placebo. Vaccines were generally safe and well tolerated. At months 6.5 and 12, CD4+ T-cell response rates and magnitudes were higher in the AS01B-adjuvanted groups than in the MF59-adjuvanted group. At month 12, HIV-specific Env-gp120 binding antibody response magnitudes in the 40 μg gp120/AS01B group were higher than in either of the 200 μg gp120 groups. CONCLUSIONS: The 40 μg dose gp120/AS01B regimen elicited the highest CD4+ T-cell and binding antibody responses. Clinical Trials Registration . NCT03122223.

QS-21 is a potent vaccine adjuvant and remains the only saponin-based adjuvant that has been clinically approved for use in humans1,2. However, owing to the complex structure of QS-21, its availability is limited. Today, the supply depends on laborious extraction from the Chilean soapbark tree or on low-yielding total chemical synthesis3,4. Here we demonstrate the complete biosynthesis of QS-21 and its precursors, as well as structural derivatives, in engineered yeast strains. The successful biosynthesis in yeast requires fine-tuning of the host's native pathway fluxes, as well as the functional and balanced expression of 38 heterologous enzymes. The required biosynthetic pathway spans seven enzyme families-a terpene synthase, P450s, nucleotide sugar synthases, glycosyltransferases, a coenzyme A ligase, acyl transferases and polyketide synthases-from six organisms, and mimics in yeast the subcellular compartmentalization of plants from the endoplasmic reticulum membrane to the cytosol. Finally, by taking advantage of the promiscuity of certain pathway enzymes, we produced structural analogues of QS-21 using this biosynthetic platform. This microbial production scheme will allow for the future establishment of a structure-activity relationship, and will thus enable the rational design of potent vaccine adjuvants.

Vaccines represent one of the most significant inventions in human history and have revolutionized global health. Generally, a vaccine functions by triggering the innate immune response and stimulating antigen-presenting cells, leading to a defensive adaptive immune response against a specific pathogens antigen. As a key element, adjuvants are chemical materials often employed as additives to increase a vaccines efficacy and immunogenicity. For over 90 years, adjuvants have been essential components in many human vaccines, improving their efficacy by enhancing, modulating, and prolonging the immune response. Here, we provide a timely and comprehensive review of the historical development and the current status of adjuvants, covering their classification, mechanisms of action, and roles in different vaccines. Additionally, we perform systematic analysis of the current licensing processes and highlights notable examples from clinical trials involving vaccine adjuvants. Looking ahead, we anticipate future trends in the field, including the development of new adjuvant formulations, the creation of innovative adjuvants, and their integration into the broader scope of systems vaccinology and vaccine delivery. The article posits that a deeper understanding of biochemistry, materials science, and vaccine immunology is crucial for advancing vaccine technology. Such advancements are expected to lead to the future development of more effective vaccines, capable of combating emerging infectious diseases and enhancing public health.

QS-21 is a potent vaccine adjuvant currently sourced by extraction from the Chilean soapbark tree. It is a key component of human vaccines for shingles, malaria, coronavirus disease 2019 and others under development. The structure of QS-21 consists of a glycosylated triterpene scaffold coupled to a complex glycosylated 18-carbon acyl chain that is critical for immunostimulant activity. We previously identified the early pathway steps needed to make the triterpene glycoside scaffold; however, the biosynthetic route to the acyl chain, which is needed for stimulation of T cell proliferation, was unknown. Here, we report the biogenic origin of the acyl chain, characterize the series of enzymes required for its synthesis and addition and reconstitute the entire 20-step pathway in tobacco, thereby demonstrating the production of QS-21 in a heterologous expression system. This advance opens up unprecedented opportunities for bioengineering of vaccine adjuvants, investigating structure-activity relationships and understanding the mechanisms by which these compounds promote the human immune response.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in a significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-year treatment period in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-year efficacy results from a prespecified overall survival (OS) interim analysis. In the intent-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with hazard ratios of 0.680 (95% CI, 0.599 to 0.772) for IDFS and 0.675 (95% CI, 0.588 to 0.774) for DRFS. This persistence of abemaciclib benefit translated to continuous separation of the curves with a deepening in 5-year absolute improvement in IDFS and DRFS rates of 7.6% and 6.7%, respectively, compared with rates of 6% and 5.3% at 4 years and 4.8% and 4.1% at 3 years. With fewer deaths in the abemaciclib plus ET arm compared with the ET-alone arm (208 v 234), statistical significance was not reached for OS. No new safety signals were observed. In conclusion, abemaciclib plus ET continued to reduce the risk of developing invasive and distant disease recurrence beyond the completion of treatment. The increasing absolute improvement at 5 years is consistent with a carryover effect and further supports the use of abemaciclib in patients with high-risk EBC.

We previously demonstrated that Alcaligenes-derived lipid A (ALA), which is produced from an intestinal lymphoid tissue-resident commensal bacterium, is an effective adjuvant for inducing antigen-specific immune responses. To understand the immunologic characteristics of ALA as a vaccine adjuvant, we here compared the adjuvant activity of ALA with that of a licensed adjuvant (monophosphoryl lipid A, MPLA) in mice. Although the adjuvant activity of ALA was only slightly greater than that of MPLA for subcutaneous immunization, ALA induced significantly greater IgA antibody production than did MPLA during nasal immunization. Regarding the underlying mechanism, ALA increased and activated CD11b+ CD103- CD11c+ dendritic cells in the nasal tissue by stimulating chemokine responses. These findings revealed the superiority of ALA as a mucosal adjuvant due to the unique immunologic functions of ALA in nasal tissue.

Background Methods Results Conclusions 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.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.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.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. [ABSTRACT FROM AUTHOR]

Background: Supraclavicular brachial plexus blockade (SBPB) is commonly performed regional anesthetic technique for forearm and hand surgeries, and its blockage provides good surgical anesthesia. Aim: Considering the efficacy of adjuvant for ropivacaine in SBPBs, we designed a double-blind randomized control study to compare the characteristics and side effects of ropivacaine along with dexamethasone versus dexmedetomidine in SBPBs in patients scheduled for upper limb surgeries. Material and Methods: Present study was single-center, prospective, randomised, double blind study, conducted patients aged 18-70 years, belonging to American Society of Anaesthesiologists physical status (ASA) of I or II, scheduled for Upper limb surgeries under SBPB. Results: In present study, 108 patients were studied, 54 patients received 20 ml 0.5% Ropivacaine with 50 mcg Dexamethasone (Group A, n=54), while other 54 patients received 20 ml 0.5% Ropivacaine with 50 mcg Dexmedetomidine (Group B, n=54). Age, weight, gender, ASA grade & duration of surgery were comparable in both groups. Dexamethasone group has earlier onset of sensory block, earlier onset of motor block, prolonged duration of sensory block & prolonged duration of motor block as compared to dexmedetomidine group & difference was statistically significant (p< 0.05). Dexamethasone group duration of analgesia, delayed first rescue analgesic requirement & less doses of rescue analgesia required as compared to dexmedetomidine group & difference was statistically significant (p< 0.05). Conclusion: Dexamethasone is a better alternative than dexmedetomidine since it shortens the onset of sensory and motor block, prolongs the duration of sensory and motor block and prolongs the duration of analgesia. [ABSTRACT FROM AUTHOR]

While the pesticide formulations are widely used for pest control, the combined effects of these formulations with adjuvants on droplet behavior, spraying characteristics, and pest control still need to be studied. To clarify their impact on droplet behavior, spraying characteristics, and control efficacy, six formulations of acetamiprid and six adjuvants were examined. A series of laboratory and field experiments were conducted to analyze the physicochemical properties, toxicity against cotton aphids, droplet deposition characteristics, and droplet drift. The results indicated that 5% acetamiprid micro-emulsion (ME) enhanced the physicochemical features and effectiveness in pest control compared to other formulations. The nongjianfei considerably enhanced the efficiency of all acetamiprid formulations when added. The addition of selected adjuvants to pesticide formulations improved the performance of certain physicochemical properties such as viscosity and surface tension and led to higher aphid mortality rates, demonstrating enhanced pest control effectiveness during the present study. In the field experiments, the combination effect of acetamiprid formulations and adjuvants exhibited a higher droplet size, coverage, and density within the cotton canopy. However, 5% acetamiprid ME was found to be most effective followed by nongjianfei. Furthermore, 5% acetamiprid ME with adjuvant reduced the droplet drift and provided better deposition when compared with other formulations. Overall, the combination of specific formulations and adjuvants led to improved physicochemical properties, enhanced droplet deposition characteristics, reduced spray drift, and increased pesticide deposition. These findings highlighted the significance of selecting appropriate pesticide formulations and adjuvants and provided a solid foundation for efficient pesticide spraying through UAVs. [ABSTRACT FROM AUTHOR]

With the continuous advancements in tumor immunotherapy, researchers are actively exploring new treatment methods. Peptide therapeutic cancer vaccines have garnered significant attention for their potential in improving patient outcomes. Despite its potential, only a single peptide-based cancer vaccine has been approved by the U.S. Food and Drug Administration (FDA). A comprehensive understanding of the underlying mechanisms and current development status is crucial for advancing these vaccines. This review provides an in-depth analysis of the production principles and therapeutic mechanisms of peptide-based cancer vaccines, highlights the commonly used peptide-based cancer vaccines, and examines the synergistic effects of combining these vaccines with immunotherapy, targeted therapy, radiotherapy, and chemotherapy. While some studies have yielded suboptimal results, the potential of combination therapies remains substantial. Additionally, we addressed the management and adverse events associated with peptide-based cancer vaccines, noting their relatively higher safety profile compared to traditional radiotherapy and chemotherapy. Lastly, we also discussed the roles of adjuvants and targeted delivery systems in enhancing vaccine efficacy. In conclusion, this review comprehensively outlines the current landscape of peptide-based cancer vaccination and underscores its potential as a pivotal immunotherapy approach. [ABSTRACT FROM AUTHOR]

AbstractMelanoma poses a challenge in oncology because of its aggressive nature and limited treatment modalities. The tumour microenvironment (TME) in melanoma contains unique properties such as an immunosuppressive and high-density environment, unusual vasculature, and a high number of stromal and immunosuppressive cells. In recent years, numerous experiments have focused on boosting the immune system to effectively remove malignant cells. Adjuvants, consisting of phytochemicals, toll-like receptor (TLR) agonists, and cytokines, have shown encouraging results in triggering antitumor immunity and augmenting the therapeutic effectiveness of anticancer therapy. These adjuvants can stimulate the maturation of dendritic cells (DCs) and infiltration of cytotoxic CD8+ T lymphocytes (CTLs). Furthermore, nanocarriers can help to deliver immunomodulators and antigens directly to the tumour stroma, thereby improving their efficacy against malignant cells. The remodelling of melanoma TME utilising phytochemicals, agonists, and other adjuvants can be combined with current modalities for improving therapy outcomes. This review article explores the potential of adjuvants, drugs, and their nanoformulations in enhancing the anticancer potency of macrophages, CTLs, and natural killer (NK) cells. Additionally, the capacity of these agents to repress the function of immunosuppressive components of melanoma TME, such as immunosuppressive subsets of macrophages, stromal and myeloid cells will be discussed. [ABSTRACT FROM AUTHOR]

Leptospirosis, a neglected zoonotic disease, is caused by pathogenic spirochetes belonging to the genus Leptospira and has one of the highest morbidity and mortality rates worldwide. Vaccination stands out as one of the most effective preventive measures for susceptible populations. Within the outer membrane of Leptospira spp., we find the LIC12287, LIC11711, and LIC13259 lipoproteins. These are of interest due to their surface location and potential immunogenicity. Thorough examination revealed the conservation of these proteins among pathogenic Leptospira spp.; we mapped the distribution of T- and B-cell epitopes along their sequences and assessed the 3D structures of each protein. This information aided in selecting immunodominant regions for the development of a chimeric protein. Through gene synthesis, we successfully constructed a chimeric protein, which was subsequently expressed, purified, and characterized. Hamsters were immunized with the chimeric lipoprotein, formulated with adjuvants aluminum hydroxide, EMULSIGEN®-D, Sigma Adjuvant System®, and Montanide™ ISA206VG. Another group was vaccinated with an inactivated Escherichia coli bacterin expressing the chimeric protein. Following vaccination, hamsters were challenged with a virulent L. interrogans strain. Our evaluation of the humoral immune response revealed the production of IgG antibodies, detectable 28 days after the second dose, in contrast to pre-immune samples and control groups. This demonstrates the potential of the chimeric protein to elicit a robust humoral immune response; however, no protection against challenge was achieved. While this study provides valuable insights into the subject, further research is warranted to identify protective antigens that could be utilized in the development of a leptospirosis vaccine. Key points: • Several T- and B-cell epitopes were identified in all the three proteins. • Four different adjuvants were used in vaccine formulations. • Immunization stimulated significant levels of IgG2/3 in vaccinated animals. [ABSTRACT FROM AUTHOR]

The development of human papillomavirus (HPV) vaccines has made substantive progress, as represented by the approval of five prophylactic vaccines since 2006. Generally, the deployment of prophylactic HPV vaccines is effective in preventing newly acquired infections and incidences of HPV-related malignancies. However, there is still a long way to go regarding the prevention of all HPV infections and the eradication of established HPV infections, as well as the subsequent progression to cancer. Optimizing prophylactic HPV vaccines by incorporating L1 proteins from more HPV subtypes, exploring adjuvants that reinforce cellular immune responses to eradicate HPV-infected cells, and developing therapeutic HPV vaccines used either alone or in combination with other cancer therapeutic modalities might bring about a new era getting closer to the vision to get rid of HPV infection and related diseases. Herein, we summarize strategies for the development of HPV vaccines, both prophylactic and therapeutic, with an emphasis on the selection of antigens and adjuvants, as well as implications for vaccine efficacy based on preclinical studies and clinical trials. Additionally, we outline current cutting-edge insights on formulation strategies, dosing schedules, and age expansion among HPV vaccine recipients, which might play important roles in addressing barriers to vaccine uptake, such as vaccine hesitancy and vaccine availability. [ABSTRACT FROM AUTHOR]

Tramadol and remifentanil, which is an opioid analgesic are known to have a local anesthetic effect and the present study aimed to evaluate the local anesthetic efficacy of them on twenty-five adult male rabbits Oryctolagus cuniculus (aged between 10-12 months and weighing 1.5±0.08g) who were divided into five groups received the following treatment subcutaneously for 5 days; G1: 5% Tramadol 15 mg/kg BW; G2: 2% Remifentanil 2 mg/kg BW; G3: 2% Lidocaine 4 mg/kg BW; G4: 2% Remifentanil with epinephrine 0.00l mg/kg BW; and G5:2% Remifentanil with Carbopol gel 2 mg/kg BW. Baseline, pre-anesthetic, and post-anesthetic physiological parameters, including temperature, respiratory rate, and heart rate, were meticulously recorded for all groups following local administration of lidocaine, tramadol, and remifentanil. The results showed that tramadol caused a significant decrease in the temperature while other groups showed non-significant effect, results also revealed that pain evaluation that performed according to Grimace Scale scores and by the behavioral analysis of pain assessment elucidated that Lidocaine treatment group showed a statistically significant lower pain response compared to the Tramadol and Remifentanil groups and further significant improvement in pain were observed with the addition of epinephrine or Carbopol gel to Remifentanil. Both combinations resulted in a statistically significant decrease in pain parameters for all measured features comparing with Tramadol and Remifentanil groups and these results leads to conclude that tramadol and remifentanil showed a comparable anaesthetic effect that improved significantly with epinephrine or carbopol gel as local anaesthetics that may surpass lidocaine local anaesthetic effect significantly. [ABSTRACT FROM AUTHOR]

Introduction: IgE-mediated peanut allergy is an important public health problem of increasing prevalence leading to anaphylactic reactions both in children and adults. Allergen-specific oral immunotherapy (OIT) is the single treatment with the potential capacity to modify the course of the disease, but it still faces some drawbacks in terms of efficacy, safety, patients' adherence, and cost. Alternative strategies, including the use of novel adjuvants, to overcome such limitations are highly demanded. The main aim of this study was to search for potential novel adjuvants for peanut OIT by assessing the capacity of free purified mannan and different toll-like receptor ligands (TLR-Ls) to immunomodulate the responses of human monocyte-derived dendritic cells (hmoDCs) to peanut allergens. Methods: Monocytes were isolated from PBMCs of healthy donors and differentiated into hmoDCs. Flow cytometry, ELISA, coculture, and suppression assay were performed to assess the effects of TLR-Ls, mannan, and crude peanut extract (CPE) in hmoDCs. Results: Purified free mannan increased the expression levels of HLA-DR, CD86, CD83, and PD-L1 and induced a higher IL-10/IL-6 cytokine ratio in hmoDCs compared to the stimulation with different TLR-Ls. Mannan significantly increased the expression of HLA-DR, the maturation marker CD83, the tolerogenic marker PD-L1, as well as the production of IL-10, IL-6, and TNF-α in CPE-stimulated hmoDCs. Supporting these tolerogenic properties, mannan also significantly increased the frequency of FOXP3+ regulatory T cells generated by CPE-treated hmoDCs with functional suppressive capacity. Conclusions: We uncover that purified free mannan induces tolerogenic responses in human DCs stimulated with peanut allergens, suggesting mannan as a suitable potential novel adjuvant to be exploited in the context of OIT for peanut allergy. [ABSTRACT FROM AUTHOR]

Adjuvants, materials added to vaccines to enhance the resulting immune response, are important components of vaccination that are many times overlooked. While vaccines always include an antigen to tell the body what to vaccinate to, of equal importance the adjuvant provides the how, a significant factor in producing a complete response. The adjuvant space has been slow to develop with the first use of an adjuvant in a licensed vaccine occurring in the 1930s, and remaining the only adjuvant in licensed vaccines for the next 80 years. However, with vaccination at the forefront of protection against new and complex pathogens, it is important to consider all components when designing an effective vaccine. Here we summarize the adjuvant space in licensed vaccines as well as the novel adjuvant space in clinical trials with a specific focus on the materials utilized and their resulting impact on the immune response. We discuss five major categories of adjuvant materials: aluminum salts, nanoparticles, viral vectors, TLR agonists, and emulsions. For each category, we delve into the current clinical trials space, the impact of these materials on vaccination, as well as some of the ways in which they could be improved. Adjuvants present an exciting opportunity to improve vaccine responses and stability, this review will help inform about the current progress of this space. Translational impact statement: In the aftermath of the COVID‐19 pandemic, vaccines for infectious diseases have come into the spotlight. While antigens have always been an important focus of vaccine design, the adjuvant is a significant tool for enhancing the immune response to the vaccine that has been largely underdeveloped. This article provides a broad review of the history of adjuvants and, the current vaccine adjuvant space, and the progress seen in adjuvants in clinical trials. There is specific emphasis on the material landscape for adjuvants and their resulting mechanism of action. Looking ahead, while the novel vaccine adjuvant space features exciting new technologies and materials, there is still a need for more to meet the protective needs of new and complex pathogens. [ABSTRACT FROM AUTHOR]

BACKGROUND Spinal anaesthesia is the most common procedure for lower limb orthopaedic surgeries. Fentanyl, a synthetic opioid and dexmedetomidine, a selective α2 agonist have been used in this study as adjuvants to 0.5% hyperbaric bupivacaine for spinal anaesthesia in lower limb orthopaedic surgeries. AIM The main aim of the study is to compare the efficacy, analgesic effects, hemodynamic stability and side effects of intrathecal fentanyl and dexmedetomidine as adjuvants to 0.5% hyperbaric bupivacaine in lower limb orthopaedic surgeries. MATERIALS AND METHODS 100 patients of ASA class 1 and 2 posted for lower limb orthopaedic surgeries were taken for this study. Patients were randomly allocated using sealed envelopes into 2 groups. Group F - 17.5mg of 0.5% hyperbaric bupivacaine with 25mcg fentanyl intrathecally and group D - 17.5mg of 0.5% hyperbaric bupivacaine with 10 mcg of dexmedetomidine intrathecally. RESULTS In patients who have received dexmedetomidine observed to have significantly longer analgesic effects than the other group who received fentanyl as adjuvant. Mean duration of sensory blockade for group D was 455.54 ± 43.09 mins when compared to Group F which was 283.32 ± 23.994 mins. Post operative shivering was more in Group F patients when compared to Group D patients. CONCLUSION Using dexmedetomidine as an adjuvant to hyperbaric bupivacaine for spinal anaesthesia in lower limb orthopaedic surgeries has longer duration of sensory and motor block and longer postoperative analgesia when compared to intrathecal fentanyl. [ABSTRACT FROM AUTHOR]

Background There is little literature about the intrathecal use of dexmedetomidine with local anaesthetics in humans. Also, levobupivacaine is known to have lesser CNS and CVS side-effects than its racemic isomer. Fentanyl is a commonly used intrathecal adjuvant. Aims To compare and evaluate the efficacy of levobupivacaine alone, with dexmedetomidine and with fentanyl as adjuvants in spinal anaesthesia for providing adequate analgesia, hemodynamic stability and minimal sedation after infra-umbilical surgeries. Methods A total of 60 patients of ASA I-II of both sexes aged between 20 and 60 years were randomly allocated into three equal groups of 20 patients each. Group L received isobaric levobupivacaine 15 mg with normal saline as control; group LD received levobupivacaine 15 mg with 5 µg dexmedetomidine and group LF received 15 mg of levobupivacaine with 25 mcg of fentanyl, all made up to 4 ml after diluting with normal saline. Results The demographic profiles were comparable among the three groups. Dexmedetomidine showed early appearance of peak sensory level (5.72±1.05) and motor blockade (2.01±0.685), and early reach T10 segments (2.253±0.69). S1 and Bromage 0 regression times were prolonged with dexmedetomidine (225.87±6.65, 194.75±4.17). Analgesic duration was also significantly prolonged with dexmedetomidine (250.33±8.92). Conclusion Adding dexmedetomidine as an adjuvant to levobupivacaine improves the duration of block and analgesia, resulting in early block achievement with minimal side effects. [ABSTRACT FROM AUTHOR]

The use of intrathecal (IT) dexamethasone during subarachnoid block (SAB) has not been evaluated. There are no pooled data available to decide on the optimal regimen of IT dexamethasone during SAB, irrespective of the type of surgery. There is uncertainty about its dosage, effectiveness, and safety, and a need to establish clear guidelines on its use. Our objective was to evaluate the effectiveness and safety of use of IT dexamethasone during SAB. We performed a meta-analysis (PROSPERO, CRD42022304944) of trials that included patients who underwent a variety of surgical procedures under SAB. Patients received concomitant IT dexamethasone as an adjuvant to spinal local anesthetics. The analyzed outcomes included sensory and motor effects as well as adverse and/or beneficial side effects. Subgroup analysis was planned based on different doses used. Trial sequential analysis (TSA) was used to estimate the required sample size information (RIS) for each outcome. Eighteen studies (2531 participants) were included in this analysis. Addition of IT dexamethasone (4-8 mg) to heavy bupivacaine effectively prolonged the duration of sensory blockade (mean difference, MD = 63.8 minutes; [95% confidence interval, CI, 33.1-94.5], P < 0.0001), two-segment regression time (MD = 20.1[95% CI, 0.96-39.2], P = 0.04) and first rescue analgesic time (MD = 143.3 [95% CI, 90.3-196.0], P = 0.001). Subgroup analyses revealed superior effects of 8 mg dose over 4 mg for sensory and analgesic effects. The effect of dexamethasone on duration of motor blockade was inconclusive. Additionally, lower risk ratios (RRs) were recorded for spinal anesthesia-related hypotension (RR = 0.74 [95% CI, 0.6-0.9], P = 0.0003) and nausea/vomiting (RR = 0.62 [95% CI, 0.41-0.93], P = 0.02) in the dexamethasone group. For outcomes such as sensory blockade, analgesia, and hypotension, the required information size was reached during TSA. In conclusion, IT dexamethasone, used as an adjuvant to spinal local anesthetic, especially at the dose of 8 mg, increases sensory blockade duration and the time for request of the first rescue analgesic. SAB-induced side effects such as hypotension, nausea, and vomiting are lesser with the use of IT dexamethasone. However, further studies are necessary to draw meaningful conclusions on its safety profile. [ABSTRACT FROM AUTHOR]

Aquaculture has rapidly emerged as one of the fastest growing industries, expanding both on global and on national fronts. With the ever-increasing demand for proteins with a high biological value, the aquaculture industry has established itself as one of the most efficient forms of animal production, proving to be a vital component of global food production by supplying nearly half of aquatic food products intended for human consumption. As in classic animal production, the prevention of diseases constitutes an enduring challenge associated with severe economic and environmental repercussions. Nevertheless, remarkable strides in the development of aquaculture vaccines have been recently witnessed, offering sustainable solutions to persistent health-related issues challenging resilient aquaculture production. These advancements are characterized by breakthroughs in increased species-specific precision, improved vaccine-delivery systems, and innovations in vaccine development, following the recent advent of nanotechnology, biotechnology, and artificial intelligence in the -omics era. The objective of this paper was to assess recent developments and milestones revolving around aquaculture vaccinology and provide an updated overview of strengths, weaknesses, opportunities, and threats of the sector, by incorporating and comparatively discussing various diffuse advances that span across a wide range of topics, including emerging vaccine technologies, innovative delivery methods, insights on novel adjuvants, and parasite vaccine development for the aquaculture sector. [ABSTRACT FROM AUTHOR]

Simple Summary: Staphylococcus skin infections in companion animals are a growing concern due to their impact on animal health and the risk of spreading these infections to humans. Traditional antibiotics are becoming less effective because bacteria are developing resistance to them, underlining the need for new alternative treatment approaches to prevent and control staphylococcal infections. This review explores new strategies to fight these infections, including novel antimicrobials, repurposing existing drugs for new uses, natural products, skin antiseptics, and other new treatments. These strategies can help maintain the health of companion animals, reduce the risk of transmission to people, and ultimately benefit public health by limiting the spread of resistant bacteria. The treatment of dermato-pathogenic Staphylococcus spp., particularly Staphylococcus pseudintermedius, in companion animals presents significant challenges due to rising antimicrobial resistance. This review explores innovative strategies to combat these infections. We examined novel antimicrobials and the repurposing of existing drugs to enhance their efficacy against resistant strains. Additionally, we evaluate the potential of natural products, nanomaterials, and skin antiseptics as alternative treatments. The review also investigates the use of antimicrobial peptides and bacteriophages, highlighting their targeted action against staphylococcal pathogens. Furthermore, the role of adjuvants in antibiotic treatments, such as antimicrobial resistance breakers, is discussed, emphasizing their ability to enhance therapeutic outcomes. Our analysis underscores the importance of a multifaceted approach in developing effective antimicrobial strategies for companion animals, aiming to mitigate resistance and improve clinical management of staphylococcal skin infections. [ABSTRACT FROM AUTHOR]

Opinion statementThe treatment landscape of renal cell carcinoma (RCC) has evolved significantly over the past three decades. Active surveillance and tumor ablation are alternatives to extirpative therapy in appropriately selected patients. Stereotactic body radiation therapy (SBRT) is an emerging noninvasive alternative to treat primary RCC tumors. The advent of immune checkpoint inhibitors (ICIs) has greatly improved the overall survival of advanced RCC, and now the ICI-based doublet (dual ICI-ICI doublet; or ICI in combination with a vascular endothelial growth factor tyrosine kinase inhibitor, ICI-TKI doublet) has become the standard frontline therapy. Based on unprecedented outcomes in the metastatic with ICIs, they are also being explored in the neoadjuvant and adjuvant setting for patients with high-risk disease. Adjuvant pembrolizumab has proven efficacy to reduce the risk of RCC recurrence after nephrectomy. Historically considered a radioresistant tumor, SBRT occupies an expanding role to treat RCC with oligometastasis or oligoprogression in combination with systemic therapy. Furthermore, SBRT is being investigated in combination with ICI-doublet in the advanced disease setting. Lastly, given the treatment paradigm is shifting to adopt ICIs at earlier disease course, the prospective studies guiding treatment sequencing in the post-ICI setting is maturing. The effort is ongoing in search of predictive biomarkers to guide optimal treatment option in RCC.

ImportancePropofol sedation is widely used for endoscopic procedures, but it poses risks of hemodynamic and respiratory depression. The addition of esketamine as an adjuvant may reduce propofol requirements and associated adverse events.ObjectiveTo evaluate the effects of low-dose esketamine added to propofol-based sedation on desaturation and hypotension during same-visit bidirectional endoscopy.Design, setting, and participantsThis multicenter, double-blind, placebo-controlled randomized clinical trial assessed patients from 3 teaching hospitals in China who were scheduled for same-visit bidirectional endoscopy between February 8 and November 30, 2022, and randomly assigned to receive esketamine or normal saline (placebo).InterventionsAfter induction of sedation with 0.1 μg/kg of sufentanil and 0.5 mg/kg of propofol, patients in the esketamine group received 0.15 mg/kg of intravenous esketamine, whereas patients in the placebo group received an equivalent volume of saline. Sedation was achieved through propofol titration.Main outcomes and measuresThe primary outcome was the composite of desaturation and hypotension during the procedures. Secondary outcomes included desaturation, hypotension, propofol requirements, postprocedure pain and fatigue, nausea or vomiting, dizziness or headache, hallucination or nightmare, endoscopist satisfaction, and patient satisfaction.ResultsAmong the 663 initially enrolled patients, 660 completed the study (median [IQR] age, 48 [36-57] years; 355 [53.8%] female), with 331 randomized to the esketamine group and 329 to the placebo group. The administration of esketamine compared with placebo significantly reduced the incidence of the composite outcome of desaturation and hypotension (8.2% vs 21.0%; difference, -12.8 percentage points; odds ratio [OR], 0.34; 95% CI, 0.21-0.54; P

Introduction. Vaccination could be the most effective means of preventing hemorrhagic fever with renal syndrome (HFRS), which is one of the leading zoonoses and a major cause of natural disease in humans. Therefore, research to develop an effective vaccine and the search for new non-toxic and effective adjuvants that can enhance and prolong the immune response, reduce the antigen concentration and reduce the frequency of dose administration is an urgent task. The aim of the study was to determine the dependence of the immunogenic activity of an experimental hantavirus vaccine based on Puumala virus (HV) on the antigen dose both in native form and in combination with carbohydrate adjuvants. Materials and methods. The immunoadjuvant effect of Ac3-LPS S. sonnei and S. flexneri 1B and emulsions of nanoemulsified squalene Sepivac SWE (SWE) as part of HV at the optimal and minimal doses was investigated by induction of neutralising antibodies after 3-fold immunisation (day 0, 14, 182) of guinea pigs (Cavia porcellus). Differences in the immunogenic activity of HV were assessed in the neutralisation reaction by 50% suppression of focal units in Vero E6 cell cultures. Results. A statistically significant increase in neutralising antibodies levels was observed after immunization both with HV at the optimal dose and for its combination with adjuvants. Ac3-LPS S. sonnei and SWE showed the most pronounced immunoadjuvant effect at concentrations of 50 and 100 μg/dose, respectively. The immunoadjuvant effect of the combination of the hantavirus vaccine with Ac3-LPS S. sonnei and SWE contributed to both an enhanced immune response and its duration. The tenfold reduction of the antigen dose in the presence of SWE allows optimization of the immune response to the vaccine. Conclusion. The results of this study show the prospects of using Ac3-LPS S. sonnei and Sepivac SWE in the vaccine for the prevention of HFRS.

Oral vaccines are drawing more attention due to their ease of administration, lesser invasiveness, and greater safety in general. The review discusses the benefits of oral vaccination in stimulating humoral and cellular immune responses at the systemic and mucosal level to provide expanded and longer-lasting protection. Aspects related to the structure of the intestine and immunological recognition of the antigen during the transformation process after penetration into the intestine are analyzed. Approaches used to improve the effectiveness of oral vaccines are considered. Problems such as instability and lack of effectiveness of oral vaccines are discussed, as well as recent developments of adjuvants and delivery systems based on mineral salts, substances of microbial origin, saponins, polymers, micro- and nanoparticles, liposomes, which have the potential to increase the effectiveness of oral vaccines. A brief analysis of licensed oral vaccines is given and the data on the development of prototype vaccine preparations using modern methods of genetics, molecular biology and immunology, as well as the mechanisms of inducing an immune response are summarized.

BACKGROUND: The DYNAMIC trial investigated the use of circulating tumor DNA (ctDNA) to guide adjuvant treatment decisions in stage II colon cancer. Despite the DYNAMIC trials assertion that a ctDNA-guided approach could minimize the use of adjuvant treatment without compromising recurrence-free survival (RFS), we raised concerns regarding the trials methodology and the practical implications of its findings in a Debate article. Here, we expand upon these concerns in a response to a correspondence by the authors of the DYNAMIC trial. MAIN BODY: We dispute the choice of a large non-inferiority margin in the DYNAMIC trial, simply because an 8.5 percentage points decrease in recurrence-free survival could result in significant harm to patients. We challenge the authors comparisons of the DYNAMIC trial outcomes with observational studies. Such comparison is subject to selection bias and changes over time that limit their relevance. The prognostic role of ctDNA do not automatically imply that more treatment in patients with ctDNA positivity would improve outcomes, which we highlight. In real-world settings, we anticipate a potential rise in chemotherapy use due to clinicians utilizing ctDNA alongside existing clinicopathologic factors, rather than using ctDNA as an entire replacement. Lastly, a key concern in DYNAMIC was an 350% higher use of oxaliplatin in the ctDNA arm compared with standard management (9.5% versus 2.7%, respectively), which poses a risk for long-term neuropathy. CONCLUSION: We look forward improvements in patient selection in the adjuvant setting, but we maintain our reservations about the DYNAMIC trial and the real-life implementation of its results. As an alternative to exploring de-escalation strategies with large margins non-inferiority trials, we propose that superiority trials in stage II patients could be a more effective strategy.

PurposeTo test the hypothesis that antitumoral immunity can be induced after cryoablation (cryo) of hepatocellular carcinoma (HCC) through coadministration of the immunostimulant CpG and an immune checkpoint (programmed cell death 1 [PD-1]) inhibitor.Materials and methodsSixty-three immunocompetent C57BL/6J mice were generated with 2 orthotopic HCC tumor foci: 1 for treatment and 1 to observe for antitumoral immunity. Tumors were treated with incomplete cryo alone or intratumoral CpG and/or a PD-1 inhibitor. The primary endpoint was death or when the following criteria for sacrifice were met: tumor > 1 cm (determined using ultrasound) or moribund state. Antitumoral immunity was assessed using flow cytometry and histology (tumor and liver) as well as enzyme-linked immunosorbent assay (serum). Analysis of variance was used for statistical comparisons.ResultsAt 1 week, the nonablated satellite tumor growth was reduced by 1.9-fold (P = .047) in the cryo + CpG group and by 2.8-fold (P = .007) in the cryo + CpG + PD-1 group compared with that in the cryo group. Compared with cryo alone, the time to tumor progression to endpoints was also prolonged for cryo + CpG + PD-1 and cryo + CpG mice, with log-rank hazard ratios of 0.42 (P = .031) and 0.27 (P < .001), respectively. Flow cytometry and histology showed increased cytotoxic T-cell infiltration (P = .002) and serum levels of the proinflammatory cytokine interferon-γ (P = .015) in tumors and serum of cryo + CpG mice compared with those in tumors and serum of mice treated with cryo alone. High serum levels of the anti-inflammatory cytokine tumor growth factor-β and the proangiogenesis chemokine C-X-C motif chemokine ligand 1 were correlated with a shorter time to endpoints and faster tumor growth.ConclusionsCryo combined with the immunostimulant CpG promoted cytotoxic T-cell infiltration into tumors, slowed tumor growth, and prolonged the time to progression to endpoints in an aggressive murine HCC model.

The neoadjuvant and adjuvant use of immune checkpoint inhibitors (ICIs) in early stage non-small cell lung cancer (NSCLC) is increasing, with pembrolizumab approved as adjuvant therapy following surgical resection and chemotherapy by the U.S. Food and Drug Administration in early 2023. However, clinical trials of these agents have several key limitations including the use of surrogate endpoints that have not been validated and a lack of demonstrated survival benefit. Further data supporting the benefits of ICIs in this setting are necessary to justify their use at the cost of greater financial burdens, time, and adverse effects.

Preventive cancer vaccines are highly effective in preventing viral infection-induced cancer, but advances in therapeutic cancer vaccines with a focus on eliminating cancer cells through immunotherapy are limited. To develop therapeutic cancer vaccines, the integration of optimal adjuvants is a potential strategy to enhance or complement existing therapeutic approaches. However, conventional adjuvants do not satisfy the criteria of clinical trials for therapeutic cancer vaccines. To improve the effects of adjuvants in therapeutic cancer vaccines, effective vaccination strategies must be formulated and novel adjuvants must be identified. This review offers an overview of the current advancements in therapeutic cancer vaccines and highlights in situ vaccination approaches that can be synergistically combined with other immunotherapies by harnessing the adjuvant effects. Additionally, the refinement of adjuvant systems using cutting-edge technologies and the elucidation of molecular mechanisms underlying immunogenic cell death to facilitate the development of innovative adjuvants have been discussed.

The use of intrathecal (IT) dexamethasone during subarachnoid block (SAB) has not been evaluated. There are no pooled data available to decide on the optimal regimen of IT dexamethasone during SAB, irrespective of the type of surgery. There is uncertainty about its dosage, effectiveness, and safety, and a need to establish clear guidelines on its use. Our objective was to evaluate the effectiveness and safety of use of IT dexamethasone during SAB. We performed a meta-analysis (PROSPERO, CRD42022304944) of trials that included patients who underwent a variety of surgical procedures under SAB. Patients received concomitant IT dexamethasone as an adjuvant to spinal local anesthetics. The analyzed outcomes included sensory and motor effects as well as adverse and/or beneficial side effects. Subgroup analysis was planned based on different doses used. Trial sequential analysis (TSA) was used to estimate the required sample size information (RIS) for each outcome. Eighteen studies (2531 participants) were included in this analysis. Addition of IT dexamethasone (4-8 mg) to heavy bupivacaine effectively prolonged the duration of sensory blockade (mean difference, MD = 63.8 minutes; [95% confidence interval, CI, 33.1-94.5], P < 0.0001), two-segment regression time (MD = 20.1[95% CI, 0.96-39.2], P = 0.04) and first rescue analgesic time (MD = 143.3 [95% CI, 90.3-196.0], P = 0.001). Subgroup analyses revealed superior effects of 8 mg dose over 4 mg for sensory and analgesic effects. The effect of dexamethasone on duration of motor blockade was inconclusive. Additionally, lower risk ratios (RRs) were recorded for spinal anesthesia-related hypotension (RR = 0.74 [95% CI, 0.6-0.9], P = 0.0003) and nausea/vomiting (RR = 0.62 [95% CI, 0.41-0.93], P = 0.02) in the dexamethasone group. For outcomes such as sensory blockade, analgesia, and hypotension, the required information size was reached during TSA. In conclusion, IT dexamethasone, used as an adjuvant to spinal local anesthetic, especially at the dose of 8 mg, increases sensory blockade duration and the time for request of the first rescue analgesic. SAB-induced side effects such as hypotension, nausea, and vomiting are lesser with the use of IT dexamethasone. However, further studies are necessary to draw meaningful conclusions on its safety profile.

Pediatric regional anesthesia has become an integral part of perioperative pain management strategies in children. Adjuvants play a pivotal role in augmenting the efficacy and prolonging the duration of regional anesthesia techniques, thereby improving postoperative pain control, and reducing opioid consumption. This review provides a comprehensive overview of the various adjuvants utilized in pediatric regional anesthesia, highlighting their mechanisms of action, clinical applications, efficacy, and safety profiles.

Introduction: Apart from general anaesthesia, brachial plexus block by the axillary approach is one of the reliable sole anaesthetic techniques for patients undergoing upper limb surgeries. In this study, levobupivacaine was chosen due to fewer adverse effects compared to Bupivacaine, and fewer studies were available for the axillary approach to brachial plexus block. Adjuvants were added to hasten the onset and also to prolong their analgesic effect. Aim: To compare the effect of Dexmedetomidine (D) 0.5 mcg/kg and Fentanyl (F) 0.5 mcg/kg when added to 0.5% Levobupivacaine (L) as an adjuvant in brachial plexus block by the axillary approach for upper limb surgeries. Materials and Methods: A randomised double-blind controlled study was carried out at the Department of Anaesthesiology, Sree Balaji Medical College, BIHER, Chennai, Tamil Nadu, India from January 2020 to October 2021 on 60 American Society of Anaesthesiologists (ASA) I and II patients of either sex posted for various types of upper limb surgeries. Subjects were divided into two equal groups by computer-generated randomisation. Group A received 0.5% levobupivacaine and dexmedetomidine 0.5 mcg/kg, and Group B received 0.5% levobupivacaine and Fentanyl 0.5 mcg/kg. Both patients and the evaluator were unaware of the type of adjuvants added to the local anaesthetic. The onset time, duration of sensory and Motor blockade were recorded. Haemodynamic variables and duration of analgesia were recorded for 24 hours postoperatively. The Mann-Whitney U test demonstrated variations in the onset and duration of sensory and motor blocks. Adverse effects, including nausea, vomiting, and hypotension, exhibited significant differences according to Fisher’s-exact test. Results: Age and weight distributions were comparable between groups (mean age: Group A=45.20 years, Group B=44.80 years; mean weight: Group A=74.13 kg, Group B=74.43 kg). Group A exhibited faster sensory and motor block onset times (sensory: Group A=6.20 minutes, Group B=8.63 minutes; motor: Group A=8.27 minutes, Group B=10.00 minutes), longer block durations (sensory: Group A=11.63 hours, Group B=9.53 hours; motor: Group A=9.67 hours, Group B=8.20 hours), and required the first rescue analgesic (Group A=12.57 hours, Group B=10.27 hours) compared to Group B (p

In the development of dendritic cell (DC) vaccines, the maturation of DCs is a critical stage. Adjuvants play a pivotal role in the maturation of DCs, with a major concern being to ensure both efficacy and safety. This study introduces an innovative approach that combines high efficacy with safety through the synthesis of micro‐adjuvants grafted with copolymers of 2‐(methacrylamido) glucopyranose (MAG) and methacryloxyethyl trimethyl ammonium chloride (DMC). The utilization of metal‐free surface‐initiated atom transfer radical polymerization enables the production of safe and recyclable adjuvants. These micrometer‐sized adjuvants surpass the optimal size range for cellular endocytosis, enabling the retrieval and reuse of them during the ex vivo maturation process, mitigating potential toxicity concerns associated with the endocytosis of non‐metabolized nanoparticles. Additionally, the adjuvants exhibit a "micro‐ligand‐mediated maturation enhancement" effect for DC maturation. This effect is influenced by the shape of the particle, as evidenced by the distinct promotion effects of rod‐like and spherical micro‐adjuvants with comparable sizes. Furthermore, the porous structure of the adjuvants enables them to function as cargo‐carrying "micro‐shuttles", releasing antigens upon binding to DCs to facilitate efficient antigen delivery. [ABSTRACT FROM AUTHOR]

Pig farming has become a strategically significant and economically important industry across the globe. It is also a potentially vulnerable sector due to challenges posed by transboundary diseases in which viral infections are at the forefront. Among the porcine viral diseases, African swine fever, classical swine fever, foot and mouth disease, porcine reproductive and respiratory syndrome, pseudorabies, swine influenza, and transmissible gastroenteritis are some of the diseases that cause substantial economic losses in the pig industry. It is a well-established fact that vaccination is undoubtedly the most effective strategy to control viral infections in animals. From the period of Jenner and Pasteur to the recent new-generation technology era, the development of vaccines has contributed significantly to reducing the burden of viral infections on animals and humans. Inactivated and modified live viral vaccines provide partial protection against key pathogens. However, there is a need to improve these vaccines to address emerging infections more comprehensively and ensure their safety. The recent reports on new-generation vaccines against swine viruses like DNA, viral-vector-based replicon, chimeric, peptide, plant-made, virus-like particle, and nanoparticle-based vaccines are very encouraging. The current review gathers comprehensive information on the available vaccines and the future perspectives on porcine viral vaccines. [ABSTRACT FROM AUTHOR]

Nanomaterials are becoming important tools for vaccine development owing to their tunable and adaptable nature. Unique properties of nanomaterials afford opportunities to modulate trafficking through various tissues, complement or augment adjuvant activities, and specify antigen valency and display. This versatility has enabled recent work designing nanomaterial vaccines for a broad range of diseases, including cancer, inflammatory diseases, and various infectious diseases. Recent successes of nanoparticle vaccines during the coronavirus disease 2019 (COVID-19) pandemic have fueled enthusiasm further. In this review, the most recent developments in nanovaccines for infectious disease, cancer, inflammatory diseases, allergic diseases, and nanoadjuvants are summarized. Additionally, challenges and opportunities for clinical translation of this unique class of materials are discussed. [ABSTRACT FROM AUTHOR]

The success of lipid nanoparticles (LNPs) in treating COVID-19 promotes further research of mRNA vaccines for cancer vaccination. Aiming at overcoming the constraints of currently available mRNA carriers, various alternative nano-vectors have been developed for delivering tumor antigen encoding mRNA and showed versatility to induce potent anti-tumor immunity. The rationally designed nano-vaccines increase the immune activation capacity of the mRNA vaccines by promoting crucial aspects including mRNA stability, cellular uptake, endosomal escape and targeting of immune cells or organs. Herein, we summarized the research progress of various mRNA based nano-vaccines that have been reported for cancer vaccination, including LNPs, lipid enveloped hybrid nanoparticles, polymeric nanoparticles etc. Several strategies that have been reported for further enhancing the immune stimulation efficacy of mRNA nano-vaccines, including developing nano-vaccines for co-delivering adjuvants, combination of immune checkpoint inhibitors, and optimizing the injection routes for boosting immune responses, have been reviewed. The progress of mRNA nano-vaccines in clinical trials and the prospect of the mRNA vaccines for cancer vaccination are also discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Squalene-based adjuvant compositions that can provide effective induction of specific humoral immune response have been developed. Recombinant receptor-binding domain (RBD) of surface S-protein of SARS-CoV-2 was used to evaluate the properties of the composition. Immunization of mice with the developed squalene-based compositions in combination with RBD allows obtaining high titers of specific antibodies: from 105 to 2×106. The blood sera from immunized mice exhibit neutralizing activity against SARS-CoV-2 Delta variant (B.1.617.2) with a titer up to 1:2000. [ABSTRACT FROM AUTHOR]

Vaccinations are vital as they protect us from various illness-causing agents. Despite all the advancements in vaccine-related research, developing improved and safer vaccines against devastating infectious diseases including Ebola, tuberculosis and acquired immune deficiency syndrome (AIDS) remains a significant challenge. In addition, some of the current human vaccines can cause adverse reactions in some individuals, which limits their use for massive vaccination program. Therefore, it is necessary to design optimal vaccine candidates that can elicit appropriate immune responses but do not induce side effects. Subunit vaccines are relatively safe for the vaccination of humans, but they are unable to trigger an optimal protective immune response without an adjuvant. Although different types of adjuvants have been used for the formulation of vaccines to fight pathogens that have high antigenic diversity, due to the toxicity and safety issues associated with human-specific adjuvants, there are only a few adjuvants that have been approved for the formulation of human vaccines. Recently, nanoparticles (NPs) have gain specific attention and are commonly used as adjuvants for vaccine development as well as for drug delivery due to their excellent immune modulation properties. This review will focus on the current state of adjuvants in vaccine development, the mechanisms of human-compatible adjuvants and future research directions. We hope this review will provide valuable information to discovery novel adjuvants and drug delivery systems for developing novel vaccines and treatments. [ABSTRACT FROM AUTHOR]

To better understand the role of pHsp90 adjuvant in immune response modulation, we proposed the use of the Receptor Binding Domain (RBD) of the Spike protein of SARS-CoV2, the principal candidate in the design of subunit vaccines. We evaluated the humoral and cellular immune responses against RBD through the strategy "protein mixture" (Adjuvant + Antigen). The rRBD adjuvanted with rAtHsp81.2 group showed a higher increase of the anti-rRBD IgG1, while the rRBD adjuvanted with rNbHsp90.3 group showed a significant increase in anti-rRBD IgG2b/2a. These results were consistent with the cellular immune response analysis. Spleen cell cultures from rRBD + rNbHsp90.3-immunized mice showed significantly increased IFN-γ production. In contrast, spleen cell cultures from rRBD + rAtHsp81.2-immunized mice showed significantly increased IL-4 levels. Finally, vaccines adjuvanted with rNbHsp90.3 induced higher neutralizing antibody responses compared to those adjuvanted with rAtHsp81.2. To know whether both chaperones must form complexes to generate an effective immune response, we performed co-immunoprecipitation (co-IP) assays. The results indicated that the greater neutralizing capacity observed in the rRBD adjuvanted with rNbHsp90.3 group would be given by the rRBD-rNbHsp90.3 interaction rather than by the quality of the immune response triggered by the adjuvants. These results, together with our previous results, provide a comparative benchmark of these two novel and safe vaccine adjuvants for their capacity to stimulate immunity to a subunit vaccine, demonstrating the capacity of adjuvanted SARS-CoV2 subunit vaccines. Furthermore, these results revealed differences in the ability to modulate the immune response between these two pHsp90s, highlighting the importance of adjuvant selection for future rational vaccine and adjuvant design. [ABSTRACT FROM AUTHOR]

In recent years, there has been a growing interest in the use of medicinal plants and phytochemicals as potential treatments for acne vulgaris. This condition, characterized by chronic inflammation, predominantly affects adolescents and young adults. Conventional treatment typically targets the key factors contributing to its development: the proliferation of Cutibacterium acnes and the associated inflammation. However, these treatments often involve the use of potent drugs. As a result, the exploration of herbal medicine as a complementary approach has emerged as a promising strategy. By harnessing the therapeutic properties of medicinal plants and phytochemicals, it may be possible to address acne vulgaris while minimizing the reliance on strong drugs. This approach not only offers potential benefits for individuals seeking alternative treatments but also underscores the importance of natural remedies of plant origin in dermatological care. The primary aim of this study was to assess the antimicrobial, antioxidant, and anti-inflammatory properties of plants and their phytochemical constituents in the management of mild acne vulgaris. A comprehensive search of scientific databases was conducted from 2018 to September 2023. The findings of this review suggest that medicinal plants and their phytochemical components hold promise as treatments for mild acne vulgaris. However, it is crucial to note that further research employing high-quality evidence and standardized methodologies is essential to substantiate their efficacy and safety profiles. [ABSTRACT FROM AUTHOR]

Porcine idiopathic vesicular disease (PIVD), one of several clinically indistinguishable vesicular diseases of pigs, is caused by the emerging pathogen Senecavirus A (SVA). Despite the widespread prevalence of porcine SVA infection, no effective commercial vaccines for PIVD prevention and control are available, due to high costs associated with vaccine testing in pigs, considerable SVA diversity, and SVA rapid evolution. In this study, SVA CH/JL/2022 (OP562896), a novel mutant SVA strain derived from an isolate obtained from a pig farm in Jilin Province, China, was inactivated then combined with four adjuvants, MONTANIDETM GEL02 PR (GEL 02), MONTANIDETM ISA 201 VG (ISA 201), MONTANIDETM IMG 1313 VG N (IMS1313), or Rehydragel LV (LV). The resulting inactivated SVA CH/JL/2022 vaccines were assessed for efficacy in mice and found to induce robust in vivo lymphocyte proliferation responses and strong IgG1, IgG2a, and neutralizing antibody responses with IgG2a/IgG1 ratios of <1. Furthermore, all vaccinated groups exhibited significantly higher levels of serum cytokines IL-2, IL-4, IL-6, and IFN as compared to unvaccinated mice. These results indicate that all vaccines elicited both Th1 and Th2 responses, with Th2 responses predominating. Moreover, vaccinated mice exhibited enhanced resistance to SVA infection, as evidenced by reduced viral RNA levels and SVA infection-induced histopathological changes. Collectively, our results demonstrate that the SVA-GEL vaccine induced more robust immunological responses in mice than did the other three vaccines, thus highlighting the potential of SVA-GEL to serve an effective tool for preventing and controlling SVA infection. [ABSTRACT FROM AUTHOR]

The inhibition of O-acetyl sulphydrylase synthase isoforms has been reported to represent a promising approach for the development of antibiotic adjuvants. This occurs via the organism developing an unpaired oxidative stress response, causing a reduction in antibiotic resistance in vegetative and swarm cell populations. This consequently increases the effectiveness of conventional antibiotics at lower doses. This study aimed to predict potential inhibitors of Salmonella typhimurium ortho acetyl sulphydrylase synthase (StOASS), which has lower binding energy than the cocrystalized ligand pyridoxal 5 phosphate (PLP), using a computer-aided drug design approach including pharmacophore modeling, virtual screening, and in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) evaluation. The screening and molecular docking of 4254 compounds obtained from the PubChem database were carried out using AutoDock vina, while a post-screening analysis was carried out using Discovery Studio. The best three hits were compounds with the PubChem IDs 118614633, 135715279, and 155773276, possessing binding affinities of −9.1, −8.9, and −8.8 kcal/mol, respectively. The in silico ADMET prediction showed that the pharmacokinetic properties of the best hits were relatively good. The optimization of the best three hits via scaffold hopping gave rise to 187 compounds, and they were docked against StOASS; this revealed that lead compound 1 had the lowest binding energy (−9.3 kcal/mol) and performed better than its parent compound 155773276. Lead compound 1, with the best binding affinity, has a hydroxyl group in its structure and a change in the core heterocycle of its parent compound to benzimidazole, and pyrimidine introduces a synergistic effect and consequently increases the binding energy. The stability of the best hit and optimized compound at the StOASS active site was determined using RMSD, RMSF, radius of gyration, and SASA plots generated from a molecular dynamics simulation. The MD simulation results were also used to monitor how the introduction of new functional groups of optimized compounds contributes to the stability of ligands at the target active site. The improved binding affinity of these compounds compared to PLP and their toxicity profile, which is predicted to be mild, highlights them as good inhibitors of StOASS, and hence, possible antimicrobial adjuvants. [ABSTRACT FROM AUTHOR]

Extracts of the Chilean soapbark tree , Quillaja Saponaria (QS) are the source of potent immune-stimulatory saponin compounds. This study compared the adjuvanticity and toxicity of QS-18 and QS-21, assessing the potential to substitute QS-18 in place of QS-21 for vaccine development. QS-18, the most abundant QS saponin fraction, has been largely overlooked due to safety concerns. We found that QS-18 spontaneously inserted into liposomes, thereby neutralizing hemolytic activity, and following administration did not induce local reactogenicity in a footpad swelling test in mice. With high-dose intramuscular administration, transient weight loss was minor, and QS-18 did not induce significantly more weight loss compared to a liposome vaccine adjuvant system lacking it. Two days after administration, no elevation of inflammatory cytokines was detected in murine serum. In a formulation including cobalt-porphyrin-phospholipid (CoPoP) for short peptide sequestration, QS-18 did not impact the formation of peptide nanoparticles. With immunization, QS-18 peptide particles induced higher levels of cancer neoepitope-specific and tumor-associated antigen-specific CD8+ T cells compared to QS-21 particles, without indication of greater toxicity based on mouse body weight. T cell receptor sequencing of antigen-specific CD8+ T cells showed that QS-18 induced significantly more T cell transcripts. In two murine cancer models, vaccination with QS-18 peptide particles induced a similar therapeutic effect as QS-21 particles, without indication of increased toxicity. Antigen-specific CD8+ T cells in the tumor microenvironment were found to express the exhaustion marker PD-1, pointing to the rationale for exploring combination therapy. Taken together, these data demonstrate that QS-18, when formulated in liposomes, can be a safe and effective adjuvant to induce tumor-inhibiting cellular responses in murine models with potential to facilitate or diminish costs of production for vaccine adjuvant systems. Further studies are warranted to assess liposomal QS-18 immunogic, reactogenic and toxicological profiles in mice and other animal species. [Display omitted] [ABSTRACT FROM AUTHOR]

Skin is the body's largest organ and serves as a protective barrier from physical, thermal, and mechanical environmental challenges. Alongside, the skin hosts key immune system players, such as the professional antigen-presenting cells (APCs) like the Langerhans cells in the epidermis and circulating macrophages in the blood. Further, the literature supports that the APCs can be activated by antigen or vaccine delivery via multiple routes of administration through the skin. Once activated, the stimulated APCs drain to the associated lymph nodes and gain access to the lymphatic system. This further allows the APCs to engage with the adaptive immune system and activate cellular and humoral immune responses. Thus, vaccine delivery via skin offers advantages such as reliable antigen delivery, superior immunogenicity, and convenient delivery. Several preclinical and clinical studies have demonstrated the significance of vaccine delivery using various routes of administration via skin. However, such vaccines often employ adjuvant/(s), along with the antigen of interest. Adjuvants augment the immune response to a vaccine antigen and improve the therapeutic efficacy. Due to these reasons, adjuvants have been successfully used with infectious disease vaccines, cancer immunotherapy, and immune-mediated diseases. To capture these developments, this review will summarize preclinical and clinical study results of vaccine delivery via skin in the presence of adjuvants. A focused discussion regarding the FDA-approved adjuvants will address the experiences of using such adjuvant-containing vaccines. In addition, the challenges and regulatory concerns with these adjuvants will be discussed. Finally, the review will share the prospects of adjuvant-containing vaccines delivered via skin. [Display omitted] • Role of various routes of vaccine administration via skin. • Skin offers reliable antigen delivery and yields superior immune responses. • Adjuvants as immune response enhancers for infectious disease, cancer vaccines. • Preclinical and clinical studies with FDA-approved adjuvants and cutaneous vaccines. • Regulatory considerations for adjuvanted vaccines delivered via skin. [ABSTRACT FROM AUTHOR]

Vibrio alginolyticus and Streptococcus agalactiae are important bacterial pathogens that yielded high losses in Nile tilapia in Egypt. The present study aimed to check the protective efficacy of inactivated whole-cell bivalent vaccines against these pathogens using incomplete Freund's adjuvant and Montanide™ IMS 1312 VG as adjuvants. The antibody titers have been determined at different weeks post-vaccination (WPV). Moreover, the protection levels against the challenged bacterial pathogens have also been examined in relation to the time-dependent protection at different WPV. The results revealed that serum antibodies were generated in all immunized fish at 1st WPV, peaked at 4th WPV, continued, and gradually decreased from 6th WPV to 14th WPV in all vaccinated groups. In addition, vaccines induced significantly higher protection of the immunized tilapia, manifested by higher survival rates. We noticed that the antibody levels and survival rates of the vaccinated fish by a vaccine adjuvanted by Montanide™ IMS 1312 VG were higher than those produced by a vaccine adjuvanted by incomplete Freund's adjuvant at different time points. Moreover, no external clinical signs, visceral adhesions, or internal lesions were recorded in the vaccinated tilapia, demonstrating the safety of the formulated vaccines. According to the aforementioned findings, we could suggest that the prepared bivalent vaccines, using the two adjuvant types, are safe and highly protective and could be utilized as promising candidate vaccines to increase the resistance of Nile tilapia against V. alginolyticus and S. agalactiae infections. Moreover, Montanide™ IMS 1312 VG enhanced the immuno-protectivity and exhibited optimum immune response and earlier protection compared to the vaccine adjuvanted by incomplete Freund's adjuvant, demonstrating its added value during the preparation of tilapia vaccines. [ABSTRACT FROM AUTHOR]

Pain is a multidimensional sensation that arises from a physiologic and psychological response to an unpleasant experience. Pain is an alarm signal that causes an organism to pull away from potentially harmful stimuli, thereby protecting itself from potential damage. In most cases, it is associated with an injury or the possibility of an injury. Here we develop and carry out drug utilization evaluations concerning the analgesics and adjuvants in pain management. The analgesics and adjuvants were further classified to include in the program standards and criteria for the selected drugs and compared with the actual drug utilization. Cross-sectional, observational case study with 377 patients. Patients aged > 18 years and < 80 years experiencing pain were included in the study. Age < 18 years, > 80 years. Pregnant or lactating women were excluded from the study. Out of the total drugs (1362), total antibiotics prescribed were about 45 (3.30%). Among them, 35(2.6%) were prescribed in tablet form, (0.44%) were prescribed in injection form either i.v or i.m, 3(0.22%) were prescribed in powder form (gastolac sachets), 1 (0.07%) was prescribed in ointment form. Cefuroxime + clavulanic acid prescribed was the most commonly used 13 (0.95%). This study reveals a pattern of analgesic use that includes the administration of extensive oral analgesic preparations, a high generic naming of medications, and the appropriate use of these pharmaceuticals concerning the dosage strength, the frequency of treatment, and the duration of therapy. [ABSTRACT FROM AUTHOR]