Prophylactic Response Research Articles

Cyclic vomiting syndrome in pediatric population: characteristics and prophylactic response to cyproheptadine

Cyclic vomiting syndrome in pediatric population: characteristics and prophylactic response to cyproheptadine

Methylomic signature of lithium response in bipolar disorder

Introduction Bipolar disorder (BD) is a chronic and severe psychiatric disorder, characterized by the alternance of episodes of (hypo)-mania and major depression. Lithium (Li) is the first-line treatment for BD but unfortunately response to Li is highly variable: after at least two consecutive years of treatment, only a fraction of patients receiving Li will display significant improvement in the frequency and/or severity of mood recurrences. This interindividual variability of treatment response is difficult to predict, in the bipolar disorder context. This could be determined by genetic factors still misidentified by available genetic studies. In addition, no clinical or biological markers are available to reliably define eligibility criteria for a lithium treatment in bipolar disorder. A consequence is a long process of therapeutic trials (18-24 months) to phenotype Li response, delaying the stabilization.ObjectivesTo identify objective biomarkers of the prophylactic response to lithium in order to improve patient care and propose therapeutic alternatives to patients who do not respond to lithium.Methods Using a genome-wide methylomic approach, and then logistic regressions incorporating as covariates the different types of treatments, we were able to identify differentially methylated regions (DMRs) whose methylation difference between responders and non-responders was not impacted by co-prescribed treatments. Then, we used Methylation Specific High-Resolution Melting (MS-HRM), a PCR based method than can be implemented in any medical laboratory at low cost and with minimal equipment, to estimate methylation proportion of 9 DMRs in 61 samples of bipolar patients.Results In the sample of 61 individuals with BD, the 9 MS-HRM-measured DMRs combined with clinical variables (age, sex, cigarette smoking status, lifetime number of hospitalizations, age at onset of BD, polarity at onset, psychotic symptoms at onset, family history of BD, lifetime alcohol/cannabis misuse, panic disorders, Li prescribed as the first mood stabilizer (vs 2nd or 3rd choice)) correctly classified 83,6% of individuals as good or non-responders (n=61, prophylactic response phenotype defined using the “Alda” scale). Excluding the partial responders, the percentage of correctly classified individuals is as high as 100% (n=43, 18 non responders and 25 responders). The AUC are respectively AUC=0.913 and AUC=1.0.ConclusionsThe MS-HMR method allow to identify the response status of individuals with BD with 9 DMR. These DMRs discriminate good from non-responders and can be used in combination with clinical variables.Disclosure of InterestNone Declared

RgpA-Engineered/Functionalized DNA Vaccine as a Novel Prophylactic Vaccination to Prevent Porphyromonas gingivalis-Induced Periodontitis: An in Vivo Study.

Arg-gingipain A (rgpA) and Arg-gingipain B (rgpB) are crucial virulence factors associated with Porphyromonas gingivalis (P. gingivalis) and have been recognized as promising targets for antibacterial vaccines. Although vaccines containing rgpA have shown efficacy, the incorporation of rgpB, which lacks the haemagglutinin adhesin (HA) domain, diminishes the vaccine's effectiveness. This study aims to assess the immunogenicity of the functional HA domain of rgpA in mouse periodontitis models. A total of 24 mice were randomly divided into four groups, each receiving different immune injections: group A received phosphate-buffered saline (PBS) as an empty control; group B received pVAX1 as a negative control (NC); group C received pVAX1-HA; and group D received pVAX1-rgpA. The mice were subjected to intramuscular injections every two weeks for a total of three administrations. Prior to each immunization, blood samples were collected for antibody detection under isoflurane anesthesia. Following the final immunization, periodontitis was induced two weeks later by using sutures soaked in a P. gingivalis solution. The mice were euthanized after an additional two-week period. To assess the safety of the procedure, major organs were examined through hematoxylin-eosin (HE) staining. Subsequently, the levels of IgG, IgG1, and IgG2a in the serum were quantified via enzyme-linked immunosorbent assay (ELISA). Additionally, the expression of inflammatory factors in the gingiva, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor alpha (TNF-α), was determined using quantitative real-time reverse transcript PCR (qRT-PCR). The extent of bone loss in periodontal tissues was evaluated using micro-computed tomography (micro-CT) and HE staining. HE staining of the organs confirmed the absence of vaccine-induced toxicity in vivo. After the second immunization, both the rgpA and HA groups displayed significantly higher specific IgG titers in comparison to the NC and PBS groups (p < 0.05). Furthermore, the rgpA and HA groups exhibited a noteworthy predominance of IgG1 antibodies after three immunization doses, while there was a noticeable reduction in IgG2a levels observed following ligation with P. gingivalis sutures, as opposed to the NC and PBS groups (p < 0.05). Additionally, both the HA and rgpA groups showed a significant decrease in the expression of inflammatory factors such as IL-6, IL-1β, and TNF-α, as well as a reduction in bone loss around periodontitis-affected teeth, when compared to the NC and PBS groups (p < 0.05). The results of this study demonstrate that the rgpA-engineered/functionalized HA gene vaccine is capable of eliciting a potent prophylactic immune response against P. gingivalis-induced periodontitis, effectively serving as an immunogenic and protective agent in vivo.

Analysis of Costs for Imaging-Assisted Pharmaceutical Intervention in Alzheimer's Disease with Lecanemab: Snapshot of the First 3 Years.

The approval of lecanemab for the treatment of Alzheimer's disease (AD) by the Food and Drug Administration in the United States has sparked controversy over issues of safety, cost, and efficacy. Furthermore, the prognostication of cognitive decline is prohibitively difficult with current methods. The inability to forecast incipient dementia in patients with biological AD suggests a prophylactic scenario wherein all patients with cognitive decline are prescribed anti-AD drugs at the earliest manifestations of dementia; however, most patients with mild cognitive impairment (approximately 77.7%) do not develop dementia over a 3-year period. Prophylactic response therefore constitutes unethical, costly, and unnecessary treatment for these patients. We present a snapshot of the costs associated with the first 3 years of mass availability of anti-AD drugs in a variety of scenarios. We consider multiple prognostication scenarios with varying sensitivities and specificities based on neuroimaging studies in patients with mild cognitive impairment to determine approximate costs for the large-scale use of lecanemab. The combination of fluorodeoxyglucose and magnetic resonance was determined to be the most cost-efficient at $177,000 for every positive outcome every 3 years under an assumed adjustment in the price of lecanemab to $9,275 per year. Imaging-assisted identification of cognitive status in patients with prodromal AD is demonstrated to reduce costs and prevent instances of unnecessary treatment in all cases considered. This highlights the potential of this technology for the ethical prescription of anti-AD medications under a paradigm of imaging-assisted early detection for pharmaceutical intervention in the treatment of AD.

Efficacy and Safety of Pre-Exposure Prophylaxis to Control HIV and Sexually Transmitted Infection Among Men Who Have Sex With Men: Protocol for a Single-Arm Interventional Study.

Pre-exposure prophylaxis (PrEP) against HIV infection is a new approach that involves the prophylactic use of the anti-HIV drug Truvada (tenofovir disoproxil fumarate [TDF] and emtricitabine [FTC]) by people not infected with HIV. The objective of this investigator-initiated clinical study of PrEP was to evaluate the incidence of HIV and sexually transmitted infection (STI), safety and efficacy of PrEP in PrEP users, and their compliance with PrEP medication. The social, medical, and economic benefits of PrEP in Japan was assessed. This single-center feasibility study of PrEP was conducted at the National Center for Global Health and Medicine, Tokyo, Japan, where a cohort of men who have sex with men without HIV was established in January 2017. This single-arm interventional study compared the efficacy and safety of PrEP in a single group of men who have sex with men who participated in PrEP cohort studies. For reference, the cohort study participants who did not participate in the PrEP study were included for comparison. Blood samples were collected for storage at baseline and clinic visits at 1, 3, and 6 months after starting PrEP and every 3 months thereafter. The participants were administered with 1 tablet of Truvada once daily as PrEP. They underwent blood and anal swab tests 1 and 3 months after starting PrEP and then HIV and STI infection assessments at 3-month intervals. Blood samples were centrifuged at the AIDS Clinical Center Laboratory. PrEP safety was evaluated by monitoring serum creatinine levels for symptoms of renal function disorders. The primary end point was the incidence of HIV in PrEP users (100 person-years). The secondary end points were the incidence of STI in PrEP users (100 person-years), incidence of adverse events caused by Truvada, frequency of high-risk sexual activity, and adherence to periodic visits and medication. The study protocol was reviewed and approved by the certified review board of the National Center for Global Health and Medicine (NCGM-C-003129-03) on April 20, 2020. Changes to the study plan were submitted for review by the certified review board and approved before implementation. Recruitment was completed on March 28, 2019, and the study was completed (last adult participant and last time point) on March 31, 2021. The data were analyzed, and the main results of the study have been published in a peer-reviewed journal. The findings indicated that PrEP is a highly effective and feasible strategy against HIV infection in terms of prophylactic response, retention, and compliance. UMIN Clinical Trials Registry UMIN000031040; https://tinyurl.com/3msdkeb8 and Japan Registry of Clinical Trials jRCTs031180134; https://tinyurl.com/2p88mhyr. RR1-10.2196/50919.

Prognostic Value of Naples Prognostic Score on Survival in Unresectable Small Cell Lung Cancer Patients Undergoing Chemoradiotherapy

Chemoradiotherapy is a major modality for treatment of small cell lung cancer (SCLC). Naples prognosis score (NPS) is a novel prognostic biomarker-based immune and nutritional status and that can be used to evaluate prognosis. Our study aimed to investigate the prognostic role of NPS in unresectable SCLC patients. Patients treated with chemoradiotherapy were retrospectively analyzed between June 2012 and August 2017. We divided patients into three groups depending on the NPS: group 0, n = 31; group 1, n = 100; and group 2, n = 48, and associations between clinical characteristics and NPS group were analyzed. Spearman correlation analyses were used to estimate the correlations among NPS parameters. The univariable and multivariable Cox analyses were used to evaluate the prognostic value of clinicopathological characteristics and laboratory indicators for overall survival (OS) and progression-free survival (PFS). Data from 179 patients were analyzed. Treatment modality (P < 0.001) and serum CEA (P = 0.03) were significantly different among the NPS groups. The age, sex, smoking status, KPS, Karnofsky performance score (KPS), disease extent, and number of metastatic sites were not correlated with NPS (all P > 0.05). Spearman correlation analyses showed that neutrophil-to-lymphocyte ratio (NLR) had a significant correlation with lymphocyte-to-monocyte ratio (LMR) (r = -0.495, P < 0.001). KPS, disease extent, prophylactic cranial irradiation, treatment response and NPS Group were associated with OS. In addition, KPS, disease extent, prophylactic cranial irradiation, treatment response and NPS Group were associated with PFS. Multivariate analysis results showed that NPS was identified as an independent prognostic factor for OS (Group 1: hazard ratio [HR] = 2.704, 95% confidence interval [CI] = 1.403-5.210; P = 0.003; Group 2: HR = 5.154, 95% CI = 2.614-10.166; P < 0.001) and PFS (Group 1: HR = 2.018, 95% CI = 1.014-4.014; P = 0.045; Group 2: HR = 3.339, 95% CI = 1.650-6.756; P = 0.001). NPS is related to clinical outcomes in patients with unresectable SCLC. NPS as an innovative scoring system, can improves prediction of survival in unresectable SCLC patients.

Prophylactic platelet transfusion response in critically ill patients: a prospective multicentre observational study

BackgroundResponse to prophylactic platelet transfusion is suspected to be inconsistent in critically ill patients questioning how to optimize transfusion practices. This study aimed to describe prophylactic platelet transfusion response, to identify factors associated with a suboptimal response, to analyse the correlation between corrected count increment and platelet count increment and to determine the association between poor platelet transfusion response and clinical outcomes.MethodsThis prospective multicentre observational study recruited patients who received at least one prophylactic platelet transfusion in one of the nine participating intensive care units for a period up to 16 months. Poor platelet transfusion response was defined as a corrected count increment (CCI) that adjusts for platelet dose and body surface area, less than 7 at 18–24 h after platelet transfusion. Factors associated with poor platelet transfusion response were assessed in a mixed-effect model. Sensitivity analyses were conducted in patients with and without haematology malignancy and chemotherapy.ResultsPoor platelet transfusion response occurred in 349 of the 472 (73.9%) prophylactic platelet transfusions and in 141/181 (77.9%) patients. The mixed-effect model identified haemoglobin at ICU admission (odds ratio (OR): 0.79 [95% confidence interval (CI) 0.7–0.89]) and body mass index (BMI) (OR: 0.93 [0.89–0.98]) being positively and independently associated with platelet transfusion response, while a haematological malignancy (OR 1.93 [1.09–3.43]), sepsis as primary ICU admission diagnosis (OR: 2.81 [1.57–5.03]), SOFA score (OR 1.10 [1.03; 1.17]) and maximum storage duration of platelet (OR: 1.24 [1.02–1.52]) were independently associated with a suboptimal platelet increment. Clinical outcomes did not differ between groups, nor the requirement for red blood cells. Poor platelet transfusion response was found in 93.5% of patients with haematology malignancy and chemotherapy.ConclusionsIn this study of critically ill patients, of whom more than half had bone marrow failure, almost three quarters of prophylactic platelet transfusions led to suboptimal platelet increment measured 18 to 24 h following platelet transfusion. Platelet storage duration was the only factor associated with poor platelet response that may be accessible to intervention.Trial registration in October 2017: ClinicalTrials.gov: NCT03325140.

Assessment of Naples prognostic score in predicting survival for small cell lung cancer patients treated with chemoradiotherapy

Backgrounds The Naples prognosis score (NPS) is a novel prognostic biomarker-based immune and nutritional status and that can be used to evaluate prognosis. Our study aimed to investigate the prognostic role of NPS in SCLC patients. Methods Patients treated with chemoradiotherapy were retrospectively analyzed between June 2012 and August 2017. We divided patients into three groups depending on the NPS: group 0, n = 31; group 1, n = 100; and group 2, n = 48, and associations between clinical characteristics and NPS group were analyzed. The univariable and multivariable Cox analyses were used to evaluate the prognostic value of clinicopathological characteristics and laboratory indicators for overall survival (OS) and progression-free survival (PFS). Results Data from 179 patients were analyzed. Treatment modality (p < 0.001) and serum CEA (p = 0.03) were significantly different among the NPS groups. The age, sex, smoking status, KPS, Karnofsky performance score (KPS), disease extent, and number of metastatic sites were not correlated with NPS (all p > 0.05). KPS, disease extent, prophylactic cranial irradiation, treatment response and NPS Group were associated with OS. In addition, KPS, disease extent, prophylactic cranial irradiation, treatment response and NPS Group were associated with PFS. Multivariate analysis results showed that NPS was identified as an independent prognostic factor for OS (Group 1: hazard ratio [HR] = 2.704, 95% confidence interval [CI] = 1.403-5.210; p = 0.003; Group 2: HR = 5.154, 95% CI = 2.614-10.166; p < 0.001) and PFS (Group 1: HR = 2.018, 95% CI = 1.014-4.014; p = 0.045; Group 2: HR = 3.339, 95% CI = 1.650-6.756; p = 0.001). Conclusions NPS is related to clinical outcomes in patients with SCLC.

Sunthi (Dry Zingiber Officinale) as a Prophylactic Agent Against SARS-CoV-2 Transmission and COVID-19 Symptomatology: Evidence From a Non-randomised Single-Arm Study

IntroductionAncient Indian medical system Ayurveda cites Sunthi (an ayurvedic preparation of dry Zingiber officinale) as ‘Vishvabhesaja’—medicine of highest relevance for the whole world—upholding its special status in managing pandemics. The present study assessed the prophylactic response of Sunthi in reducing SARS-CoV-2 transmission, moderating COVID-19 symptomatology, and improving individuals’ quality of life. The COVID-19-relevant phytochemicals in Z.officinale were analysed, and the prominent predictive factors for quality of life were identified. MethodsThis study used multicentre, non-randomised, open-label, single-arm, pre-post design. The sample (n = 824) comprised household members of hospitalised coronavirus-infected patients (n = 770) and the frontline health care workers (n = 54) operating in COVID-19 hospitals. Participants consumed Sunthi powder four times daily, twice via oral (2 g) and twice via nasal (0.5 g) routes, for 15 days. They were followed up after 15, 30, and 90 days. For phytochemical analysis, liquid chromatography coupled with mass spectrometry, and for data analysis, McNemar's test, repeated measures t-test, and multiple linear regression were performed. ResultsZ.officinale comprises phytoconstituents with anti-SARS-CoV-2 properties, has no severe effects, alleviates coronavirus-compatible symptoms, and improves the quality of life. ConclusionsDry Z.officinale can be a safe, effective, readily deployable, and affordable treatment for preventing coronavirus infection and managing COVID-19 symptomatology. Incorporating it into the COVID-19 prevention and management protocol can be of relevance for public health systems globally. However, this is a preliminary observation that may be informative for future research. No causal inference pertaining to the observed association could be drawn, and this result shall be interpreted with caution.

Computational design of nanomolar-binding antibodies specific to multiple SARS-CoV-2 variants by engineering a specificity switch of antibody 80R using RosettaAntibodyDesign (RAbD) results in potential generalizable therapeutic antibodies for novel SARS-CoV-2 virus

The human infectious disease COVID-19 caused by the SARS-CoV-2 virus has become a major threat to global public health. Developing a vaccine is the preferred prophylactic response to epidemics and pandemics. However, for individuals who have contracted the disease, the rapid design of antibodies that can target the SARS-CoV-2 virus fulfils a critical need. Further, discovering antibodies that bind multiple variants of SARS-CoV-2 can aid in the development of rapid antigen tests (RATs) which are critical for the identification and isolation of individuals currently carrying COVID-19. Here we provide a proof-of-concept study for the computational design of high-affinity antibodies that bind to multiple variants of the SARS-CoV-2 spike protein using RosettaAntibodyDesign (RAbD). Well characterized antibodies that bind with high affinity to the SARS-CoV-1 (but not SARS-CoV-2) spike protein were used as templates and re-designed to bind the SARS-CoV-2 spike protein with high affinity, resulting in a specificity switch. A panel of designed antibodies were experimentally validated. One design bound to a broad range of variants of concern including the Omicron, Delta, Wuhan, and South African spike protein variants.

Liposomal celecoxib combined with dendritic cell therapy enhances antitumor efficacy in melanoma.

Cancer vaccine efficacy is limited by the immunosuppressive nature of the tumor microenvironment created by inflammation, immune inhibitory factors, and regulatory T cells (Tregs). Inspired by the role of cyclooxygenase-2 (COX-2) in inflammation in the tumor site, we proposed that normalization of the tumor microenvironment by celecoxib as a COX-2 inhibitor might improve the efficacy of Dendritic Cell (DC) therapy in a melanoma model. In the present study, liposomal celecoxib (Lip-CLX) was combined with ex vivo generated DC vaccines pulsed with gp100 peptide (in liposomal and non-liposomal forms) for prophylactic and therapeutic evaluation in the B16F10 melanoma model. Tumor site analysis by flow cytometry demonstrated that intravenous administration of Lip-CLX at a dose of 1 mg/kg in four doses effectively normalized the tumor microenvironment by reducing Tregs and IL-10 production. Furthermore, in combination with DC vaccination (DC + Lip-peptide+Lip-CLX), it significantly increased tumor-infiltrating CD4+ and CD8+ T cells and secretion of IFN-γ. This combinatorial strategy produced an effective prophylactic and therapeutic antitumor response, which reduced tumor growth and prolonged the overall survival. In conclusion, our findings suggest that the liposomal celecoxib targets the inhibitory mechanisms of the tumor microenvironment and broadens the impact of DC therapy to improve the outcome of immunotherapy in solid tumors.

No evidence that spice consumption is a cancer prevention mechanism in human populations.

Why humans historically began to incorporate spices into their diets is still a matter of unresolved debate. For example, a recent study (Bromham et al. There is little evidence that spicy food in hot countries is an adaptation to reducing infection risk. Nat Hum Behav 2021;5:878-91.) did not support the most popular hypothesis that spice consumption was a practice favoured by selection in certain environments to reduce food poisoning, parasitic infections, and foodborne diseases. Because several spices are known to have anticancer effects, we explored the hypothesis that natural selection and/or cultural evolution may have favoured spice consumption as an adaptive prophylactic response to reduce the burden of cancer pathology. We used linear models to investigate the potential relationship between age-standardized gastrointestinal cancer rates and spice consumption in 36 countries. Patterns of spice are not consistent with a cancer mitigation mechanism: the age-standardized rate of almost all gastrointestinal cancers was not related to spice consumption. Direction other than foodborne pathogens and cancers should be explored to understand the health reasons, if any, why our ancestors developed a taste for spices.

Efficacy of erenumab and factors predicting response after 3 months in treatment resistant chronic migraine: a clinical service evaluation

BackgroundCalcitonin gene-related peptide (CGRP) inhibitors have been developed as options for treatment of chronic and episodic migraine. We present our experience of the use of erenumab in a tertiary headache centre.MethodsThis was a prospective clinical audit of all patients commenced on erenumab following a locally agreed pathway and criteria over a consecutive period. Patients received monthly erenumab 140 mg for 3 months. Data were collected prospectively at baseline and 3 months follow up.ResultsOne hundred three patients were commenced on erenumab during the study period. Patients had tried a median of 7 previous prophylactics, including onabotulinum toxin A in 94%. At 3 months there was a reduction in median total (28 to 20, 29% reduction, p < 0.0001) and severe (15 to 5, 67% reduction, p < 0.0001) headache days. 39.8% of patients achieved at least a 30% reduction in total headache days; 61.8% of patients achieved at least a 50% reduction in severe headache days. Meeting either of these thresholds was considered a positive response, 68% of patients achieved this. Presence of daily headache pattern was negatively associated with response, (56% response vs. 90% without daily headache, p = 0.0003). There was no association between age, gender, presence of medication overuse or number of previously tried prophylactic treatments and response to erenumab. 43% of patients reported at least one adverse effect, most commonly constipation (26%); treatment was discontinued in 3 patients due to adverse effects.ConclusionsErenumab was an effective treatment for chronic migraine in this treatment resistant population over 3 months of follow up. Presence of daily headache predicted poorer response but there was still a significant positive response rate in this group.

Increasing adult density compromises survival following bacterial infections in Drosophila melanogaster

The density-dependent prophylaxis hypothesis predicts that risk of pathogen transmission increases with increase in population density, and in response to this, organisms mount a prophylactic immune response when exposed to high density. This prophylactic response is expected to help organisms improve their chances of survival when exposed to pathogens. Alternatively, organisms living at high densities can exhibit compromised defense against pathogens due to lack of resources and density associated physiological stress; the crowding stress hypothesis. We housed adult Drosophila melanogaster flies at different densities and measured the effect this has on their post-infection survival and resistance to starvation. We find that flies housed at higher densities show greater mortality after being infected with bacterial pathogens, while also exhibiting increased resistance to starvation. Our results are more in line with the crowding stress hypothesis that postulates a compromised immune system when hosts are subjected to high densities.

Vaccines and Therapeutics: Quality System Approach to Clinical Applications

Molecular bio-science developments involve applications of mRNA vaccines focused on diagnostic, prophylactic, and therapeutic aspects of COVID-19 related infectious diseases. These applications offer potential solutions for many of the current challenges in treating virus related infectious diseases. The goal of vaccine design and development is to manufacture and consistently produce a vaccine that is safe and effective. The vaccine discovery starts with design input in terms of identification of etiologic agent, immunogenicity, adjuvant, basic scientific concepts, non-clinical and clinical studies, and finally vaccine licensure (FDA approvals). The Lipid Nanoparticle Technology (LNT) for messenger RNA is being used for COVID-19 vaccines. This technology comprises of identifying and mapping signature features of the virus which encompasses the readability of the virus’s blueprint, its neutralization and activation processes in order to deliver antibody proteins to protect the vaccine recipients’ bodies from encounters with the virus. The administering regimens are studied in clinical research laboratory and study materials are tested in suitable bench testing and biological models projecting vaccine candidate’s prophylactic immune response that is safe and effective. The vaccine manufacturing process requires critical quality control points (CQCPs) monitoring in order to maintain the steriochemical and immunological characteristics of the vaccine molecules and enable production of the vaccine in increasingly dosage quantities for ultimate human use. These aspects of vaccine development are well integrated into the total vaccinology life cycle (TVLC) regulatory requirements. The ultimate regulatory safety and efficacy requirements of the vaccine are proven through phases of clinical trials (class I, II, and III studies). The final process for human use to produce safe vaccine is part of pivotal clinical trials and data under the US FDA’s premarket approval process for full-scale production and availability of safe vaccines for clinical use.&#x0D; Keywords: mRNA Vaccines, Diagnosis, Prophylaxis, Therapy, COVID-19

Protein corona-driven nanovaccines improve antigen intracellular release and immunotherapy efficacy.

During vaccine delivery in vivo, the vaccine carrier dynamically adsorbs the surrounding proteins or biomacromolecules to form a protein corona layer, which determines the physiological and therapeutic responses of the vaccine. Although the importance of the protein corona effect in drug delivery is widely accepted, understanding of the rational use of the protein corona to improve antigen controlled release is still sparse. Here, we constructed a protein corona-driven nanovaccine (PCNV), which has the dual effects of resisting the protein corona-induced antigen extracellular release and promoting protein corona-triggered antigen cytosolic release under reductive conditions. Specifically, the nanovaccine was formulated via the assembly of fluorinated dendrigraft-poly-lysine and cleavable antigen-CpG conjugate. Before entering antigen-presenting cells (APCs), the anchoring effect of CpG was used to avoid the dissociation of antigens from the carrier even under the protein corona effect. While nanovaccine enters the APCs, the intracellular reducing conditions can induce a break in the disulfide bond between CpG and antigen. Notably, at the same time, the intracellular protein corona effect triggers antigen release from the carrier and achieves efficient antigen presentation. In addition, the PCNV produced a significant prophylactic and therapeutic antitumor response in the mouse model. Therefore, the rational use of the protein corona effect provides an effective strategy for vaccine delivery.

Improving potency of Nanoliposomal AE36 peptide vaccine by adding CD4+ T cell helper epitope and MPL in TUBO breast cancer mice model

Cancer peptide vaccines stimulate the immune system and activate efficient T cell responses towards cancerous cells. Despite this, the scant efficacy of peptide vaccines has led to modest clinical success in most instances. Hence, optimizing cancer peptide vaccines to enhance their effectiveness appeared to be critical to achieving successful treatment. Designing multiepitope peptide formulations using appropriate delivery systems is a promising strategy for increasing peptide vaccines' efficacy and triggering robust immune responses. Therefore, we studied a liposomal-based peptide vaccine composed of AE36 (HER2/neu-derived peptide) and PADRE (Pan HLA-DR peptide) as well as monophosphoryl lipid A (MPL) adjuvant. Then the prophylactic immune response was evaluated in BALB/c mice breast cancer models bearing TUBO tumors. We found that the liposomal form of AE36 peptide plus PADRE resulted in improved activation of CD4+ and CD8+ T cell responses and considerably increased production of IFN-γ. In addition, the presence of PADRE, as a CD4+ T helper epitope could enhance the potency of the liposomal AE36 peptide vaccine. Furthermore, this formulation resulted in a considerable reduction in tumor volume and increased survival in a murine model. Our findings suggest that a liposomal formulation containing the multiepitope peptides AE36, PADRE, and MPL could be a potential prophylactic vaccine candidate that triggers a robust antigen-specific immune response of CD8+ CTLs.

Vaccinology: Design, Development and Approvals

The goal of vaccine design and development is to manufacture and consistently produce a vaccine that is safe and effective. The vaccine discovery starts with design input in terms of identification of etiologic agent, immunogenicity, adjuvant, basic scientific concepts, non-clinical and clinical studies, and finally vaccine licensure (FDA approvals). The administering regimens are studied in clinical research laboratory and study materials are tested in suitable bench testing and biological models projecting vaccine candidate’s prophylactic immune response that is safe and effective. The vaccine manufacturing process requires critical quality control points (CQCPs) monitoring in order to maintain the steriochemical and immunological characteristics of the vaccine molecules and enable production of the vaccine in increasingly dosage quantities for ultimate human use. These aspects of vaccine development are well integrated into the total vaccinology life cycle (TVLC) regulatory requirements. The ultimate regulatory safety and efficacy requirements of the vaccine are proven through phases of clinical trials (class I, II, and III studies). The final process for human use to produce safe vaccine is part of pivotal clinical trials and data under the US FDA’s premarket approval process for full-scale production and availability of safe vaccines for clinical use.&#x0D; Keywords: vaccine design and development, etiologic agent, immunogenicity

Utility of a Recombinant HSV-1 Vaccine Vector for Personalized Cancer Vaccines.

Current approaches to cancer immunotherapy include immune checkpoint inhibitors, cancer vaccines, and adoptive cellular therapy. These therapies have produced significant clinical success for specific cancers, but their efficacy has been limited. Oncolytic virotherapy (OVT) has emerged as a promising immunotherapy for a variety of cancers. Furthermore, the unique characteristics of OVs make them a good choice for delivering tumor peptides/antigens to induce enhanced tumor-specific immune responses. The first oncolytic virus (OV) approved for human use is the attenuated herpes simplex virus type 1 (HSV-1), Talimogene laherparepvec (T-VEC) which has been FDA approved for the treatment of melanoma in humans. In this study, we engineered the recombinant oncolytic HSV-1 (oHSV) VC2-OVA expressing a fragment of ovalbumin (OVA) as a fusion protein with VP26 virion capsid protein. We tested the ability of VC2-OVA to act as a vector capable of stimulating strong, specific antitumor immunity in a syngeneic murine melanoma model. Therapeutic vaccination with VC2-OVA led to a significant reduction in colonization of tumor cells in the lungs of mice intravenously challenged B16cOVA cells. In addition, VC2-OVA induced a potent prophylactic antitumor response and extended survival of mice that were intradermally engrafted with B16cOVA tumors compared with mice immunized with control virus.

Methylomic Biomarkers of Lithium Response in Bipolar Disorder: A Proof of Transferability Study.

Response to lithium (Li) is highly variable in bipolar disorders (BD) and no clinical or biological predictors of long-term response have been validated to date. Using a genome-wide methylomic approach (SeqCapEpi), we previously identified seven differentially methylated regions (DMRs) that discriminated good from non-responders (prophylactic response phenotype defined using the “Alda” scale). This study is a proof of transferability from bench to bedside of this epigenetic signature. For this purpose, we used Methylation Specific High-Resolution Melting (MS-HRM), a PCR based method that can be implemented in any medical laboratory at low cost and with minimal equipment. In 23 individuals with BD, MS-HRM measures of three out of seven DMRs were technically feasible and consistencies between SeqCapEpi and MS-HRM-measures were moderate to high. In an extended sample of individuals with BD (n = 70), the three MS-HRM-measured DMRs mainly predicted nonresponse, with AUC between 0.70–0.80 according to different definitions of the phenotype (Alda- or machine-learning-based definitions). Classification tree analyses further suggested that the MS-HRM-measured DMRs correctly classified up to 84% of individuals as good or non-responders. This study suggested that epigenetic biomarkers, identified in a retrospective sample, accurately discriminate non-responders from responders to Li and may be transferrable to routine practice.