Vaccine Therapy Research Articles

Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy.

Hepatocellular carcinoma (HCC) mortality rates are increasing globally, and particularly in the Western world. Cirrhosis remains the predominant risk factor for HCC. However, epidemiological shifts in the incidence of HCC from patients with virus-related liver disease to those with non-viral aetiologies, including alcohol-associated and metabolic dysfunction-associated steatotic liver disease, have important implications for prevention, surveillance and treatment. Hepatitis B vaccination and antiviral therapy for hepatitis B and C are effective for primary prevention of virus-related HCCs, but chemoprevention strategies for non-viral liver disease remain an unmet need. Emerging data suggest associations between aspirin, statins, metformin and coffee and reduced HCC incidence, although none has been proved to be causally related. Secondary prevention of HCC via semi-annual surveillance is associated with improvements in early detection and thus reduced mortality; however, current tools, including abdominal ultrasonography, have suboptimal sensitivity for thedetection of earlystage HCC, particularly in patients with obesity and/or non-viral liver disease. Promising blood-based or imaging-based surveillance strategies are emerging, although these approaches require further validation before adoption in clinical practice. In the interim, efforts should be focused on maximizing use of the existing surveillance tools given their prevalent underuse globally. Remarkable advances have been made in the treatment of HCC, including expanded eligibility for surgical therapies, improved patient selection for locoregional treatments and increased systemic treatment options, including immune-checkpoint inhibitors. In this Review, we discuss trends in the epidemiology of HCC and their implications for screening, prevention and therapy.

Cytokine Gene Vaccine Therapy for Treatment of a Brain Tumor.

A glioma is a malignant brain tumor with a poor prognosis. Attempts at the surgical removal of the tumor are the first approach, but additional treatment strategies, including radiation therapy and systemic or local chemotherapy, are necessary. Furthermore, the treatments are often associated with significant adverse side effects. Normal and malignant cells generally have antigenic differences, and this is the rationale for clinical immunotherapeutic strategies. Cytokines such as IL-15 or IL-2, which stimulate an anti-tumor immune response, have been shown to have a particularly high potential for use in immunotherapy against various tumors. In this review, treatments with either a poxvirus, genetically engineered to secrete IL-15, or allogeneic fibroblasts, transfected with tumor DNA and engineered to secrete IL-2, are shown to be effective strategies in extending the survival of mice with malignant brain tumors upon intracerebral injection of the treatment cells. Future studies with these treatment strategies in patients with intracerebral tumors are urgently needed.

Attitudes, expectations, and lived experiences of cancer patients receiving dendritic cell vaccine therapy in Japan

ObjectiveImmunotherapeutic approaches to cancer, such as dendritic cell vaccine therapy, promise to improve survival rate but may present unique challenges to patients. However, there is no research on the lived experiences of cancer patients receiving dendritic cell vaccine therapy. The aim of this study was to explore the attitudes, expectations, and experiences of cancer patients receiving dendritic cell vaccine therapy in Japan. MethodsThis was an exploratory qualitative study. A descriptive phenomenological approach was used to investigate the experiences of eight advanced-stage cancer patients (median age: 59.5 years). Data were collected between July 2018 and March 2020 using in-depth semi-structured interviews. Data were analyzed according to Colaizzi's seven-step phenomenological strategy, and EQUATOR's Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines for qualitative studies were followed. ResultsFour themes emerged from the data analysis: strong concerns about chemotherapy, faith in dendritic cell vaccine therapy, motivation to succeed, and physical and mental changes. The first two themes related to pretreatment attitudes and expectations. The latter two themes expressed participants’ experiences during and after therapy. ConclusionsDendritic cell vaccine therapy patients expressed fears about the effects of standard treatment, and hope and uncertainty regarding immunotherapy treatment decisions and efficacy. The findings suggest that such patients require nursing care that includes prevention and reduction of chemotherapy side effects, careful observation of patients' well-being, management of patients’ expectations and uncertainty, formation of patient–health care practitioner partnerships, and team medicine.

Guarding Against Rabies: The Power of Vaccination in Rabies Disease Management

Rabies, a lethal viral disease caused by the rabies virus, presents a critical public health challenge globally. The disease's etiology involves transmission through the bite or scratch of infected animals, primarily dogs, with the virus targeting the central nervous system and leading to devastating neurological symptoms. Early diagnosis is crucial but challenging due to the disease's non-specific initial manifestations. Vaccination strategies serve as the cornerstone of rabies prevention, encompassing pre-exposure prophylaxis for high-risk individuals and post-exposure prophylaxis for those bitten or scratched by potentially rabid animals. In this article we provide an in-depth exploration of vaccination therapy as a pivotal strategy in the deterrence and management of rabies. The evolution of rabies vaccines, particularly inactivated virus vaccines, is explored, underscoring their role in reducing human rabies cases. The article concludes by emphasizing the significance of continuous research to enhance vaccine effectiveness and promote a comprehensive approach to rabies prevention.

Immunological analysis of hybrid neoantigen peptide encompassing class I/II neoepitope-pulsed dendritic cell vaccine.

Neoantigens/ are tumor-specific antigens that evade central immune tolerance mechanisms in the thymus. Long-term tumor-specific cytotoxic T lymphocyte activity maintenance requires class II antigen-reactive CD4+ T cells. We had previously shown that intranodal vaccination with class I neoantigen peptide-pulsed dendritic cells (DCs) induced a robust immune response in a subset of patients with metastatic cancer. The present study aimed to perform a detailed ex vivo analysis of immune responses in four patients receiving an intranodal hybrid human leukocyte antigen class II neoantigen peptide encompassing a class I neoantigen epitope (hybrid neoantigen)-pulsed DC vaccine. After vaccination, strong T-cell reactions against the hybrid class II peptide and the class I-binding neoantigen peptide were observed in all four patients. We found that hybrid class II neoantigen peptide-pulsed DCs stimulated CD4+ T cells via direct antigen presentation and CD8+ T cells via cross-presentation. Further, we demonstrated that hybrid class II peptides encompassing multiple class I neoantigen epitope-pulsed DCs could present multiple class I peptides to CD8+ T cells via cross-presentation. Our findings provide insight into the mechanisms underlying hybrid neoantigen-pulsed DC vaccine therapy and suggest future neoantigen vaccine design.

Designed for a pandemic: Mitigating the risk of SARS-CoV-2 transmission through hospital design and infrastructure

BackgroundTo describe the new Royal Adelaide Hospital (RAH) design and infrastructure features that helped mitigate the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission within the hospital during the pre-vaccination and pre-antiviral period. MethodThe RAH infrastructure, design and initial pandemic response was assessed. A retrospective review of all confirmed or suspected coronavirus disease 2019 (COVID-19) patients admitted from 1 February 2020 to 30 May 2020 was also performed to assess risk of transmission. Outbreak response reports were reviewed to identify episodes of nosocomial COVID-19. ResultsKey infrastructure features include single-bed overnight rooms with dedicated bathrooms, creation of pandemic areas accessible only to pandemic staff, and sophisticated air-handling units with improved ventilation. A total of 264 COVID-19 related admission occurred, with 113 confirmed cases and 1579 total cumulative bed days. Despite a limited understanding of SARS-CoV-2 transmission, no vaccination or anti-viral therapy, global shortages of particulate filter respirators and restricted testing during this period, only one probable nosocomial COVID-19 case occurred in a healthcare worker, with no nosocomial cases involving patients. ConclusionsThe RAH design and pandemic features complimented existing infection control interventions and was important in limiting nosocomial spread of SARS-CoV-2.

THU284 BCG Clinical Trial Programs In Advanced Type 1 Diabetes - 2023 Update

Abstract Disclosure: W.M. Kühtreiber: None. E. Hostetter: None. A.H. Lee: None. N. Ng: None. G. Wolfe: None. A. Aristarkhova: None. J. Braley: None. H. Zheng: None. D.L. Faustman: None. The bacillus Calmette-Guerin (BCG) vaccine, first introduced a century ago for tuberculosis prevention, is today being tested in double-blinded, randomized clinical trials for treatment of diverse forms of autoimmunity, including type 1 diabetes (T1D) and multiple sclerosis (MS). There are multiple clinical protocols underway at our institution testing various aspects of BCG’s ability to lower HbA1c, reduce insulin requirements and change day-to-day fluctuations in blood sugars, including: 1) Ten-year follow up of a Phase I study of BCG vaccination in longstanding T1D to study the durability of lowered HbA1c values after BCG treatment; 2) Randomized, double-blinded Phase II clinical trial testing the BCG vaccine in adults with longstanding T1D to demonstrate the reproducibility of BCG’s effects seen in the Phase I trial; 3) Radiologic study to quantify and identify through FDG-CAT scans the organs and organ systems that utilize more sugar after BCG treatment; 4) Study in adults with longstanding T1D to evaluate the effects of two doses of BCG compared to 6 doses of BCG over 5 years of observation; and 5) A multi-center clinical trial of adolescents with > 2 years since T1D diagnosis to evaluate the potential benefits of BCG vaccination. To date, we have enrolled 295 patients as part of a planned enrollment of 500, including 272 BCG-vaccinated patients. Global studies on the effects of BCG on the immune system show that the impact of multi-dose vaccination in MS and T1D is optimized by at least 2 years of follow up and that the effects appear durable without further treatment in both MS and T1D to 5+ years. BCG vaccine therapy may provide a safe and affordable medical intervention in individuals with longstanding autoimmunity. Presentation: Thursday, June 15, 2023

Extracorporeal Membrane Oxygenation Support and Critically Ill COVID-19 Patient Outcomes: A Population-Based Cohort Study.

We selected critically ill patients with coronavirus disease 2019 (COVID-19) who were receiving extracorporeal membrane oxygenation (ECMO) support and had been transferred to experienced centers. Thus, we aimed to evaluate factors that were associated with receiving ECMO support and factors that were associated with patient mortality. Using data from the National Health Insurance Service and Korea Disease Control and Prevention Agency in South Korea, adult patients admitted to an intensive care unit from October 8, 2020, to December 31, 2021, with a main diagnosis of COVID-19 were included. They were divided into two groups: ECMO group (n = 455) and non-ECMO group (n = 12,648). Receiving ECMO support was less associated with old age [odds ratio (OR), 0.95; 95% confidence interval (CI), 0.94-0.96; p < 0.001], underlying severe disabilities (OR, 0.49; 95% CI, 0.29-0.83; p = 0.008), and booster vaccination status (second: OR, 0.61; 95% CI, 0.39-0.94; p = 0.024; third: OR, 0.40; 95% CI, 0.25-0.65; p < 0.001). In addition, after adjusting for various variables, low mortality in patients with ECMO support was associated with having previously received a second booster vaccination (OR, 0.33; 95% CI, 0.14-0.77; p = 0.010). Vaccination and booster therapy may lower the need for ECMO support and lower mortality among critically ill patients with COVID-19 with ECMO support.

Research Progress of Immune Heterogeneity in Leukemia Microenvironment--Review

Although the body has a strong immune system which can resists the invasion of leukemia cells, leukemia cells disseminate systemically and form an immunosuppressive microenvironment through a variety of mechanisms, including regulation of antigen presentation, utilization of immunosuppressive enzyme AXL, immune cell inhibitory checkpoint NKG2A and immunoregulatory gene VISTA, resulting in immune escape. Therefore, most types of leukemia are inevitable for the affliction of drug resistance or relapse, and the immune efficacy is not as significant as that of other hematological tumors and the prognosis is suboptimal. This article reviews the immune heterogeneity of leukemia microenvironment from many aspects, including anti-leukemia immunity and immune escape. In addition, it also reviews the latest progress and future prospects of immune checkpoint inhibition, adoptive cell therapy and vaccine therapy in leukemia, providing a theoretical basis for the development of personalized combination therapy strategies with less toxic side effects.

Formulation of Chitosan-Zein Nano-in-Microparticles for Oral DNA Delivery.

Gene delivery via the oral route offers a promising strategy for improving DNA vaccination and gene-based therapy outcomes. The noninvasive nature of oral delivery lends to ease of dosing, which can facilitate convenience and patient compliance. Moreover, oral administration allows for both local and systemic production of therapeutic genes or, in the case of DNA vaccination, mucosal and systemic immunity. Here, we describe the methods to produce a dual biomaterial, oral DNA delivery system composed of chitosan (CS) and zein (ZN). In this system, CS serves to encapsulate and deliver DNA cargo to intestinal cells in the form of CS-DNA nanoparticles (CS-DNA NPs), while ZN is used to form a protective matrix around the CS-DNA NPs that prevent degradation during gastric transit but then degrades to release the CS-DNA NPs for transfection upon entry into the intestines. These particles have demonstrated the ability to effectively protect cargo DNA from simulated gastric degradation in vitro and mediate transgene production in vivo, making them an effective oral gene delivery system.

Clinical Applications of Combined Immunotherapy Approaches in Gastrointestinal Cancer: A Case-Based Review.

Malignant neoplasms arising from the gastrointestinal (GI) tract are among the most common types of cancer with high mortality rates. Despite advances in treatment in a small subgroup harboring targetable mutations, the outcome remains poor, accounting for one in three cancer-related deaths observed globally. As a promising therapeutic option in various tumor types, immunotherapy with immune checkpoint inhibitors has also been evaluated in GI cancer, albeit with limited efficacy except for a small subgroup expressing microsatellite instability. In the quest for more effective treatment options, energetic efforts have been placed to evaluate the role of several immunotherapy approaches comprising of cancer vaccines, adoptive cell therapies and immune checkpoint inhibitors. In this review, we report our experience with a personalized dendritic cell cancer vaccine and cytokine-induced killer cell therapy in three patients with GI cancers and summarize current clinical data on combined immunotherapy strategies.

A review of strategies to overcome immune resistance in the treatment of advanced prostate cancer.

Immunotherapy has become integral in cancer therapeutics over the past two decades and is now part of standard-of-care treatment in multiple cancer types. While various biomarkers and pathway alterations such as dMMR, CDK12, and AR-V7 have been identified in advanced prostate cancer to predict immunotherapy responsiveness, the vast majority of prostate cancer remain intrinsically immune-resistant, as evidenced by low response rates to anti-PD(L)1 monotherapy. Since regulatory approval of the vaccine therapy sipuleucel-T in the biomarker-unselected population, there has not been much success with immunotherapy treatment in advanced prostate cancer. Researchers have looked at various strategies to overcome immune resistance, including the identification of more biomarkers and the combination of immunotherapy with existing effective prostate cancer treatments. On the horizon, novel drugs using bispecific T-cell engager (BiTE) and chimeric antigen receptors (CAR) technology are being explored and have shown promising early efficacy in this disease. Here we discuss the features of the tumour microenvironment that predispose to immune resistance and rational strategies to enhance antitumour responsiveness in advanced prostate cancer.

SARS-CoV-2 antibodies recognize 23 distinct epitopic sites on the receptor binding domain

The COVID-19 pandemic and SARS-CoV-2 variants have dramatically illustrated the need for a better understanding of antigen (epitope)-antibody (paratope) interactions. To gain insight into the immunogenic characteristics of epitopic sites (ES), we systematically investigated the structures of 340 Abs and 83 nanobodies (Nbs) complexed with the Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein. We identified 23 distinct ES on the RBD surface and determined the frequencies of amino acid usage in the corresponding CDR paratopes. We describe a clustering method for analysis of ES similarities that reveals binding motifs of the paratopes and that provides insights for vaccine design and therapies for SARS-CoV-2, as well as a broader understanding of the structural basis of Ab-protein antigen (Ag) interactions.

Isolation of novel simian adenoviruses from macaques for development of a vector for human gene therapy and vaccines.

Adenoviruses are widely used in gene therapy and vaccine delivery. Due to the high prevalence of human adenoviruses (HAdVs), the pre-existing immunity against HAdVs in humans is common, which limits the wide and repetitive use of HAdV vectors. In contrast, the pre-existing immunity against simian adenoviruses (SAdVs) is low in humans. Therefore, we performed epidemiological investigations of SAdVs in simians and found that the SAdV prevalence was as high as 33.9%. The whole-genome sequencing and sequence analysis showed SAdV diversity and possible cross species transmission. One isolate with low level of pre-existing neutralizing antibodies in humans was used to construct replication-deficient SAdV vectors with E4orf6 substitution and E1/E3 deletion. Interestingly, we found that the E3 region plays a critical role in its replication in human cells, but the absence of this region could be compensated for by the E4orf6 from HAdV-5 and the E1 expression intrinsic to HEK293 cells.

Shear-reversible clusters of HIV-1 in solution: stabilized by antibodies, dispersed by mucin.

The phenomenon of reversible clustering is expected to further nuance HIV immune stealth because virus surfaces can escape interaction with antibodies (Abs) by hiding temporarily within clusters. It is well known that mucin reduces HIV virulence, and the current perspective is that mucin aggregates HIV-1 to reduce infections. Our findings, however, suggest that mucin is dispersing HIV clusters. The study proposes a new paradigm for how HIV-1 may broadly evade Ab recognition with reversible clustering and why mucin effectively neutralizes HIV-1.

Gold nanoparticle-based strategies against SARS-CoV-2: A review

Abstract The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 has been an immense threat to global public health and has also had a negative socioeconomic impact worldwide. However, although the pandemic is now under control, it has demonstrated that society is unprepared to use analysis methods that are applicable to various types of viruses nor apply new therapies to prevent infections, considering the extensive time needed for vaccine development. The use of nanomaterial-based diagnostics and therapeutics can provide essential strategies for both virus detection and treatment. Gold nanoparticles (AuNPs) are the nanomaterials most commonly used to enhance virus detection because of their bioconjugation, high plasmon resonance, and excellent electrical, optical, and catalytic properties. The present review outlines the recent advances reported in the literature regarding using AuNPs for their antiviral activities with respiratory viruses, analysis techniques such as AuNP-assisted polymerase chain reaction, biosensors (electrochemical, piezoelectric, and optical), lateral flow analysis, nucleic acid assays, and gene and vaccine therapy. Finally, as a potential antiviral treatment, this review provides in vitro and in vivo toxicity results of AuNPs for respiratory viruses, as well as those related to their toxicity in humans, to evaluate their use as a future antiviral treatment.

Inhibition of Trichinella spiralis Membrane-Associated Progesterone Receptor (MAPR) Results in a Reduction in Worm Burden.

Trichinella spiralis (T. spiralis), a nematode parasite, is the major cause of Trichinellosis, a zoonotic disease. A key role of MAPR in the reproductive system is to maintain pregnancy. Previous studies found that antihormone drug design and vaccine therapy of recombinant protein (rTs-MAPRC2) control T. spiralis infection. The current study investigates the inhibitory effects of different ratios of antibodies against Ts-MAPRC2 on the development of muscle larvae (ML) and newborn larvae (NBL). First, we performed indirect immunofluorescence assays and examined the effects of rTs-MAPRC2-Ab on ML and NBL in vitro as well as in vivo. Afterward, siRNA-Ts-MAPRC2 was transfected into T. spiralis muscle larvae. Following that, Ts-MAPRC2 protein was detected by Western Blotting, and mRNA levels were determined by qPCR. We also assessed whether siRNA-treated NBLs were infective by analyzing muscle larvae burden (MLs). Our results showed that rTs-MAPRC2-Ab greatly inhibited the activity of the Ts-MAPRC2 in ML and NBL of T. spiralis and rTs-MAPRC2-Ab reduced larval infectivity and survival in the host in a dose-dependent manner (1:50, 1:200, 1:800 dilutions). Furthermore, siRNA-Ts-MAPRC2 effectively silenced the Ts-MAPRC2 gene in muscle larvae (ML) in vitro, as well as in newborn larvae (NBL) of T. spiralis in vivo. In addition, siRNA-Ts-MAPRC2 (siRNA180, siRNA419, siRNA559) reduced host larval survival and infectivity significantly. This study, therefore, suggests that Ts-MAPRC2 might be a novel molecular target useful in the development of vaccines against T. spiralis infection.

Cancer Vaccine Therapeutics: Limitations and Effectiveness-A Literature Review.

In recent years, there has been a surge of interest in tumor microenvironment-associated cancer vaccine therapies. These innovative treatments aim to activate and enhance the body's natural immune response against cancer cells by utilizing specific antigens present in the tumor microenvironment. The goal is to achieve a complete clinical response, where all measurable cancer cells are either eliminated or greatly reduced in size. With their potential to revolutionize cancer treatment, these therapies represent a promising avenue for researchers and clinicians alike. Despite over 100 years of research, the success of therapeutic cancer vaccines has been variable, particularly in advanced cancer patients, with various limitations, including the heterogeneity of the tumor microenvironment, the presence of immunosuppressive cells, and the potential for tumor escape mechanisms. Additionally, the effectiveness of these therapies may be limited by the variability of the patient's immune system response and the difficulty in identifying appropriate antigens for each patient. Despite these challenges, tumor microenvironment-targeted vaccine cancer therapies have shown promising results in preclinical and clinical studies and have the potential to become a valuable addition to current cancer treatment and "curative" options. While chemotherapeutic and monoclonal antibody treatments remain popular, ongoing research is needed to optimize the design and delivery of these therapies and to identify biomarkers that can predict response and guide patient selection. This comprehensive review explores the mechanisms of cancer vaccines, various delivery methods, and the role of adjuvants in improving treatment outcomes. It also discusses the historical background of cancer vaccine research and examines the current state of major cancer vaccination immunotherapies. Furthermore, the limitations and effectiveness of each vaccine type are analyzed, providing insights into the future of cancer vaccine development.

Advances in Immunotherapeutics in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 95% of all pancreatic cancer cases and is the seventh-leading cause of cancer death. Poor prognosis is a result of late presentation, a lack of screening tests and the fact some patients develop resistance to chemotherapy and radiotherapy. Novel therapies like immunotherapeutics have been of recent interest in pancreatic cancer. However, this field remains in its infancy with much to unravel. Immunotherapy and other targeted therapies have yet to yield significant progress in treating PDAC, primarily due to our limited understanding of the disease immune mechanisms and its intricate interactions with the tumour microenvironment (TME). In this review we provide an overview of current novel immunotherapies which have been studied in the field of pancreatic cancer. We discuss their mechanisms, evidence available in pancreatic cancer as well as the limitations of such therapies. We showcase the potential role of combining novel therapies in PDAC, postulate their potential clinical implications and the hurdles associated with their use in PDAC. Therapies discussed with include programmed death checkpoint inhibitors, Cytotoxic T-lymphocyte-associated protein 4, Chimeric Antigen Receptor-T cell therapy, oncolytic viral therapy and vaccine therapies including KRAS vaccines, Telomerase vaccines, Gastrin Vaccines, Survivin-targeting vaccines, Heat-shock protein (HSP) peptide complex-based vaccines, MUC-1 targeting vaccines, Listeria based vaccines and Dendritic cell-based vaccines.

Ups and downs in PCSK9 inhibition in the cardiovascular arena: a review.

This article reviews PCSK9 inhibitors (PCSK9i) with a focus on clinically relevant studies published in the last 18 months. Prespecified subgroup evaluations, secondary analyses, and open-label extension studies from the two landmark trials, FOURIER and ODYSSEY Outcomes, have provided new data on the safety and efficacy of the monoclonal PCSK9 antibodies evolocumab and alirocumab. Recent studies of PCSK9i early in ACS and post percutaneous coronary intervention have explored early effects on biomarkers and plaque morphology with various imaging modalities. Two large outcome trials with PCSK9i in lower risk patients without prior myocardial infarction or stroke are ongoing and could expand the eligible population for these potent therapies. Additionally, novel methods to inhibit PCSK9 using oral administration, vaccination, and gene therapy are in various stages of clinical development. PCSK9i represent a potent class of lipid-lowering therapies that are well tolerated and effective in a wide group of patients with high-risk atherosclerotic cardiovascular disease. Ongoing studies of PCSK9i in patients at lower risk and with acute myocardial infarction have the potential to broaden their indication. Alternative methods of PCSK9i are being evaluated and could provide easier and less expensive options for this important class of medication.