ABSTRACT
INTRODUCTION: The total number of cancer-related deaths and new cancer cases in 2020 was 19.3 billion and 10.8 billion, respectively. Therefore, prevention, diagnosis, and treatment of neoplastic disease, as well as management of comorbidities, are of paramount importance. In this regards, poor nutritional status and mental disorders are comorbidity conditions frequently observed in cancer patients. The aim of this study was to assess the association between malnutrition and anxiety in hospitalized adult cancer patients. METHODS: This is a retrospective study. Nutrition Risk Screening (NRS) 2002, body mass index (BMI), daily calorie intake, and weight difference between admission and discharge were used to evaluate nutritional status. Anxiety was assessed with the Hospital Anxiety and Depression Scale (HADS-A). Ordered logistic and linear logistic regressions adjusted for sex and age were used to estimate the association between malnutrition and anxiety in cancer patients. RESULTS: A total of 90 patients were included. Higher NRS risk [aß = 0.85; 95% CI (0.28-1.42); p = 0.004], disease stage [aß = 0.77; 95% CI (0.08-1.47); p = 0.029], and cachexia [aß = 2.20; 95% CI (0.75-3.65); p = 0.003] were significantly associated with anxiety symptoms. Moreover, cancer site different than gastrointestinal cancers was associated with a lower risk of anxiety symptoms [aß = - 2.11; 95% CI (- 3.55/ - 0.66); p = 0.005]. CONCLUSION: In the current study, we found a relatively high rate of malnourished patients, indicating the importance of routinely assessing nutritional status and screening cancer patients for mental health issues. This approach could help physicians to treat both in a timely manner, thereby significantly reducing the burden of the disease and improving the quality of life of patients.
Subject(s)
Malnutrition , Neoplasms , Adult , Humans , Retrospective Studies , Nutrition Assessment , Quality of Life , Malnutrition/epidemiology , Malnutrition/etiology , Malnutrition/diagnosis , Nutritional Status , Anxiety/epidemiology , Anxiety/etiology , Neoplasms/complications , Neoplasms/epidemiologyABSTRACT
The COVID-19 pandemic and the need for additional safe, effective, and affordable vaccines gave new impetus into development of vaccine genetic platforms. Here we report the findings from the phase 1, first-in-human, dose-escalation study of COVID-eVax, a DNA vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Sixty-eight healthy adults received two doses of 0.5, 1, or 2 mg 28 days apart, or a single 2-mg dose, via intramuscular injection followed by electroporation, and they were monitored for 6 months. All participants completed the primary safety and immunogenicity assessments after 8 weeks. COVID-eVax was well tolerated, with mainly mild to moderate solicited adverse events (tenderness, pain, bruising, headache, and malaise/fatigue), less frequent after the second dose, and it induced an immune response (binding antibodies and/or T cells) at all prime-boost doses tested in up to 90% of the volunteers at the highest dose. However, the vaccine did not induce neutralizing antibodies, while particularly relevant was the T cell-mediated immunity, with a robust Th1 response. This T cell-skewed immunological response adds significant information to the DNA vaccine platform and should be assessed in further studies for its protective capacity and potential usefulness also in other therapeutic areas, such as oncology.
Subject(s)
COVID-19 , Vaccines, DNA , Adult , Humans , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Double-Blind Method , Pandemics/prevention & control , SARS-CoV-2 , Vaccines, DNA/adverse effectsABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has caused more than 760 million cases and over 6.8 million deaths as of March 2023. Vaccination has been the main strategy used to contain the spread of the virus and to prevent hospitalizations and deaths. Currently, two mRNA-based vaccines and one adenovirus-vectored vaccine have been approved and are available for use in the U.S. population. The versatility, low cost, and rapid production of DNA vaccines provide important advantages over other platforms. Additionally, DNA vaccines efficiently induce both B- and T-cell responses by expressing the antigen within transfected host cells, and the antigen, after being processed into peptides, can associate with MHC class I or II of antigen-presenting cells (APCs) to stimulate different T cell responses. However, the efficiency of DNA vaccination needs to be improved for use in humans. Importantly, in vivo DNA delivery combined with electroporation (EP) has been used successfully in the field of veterinary oncology, resulting in high rates of response after electrochemotherapy. Here, we evaluate the safety, immunogenicity, and protective efficacy of a novel linear SARS-CoV-2 DNA vaccine candidate delivered by intramuscular injection followed by electroporation (Vet-ePorator™) in ferrets. The linear SARS-CoV-2 DNA vaccine candidate did not cause unexpected side effects. Additionally, the vaccine elicited neutralizing antibodies and T cell responses on day 42 post-immunization using a low dose of the linear DNA construct in a prime-boost regimen. Most importantly, vaccination significantly reduced shedding of infectious SARS-CoV-2 through oral and nasal secretions in a ferret model.
Subject(s)
COVID-19 , Vaccines, DNA , Viral Vaccines , Humans , Animals , COVID-19 Vaccines , SARS-CoV-2 , COVID-19/prevention & control , Vaccines, DNA/genetics , Ferrets , Virus Shedding , Antibodies, Viral , Antibodies, Neutralizing , DNA , Spike Glycoprotein, Coronavirus/genetics , Immunogenicity, VaccineABSTRACT
The COVID-19 pandemic caused by SARS-CoV-2 has made the development of safe and effective vaccines a critical priority. To date, four vaccines have been approved by European and American authorities for preventing COVID-19, but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle. We constructed a set of prototype DNA vaccines expressing various forms of the SARS-CoV-2 spike (S) protein and assessed their immunogenicity in animal models. Among them, COVID-eVax-a DNA plasmid encoding a secreted monomeric form of SARS-CoV-2 S protein receptor-binding domain (RBD)-induced the most potent anti-SARS-CoV-2 neutralizing antibody responses (including against the current most common variants of concern) and a robust T cell response. Upon challenge with SARS-CoV-2, immunized K18-hACE2 transgenic mice showed reduced weight loss, improved pulmonary function, and lower viral replication in the lungs and brain. COVID-eVax conferred significant protection to ferrets upon SARS-CoV-2 challenge. In summary, this study identifies COVID-eVax as an ideal COVID-19 vaccine candidate suitable for clinical development. Accordingly, a combined phase I-II trial has recently started.
Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunization/methods , Models, Animal , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/immunology , Vaccines, DNA/administration & dosage , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/genetics , COVID-19/virology , Female , Ferrets , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Protein Domains , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: To identify the most prevalent symptoms and those with greatest impact upon health-related quality of life (HRQOL) among esophageal cancer survivors. BACKGROUND: Long-term symptom burden after esophagectomy, and associations with HRQOL, are poorly understood. PATIENTS AND METHODS: Between 2010 and 2016, patients from 20 European Centers who underwent esophageal cancer surgery, and were disease-free at least 1 year postoperatively were asked to complete LASER, EORTC-QLQ-C30, and QLQ-OG25 questionnaires. Specific symptom questionnaire items that were associated with poor HRQOL as identified by EORTC QLQ-C30 and QLQ-OG25 were identified by multivariable regression analysis and combined to form a tool. RESULTS: A total of 876 of 1081 invited patients responded to the questionnaire, giving a response rate of 81%. Of these, 66.9% stated in the last 6 months they had symptoms associated with their esophagectomy. Ongoing weight loss was reported by 10.4% of patients, and only 13.8% returned to work with the same activities.Three LASER symptoms were correlated with poor HRQOL on multivariable analysis; pain on scars on chest (odds ratio (OR) 1.27; 95% CI 0.97-1.65), low mood (OR 1.42; 95% CI 1.15-1.77) and reduced energy or activity tolerance (OR 1.37; 95% CI 1.18-1.59). The areas under the curves for the development and validation datasets were 0.81â±â0.02 and 0.82â±â0.09 respectively. CONCLUSION: Two-thirds of patients experience significant symptoms more than 1 year after surgery. The 3 key symptoms associated with poor HRQOL identified in this study should be further validated, and could be used in clinical practice to identify patients who require increased support.
Subject(s)
Esophageal Neoplasms/surgery , Esophagectomy , Postoperative Complications/epidemiology , Quality of Life , Aged , Cross-Sectional Studies , Europe , Female , Humans , Male , Middle Aged , Self Report , Symptom AssessmentABSTRACT
BACKGROUND: Esophagectomy for cancer strongly impairs quality of life. The aim of this trial was to evaluate the effect of the nutritional and respiratory counseling on postoperative quality of life. METHODS: At hospital discharge, patients were randomized into four groups receiving respectively: nutritional and respiratory counseling, nutritional counseling alone, respiratory counseling alone, or standard care. The main endpoint was the impairment in quality of life in the first month after surgery. Linear mixed effect models were estimated to assess mean score differences (MDs) in quality of life scores. RESULTS: Patients receiving nutritional counseling reported less appetite loss (MD - 17.7, 95% CI - 32.2 to -3.3) than those not receiving nutritional counseling at 1 month after surgery. Dyspnea was similar between patients receiving vs. those not receiving respiratory counseling (MD - 3.1, 95% CI - 10.8 to 4.6). Global quality of life was clinically similar between patients receiving vs. those not receiving nutritional counseling over time (MD 0.9, 95% CI - 5.5 to 7.3), as well as in patients receiving vs. those not receiving respiratory counseling over time (MD 0.7, 95% CI - 5.9 to 7.2). CONCLUSIONS: Intensive postoperative care does not affect global quality of life even if nutritional counseling reduced appetite loss.
Subject(s)
Counseling/methods , Esophageal Neoplasms/diet therapy , Esophageal Neoplasms/surgery , Esophagectomy/methods , Nutrition Therapy/methods , Quality of Life/psychology , Respiration/drug effects , Aged , Female , Health Education , Humans , Male , Middle Aged , Surveys and QuestionnairesABSTRACT
BACKGROUND AND OBJECTIVES: Data on long-term health-related quality of life (HRQL) after esophagectomy for cancer show contradictory results. The aim was to analyze long-term HRQL at 3 or more years after esophagectomy. METHODS: Survivors were identified among patients who had undergone esophagectomy during 2007-2013 using the local clinic database. Quality of life was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 and OG25 questionnaires. Specific aspects were selected a priori and compared with published scores from European healthy subjects (mean difference, MD). RESULTS: Sixty-five long-term survivors (median follow-up 4 years) were identified. All functional scales and most symptom scales were clinically similar between EC long-term survivors and European healthy subjects. Survivors reported more problems concerning eating (MD 13.1, 95% C.I. 10.6-15.6) and reflux (MD 19.7, 95% C.I. 15.9-23.5). HQRL variation from discharge to long term was available in 27 participants who reported improvements in role functioning (MD 40.1, 95%C.I. 24.3-56.0) and dysphagia (MD -41.9, 95% C.I. -51.7 to 32.0). CONCLUSIONS: Long-term HRQL after esophagectomy is similar between EC survivors and European healthy subjects, despite persisting reflux and eating problems. Further research may focus on improvements of postoperative alimentary habits.
Subject(s)
Adenocarcinoma/surgery , Carcinoma, Squamous Cell/surgery , Esophageal Neoplasms/surgery , Esophagectomy/adverse effects , Gastroesophageal Reflux/etiology , Postoperative Complications , Quality of Life , Aged , Female , Follow-Up Studies , Health Status , Humans , Male , Middle Aged , Prognosis , Surveys and Questionnaires , SurvivorsABSTRACT
PURPOSE: This study aimed to evaluate patients' perceived receipt of information according to the possibility of cure in esophageal cancer. METHODS: One hundred and twelve consecutive patients presenting at the multidisciplinary visit at the Veneto Institute of Oncology for esophageal cancer between 2014 and 2016 were included in the study. The Italian version of the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires C30 (core questionnaire), OG25 (esophago-gastric cancer module), and INFO25 (information module) were used. RESULTS: Candidates for palliative treatment were less informed about the disease (adjusted mean difference - 11.5, 95% CI - 23.0 to - 0.02) and less satisfied with information provided (adjusted mean difference - 18.3, 95% CI - 31.9 to - 4.7) than candidates for curative treatment. In addition, candidates for palliative treatment wanted to receive more information than candidates for curative treatment (adjusted mean difference 26.1, 95% CI 0.5 to 51.6). Better quality of life was associated with satisfaction of received information (ß = 0.77, p < 0.0001) and of receiving information about things that the patient can do to help himself (ß = 0.26, p = 0.04). More anxiety was associated to receiving more information about disease (ß = 0.46, p = 0.02) but less information about things that the patient can do to help himself (ß = - 0.38, p = 0.02). CONCLUSIONS: Candidates for palliative treatment were less satisfied with information about the disease and wanted to receive more information. Additionally, some aspects of quality of life were found to be associated with perceived receipt of information. Appropriate training in communication of prognostic information may improve clinical management of incurable cancer patients.
Subject(s)
Esophageal Neoplasms/therapy , Quality of Life/psychology , Aged , Cross-Sectional Studies , Esophageal Neoplasms/pathology , Female , Humans , Male , Middle Aged , Perception , Surveys and QuestionnairesABSTRACT
Preoperative oral immunonutrition was demonstrated to improve immune response and to decrease the infection rate in patients with cancer. This study aimed to assess how immunonutrition could influence the immune cell response in the mucosal microenvironment of esophageal adenocarcinoma. Therefore, A prospective cohort of consecutive patients undergoing esophagectomy for esophageal adenocarcinoma was enrolled. A subgroup of them was given preoperative oral immunonutrition with Oral Impact® and was compared to those who received no preoperative supplementation. Mucosal samples from healthy esophagus were obtained at esophagectomy. Histology, immunohistochemistry, gene expression analysis, and cytofluorimetry were performed. Markers of activation of antigen-presenting cells (CD80, CD86, and HLA-I), innate immunity (TLR4 and MyD88), and cytotoxic lymphocyte infiltration and activation (CD8, CD38, CD69, and CD107) were measured. In all, 50 patients received preoperative Oral Impact® and 129 patients received no nutritional support. CD80, CD86, MyD88, and CD69 messenger RNA expression was significantly increased in patients receiving immunonutrition compared to controls. In the subgroup of patients with stages I-II cancer, the rate of epithelial cells expressing CD80 and HLA-ABC was significantly higher in those receiving immunonutrition compared to controls as well as CD8+ CD28+ cell rate. Immunonutrition administration before surgery was significantly associated to increased degranulating CD8 and natural killer cells (CD107+) infiltrating the healthy esophageal mucosa. All the comparisons were adjusted for cancer stage and preoperative therapy. In conclusion, in healthy esophageal mucosa of patients undergoing esophagectomy, a 5-day course of immunonutrition enhances expression of antigen-presenting cells activity and increased CD8+ T cell activation and degranulating activity. Further studies are warranted to understand the clinical implication in terms of cancer recurrence.
Subject(s)
Adenocarcinoma/diet therapy , Adenocarcinoma/surgery , Dietary Supplements , Esophageal Neoplasms/diet therapy , Esophageal Neoplasms/surgery , Adenocarcinoma/pathology , Aged , CD8-Positive T-Lymphocytes/metabolism , Esophageal Neoplasms/pathology , Esophagectomy , Fatty Acids, Omega-3/administration & dosage , Female , Humans , Immunity, Cellular/drug effects , Male , Middle Aged , Neoplasm Staging , Preoperative CareABSTRACT
BACKGROUND: Oesophagectomy for cancer could be safe and worthwhile in selected older patients, but less is known about the effect of oesophagectomy on perceived quality of life of such delicate class of cancer patients. The aim of this study was to evaluate the impact of oesophagectomy for cancer in elderly patients in term of health-related quality of life. METHODS: We retrospectively evaluated all consecutive patients who underwent oesophagectomy for cancer at the Surgical Oncology Unit of the Veneto Institute of Oncology between November 2009 and March 2014. Quality of life was evaluated using EORTC C-30 and OES-18 questionnaires at admission, at discharge and 3 months after surgery. Adjusted multivariable linear mixed effect models were estimated to assess mean score differences (MDs) of selected aspects in older (≥70 years) and younger (<70 years) patients. RESULTS: Among 109 participating patients, 23 (21.1 %) were at least 70 years old and 86 (78.9 %) were younger than 70 years. Global quality of life was clinically similar between older and younger patients over time (MD 4.4). Older patients reported clinically and statistically significantly worse swallowing saliva (MD 17.4, 95 % C.I. 3.6 to 31.2), choking when swallowing (MD 13.8, 95 % C.I. 5.8 to 21.8) and eating difficulties (MD 20.1 95 % C.I. 7.4 to 32.8) than younger patients only at admission. CONCLUSIONS: Early health-related quality of life perception after surgery resulted comparable in older and younger patients. This result may also be due to some predisposition of the elderly to adapt to the new status.
Subject(s)
Esophageal Neoplasms/epidemiology , Quality of Life , Age Factors , Aged , Aged, 80 and over , Combined Modality Therapy , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/surgery , Esophagectomy/adverse effects , Female , Humans , Male , Middle Aged , Morbidity , Neoplasm Staging , Postoperative Complications , Retrospective StudiesABSTRACT
BACKGROUND: The aims of this prospective study were to analyze the predictors of postoperative sleep disturbance after esophagectomy for cancer and to identify patients at risk for postoperative hypnotic administration. METHODS: Sixty two consecutive patients who underwent cancer-related esophagectomy were enrolled in this study from May 2011 to February 2012. Data about perioperative management, postoperative complications, ICU stay, and vasopressor, hypnotic, and painkiller administration were retrieved. The EORTC QLQ-C30 was used and global quality of life (QL2 item) and sleep disturbance (SL item) were the primary endpoints. Univariate and multivariate analyses were performed. RESULTS: Postoperative request of hypnotics independently predicted bad quality of life outcome. Sleep disturbance after esophagectomy was independently predicted by the duration of dopamine infusion in the ICU and the daily request of benzodiazepines. Even in this case, only sleep disturbance at diagnosis revealed to be an independent predictor of hypnotic administration need. ROC curve analysis showed that sleep disturbance at diagnosis was a good predictor of benzodiazepine request (AUC = 73%, P = 0.02). CONCLUSIONS: The use of vasopressors in the ICU affects sleep in the following postoperative period and the use of hypnotics is neither completely successful nor lacking in possible consequences. Sleep disturbance at diagnosis can successfully predict patients who can develop sleep disturbance during the postoperative period.
Subject(s)
Esophageal Neoplasms/complications , Esophagectomy/adverse effects , Hypnotics and Sedatives/therapeutic use , Postoperative Complications/drug therapy , Quality of Life , Sleep Initiation and Maintenance Disorders/drug therapy , Adult , Aged , Aged, 80 and over , Disease Management , Esophageal Neoplasms/pathology , Esophageal Neoplasms/surgery , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Postoperative Complications/etiology , Postoperative Period , Prognosis , Prospective Studies , Sleep Initiation and Maintenance Disorders/etiology , Surveys and QuestionnairesABSTRACT
BACKGROUND: The aim of this study was to evaluate the impact of jejunostomy during esophagectomy for cancer on postoperative health-related quality of life (HRQL). METHODS: We evaluate all consecutive patients who underwent esophagectomy for cancer at the surgical oncology unit of the Veneto Institute of Oncology (IOV-IRCCS) between January 2008 and March 2014. The primary outcome was HRQL, which was assessed using nine scales of EORTC C30 and OES18 questionnaires. General linear models were estimated to evaluate mean score difference (MD) of each selected scale in patients with and without jejunostomy, adjusting for clinically relevant confounders. The secondary outcomes were morbidity, hospital stay, postoperative weight loss and postoperative albumin impairment. RESULTS: Jejunostomy was performed in 40 on 109 patients (41.3%) who participated in quality of life investigation. A clinically and statistically significantly worse eating at admission (P=0.009) became not clinically significant at 3 months after surgery (MD =9.1). Jejunostomy was associated to clinically and statistically significantly poorer emotional function (EF) at 3 months after surgery (MD =-15.6; P=0.04). Hospital stay was longer in jejunostomy group (median, 20 vs. 17 days, P=0.02). CONCLUSIONS: In our series patients who had a jejunostomy during esophagectomy had been selected for their risk for postoperative complication. However, their postoperative outcome was actually similar compared to those without jejunostomy. Nevertheless, jejunostomy was associated to clinically and statistically significantly poorer EF at 3 months after surgery. Therefore, patient candidate to esophagectomy and feeding jejunostomy should receive additional psychological support.
ABSTRACT
The COVID-19 pandemic, once a global crisis, is now largely under control, a testament to the extraordinary global efforts involving vaccination and public health measures. However, the relentless evolution of SARS-CoV-2, leading to the emergence of new variants, continues to underscore the importance of remaining vigilant and adaptable. Monoclonal antibodies (mAbs) have stood out as a powerful and immediate therapeutic response to COVID-19. Despite the success of mAbs, the evolution of SARS-CoV-2 continues to pose challenges and the available antibodies are no longer effective. New variants require the ongoing development of effective antibodies. In the present study, we describe the generation and characterization of neutralizing mAbs against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein by combining plasmid DNA and recombinant protein vaccination. By integrating genetic immunization for rapid antibody production and the potent immune stimulation enabled by protein vaccination, we produced a rich pool of antibodies, each with unique binding and neutralizing specificities, tested with the ELISA, BLI and FACS assays and the pseudovirus assay, respectively. Here, we present a panel of mAbs effective against the SARS-CoV-2 variants up to Omicron BA.1 and BA.5, with the flexibility to target emerging variants. This approach ensures the preparedness principle is in place to address SARS-CoV-2 actual and future infections.
ABSTRACT
BACKGROUND: The purpose of this multicentric prospective study was to evaluate postoperative HRQL and satisfaction with care after laparoscopic colonic resection for colorectal cancer in elderly patients. METHODS: A total of 116 patients were enrolled in this study: 33 patients older than age 70 years had laparoscopic colectomy, whereas 24 had open colectomy; 44 patients younger than age 70 years had laparoscopic colectomy and 15 of them had open colectomy. The patients answered to three questionnaires about generic (EORTC QLQ C30) and disease-specific quality of life (EORTC CR29) and about treatment satisfaction (EORTC IN-PATSAT32). Nonparametric tests and forward stepwise multiple regression analysis were used for statistical analysis. RESULTS: One month after surgery, global quality of life (QL2 item) was significantly impaired in elderly patients who had laparoscopic colectomy compared with younger patients who had the same operation (p = 0.003). Similarly, role function (RF), physical function (PF), emotional function (EF), cognitive function (CF), and social function (SF) were impaired in elderly patients who had laparoscopic colectomy compared with younger patients (p < 0.001, p < 0.001, p = 0.013, p < 0.001, p = 0.01, respectively). Fatigue (FA), sleep disturbances (SL), appetite loss (AP), and dyspnea (DY) affected the quality of life of these patients more than younger patients (p < 0.001, p = 0.055, p = 0.051, and p = 0.003, respectively). CONCLUSIONS: Elderly patients undergoing laparoscopic colectomy for cancer experience less postoperative local complications than elderly patients undergoing open colectomy. Nevertheless, in the first postoperative month, these patients experience a worse global quality of life than younger patients undergoing the same operation with impairment of all the functions and the presence of fatigue, sleep disturbances, appetite loss, and dyspnea.
Subject(s)
Colorectal Neoplasms/surgery , Minimally Invasive Surgical Procedures/methods , Patient Satisfaction , Quality of Life , Aged , Aged, 80 and over , Colorectal Neoplasms/psychology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Surveys and Questionnaires , Treatment OutcomeABSTRACT
Cancer remains a highly fatal disease, a major cause of mortality and a huge health burden around the world, requiring increased primary prevention efforts, screenings and treatments [...].
ABSTRACT
Tumor-associated antigens (TAAs) represent attractive targets in the development of anti-cancer vaccines. The filamentous bacteriophage is a safe and versatile delivery nanosystem, and recombinant bacteriophages expressing TAA-derived peptides at a high density on the viral coat proteins improve TAA immunogenicity, triggering effective in vivo anti-tumor responses. To enhance the efficacy of the bacteriophage as an anti-tumor vaccine, we designed and generated phage particles expressing a CD8+ peptide derived from the human cancer germline antigen NY-ESO-1 decorated with the immunologically active lipid alpha-GalactosylCeramide (α-GalCer), a potent activator of invariant natural killer T (iNKT) cells. The immune response to phage expressing the human TAA NY-ESO-1 and delivering α-GalCer, namely fdNY-ESO-1/α-GalCer, was analyzed either in vitro or in vivo, using an HLA-A2 transgenic mouse model (HHK). By using NY-ESO-1-specific TCR-engineered T cells and iNKT hybridoma cells, we observed the efficacy of the fdNY-ESO-1/α-GalCer co-delivery strategy at inducing activation of both the cell subsets. Moreover, in vivo administration of fdNY-ESO-1 decorated with α-GalCer lipid in the absence of adjuvants strongly enhances the expansion of NY-ESO-1-specific CD8+ T cells in HHK mice. In conclusion, the filamentous bacteriophage delivering TAA-derived peptides and the α-GalCer lipid may represent a novel and promising anti-tumor vaccination strategy.
Subject(s)
Membrane Proteins , Neoplasms , Humans , Mice , Animals , Membrane Proteins/metabolism , CD8-Positive T-Lymphocytes , Galactosylceramides/metabolism , Antigens, Neoplasm , Peptides , Mice, Transgenic , Antibodies/metabolismABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the COVID-19 pandemic, has been shown to infect a wide range of animal species, especially mammals, and besides human-to-human transmission, human-to-animal transmission has also been observed in some wild animals and pets, especially in cats. It has been demonstrated that cats are permissive to COVID-19 and are susceptible to airborne infections. Given the high transmissibility potential of SARS-CoV-2 to different host species and the close contact between humans and animals, it is crucial to find mechanisms to prevent the transmission chain and reduce the risk of spillover to susceptible species. Here, we show results from a clinical trial conducted in domestic cats to assess safety and immunogenicity of a linear DNA (linDNA) vaccine encoding the receptor-binding domain (RBD) from SARS-CoV-2 (Lin-COVID-eVax). Lin-COVID-eVax proved to be safe, with no significant adverse events, and was able to elicit both RBD-specific antibodies and T cells. Also, the linDNA vaccine induced neutralizing antibody titers against ancestral SARS-CoV-2 virus and its variants. These findings demonstrate the safety and immunogenicity of a genetic vaccine against COVID-19 administered to cats and strongly support the development of vaccines for preventing viral spread in susceptible species, especially those in close contact with humans.
ABSTRACT
DNA integrity is a key issue in gene therapy and genetic vaccine approaches based on plasmid DNA. In contrast to messenger RNA that requires a controlled cold chain for efficacy, DNA molecules are considered to be more stable. In this study, we challenged this concept by characterizing the immunological response induced by a plasmid DNA vaccine delivered using electroporation. As a model, we used COVID-eVax, a plasmid DNA-based vaccine that targets the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Increased nicked DNA was produced by using either an accelerated stability protocol or a lyophilization protocol. Surprisingly, the immune response induced in vivo was only minimally affected by the percentage of open circular DNA. This result suggests that plasmid DNA vaccines, such as COVID-eVax that have recently completed a phase I clinical trial, retain their efficacy upon storage at higher temperatures, and this feature may facilitate their use in low-/middle-income countries.
ABSTRACT
Background: Few data are available about the durability of the response, the induction of neutralizing antibodies, and the cellular response upon the third dose of the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in hemato-oncological patients. Objective: To investigate the antibody and cellular response to the BNT162b2 vaccine in patients with hematological malignancy. Methods: We measured SARS-CoV-2 anti-spike antibodies, anti-Omicron neutralizing antibodies, and T-cell responses 1 month after the third dose of vaccine in 93 fragile patients with hematological malignancy (FHM), 51 fragile not oncological subjects (FNO) aged 80-92, and 47 employees of the hospital (healthcare workers, (HW), aged 23-66 years. Blood samples were collected at day 0 (T0), 21 (T1), 35 (T2), 84 (T3), 168 (T4), 351 (T pre-3D), and 381 (T post-3D) after the first dose of vaccine. Serum IgG antibodies against S1/S2 antigens of SARS-CoV-2 spike protein were measured at every time point. Neutralizing antibodies were measured at T2, T3 (anti-Alpha), T4 (anti-Delta), and T post-3D (anti-Omicron). T cell response was assessed at T post-3D. Results: An increase in anti-S1/S2 antigen antibodies compared to T0 was observed in the three groups at T post-3D. After the third vaccine dose, the median antibody level of FHM subjects was higher than after the second dose and above the putative protection threshold, although lower than in the other groups. The neutralizing activity of antibodies against the Omicron variant of the virus was tested at T2 and T post-3D. 42.3% of FHM, 80,0% of FNO, and 90,0% of HW had anti-Omicron neutralizing antibodies at T post-3D. To get more insight into the breadth of antibody responses, we analyzed neutralizing capacity against BA.4/BA.5, BF.7, BQ.1, XBB.1.5 since also for the Omicron variants, different mutations have been reported especially for the spike protein. The memory T-cell response was lower in FHM than in FNO and HW cohorts. Data on breakthrough infections and deaths suggested that the positivity threshold of the test is protective after the third dose of the vaccine in all cohorts. Conclusion: FHM have a relevant response to the BNT162b2 vaccine, with increasing antibody levels after the third dose coupled with, although low, a T-cell response. FHM need repeated vaccine doses to attain a protective immunological response.