Severe Systemic Adverse Events Research Articles

Safety of a controlled human infection model of tuberculosis with aerosolised, live-attenuated Mycobacterium bovis BCG versus intradermal BCG in BCG-naive adults in the UK: a dose-escalation, randomised, controlled, phase 1 trial.

Mycobacterium tuberculosis is the main causative agent of tuberculosis. BCG, the only licensed vaccine, provides inadequate protection against pulmonary tuberculosis. Controlled human infection models are useful tools for vaccine development. We aimed to determine a safe dose of aerosol-inhaled live-attenuated Mycobacterium bovis BCG as a surrogate for M tuberculosis infection, then compare the safety and tolerability of infection models established using aerosol-inhaled and intradermally administered BCG. This phase 1 controlled human infection trial was conducted at two clinical research facilities in the UK. Healthy, immunocompetent adults aged 18-50 years, who were both M tuberculosis-naive and BCG-naive and had no history of asthma or other respiratory diseases, were eligible for the trial. Participants were initially enrolled into group 1 (receiving the BCG Danish strain); the trial was subsequently paused because of a worldwide shortage of BCG Danish and, after protocol amendment, was restarted using the BCG Bulgaria strain (group 2). After a dose-escalation study, during which participants were sequentially allocated to receive either 1 × 103, 1 × 104, 1 × 105, 1 × 106, or 1 × 107 colony-forming units (CFU) of aerosol BCG, the maximum tolerated dose was selected for the randomised controlled trial. Participants in this trial were randomly assigned (9:12), by variable block randomisation and using sequentially numbered sealed envelopes, to receive aerosol BCG (1 × 107 CFU) and intradermal saline or intradermal BCG (1 × 106 CFU) and aerosol saline. Participants were masked to treatment allocation until day 14. The primary outcome was to compare the safety of a controlled human infection model based on aerosol-inhaled BCG versus one based on intradermally administered BCG, and the secondary outcome was to evaluate BCG recovery in the airways of participants who received aerosol BCG or skin biopsies of participants who received intradermal BCG. BCG was detected by culture and by PCR. The trial is registered at ClinicalTrials.gov, NCT02709278, and is complete. Participants were assessed for eligibility between April 7, 2016, and Sept 29, 2018. For group 1, 15 participants were screened, of whom 13 were enrolled and ten completed the study; for group 2, 60 were screened and 33 enrolled, all of whom completed the study. Doses up to 1 × 107 CFU aerosol-inhaled BCG were sufficiently well tolerated. No significant difference was observed in the frequency of adverse events between aerosol and intradermal groups (median percentage of solicited adverse events per participant, post-aerosol vs post-intradermal BCG: systemic 7% [IQR 2-11] vs 4% [1-13], p=0·62; respiratory 7% [1-19] vs 4% [1-9], p=0·56). More severe systemic adverse events occurred in the 2 weeks after aerosol BCG (15 [12%] of 122 reported systemic adverse events) than after intradermal BCG (one [1%] of 94; difference 11% [95% CI 5-17]; p=0·0013), but no difference was observed in the severity of respiratory adverse events (two [1%] of 144 vs zero [0%] of 97; 1% [-1 to 3]; p=0·52). All adverse events after aerosol BCG resolved spontaneously. One serious adverse event was reported-a participant in group 2 was admitted to hospital to receive analgesia for a pre-existing ovarian cyst, which was deemed unrelated to BCG infection. On day 14, BCG was cultured from bronchoalveolar lavage samples after aerosol infection and from skin biopsy samples after intradermal infection. This first-in-human aerosol BCG controlled human infection model was sufficiently well tolerated. Further work will evaluate the utility of this model in assessing vaccine efficacy and identifying potential correlates of protection. Bill & Melinda Gates Foundation, Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, Thames Valley Clinical Research Network, and TBVAC2020.

A multicenter randomized controlled trial (RCT) for the effectiveness of comprehensive geriatric assessment (CGA) with extensive patient coaching on quality of life (QoL) in older patients with solid tumors receiving systemic therapy: G-oncoCOACH study.

12000 Background: CGA is internationally recommended in the care for older patients with cancer (e.g. ASCO). Only a few recent RCTs have examined the impact on patient’s QoL. Aim of this study is to evaluate the effectiveness of CGA coordinated by a geriatric team combined with intensive patient coaching ( = intervention group (IG)) versus standard of care, which is CGA coordinated by an oncology team ( = control group (CG)) on QoL in older patients with solid tumors receiving systemic therapy. Methods: The G-oncoCOACH study was a multicenter RCT in two academic Belgian hospitals (NCT04069962). Eligibility criteria were 70+ years, solid tumor, systemic therapy with curative or non-curative intent (first/second-line), and physician-estimated life expectancy > 6 months. IG patients received CGA coordinated by the geriatric team in close collaboration with the oncology team, increasing multidisciplinary care and in combination with intensive patient coaching to increase patient compliance. This supports patient empowerment by improving self-efficacy and supporting self-management of age-related problems. It included an individual counselling session at start of systemic therapy to discuss CGA results and recommendations with the patient and to determine their priorities, followed by individual counselling organized at 2, 4.5, 8 and 10 months. Primary endpoint was global health status (GHS) of the European Organisation for Research and Therapy of Cancer (EORTC) QOL questionnaire measured at 6 months after start of systemic therapy. Sample size calculation required > 195 included patients for primary endpoint (≥10 points QoL change at 6 months) for 80% power at 2-sided 5% significance level. After exclusion of multicollinearity, the change in QoL GHS between baseline and 6 months follow-up was analyzed with a mixed model. Results: From 10/2019 to 9/2021, 212 participants were enrolled (CG (n = 107); IG (n = 105)). Mean age was 76.8 years; 52.4% were female (n = 111). The 3 most common tumor types were digestive (n = 65; 30.7%), thorax (n = 44; 20.8%), and urogenital (n = 33; 15.6%). Cancer therapy was started mostly with non-curative intent. After 6 months, the difference between CG and IG in change of adjusted QoL GHS versus baseline amounted 12.8 points in favor of the IG (95%CL 6.7-18.8; p < 0.0001). This difference consisted of an improvement of 4.5 point versus baseline in the IG and decline of 8.2 points in the CG. Secondary endpoints (e.g. QoL at 3 and 12 months, patient satisfaction, severe systemic therapy-related adverse events, survival) will be presented at the meeting. Conclusions: CGA coordinated by a geriatric team combined with extensive patient coaching improves QoL GHS in older patients with cancer compared to CGA coordinated by an oncology team. Clinical trial information: NCT04069962 .

Real-world outcomes of anti-vascular endothelial growth factor therapy for retinal vascular vein occlusion in Tibet, China.

To evaluate the outcomes of intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents for patients with retinal vein occlusion (RVO) related-macular edema (ME) in Tibetan. A retrospective, observational, single-center study. The demographic and clinical data of 90 RVO Tibetan patients (93 eyes) treated with either ranibizumab or conbercept in Tibet Autonomous Region People's Hospital from Jan 2018 to December 2019 were collected. The mean patient age was 56.8±10.6y, 45 (50%) of them were female. The mean living altitude was 3867.8±567.9 m. At the last visit, the best-corrected visual acuity (BCVA) significantly increased (52.2±21.8 letters) in comparison with the baseline (38.2±24.1 letters, P<0.001); while the central retinal thickness (CRT) significantly reduced (245.5±147.6 µm) in comparison with the baseline (504.1±165.2 µm, P<0.001). The 43.0% of the eyes gained ≥15 letters, 60.2% of the eyes gained ≥10 letters, and 78.5% of the eyes gained ≥5 letters. No vision loss was noted in 92.5% of the eyes, 4 eyes lost more than 10 letters during follow-up period. The mean number of injections was 2.4±1.8. No severe ocular or systemic adverse events related to either the drug or injection were noted. Anti-VEGF therapy is effective and safe in Tibetan patients for the treatment of RVO related ME.

Association between history of SARS-CoV-2 infection and severe systemic adverse events after mRNA COVID-19 vaccination among U.S. adults

BackgroundRisk of experiencing a systemic adverse event (AE) after mRNA coronavirus disease 2019 (COVID-19) vaccination may be greater among persons with a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; data on serious events are limited. We assessed if adults reporting systemic AEs resulting in emergency department visits or hospitalizations during days 0–7 after mRNA COVID-19 vaccine dose 1 were more likely to have a history of prior SARS-CoV-2 infection compared with persons who reported no or non-severe systemic AEs. MethodsWe conducted a nested case-control study using v-safe surveillance data. Participants were ≥ 18 years and received dose 1 during December 14, 2020─May 9, 2021. Cases reported severe systemic AEs 0–7 days after vaccination. Three controls were frequency matched per case by age, vaccination date, and days since vaccination. Follow-up surveys collected SARS-CoV-2 histories. ResultsFollow-up survey response rates were 38.6 % (potential cases) and 56.8 % (potential controls). In multivariable analyses including 3,862 case-patients and 11,586 controls, the odds of experiencing a severe systemic AE were 2.4 (Moderna, mRNA-1273; 95 % confidence interval [CI]: 1.89, 3.09) and 1.5 (Pfizer-BioNTech, BNT162b2; 95 % CI: 1.17, 2.02) times higher among participants with pre-vaccination SARS-CoV-2 histories compared with those without. Medical attention of any kind for symptoms during days 0–7 following dose 2 was not common among case-patients or controls. ConclusionsHistory of SARS-CoV-2 infection was significantly associated with severe systemic AEs following dose 1 of mRNA COVID-19 vaccine; the effect varied by vaccine received. Most participants who experienced severe systemic AEs following dose 1 did not require medical attention of any kind for symptoms following dose 2. Vaccine providers can use these findings to counsel patients who had pre-vaccination SARS-CoV-2 infection histories, experienced severe systemic AEs following dose 1, and are considering not receiving additional mRNA COVID-19 vaccine doses.

Immunogenicity and safety of two doses of SARS-CoV-2 mRNA vaccine in kidney transplant recipients with low-dose rituximab.

ObjectivesWe evaluated whether the treatment history of low‐dose rituximab affected safety profiles, and humoral and cellular responses induced by severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid vaccine in healthy controls and kidney transplant recipients.MethodsWe enrolled 10 healthcare workers as controls, 22 kidney transplant recipients with rituximab, and 36 kidney transplant recipients without rituximab without history of coronavirus disease 2019 who received two doses of vaccine. We assessed anti‐severe acute respiratory syndrome coronavirus 2 spike antibody and the antigen‐specific T cells using enzyme‐linked immunospot against spike protein at baseline and after two doses of vaccine.ResultsAll controls showed anti‐severe acute respiratory syndrome coronavirus 2 antibody seroconversion and enzyme‐linked immunospot positivity. Only 19/58 (33%) kidney transplant recipients experienced anti‐severe acute respiratory syndrome coronavirus 2 antibody seroconversion and 31/58 (53%) kidney transplant recipients developed enzyme‐linked immunospot assay positivity after vaccination. The anti‐severe acute respiratory syndrome coronavirus 2 antibody seroconversion rate and enzyme‐linked immunospot assay positivity rate after vaccination were not significantly different between kidney transplant recipients with or without rituximab. Multivariate regression analysis demonstrated rituximab was not associated with a lack of humoral and cellular responses to the vaccine.ConclusionsLow‐dose rituximab in kidney transplant recipients did not affect humoral or cellular responses to the severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid vaccine without severe systemic adverse events including the deterioration of kidney function.

Cutaneous adverse events following 771 doses of the inactivated and mRNA COVID-19 vaccines: A survey study among health care providers.

IntroductionAs Coronavirus disease 19 (COVID‐19) still continues to affect humanity worldwide, different types of COVID‐19 vaccines are being administered to maintain immunization against COVID‐19. As both the inactivated and mRNA vaccines are now being applied prevalently, systemic adverse events along with cutaneous side effects are frequently being reported in the literature.AimIn our study, we aimed to determine the cutaneous adverse effects of the inactivated (Sinovac‐CoronaVac) and mRNA (Pfizer‐BioNTech) vaccines in healthcare providers in a tertiary referral hospital.MethodsA web‐based survey consisting of 26 questions related to the systemic and cutaneous side effects of the inactivated and mRNA COVID‐19 vaccines, was formed. The online questionnaire was spread among the healthcare professionals working in a tertiary referral hospital via common instant messaging groups and e‐mail.FindingsA total number of 234 participants were included in the study. One hundred fifty‐seven were female whereas 77 were male. The mean age was 31.51 years. Eighty‐nine respondents reported to have at least one cutaneous side effect after COVID‐19 vaccination. Most commonly observed cutaneous side effects were local injection site reactions. Pfizer‐BioNTech vaccine at the first and second doses, was shown to have statistically significantly higher rates of systemic and cutaneous adverse events compared to the Sinovac‐CoronaVac vaccine.ResultsOur study shows that both inactivated and mRNA COVID‐19 vaccines are associated with transient local injection site reactions, no severe systemic or cutaneous adverse events were observed in our study population.

Clinical Efficacy and Safety of Artesimia annua-Sublingual Immunotherapy in Seasonal Allergic Rhinitis Patients Based on Different Intervention Time

Introduction: Artemisia is a major kind of grass pollen in Northern China that can cause multiple kinds of common allergic diseases, such as allergic rhinitis (AR), conjunctivitis, or asthma. Recently, Artemisia annua Allergens Sublingual Immunotherapy Drops have been proved effective and safe for treating seasonal AR (SAR) with or without allergic conjunctivitis patients and were available in China. We sought to further investigate the different intervention times of A. annua-sublingual immunotherapy (SLIT) for evaluating efficacy and safety in patients with SAR. Methods: A total of 88 subjects aged 18–52 years with SAR were enrolled and randomized into the SLIT group and control group. Forty-five patients received a course of SLIT with A. annua extracts along with pharmacotherapy as SLIT group and 43 patients only used symptomatic drugs as control group. Furthermore, SLIT group was randomly divided into 12–13 weeks’ pre-seasonal treatment group and 8–9 weeks’ pre-seasonal treatment group to receive different duration of SLIT before pollen season. Monosensitized and polysensitized groups were also the subgroups of SLIT group according to the sensitization status of patients. The combined symptom and medication score (CSMS), total nasal symptom score (TNSS), total medication score (TMS), visual analog score (VAS) were evaluated during the peak pollen phase in 2020 and 2021, respectively. Safety was assessed according to adverse events (AEs) reported. Results: Compared to control group, CSMS, TNSS, TMS, VAS were significantly improved during the course of SLIT (p < 0.001). Besides, clinical improvement in nasal symptoms and reduction of medication use was also observed in SLIT group, compared to the baseline value (p < 0.001). Meanwhile, we observed that there was no significant difference between monosensitized group (n = 8) and polysensitized group (n = 29), as well as 12–13 weeks’ preseasonal treatment group (n = 20) and 8–9 weeks’ pre-seasonal treatment group (n = 17) belonging to the SLIT group in clinical efficacy (p > 0.05). No severe systemic AEs were reported. Conclusions: This study proved that A. annua-SLIT can provide equivalent efficacy and safety for SAR patients under the circumstance of accepting the pre-seasonal treatment of 8–9 or 12–13 weeks, regardless of monosensitization or polysensitization.

Anal Canal Condyloma Acuminatum Treated with Anti-HPV Biological Dressing: Clinical Analysis of 64 Cases.

Background:Anal canal condyloma acuminatum (CA) is a refractory disease with a high recurrence rate caused by human papillomavirus (HPV). Multiple clinical trials demonstrate that anti-HPV biological dressing is safe and effective in treating HPV infection, which has been used in treating high-risk HPV-positive and cervical intraepithelial neoplasia I (CIN I) patients. Yet, there is still a lack of clinical data for the treatment of anal canal CA.Aims and Objectives:To evaluate the clinical efficacy and application value of anti-HPV biological dressing in anal canal CA.Materials and Methods:Taken currently recommended treatment 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) as a positive control, 128 patients were included with 64 in each group, and a prospective, randomized, positive controlled, non-inferiority clinical trial was conducted. After removing visible skin lesions with conventional microwave, the treatment group was given anti-HPV biological dressing, while the control group received the conventional ALA-PDT treatment. Patients were followed up on the 1st, 12th and 24th weeks after the treatment. The cure rate, recurrence rate, HPV-negative conversion rate, and adverse events were recorded.Results:In the 1st, 12th and 24th weeks after treatment, the cure rate, recurrence rate and HPV-negative conversion rate of the treatment group and the control group showed no statistically significant difference. In the treatment group, 56 patients developed transient mild itching and all were relieved spontaneously, while in the control group, most of the patients experienced obvious pain and some patients needed symptomatic treatment. No severe systemic adverse events were observed.Conclusion:Compared with ALA-PDT, topical application of anti-HPV biological dressing has comparable promising outcomes in the treatment of anal canal CA, with fewer side effects and simpler operation making it suitable for clinical applications.

Selective Ophthalmic Artery Chemotherapy with Melphalan in the Management of Unilateral Retinoblastoma: A Prospective Study

To determine prospectively the efficacy and to assess potential side effects of melphalan selective ophthalmic artery chemotherapy (SOAC) as first-line treatment for unilateral retinoblastoma. Phase 2 nonrandomized, prospective study. Patients with unilateral retinoblastoma group B, C, or D of the International Classification for Intraocular Retinoblastoma (IRC). Group D eyes with massive vitreous seeding were not eligible. Melphalan SOAC associated with diode laser thermotherapy, cryotherapy, or both at 4-week intervals (3-6 cycles). For persistent vitreous seeding, intravitreal melphalan chemotherapy also was used. The primary outcome was globe preservation rate. Secondary outcomes were tumor relapse rate, occurrence of ocular or systemic adverse events, and measurement of the dose area product (DAP). Between 2012 and 2017, 39 patients (39 eyes) with unilateral retinoblastoma were included prospectively. Three included patients did not receive SOAC (2 catheterization failures and 1 case of viral syndrome) and were considered failures. At diagnosis, IRC groups for the 36 treated patients were: B, n= 4 (11%); C, n= 13 (36%); and D, n= 19 (53%); median age was 21.5 months (range, 3.2-61.6 months). Median number of SOAC cycles was 3.9 (range, 1-6 cycles), and median melphalan dose was 4.9 mg/procedure. The median DAP was 1.24 Gy.cm2/procedure. Median follow-up was 63 months (range, 34-93 months). SOAC was associated with local treatments for 31 patients (86%): diode laser thermotherapy for all of them and cryotherapy or intravitreal chemotherapy for 10 (32%) and 9 patients (25%), respectively. SOAC treatment was interrupted in 5 patients because of severe ophthalmic (ptosis, n= 2; retinal ischemia, n= 2) or systemic (hypotension, n= 1) adverse events. At the cutoff date analysis, all patients were alive without metastasis. The 18-month eye preservation rate was 80% (range, 68.6%-94.6%). After a follow-up of at least 30 months, the ocular preservation rate was 69% (n= 24 preservations). This first prospective trial demonstrated that SOAC with melphalan alone as first-line treatment for retinoblastoma is efficient and well tolerated with no metastatic events, although ocular ischemic complications were observed.

Biomarkers of the Severity of Honeybee Sting Reactions and the Severity and Threshold of Systemic Adverse Events During Immunotherapy

A biomarker that could identify individuals at high risk for severe honeybee sting allergic reaction and/or systemic adverse events (SAEs) during venom immunotherapy (VIT) would improve the management of patients with honeybee (HB) venom allergy. To identify biomarkers for risk of severe sting reactions or SAEs during VIT. We recruited 332 patients undergoing HB VIT. We ascertained predictors of the severity of the field-sting reaction and the severity and threshold of SAEs during VIT. We assessed the use of cardiovascular medications; baseline serum tryptase (BST) levels; specific IgEs to HB venom, rApi m 1, and rApi m 10; and basophil activation test (BAT) response. Significant and independent predictors of a severe HB field-sting reaction were age (P= .008), an absence of skin symptoms (P= .001), BST (P= .014), and BAT response at an HB venom concentration of 0.1 μg/mL (P= .001). Predictors of severe SAEs during HB VIT were age (P= .025), BST (P= .006), and BAT response (P= .001). BAT response was also an individual and significant predictor of any SAEs and SAEs at a low cumulative allergen dose (median, 55 μg) during VIT build-up (P < .001). The use of β-blockers and angiotensin-converting-enzyme inhibitors and specific IgE levels were not associated with the severity of HB field-sting reactions or VIT SAEs. BST and basophil activation are independent risk factors for severe HB sting anaphylaxis and SAEs during HB VIT. BAT response was the best biomarker for any SAEs and a lower threshold of SAEs during HB VIT. These risk factors can help guide recommendations for VIT and overcome systemic reactions to HB VIT.

Injectable Hydrogels as Local Depots at Tumor Sites for Antitumor Immunotherapy and Immune-Based Combination Therapy.

Despite the encouraging clinical responses of several human cancers to immunotherapy, the efficacy of this treatment remains limited by variable objective response rates and severe systemic immune-related adverse events. To overcome these issues, injectable hydrogels have been developed as local depots that permit the sustained release of single or multiple immunotherapy agents, including traditional immunomodulatory factors, immune checkpoint blocking antibodies, and exogenous immune cells. The antitumor efficacy of immunotherapy can also be enhanced by its combination with other therapeutic approaches, including chemotherapy, radiotherapy, and phototherapy. Despite local treatment strategies, potent systemic antitumor immune responses with low systemic toxicity can be obtained, leading to significant local and abscopal tumor-killing, reduced tumor metastasis, and the prevention of tumor recurrence. This review highlights recent progress in injectable hydrogel-based local depots for tumor immunotherapy and immune-based combination therapy. Moreover, the proposed mechanisms responsible for these antitumor effects are discussed.

Real-world outcomes of two-year Conbercept therapy for diabetic macular edema

To evaluate the two-year outcomes of patients treated for diabetic macular edema (DME) with intravitreal Conbercept (IVC). The clinical data of 30 DME patients (36 eyes) were retrospectively reviewed. The patients were treated with IVC for 3mo. Additional IVC was given at subsequent monthly visits, if needed (3+PRN). The patients were followed up for 24mo. The best-corrected visual acuity (BCVA) at 24mo significantly increased (66.7±15.3 letters) in comparison with the baseline (54.4±15.4 letters, P<0.0001). The mean improvement in BCVA was 11.0±2.9 letters. At 24mo, 44.1% of the eyes surveyed gained ≥15 letters, 52.9% of the eyes gained ≥10 letters, and 70.6% of the eyes gained ≥5 letters. No vision loss was noted in 96.8% of the eyes, and 5.9% of the eyes lost ≥5 letters, but ≤10 letters. The central retinal thickness (CRT) at 24mo was significantly reduced (277.1±122.9 µm) in comparison with the baseline (510.9±186.1 µm, P<0.0001). At 24mo, 43.3% of the patients had a CRT ≤250 µm. The mean number of injections over 24mo was 10.6±2.0. No severe eye or systemic adverse events related to either the drug or injection were noted. IVC is safe and effective for the treatment of DME.

Intravitreal conbercept for choroidal neovascularisation secondary to pathological myopia in a real\u2010world setting in China

BackgroundTo evaluate the 12-month efficacy and safety of intravitreal conbercept for myopic choroidal neovascularization (CNV).MethodsA retrospective, observational study. Thirty-four eyes of 34 pathologic myopic patients with CNV were treated with intravitreal conbercept (IVC) 0.5 mg with a follow up of 12 months. After the first injection, administration of conbercept followed a pro re nata (PRN) regimen. Outcomes included best corrected visual acuity (BCVA), central retinal thickness (CRT), CNV size, the total number of treatments, and adverse events.ResultsThe mean patient age was 55.88 ± 16.17 years, and the mean eye spherical equivalent was − 8.72 ± 3.75 D. The mean number of IVC over 12 months was 2.12 ± 0.69. Overall, best-corrected visual acuity(BCVA)improved from 0.86 ± 0.33 logMAR at baseline to 0.44 ± 0.32 logMAR at month 12 (p < 0.001), mean improvement of vision was 4.12 ± 2.69 lines. Mean central retinal thickness reduced from 285.9 ± 104.6 µm at baseline to 192.1 ± 97.5 µm at month 12 (p < 0.001). Mean CNV size decreased from 0.52 ± 0.38 mm2 at baseline to 0.31 ± 0.19 mm2 at 12 months (p < 0.05). All the 34 eyes had reduced or stable size of CNV. Thirty-two eyes (94.12 %) showed the absence of CNV leakage at the end of the study period. No severe systemic or ocular adverse events were observed.ConclusionsIntravitreal conbercept 0.5 mg was safe and effective for treatment of myopic CNV over 12 months in a real-world setting.

Glyco-Nanoadjuvants: Sugar Structures on Carriers of a Small Molecule TLR7 Ligand Affect Their Immunostimulatory Activities.

Toll-like receptors (TLRs) are pattern recognition receptors that activate innate immunity, and their ligands are promising adjuvants for vaccines and immunotherapies. Small molecule TLR7 ligands are ideal vaccine adjuvants as they induce not only proinflammatory cytokines but also type I interferons. However, their application has only been approved for local administration due to severe systemic immune-related adverse events. In a previous study, we prepared the gold nanoparticles coimmobilized with synthetic small molecule TLR7 ligand, 1V209, and α-mannose (1V209-αMan-GNPs). 1V209-αMan-GNPs were selectively delivered via a cell surface sugar-binding protein, mannose receptor, which enabled selective delivery of TLR7 ligands to immune cells. Besides the mannose receptor, immune cells express various sugar-binding proteins such as macrophage galactose binding lectins and sialic acid-binding immunoglobulin-type lectins and recognize distinct sugar structures. Hence, in the present study, we investigated whether sugar structures on GNPs affect the efficiency and selectivity of intracellular delivery and subsequent immunostimulatory potencies. Five neutral sugars and two sialosides were selected and each sugar was coimmobilized with 1V209 onto GNPs (1V209-SGNPs) and their innate immunostimulatory potencies were compared to that of 1V209-αMan-GNPs. The in vitro study using mouse bone marrow derived dendritic cells (BMDCs) demonstrated that α-glucose, α-N-acetylglucosamine, or α-fucose immobilized 1V209-SGNPs increased interleukin-6 and type I interferon release similar to that of 1V209-αMan-GNPs, whereas galacto-type sugar immobilized 1V209-SGNPs predominantly enhanced type I interferon release. In contrast, sialoside immobilized 1V209-SGNPs did not enhance the potency of 1V209. In the in vivo immunization study using ovalbumin as a model antigen, neutral sugar immobilized 1V209-SGNPs induced comparable T helper-1 immune response to that of 1V209-αMan-GNPs and by 10-fold higher than that of sialoside immobilized 1V209-SGNPs. These results indicate that the sugar structures on 1V209-SGNPs affect their immunostimulatory activities, and functionalization of the carrier particles is important to shape immune responses.

Adjuvant effect of TLR7 agonist adsorbed on aluminum hydroxide (AS37): A phase I randomized, dose escalation study of an AS37-adjuvanted meningococcal C conjugated vaccine

An adjuvant system (AS37) has been developed containing a synthetic toll-like receptor agonist (TLR7a). We conducted a phase I randomized, observer-blind, dose-escalation study to assess the safety and immunogenicity of an investigational AS37-adjuvanted meningococcus C (MenC) conjugate vaccine in healthy adults (NCT02639351). A control group received a licensed MenC conjugate alum-adjuvanted vaccine. Eighty participants were randomized to receive one dose of control or investigational vaccine containing AS37 (TLR7a dose 12.5, 25, 50, 100 μg). All vaccines were well tolerated, apart from in the TLR7a 100 μg dose group, which had three reports (18.8%) of severe systemic adverse events. Four weeks after vaccination, human complement serum bactericidal assay seroresponse rates against MenC were 56–81% in all groups, and ELISA seroresponses were ≥81% for all AS37-adjuvanted vaccine groups (100% in 50 and 100 μg dose groups) and 88% in the control group. Antibody responses were maintained at six months after vaccination.

Are all vaccines safe for the pregnant traveller? A systematic review and meta-analysis.

Pregnant travellers and their offspring are vulnerable to severe outcomes following a wide range of infections. Vaccine-preventable diseases can have a particularly severe course in pregnant women, but little is known about the safety of travel vaccines in pregnant women. We performed a systematic review of all published literature concerning the safety of vaccines frequently given to travellers such as yellow fever, MMR (mumps, measles and rubella), influenza, Tdap (tetanus, diphtheria and pertussis), meningococcus, hepatitis A and B, rabies, polio, typhoid fever, tick-borne encephalitis and Japanese encephalitis vaccines. We included case series, cohort studies and randomized controlled trials (RCTs). For the meta-analysis, we included only RCTs that compared the administration of a vaccine to placebo or to no vaccine. Outcome measures included severe systemic adverse events, maternal outcomes related to the course of pregnancy, neonatal outcomes and local adverse events. We calculated the risk ratio and its 95% confidence interval as the summary measure. The safety of influenza vaccine is supported by high-quality evidence. For Tdap vaccine, no evidence of any harm was found in the meta-analysis of RCTs. A slight increase in chorioamnionitis rate was reported in 3 out of 12 observational studies. However, this small possible risk is far outweighed by a much larger benefit in terms of infant morbidity and mortality. Meningococcal vaccines are probably safe during pregnancy, as supported by RCTs comparing meningococcal vaccines to other vaccines. Data from observational studies support the safety of hepatitis A, hepatitis B and rabies vaccines, as well as that of the live attenuated yellow fever vaccine. We found little or no data about the safety of polio, typhoid, Japanese encephalitis, tick-borne encephalitis and MMR vaccines during pregnancy.

A Pilot Study of Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma

High-grade gliomas (HGGs) carry a dismal prognosis despite current treatments. We previously confirmed the safety and immunogenicity of a vaccine treatment targeting tumor angiogenesis with synthetic peptides, for vascular endothelial growth factor receptor (VEGFR) epitopes in recurrent HGG patients. In this study, we evaluated a novel vaccine therapy targeting not only tumor vasculature but also tumor cells, using multiple glioma oncoantigen (GOA)/glioma angiogenesis-associated antigen (GAAA) peptides in HLA-A2402+ recurrent/progressive HGG patients. The vaccine included peptide epitopes from four GOAs (LY6K, DEPDC1, KIF20A, and FOXM1) and two GAAAs (VEGFR1 and VEGFR2). Ten patients received subcutaneous vaccinations. The primary endpoint was the safety of the treatment. T-lymphocyte responses against GOA/GAAA epitopes and treatment response were evaluated secondarily. The treatment was well tolerated without any severe systemic adverse events. The vaccinations induced immunoreactivity to at least three vaccine-targeted GOA/GAAA in all six evaluable patients. The median overall survival time in all patients was 9.2 months. Five achieved progression-free status lasting at least six months. Two recurrent glioblastoma patients demonstrated stable disease. One patient with anaplastic oligoastrocytoma achieved complete response nine months after the vaccination. Taken together, this regimen was well tolerated and induced robust GOA/GAAA-specific T-lymphocyte responses in recurrent/progressive HGG patients.

Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis.

Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis.

Combined encapsulation of a tumor antigen and immune cells using a self-assembling immunostimulatory DNA hydrogel to enhance antigen-specific tumor immunity

Our previous study demonstrated that the incorporation of a tumor antigen into a self-assembling DNA hydrogel, comprised of a DNA containing un-methylated cytosine-phosphate-guanine (CpG) dinucleotides (CpG DNA), efficiently induced antigen-specific tumor immunity after intra-tumoral injection into tumor-bearing mice. We hypothesized that the additional incorporation of immune cells, the target for the antigen and immunostimulatory CpG DNA, would increase the antitumor response. To prove this, immune cells were also encapsulated into the CpG DNA hydrogel and delivered along with the antigen. Mouse dendritic DC2.4 cells maintained their form even after incorporation into the DNA hydrogel. The incorporation of mouse macrophage-like J774.1 cells and RAW264.7 cells into CpG DNA hydrogel did not significantly affect their viability. J774.1, RAW264.7, DC2.4, and mouse bone marrow-derived dendritic cells (BMDCs) were efficiently activated when incorporated into the CpG DNA hydrogel. The CpG DNA hydrogel incorporated with both the tumor antigen and BMDCs effectively induced antigen-specific immune responses, and retarded tumor growth following intradermal administration before and after tumor inoculation without severe local and systemic adverse events. These data indicate that the combined delivery of a tumor antigen and immune cells using an immunostimulatory CpG DNA hydrogel is effective in inducing antigen-specific antitumor immunity.

Efficacy of Transdermal Oxybutynin in the Treatment of Overactive Bladder Syndrome: Does It Make Sense Using It in 2017?

Objectives Evaluation of changes in symptoms among patients with overactive bladder syndrome treated with transdermal oxybutynin and tolerability after 12 months of follow-up. Methods This was a multicenter, retrospective, single-cohort, observational study. Changes in symptoms were evaluated primarily with a 3-day voiding diary. Results were compared to baseline. Subgroup analyses were performed in patients previously treated for OAB or not and aged < 65 years versus ≥65 years. Results Clinical records of 105 patients were examined; 92.4% were women. At 12 months, 58 patients continued to receive transdermal oxybutynin. Changes in symptoms according to the voiding diary were evaluated in 47 patients. Significant improvements from baseline were observed in urinary frequency (−2.6 voids/24 hours (95% CI: −3.5; −1.8), p < 0.001); daily number of urgent episodes (−4.7 episodes/day (95% CI: −6.1; −3.6), p < 0.001); and urge incontinence (−1.9 episodes/day (95% CI: −2.9; −1.3), p < 0.001). No statistically significant differences were found in subgroup analyses. In total, 38.1% of patients had adverse events, primarily in the application site (27.6%). No severe systemic adverse events occurred. Only 6 patients (5.7%) reported dry mouth. Conclusions Improved symptoms and good tolerability observed after 1 year of treatment with transdermal oxybutynin shows that it currently has a place in the treatment of OAB patients.