Local Injection Site Research Articles

N-protein vaccine is effective against COVID-19: Phase 3, randomized, double-blind, placebo-controlled clinical trial

Despite the success of first-generation COVID-19 vaccines targeting the spike (S) protein, emerging SARS-CoV-2 variants have led to immune escape, reducing the efficacy of these vaccines. Additionally, some individuals are unable to mount an effective immune response to S protein-based vaccines. This has created a need for alternative vaccine strategies that are less susceptible to mutations and capable of providing broad and durable protection. This study aimed to evaluate the efficacy and safety of a novel COVID-19 vaccine based on the full-length recombinant nucleocapsid (N) protein of SARS-CoV-2. We conducted a prospective, multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial (NCT05726084) in Russia. Participants (n=5229) were adults aged 18 years and older, with a BMI of 18.5-30kg/m², and without significant clinical abnormalities. They were randomized in a 2:1 ratio to receive a single intramuscular dose of either the N protein-based vaccine (50µg) or placebo. Randomization was done through block randomization, and masking was ensured by providing visually identical formulations of vaccine and placebo. The primary outcome was the incidence of symptomatic COVID-19 confirmed by PCR more than 15 days after vaccination within a 180-day observation period, analyzed on an intention-to-treat basis. Between May 18, 2023, and August 9, 2023, 5229 participants were randomized, with 3486 receiving the vaccine and 1743 receiving the placebo. Eight cases of PCR-confirmed symptomatic COVID-19 occurred in the vaccine group (0.23%) compared to 27 cases in the placebo group (1.55%), yielding a vaccine efficacy of 85.2% (95% CI: 67.4-93.3; p<0.0001). Adverse events were mostly mild and included local injection site reactions. There were no vaccine-related serious adverse events. The N protein-based COVID-19 vaccine demonstrated significant efficacy and a favorable safety profile, suggesting it could be a valuable addition to the global vaccination effort, particularly in addressing immune escape variants and offering an alternative for those unable to respond to S protein-based vaccines. These results support the continued development and potential deployment of N protein-based vaccines in the ongoing fight against COVID-19.

Efficacy and outcomes of BCG re-vaccination in COVID-19: a systematic review, meta-analysis, and meta-regression of randomized controlled trials.

The Bacillus Calmette-Guerin (BCG) vaccine has a beneficial "off-target" effect that offers heterologous protection against respiratory tract infections by inducing trained immunity. The need for producing antigen-specific COVID-19 vaccines leads to delays in vaccine administration. Current randomized controlled trials (RCTs) report conflicting data on BCG's efficacy in COVID-19 infection. A comprehensive literature search was conducted using major bibliographic databases to identify RCTs evaluating the outcomes of BCG re-vaccination in COVID-19. For dichotomous outcomes, odds ratios (ORs) with 95% CIs were pooled using the DerSimonian-Laird random-effects model. Statistical significance was set at P less than 0.05. Thirteen RCTs with 13939 participants (7004 in the BCG re-vaccination group and 6935 in the placebo group) were included. BCG re-vaccination did not lead to a statistically significant difference in the incidence of COVID-19 infection [OR: 1.04; 95% CI: 0.91, 1.19; P=0.56], COVID-19-related hospitalizations [OR: 0.81; 95% CI: 0.38, 1.72; P=0.58), ICU admissions [OR: 0.43; 95% CI: 0.13, 1.46; P=0.18], or mortality [OR: 0.67; 95% CI 0.15, 3.04; P=0.60]. For safety outcomes, BCG re-vaccination led to a significant increase in the local injection site complications [OR: 99.79; 95% CI: 31.04, 320.80; P<0.00001], however, the risk of serious adverse events was similar [OR: 1.19; 95% CI: 0.84, 1.67; P=0.33]. BCG re-vaccination does not decrease the incidence of COVID-19 infection, COVID-19-related hospitalizations, ICU admissions, COVID-19-related mortality, and serious adverse events; however, it leads to a rise in local injection site complications. Caution should be exercised when overstating BCG's efficacy in COVID-19 prevention.

Safety profile of proprotein convertase subtilisin/kexin type 9 inhibitors alirocumab and evolocumab: an updated meta-analysis and meta-regression

Background The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator. Methods Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration. Results We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, p = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, p = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, p < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, p < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, p = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p = 0.03; 12–24 weeks OR 2.12, 95% CI 1.20 to 3.73, p = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, p = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, p = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, p = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, p < 0.01). Conclusion Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.

Accelerated Bacille Calmette-Guérin reactions: More than meets the eye

An accelerated local injection site reaction following Bacille Calmette-Guérin (BCG) vaccination has been associated with underlying active tuberculosis (TB) in high TB-prevalence settings. The clinical significance of this accelerated BCG reaction in individuals without TB symptoms, particularly in low TB-prevalence countries, is unclear.Using safety surveillance data and baseline interferon-gamma release assays (IGRA) within an international randomised trial of BCG vaccination in healthcare workers (the BRACE trial), we aimed to determine the incidence, and investigate for clinical implications, of an accelerated BCG reaction in asymptomatic adults in low and high TB-prevalence settings.An accelerated BCG reaction occurred in 755/1984 (38 %) of BCG-vaccinees. Although more frequently painful, tender, erythematous and/or swollen within the first fourteen days of vaccination, compared with non-accelerated reactions, the majority of injection site reactions were mild and did not meet criteria for an adverse event.Prior mycobacterial exposure, through prior BCG vaccination (OR 2.46, 95%CI 1.93–3.13, p < 0.001) or latent TB infection (OR 4.17, 95%CI 1.16–14.93, p = 0.03), and female sex (OR 1.27, 95%CI 1.03–1.57, p = 0.02), were key determinants for the occurrence of an accelerated BCG reaction.The development of an accelerated local reaction to BCG vaccination in an individual without prior history of BCG vaccination, should prompt consideration of further investigations for potential underlying TB infection.

The pathophysiology and clinical phenotypes of COVID-19 mRNA vaccine-related cutaneous adverse reactions: A narrative review

Cutaneous adverse reactions (CARs) after COVD-19 messenger ribonucleic acid (mRNA) vaccines have been reported worldwide, but the pathophysiology of CARs remains to be elucidated. To understand the pathophysiology, it is essential to know how the innate and adaptive immunity are activated after vaccination. At present, majority of CARs are presumed to be evoked by innate immunity response. Reviewing the previous articles, I propose the clinical classification of CARs; local injection site reaction, generalized eruption, localized eruption and others. Since COVID-19 mutates continuously to overcome the existing vaccines, our steady efforts are indispensable to clarify the pathophysiology of CARs and contribute to the development of novel vaccines with least adverse events and high efficacy.

MIP vaccine in leprosy: A scoping review and future horizons.

Mycobacterium Indicus Pranii (MIP) vaccine is a killed vaccine developed in India for leprosy with immunotherapeutic as well as immunoprophylactic effects. MIP, earlier known as Mycobacterium welchii, is a rapidly growing non-pathogenic mycobacterium. The novelty of this bacterium is due to its translational application as an immunotherapeutic agent. When administered intradermally, the vaccine induces cell-mediated immunity in the host towards Mycobacterium leprae. It leads to faster clinical and histopathological improvement, rapid bacillary clearance, and also lepromin conversion in anergic leprosy patients. The beneficial role of the MIP vaccine in augmenting the therapeutic efficacy of Multidrug Therapy (MDT), particularly in highly bacillated leprosy patients, is well documented in various studies from India. The role of the vaccine in reactional states is controversial, with varied results in different studies. Overall, it is found to decrease the frequency of type 2 lepra reactions and is useful in recalcitrant erythema nodosum leprosum. Even though there may be an increased likelihood of type 1 reactions, no additional nerve function impairment is attributed to the vaccine in various studies. In household contacts of leprosy who are administered MIP, it is noted to confer protection from disease lasting up to 10 years. It may prove to be a cost-effective strategy in national leprosy programmes. Apart from local injection site reactions, the vaccine is relatively safe, but it is not recommended in pregnancy and lactation. This article provides an overview of the MIP vaccine's clinical application in the context of leprosy spanning over 40 years. It also considers the vaccine's possible future applications in the management of disease-related complications and achieving the long-term goal of zero leprosy.

Review of Evolocumab for the Reduction of LDL Cholesterol and Secondary Prevention of Atherosclerotic Cardiovascular Disease.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide. Statins are the recommended first-line lipid-lowering therapy (LLT) for patients with primary hypercholesterolemia and established ASCVD, with LLT intensification recommended in the substantial proportion of patients who do not achieve levels below guideline-recommended LDL-C thresholds with statin treatment alone. The proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody evolocumab has demonstrated significant LDL-C reductions of 60% in the clinical trial and open-label extension settings, with LDL-C reductions observed early post-evolocumab initiation and maintained long term, during up to 8.4 years of follow-up. Evolocumab therapy, when added to a statin, also conferred a significant reduction in major cardiovascular (CV) events, including a 20% reduction in the composite of CV death, myocardial infarction (MI), or stroke. The absolute benefits were enhanced among various patient types at high and very high risk for secondary ASCVD (e.g., with recent MI, multiple events or peripheral artery disease). Importantly, evolocumab treatment resulted in incremental CV risk reductions during the extended follow-up, including a 23% reduction in CV mortality and no apparent LDL-C level below which there is no further CV risk reduction. Hence, the evolocumab clinical data support the need for early and significant LDL-C lowering, especially in vulnerable ASCVD patients, in order to derive the greatest benefit in the long term. Importantly, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions. A growing body of real-world evidence (RWE) for evolocumab in heterogeneous populations is consistent with the trial data, including robust LDL-C reductions below guideline-recommended thresholds, a favourable safety profile even at the lowest levels of LDL-C achieved, and a high treatment persistence rate of 90%. Altogether, this review highlights findings from 50 clinical trials and RWE studies in 51,000 patients treated with evolocumab, to demonstrate the potential of evolocumab to address the healthcare gap in LDL-C reduction and secondary prevention of ASCVD in a variety of high- and very high-risk patients.

Differential Regulation of DC Function, Adaptive Immunity, and MyD88 Dependence by MF59 and AS03-like Adjuvants.

MF59 and AS03 are squalene emulsion-based vaccine adjuvants with similar compositions and droplet sizes. Despite their broad use in licensed influenza vaccines, few studies compared their adjuvant effects and action mechanisms side by side. Considering the majority of adjuvants act on dendritic cells (DCs) to achieve their adjuvant effects, this study compared MF59 and AS03-like adjuvants (AddaVax and AddaS03, respectively) to enhance antigen uptake, DC maturation, ovalbumin (OVA) and seasonal influenza vaccine-induced immune responses. Considering MF59 was reported to activate MyD88 to mediate its adjuvant effects, this study also investigated whether the above-explored adjuvant effects of AddaVax and AddaS03 depended on MyD88. We found AddaVax more potently enhanced antigen uptake at the local injection site, while AddaS03 more potently enhanced antigen uptake in the draining lymph nodes. AddaS03 but not AddaVax stimulated DC maturation. Adjuvant-enhanced antigen uptake was MyD88 independent, while AddaS03-induced DC maturation was MyD88 dependent. AddaVax and AddaS03 similarly enhanced OVA-induced IgG and subtype IgG1 antibody responses as well as influenza vaccine-induced hemagglutination inhibition antibody titers, whileAddaS03 more potently enhanced OVA-specific IgG2c antibody responses. Both adjuvants depended on MyD88 to enhance vaccine-induced antibody responses, while AddaVax depended more on MyD88 to achieve its adjuvant effects. Our study reveals similarities and differences of the two squalene emulsion-based vaccine adjuvants, contributing to our improved understanding of their action mechanisms.

Side Effects Reported by Moroccan Medical Students Who Received COVID-19 Vaccines.

Low confidence in the safety of COVID-19 vaccines was found to be a key promoter of vaccine reluctance especially among youth. Furthermore, young adults are an important demographic for building herd immunity through vaccination. As a result, their reactions to getting COVID-19 vaccines are crucial in our fight against SARS-CoV-2. The overall goal of this study was to look into the shortterm side effects experienced by Moroccan medical and pharmacy students after receiving COVID-19 vaccines. A cross-sectional survey-based study to assess the COVID-19 vaccines' short-term AEFIs among Moroccan medical and pharmacy students. The validated questionnaire was delivered in a digital form to explore the side effects (SE) they encountered after the first or the second dose of one of three vaccines namely: AstraZeneca Vaxzevria, PfizerBioNTeck, and SinoPharm vaccines. There were 510 students in total who took part. After the first and second doses, approximately 72 percent and 78 percent of subjects, respectively, reported no SE. The remainder had localized injection site side effects (26%). Fatigue (21%), fever (19%), headache (17%), and myalgia (16%) were the most common systemic adverse effects after the first dose. There were no serious SEs reported. The majority of the reported AEFIs in our data were mild to moderate in intensity and lasted only one or two days. COVID-19 vaccinations are highly likely safe for young adults, according to the findings of this study.

Safety of the PCSK9 inhibitor alirocumab: insights from 47296 patient-years of observation.

The ODYSSEY OUTCOMES trial, comprising over 47000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

Effect of treatment with sublingual vitamin B12 in patients with B12 deficiency

Introduction: The efficacy of the intramuscular administration of vitamin B12 is well established, but it is limited by the fact that it should be administered by a healthcare professional and the associated local injection site reaction. Aim: To investigate the effectiveness of sublingual vitamin B12 administration in patients with low serum B12 levels. Patients and Methods: This is a retrospective study including patients with low serum levels of B12 (&lt;200 pg/mL) and treated with 1000 μg/day sublingually (B12-SOLGAR®) for 3 months. Subjects’ main characteristics and personal history were recorded, as well as laboratory parameters before and 3 months after therapy initiation. Results: 314 patients (men: 43%, age: 64 [54-75] years) were included in this study. Most participants were on metformin (48%) and/or a proton pump inhibitor/H2 antagonist (50%). The administration of sublingual vitamin B12 was associated with a significant increase in serum B12 levels (from 182 [152-196] to 403 [312-590] pg/mL, p&lt;0.05). Likewise, a significant increase was also noted in the patients with very low vitamin B12 levels (&lt;100 pg/mL, n=21) (from 85 [74-92] pg/mL to 298 [294-340] pg/mL, p&lt;0.05). Furthermore, significant improvements in hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, white blood cells, and platelets were observed. Conclusions: The sublingual administration of vitamin B12 (1000 μg/day) for 3 months in patients with low B12 serum levels results in significant increases of B12 levels and improves hematologic parameters, and thus may be considered as an alternative to the intramuscular administration.

Efficacy of foam sclerotherapy with polidocanol for the management of oral venous malformations.

The present aimed to examine the effectiveness of polidocanol-based foam sclerotherapy for oral venous malformations (OVMs). The present study performed a retrospective analysis of patients with OVMs who underwent sclerotherapy using polidocanol. Patients achieving the complete resolution of OVM were categorized as having a complete response (CR), those with a reduction in size from the initial diagnosis were categorized as having a partial response (PR), those with no change in size as stable disease (SD), and those with an increase in size as progressive disease (PD). A total of 16 patients, comprising 4 males and 12 females, underwent treatment with polidocanol foam therapy, covering 22 affected areas. The treatment administered resulted in CR in 6 cases and PR in 10 cases, with no instances of SD or PD. Apart from localized injection site pain or swelling, there were no severe side-effects reported, such as circulatory dynamic changes or skin necrosis. On the whole, these findings underscore the effectiveness of foam sclerotherapy with polidocanol as a viable treatment for venous malformations in the oral and maxillofacial regions.

Extensive Cerebral Venous Thrombosis following by COVID-19 Vaccine with Concomitant COVID-19 Infection

Coronavirus disease 2019 (COVID-19) vaccines have been introduced to the masses for just over two years. Majority reported adverse events post vaccination are minor side effect such as pain or inflammation at local injection site. Serious side effects such as thrombotic events or myocarditis are rarely reported. Cerebral venoussinus thrombosis (CVST) is a thrombotic complication that may occur within one to two weeks from vaccine administration. W illustrated a case from our centre involving a healthy young lady who presented with headache and an episode of seizure following by vaccination. She was concurrently diagnosed with CVST and COVID-19 infection later with the aid of neuroimaging. The patient's normal platelet count made the diagnosis of vaccine induced immune related thrombotic thrombocytopenia unlikely. While serious adverse events are reported, such as our case, this should not support the growing vaccine hesitancy among the public as its benefits still greatly outweigh its risk at this juncture.

(050) Safety and Efficacy of Hyaluronic Acid Injections Using the UroFill™ Technique for Penile Girth Enhancement

Abstract Introduction Penile girth enhancement (PGE) has gained significant popularity and is in high demand among individuals seeking to improve their sexual experiences and self-confidence. Perception of penile length and girth are integral components of the male psyche. Unfortunately, current treatment options for motivated patients looking to enhance penile girth fall short of patient and clinical expectations. While the safety of penile augmentation methods has been a subject of debate, hyaluronic acid (HA) fillers have demonstrated proven efficacy and safety, offering potential solutions for those interested in PGE. Advancements in the field of penile cosmetics with HA has led to the development of the UroFill™ patented technique for PGE. Objective To assess the safety and efficacy of injecting HA using the UroFill™ technique for PGE. Methods We performed a retrospective analysis of men undergoing penile girth enhancement with FDA-approved HA fillers between October 2021 and March 2023. Patients completed a series of validated questionnaires including the COPS-P, IIEF, and BAPS. Peri- and post-procedure adverse events were closely monitored. Physician follow-up appointments and patient questionnaires were utilized to identify and document these events. The determination of unsatisfactory cosmetic outcomes and the need for revision was made by the treating physician in consultation with the patient. The UroFill™ standardized technique was employed for all injections. Results A total of 300 men (mean age: 37, range 21-80) received treatment using the UroFill™ standardized technique. 4,879 injections were performed over this time. Mean injection volume was 16.5 cc (range: 4-78cc) of HA once treatment had been completed. The study observed an average of 3.85 injection sessions (range: 1-44 sessions) and 5.25 post-injection modeling sessions (range 0-55) per patient. After receiving HA dermal fillers, patients experienced local injection site reactions such as bruising, tenderness, swelling, and erythema. These events were generally mild in intensity, and no patient reported bruising lasting longer than 7 days. None of the patients in this cohort required removal of filler. Adverse reactions were limited to 8 cases of localized skin infections which were successfully treated with conservative antibiotic therapy. All localized skin infections were a result of premature sexual intercourse or shaving in the area following injection. Patients reported high levels of satisfaction with 272/300 (91%) reporting “completely satisfied” or “mostly satisfied”. Mean filler retention was 90% after 12 months. Conclusions This study provides evidence that the UroFill™ standardized technique for penile girth enhancement using HA fillers is both safe and efficacious. With no instances of filler removal and successful management of adverse reactions, the safety profile of HA fillers is further supported. These findings reinforce HA’s potential for sustainable penile enhancement. It is essential these procedures be performed in the described fashion by qualified urological professionals. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast, Boston Scientific, UroFill.

Prospective monitoring of adverse events following vaccination with Modified vaccinia Ankara - Bavarian Nordic (MVA-BN) administered to a Canadian population at risk of Mpox: A Canadian Immunization Research Network study

MVA-BN is an orthopoxvirus vaccine that provides protection against both smallpox and mpox. In June 2022, Canada launched a publicly-funded vaccination campaign to offer MVA-BN to at-risk populations including men who have sex with men (MSM) and sex workers. The safety of MVA-BN has not been assessed in this context. To address this, the Canadian National Vaccine Safety Network (CANVAS) conducted prospective safety surveillance during public health vaccination campaigns in Toronto, Ontario and in Vancouver, British Columbia. Vaccinated participants received a survey 7 and 30 days after each MVA-BN dose to elicit adverse health events. Unvaccinated individuals from a concurrent vaccine safety project evaluating COVID-19 vaccine safety were used as controls. Vaccinated and unvaccinated participants that reported a medically attended visit on their 7-day survey were interviewed. Vaccinated participants and unvaccinated controls were matched 1:1 based on age group, gender, sex and provincial study site. Overall, 1,173 vaccinated participants completed a 7-day survey, of whom 75 % (n = 878) also completed a 30-day survey. Mild to moderate injection site pain was reported by 60 % of vaccinated participants. Among vaccinated participants 8.4 % were HIV positive and when compared to HIV negative vaccinated individuals, local injection sites were less frequent in those with HIV (48 % vs 61 %, p = 0.021), but health events preventing work/school or requiring medical assessment were more frequent (7.1 % vs 3.1 %, p = 0.040). Health events interfering with work/school, or requiring medical assessment were less common in the vaccinated group than controls (3.3 % vs. 7.1 %, p < 0.010). No participants were hospitalized within 7 or 30 days of vaccination. No cases of severe neurological disease, skin disease, or myocarditis were identified. Our results demonstrate that the MVA-BN vaccine appears safe when used for mpox prevention, with a low frequency of severe adverse events and no hospitalizations observed.

Aluminum hydroxide nanoparticle adjuvants can reduce the inflammatory response more efficiently in a mouse model of allergic asthma than traditional aluminum hydroxide adjuvants.

Traditional aluminum hydroxide is widely used as a vaccine adjuvant. Despite its favorable safety profile, it can cause an inflammatory response at the injection sites. However, multiple studies have shown that aluminum hydroxide nanoparticles have more potent adjuvant activity than their traditional aluminum hydroxide counterparts as antigen carriers; it has also been found that the local inflammation caused by aluminum hydroxide nanoparticle adjuvants is milder than that of other adjuvants. The aim of the present study was to compare the degree of inflammatory response between the aluminum hydroxide nanoparticle adjuvants and the traditional aluminum hydroxide adjuvants in the desensitization treatment of a mouse model of house dust mite (HDM)-induced allergic asthma. Mice were sensitized intraperitoneally with HDM. Subcutaneous desensitization was performed with PBS, traditional aluminum hydroxide adjuvants and aluminum hydroxide nanoparticle adjuvants. The mice were challenged and subsequently euthanized. The skin tissue at the local injection sites was assessed and specific indices were measured, such as the response of specific immunoglobulins, the airway hyper-responsiveness (AHR), and the inflammation in the bronchoalveolar lavage and lung tissues. Early hypersensitivity responses were suppressed in mice treated with subcutaneous immunotherapy (SCIT). Both traditional aluminum hydroxide-SCIT and aluminum hydroxide nanoparticle-SCIT could inhibit AHR. However, aluminum hydroxide nanoparticle-SCIT was able to significantly inhibit the secretion of eosinophils in the lung tissue and the production of type 2 cytokine Interleukin (IL)-5 in blood compared with the corresponding effects noted by traditional aluminum hydroxide adjuvants. Moreover, the aluminum hydroxide nanoparticle group reduced the inflammatory response at the local injection site. Collectively, the data indicated that allergen-specific immunotherapy using aluminum hydroxide nanoparticle adjuvants reduces lung and local inflammation compared with traditional aluminum hydroxide adjuvants.

Co-overexpression of OPN, IGF-1 and CNTF augment the therapeutic effect of DPSC on spinal cord injury

Background aimsSpinal cord injury (SCI) is one of the most complex and destructive diseases of the nervous system, which can lead to permanent loss of tactile perception. But existing treatment methods have limited effects. To establish a novel method that may be therapeutic in repairing the injured spinal cord, gene-modified dental pulp stem cells (DPSCs) were injected in situ. MethodsAdenovirus carrying osteopontin (OPN), Insulin-like growth factor 1 (IGF-1) and cailiary-derived neurotrophic factor (CNTF) (Ad-OIC) was constructed. After modified with Ad-OIC, supernatant of DPSC were co-cultured with HT-22 cells and the effect of DPSC-OIC on the HT-22 cells were evaluated via Cell Counting Kit-8 (CCK-8) assay, Real-Time polymerase chain reaction (PCR) analysis, laser confocal microscopy and fluorescence activating cell sorter (FACS). DPSC-OIC were injected in the lesion area of injured spinal cord and the survival time of transplanted cells were measured by bioluminescence imaging system. The recovery of the injured spinal cord was evaluated by behavioral score, radiological evaluation and immunopathological analysis. ResultsDPSC-OIC could enhance the proliferation and axon growth of HT-22 cells, and protect HT-22 cells from H2O2 induced apoptosis. The transplanted DPSC-Null or DPSC-OIC could survive for more than two weeks in local injection site. DPSC-OIC treatment could increase Basso-Mouse Scale (BMS) scores, improve Magnetic Resonance Imaging (MRI) manifestation and promote bladder function recovery. Less apoptotic neurons and more proliferative cells were found in the lesion area of DPSC-OIC treated spinal cord. Nestin+ cells and neural stem cell marker (Sox2) were both up-regulated after DPSC-OIC treatment. Additionally, inhibitory extracellular matrix proteoglycan Neural/Glial Antigen 2 (NG2) was down-regulated and axon growth promotive factor fibronectin was up-regulated after both DPSC-Null (DPSCs infected with Ad-Null) and DPSC-OIC treatments. ConclusionsDPSC-OIC could be a novel effective method for treating SCI.

Big data- and machine learning-based analysis of a global pharmacovigilance database enables the discovery of sex-specific differences in the safety profile of dual IL4/IL13 blockade.

Background: Due to its apparent efficacy and safety, dupilumab, a monoclonal antibody that blocks Interleukin 4 (IL-4) and Interleukin 13 (IL-13), has been approved for treating T-helper 2 (Th2) disorders. However, adverse effects like local injection site reactions, conjunctivitis, headaches, and nasopharyngitis have been reported. Sex differences are known to influence both adaptive and innate immune responses and, thus, may have a bearing on the occurrence of these adverse effects. Nevertheless, the literature lacks a comprehensive exploration of this influence, a gap this study aims to bridge. Materials and Methods: A comprehensive data mining of VigiBase, the World Health Organization (WHO) global pharmacovigilance database which contains case safety reports of adverse drug reactions (ADRs) was performed to test for sex -specific safety response to dual IL4/IL13 blockade by dupilumab. The information component (IC), a measure of the disproportionality of ADR occurrence, was evaluated and compared between males and females to identify potential sexual dimorphism. Results: Of the 94,065 ADRs recorded in the WHO global pharmacovigilance database, 2,001 (57.4%) were reported among female dupilumab users, and 1,768 (50.7%) were among males. Immune/autoimmune T-helper 1 (Th1)-, innate- and T-helper 17 (Th17)-driven diseases and degenerative ones were consistently reported with a stronger association with Dupilumab in males than females. Some adverse events were more robustly associated with Dupilumab in females. Conclusion: Dupilumab has an excellent safety profile, even though some ADRs may occur. The risk is higher among male patients, further studies, including ad hoc studies, are needed to establish causality.

Adverse Reactions to Vaccines

Vaccination is one of the most impactful and cost-effective interventions for improving global health. Routine immunization has reduced mortality and morbidity resulting from numerous types of infectious diseases. The widespread use of any reagent is always associated with the risk of adverse reactions, including expected and common side effects, as well as those that are unexpected or idiosyncratic. Mild, local injection site reactions such as redness, tenderness, swelling, or constitutional symptoms such as fever and malaise, are common after vaccination and are not contraindications to further vaccination; they are generally manifestations of the physiologic response to vaccination. Uncommon reactions can vary; they may manifest as delayed hypersensitivity to vaccine components causing injection site nodules or severe, rare anaphylactic reactions. Anaphylaxis occurs at approximately one per million doses administered. The extremely rare Arthus reaction, a type of local Type 3 hypersensitivity reaction, resulting in local immune complex deposition due to the presence of pre-existing IgG antibodies, is typically limited in duration and is not a contraindication to further tetanus vaccination. Allergists are often seen as stewards of information regarding many of these reactions, although most of these reactions are not allergic in nature. It can be difficult to distinguish between a true allergic reaction to a vaccine and other clinical manifestations that may occur during or acutely after vaccination, such as anxiety, vasovagal responses, and pronounced local reactions. Patients who have had adverse reactions to vaccines may be unnecessarily advised to avoid subsequent immunization, which can put them at risk of morbidity or mortality. The importance of making this clinical distinction has become particularly significant during the ongoing COVID-19 pandemic. The allergist plays an important role in investigating adverse reactions to vaccines and ensuring that patients who are eligible can be safely vaccinated following appropriate investigation. For those patients with true immediate-onset allergic reactions, allergists are able to provide safe revaccination following established protocols.

Safety of BCG vaccination and revaccination in healthcare workers

ABSTRACT BCG vaccination and revaccination are increasingly being considered for the protection of adolescents and adults against tuberculosis and, more broadly, for the off-target protective immunological effects against other infectious and noninfectious diseases. Within an international randomized controlled trial of BCG vaccination in healthcare workers (the BRACE trial), we evaluated the incidence of local and serious adverse events, as well as the impact of previous BCG vaccination on local injection site reactions (BCG revaccination). Prospectively collected data from 99% (5351/5393) of participants in Australia, Brazil, Spain, The Netherlands and the UK was available for analysis. Most BCG recipients experienced the expected self-limiting local injection site reactions (pain, tenderness, erythema, swelling). BCG injection site itch was an additional common initial local symptom reported in 49% of BCG recipients. Compared to BCG vaccination in BCG-naïve individuals, BCG revaccination was associated with increased frequency of mild injection site reactions, as well as earlier onset and shorter duration of erythema and swelling, which were generally self-limiting. Injection site abscess and regional lymphadenopathy were the most common adverse events and had a benign course. Self-resolution occurred within a month in 80% of abscess cases and 100% of lymphadenopathy cases. At a time when BCG is being increasingly considered for its off-target effects, our findings indicate that BCG vaccination and revaccination have an acceptable safety profile in adults.