Rates Of Systemic Adverse Events Research Articles

Transverse myelitis following bivalent COVID‐19 booster vaccine and quadrivalent seasonal influenza vaccine

Transverse myelitis following bivalent <scp>COVID</scp>‐19 booster vaccine and quadrivalent seasonal influenza vaccine

1955. Immunogenicity And Safety of a Virus-Like Particle (VLP) Protein Subunit SARS-CoV-2 Vaccine in Adults: a Phase 1/2 Study

Abstract Background COVID-19 continues to cause substantial morbidity and mortality globally. It is likely that booster vaccinations will be needed in future years to protect older adults and those with chronic medical conditions. We present interim topline results of a phase 1/2 study of IVX-411 [ACTRN12621000738820.; ACTRN12621000882820], an investigational VLP protein subunit SARS-CoV-2 vaccine, in adults aged 18–69 years (Figure 1). Methods In Part 1, 84 SARS-CoV-2-naïve adults were randomized to receive two doses on Days 0 and 28 of either IVX-411 (5, 25, or 125µg) ± adjuvant, or placebo (Figure 2a). In Part 2, 84 subjects received a single dose of either IVX-411 ± adjuvant or placebo 3–6 months after completion of a primary licensed vaccine regimen (Figure 2b). Solicited adverse events (AEs) were collected for 7 days after each dose, with immunogenicity assessed on Days 0, 28, and 49 [(Part 1) and on Days 0, 7 and 28 (Part 2). Primary outcomes in both parts were solicited and unsolicited AEs, neutralizing antibody titers, and spike protein-specific IgG antibody titers. Results Demographics were similar in the IVX-411 groups vs placebo. In Part 1 and Part 2, local reactogenicity was mild-to-moderate, with higher rates of AEs with increasing doses and addition of adjuvant (Figure 3a). Rates of systemic AEs were similar to placebo across groups (Figure 3b). No vaccine-related severe or serious AEs were noted. IVX-411 was immunogenic in both primary and booster vaccination: in SARS-CoV-2-naïve subjects, a limited dose effect was seen, with significantly higher antibody titers in the groups receiving adjuvanted IVX-411 vaccine (p&amp;lt; 0.01; Figure 4a). The magnitude of antibody responses was similar to, or below, Human Convalescent Sera levels. In previously vaccinated subjects, IVX-411 boosted baseline antibody titers, with no conclusive dose or adjuvant effect (Figure 4b). Immunogenicity was observed across all variants of concern (beta, delta, and omicron) in both parts, with up to 7- fold rises from baseline (Figure 5). Conclusion The study met all primary safety and immunogenicity objectives, with acceptable tolerability profiles in primary and booster vaccination. A clear adjuvant effect was observed in SARS-CoV-2-naïve subjects. Disclosures All Authors: No reported disclosures.

COVID-19 vaccines in pregnancy.

COVID-19 caused by SARS-CoV-2 coronavirus has been associated with severe illness in pregnant women. Furthermore, COVID-19 during pregnancy is associated with adverse fetal outcomes including preterm labor. Pregnant women were largely excluded from initial clinical trials investigating the safety and efficacy of COVID-19 vaccines; however, they have since been included as part of the routine roll-out of these vaccines. This narrative review synthesizes the evidence on the safety, immunogenicity, and effectiveness predominantly of the mRNA COVID-19 vaccines which have been most widely used in pregnant women.

Early Safety Monitoring of COVID-19 Vaccines in Healthcare Workers.

Hospital-based surveillance for adverse events was conducted on healthcare workers after they received the first dose of coronavirus disease 2019 (COVID-19) vaccine. Among the two new platform vaccines (messenger RNA- and adenoviral vector-based vaccines), the rates of systemic adverse events were significantly higher among adenovirus-vectored vaccine recipients. Fatigue (87.6% vs. 53.8%), myalgia (80.8% vs. 50.0%), headache (72.0% vs. 28.8%), and fever (≥ 38.0°C, 38.7% vs. 0%) were the most common adverse events among adenovirus-vectored vaccine recipients, but most symptoms resolved within 2 days. Both types of COVID-19 vaccines were generally safe, and serious adverse events rarely occurred.

Immune Globulin Subcutaneous (Human) 20% (Hizentra®): A Review in Chronic Inflammatory Demyelinating Polyneuropathy.

Intravenous immunoglobulin (IVIg) is well-established in the treatment of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Immune globulin subcutaneous (human) 20% liquid (Hizentra®; referred to as IgPro20 hereafter) has recently been approved in a number of countries, including the USA and those of the EU, as maintenance therapy in patients with CIDP. In the pivotal phase III PATH trial in adults with CIDP who were first stabilized on IVIg therapy, maintenance therapy with IgPro20 for 24weeks significantly reduced CIDP relapse or study withdrawal rates versus placebo. Efficacy was sustained during ≤ 48weeks of additional treatment with IgPro20 in the open-label PATH extension study. IgPro20 was generally well tolerated, with low rates of systemic adverse events (AEs); the most common AEs were local reactions (e.g. infusion-site erythema, infusion-site swelling). In PATH, more than one-half of IgPro20 recipients preferred this therapy to their previous IVIg therapy. IgPro20 offers a convenient alternative to IVIg with a better systemic AEs profile and thus extends the options for maintenance therapy in CIDP.

Topical Timolol Vs. Oral Propranolol for the Treatment of Superficial Infantile Hemangiomas.

Objective: Infantile hemangiomas (IHs) are the most common vascular tumors of infancy. Oral propranolol has achieved great success in treating IHs since 2008. To minimize the systemic side events caused by oral administration of propranolol, topical timolol started to be applied in the treatment of IHs, especially for superficial lesions.Methods: We treated 724 children with superficial IHs using oral propranolol or topical timolol, and investigated the efficacy and safety of the two treatment patterns.Results: Both oral propranolol and topical timolol achieved a satisfactory therapeutic outcome, with an effective response rate of 97 and 96.4%, respectively. No significant differences in visual analog scale (VAS) improvement between the two groups were observed. Occurrence rate of systemic adverse events for patients treated with oral propranolol (3.9%) was significantly higher than that for patients treated with topical timolol (0%). Clinical response was not associated with gender, duration of treatment, lesion location, lesion size, gestational age, and progesterone use during pregnancy, but closely associated with age at treatment initiation, which indicated that younger age at treatment initiation predicted for a better regression rate.Conclusions: We recommend that topical timolol instead of oral propranolol could be the first-line therapy for superficial IHs because of its good efficacy and improved safety.

ACTR-01. SAFETY ANALYSES OF TUMOR TREATING FIELDS IN COMBINATION WITH LOMUSTINE IN THE EF14 PHASE 3 CLINICAL STUDY

INTRODUCTION: Tumor Treating Fields (TTFields) are low intensity (1-3V/cm), intermediate frequency (100–300 KHz) alternating electrical fields approved for glioblastoma (GBM). In the EF-14 phase 3 study, TTFields showed a significant overall and progression-free survival benefit for patients with newly diagnosed GBM in combination with Temozolomide (TMZ). TTFields were not associated with systemic toxicity. At recurrence, patients continued TTFields with second line therapies. We analyzed the safety and feasibility of TTFields + lomustine (CCNU) combination. Patients in the EF-14 trial received TTFields until second progression, or for 24 months. Change in chemotherapy regimen was allowed in both groups after tumor progression. We compared patients who received lomustine as second-line chemotherapy in combination with TTFields (n=134) to patients who received lomustine as monotherapy after first progression (n=39). We compared baseline characteristics and the adverse event profile between the two groups. Baseline characteristics were well balanced; there were less female patients in the lomustine only group (7.7% vs. 22.4%). Median age in the TTFields/lomustine group was 55.5 years (29–83) versus 50.0 years (19–71) for lomustine alone. The addition of TTFields to lomustine therapy was not associated with any significant increase in rates of systemic adverse events compared to lomustine therapy alone (number of patients with ≥ 1 SAE 30 % vs. 31 %) and the distribution, severity and overall incidence of adverse events were not statistically different in patients in the two treatment groups. CONCLUSION: The combination of TTFields and lomustine is safe and feasible. This analysis emphasizes again the strong safety profile of TTFields and the high potential of combining TTFields with other therapy modalities. This data is especially important in light of the recently presented promising data from a small randomized trial that tested the combination of lomustine plus TMZ in newly diagnosed (MGMT promotor-methylated only) GBM patients.

Abstract CT105: The safety of TTFields applied to the torso: A meta-analysis of 176 patients from four phase I-II trials

Abstract Tumor Treating Fields (TTFields) is a non-invasive, loco-regional, antimitotic treatment modality, approved for treatment of glioblastoma. TTFields are delivered to the tumor through transducer arrays applied non-invasively to the region of the body with the highest tumor burden. In a phase 3 trial in newly diagnosed glioblastoma (GBM), addition of TTFields to temozolomide was not associated with any significant increase in rates of systemic adverse events (AEs) versus temozolomide alone. The only common treatment related AE seen in TTFields-treated patients was localized dermatitis underneath the arrays. Mild-moderate dermatitis was reported in 52% of patients (2% had grade 3 skin toxicity). The safety of TTFields was investigated in four phase I-II studies for malignancies located outside of the brain: non-small-cell lung cancer (NSCLC), mesothelioma, pancreatic cancer and ovarian cancer. Methods Four phase I-II clinical studies of TTFields were included in the analysis: EF-15 (n=41, advanced NSCLC; combined with pemetrexed), PANOVA (n=40, advanced pancreatic adenocarcinoma; combined with gemcitabine with or without nab-paclitaxel), STELLAR (n=64, malignant pleural mesothelioma; combined with platinum and pemetrexed) and INNOVATE (n=31, recurrent ovarian carcinoma; combined with weekly paclitaxel). The frequency of TTFields applied was 150-200 kHz depending on tumor histology. The compliance required per protocol with TTFields was 12 - 18 hours/day. All patients received standard of care systemic chemotherapy for their disease in addition to TTFields. Severity and frequency of AEs, and association with the experimental treatment were evaluated using CTCAE criteria. Results The median age of patients was 69 (range: 41-81), 73 (49-81), 68 (43-78) and 60 (45-77) for EF-15, PANOVA, STELLAR and INNOVATE, respectively. Patients enrolled in the trials had an ECOG score of 0-1, except for 7 patients enrolled in the EF-15 study with ECOG score of 2. The incidence of grade 1-2 gastrointestinal (GI) toxicities was ≥5%: constipation (16%), diarrhea (14%), nausea (27%) and vomiting (13%). GI toxicity was related to standard chemotherapy or underlying disease in all cases. Grade 1-2 general disorders such as asthenia, fatigue and anorexia were common but less than 20% for each, and were related to the underlying disease or standard chemotherapy. Grade 3-4 dyspnea (6%) was reported in patients with lung tumors, related to exacerbation of the underlying disease. The incidence of all types of arrhythmias was ≤2% and none were severe. The only common TTFields related adverse event was dermatitis beneath the device transducer arrays. Half of the patients (50%) had grade 1-2 dermatitis, while grade 3 dermatitis was seen in 6% of patients. 7% of patients complained of grade 1-2 pruritus. Dermatologic AEs were managed using published guidelines leading to full resolution in all cases. Conclusions Treatment of solid tumor patients with TTFields at 150-200 kHz to the lungs, abdomen and upper pelvis did not result in treatment related pulmonary, cardiac, hematological or gastrointestinal toxicity. Expected dermatological toxicity beneath the device transducer arrays was seen in half of the patients, and resolved after treatment termination in all cases. Citation Format: Ignace Vergote, Manuel Benavides, Miklos Pless, Giovanni Ceresoli. The safety of TTFields applied to the torso: A meta-analysis of 176 patients from four phase I-II trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT105.

Abstract CT108: Tumor treating fields (TTFields) in combination with Lomustine (CCNU) in the EF-14 phase III clinical study: A safety analysis

Abstract Introduction: TTFields are low intensity (1-3V/cm), intermediate frequency (100-300 KHz) alternating electrical fields for the treatment of solid tumors. In the EF-14 phase 3 study, TTFields showed a significant overall and progression-free survival benefit for patients with newly diagnosed glioblastoma (GBM), in combination with Temozolomide (TMZ) (OS from randomization 20.9 vs. 16.0 months, p-value&amp;lt;0.001). The OS and PFS benefit of TTFields was seen in all patient subgroups, and was independent of MGMT promotor methylation-status, age, performance status and gender. TTFields were not associated with additional systemic toxicity. At recurrence, patients were allowed to continue TTFields with second line therapies. Here, we analyzed the safety data of TTFields + lomustine (CCNU) to evaluate the safety and feasibility of this combination. Methods: Patients in the EF-14 trial received TTFields until second progression, or for 24 months. Change in chemotherapy regimen was allowed in both groups after tumor progression. We compared the patients who received lomustine as second-line chemotherapy in combination with TTFields (n=134) to the patients who received lomustine as monotherapy after first progression (n=39). We compared baseline characteristics and the adverse event profile between the two groups. Results: Baseline characteristics were well balanced between both groups except for less female patients in the lomustine only group (7.7% vs. 22.4%). Median age in the TTFields/lomustine group was 55.5 years (29-83) compared to 50.0 years (19-71) for lomustine alone. The addition of TTFields to lomustine therapy was not associated with any significant increase in rates of systemic adverse events compared to lomustine therapy alone (number of patients with &amp;gt; 1 SAE 30 % vs. 31 %) and the distribution, severity and overall incidence of adverse events were not statistically different in patients in the two treatment groups. Discussion: The data show that the combination of TTFields and lomustine is a safe and feasible combination. This analysis emphasizes again the strong safety profile of TTFields and the high potential of combining TTFields with other therapy modalities. This data is especially important in light of the recently presented promising data from a small randomized trial that tested the combination of lomustine + TMZ in newly diagnosed (MGMT promotor-methylated only) GBM patients. Citation Format: Adrian Kinzel, Gitit Lavy-Shahaf, Eilon D Kirson. Tumor treating fields (TTFields) in combination with Lomustine (CCNU) in the EF-14 phase III clinical study: A safety analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT108.

Severity of cerebral palsy and likelihood of adverse events after botulinum toxin A injections.

To determine the incidence of common adverse events after botulinum toxin A (BoNT-A) injections in children with cerebral palsy (CP) and to identify whether the severity of CP influences the incidence of adverse events. This was an observational study of patients attending a BoNT-A clinic at a tertiary paediatric hospital (2010-2014). Data examined included procedural adverse events at the time of injection and at follow-up. Systemic adverse events were defined as lower respiratory tract illnesses, generalized weakness, dysphagia, and death. Severity of CP was categorized by the Gross Motor Function Classification System (GMFCS). The relationships between GMFCS and adverse events were analysed using negative binomial regression models. In total, 591 children underwent 2219 injection episodes. Adverse events were reported during the procedure (130 [6%] injection episodes) and at follow-up (492 [22%] injection episodes). There were significantly increased rates of systemic adverse events in injection episodes involving children in GMFCS level IV (incidence rate ratio [IRR] 3.92 [95% confidence interval] 1.45-10.57]) and GMFCS level V (IRR 7.37 [95% confidence interval 2.90-18.73]; p<0.001). Adverse events after BoNT-A injections are common but mostly mild and self-limiting. Children in GMFCS levels IV and V are at increased risk of systemic adverse events. The relationship between CP severity and BoNT-A adverse events is complex and further research is required to better understand this relationship. Adverse events reported at the time of botulinum toxin A injection occurred in 6% of injection episodes. Adverse events were reported at follow-up in 22% of injection episodes. Children in Gross Motor Function Classification System (GMFCS) levels IV and V have increased rates of systemic adverse events. Children in GMFCS levels IV and V report less local weakness and pain.

Immunotherapy for Food Allergy: Are We There Yet?

Current clinical research focuses on food allergen-specific immunotherapy through oral (OIT), sublingual (SLIT), or epicutaneous (EPIT) routes. Immunotherapy relies on the delivery of gradually increasing doses of specific allergens to induce desensitization (defined as temporary antigen hyporesponsiveness that depends on regular food ingestion) and, ultimately, tolerance (defined as the ability to ingest food without symptoms despite prolonged periods of avoidance or irregular intake). Although the majority of the patients treated with OIT achieve desensitization, only a minority achieves tolerance. OIT involves higher maintenance doses of food protein (300 mg-4g) compared with SLIT (2.5-7.5 mg) and EPIT (250-500 mcg). OIT efficacy is higher compared with SLIT, but OIT is associated with higher rate of systemic adverse events compared with SLIT and EPIT. OIT is also associated with a minor risk of eosinophilic esophagitis. Combined treatment of OIT and anti-IgE monoclonal antibody has improved safety but not efficacy compared with OIT alone. Early initiation of peanut OIT in peanut-allergic infants and young children may afford superior efficacy and safety. In this review, we discuss the allergen-specific strategies currently explored for the treatment of food allergy, including immunotherapy with native and heat-modified food proteins. Additional research employs strategies to improve the safety and efficacy of allergen immunotherapy through modifications of allergen structure and addition of immunomodulatory adjuvants.

A randomised controlled trial of resistance exercise prior to administration of influenza vaccination in older adults

The low rate of vaccine efficacy in the older adult population poses a major challenge to public health. Previous investigation has found acute exercise can enhance immune responses to vaccines within a young adult population. To date, no study has investigated the effect of exercise on vaccine responses in immune-compromised groups such as older adults, a group who could potentially benefit from enhanced responses. Forty-six healthy older adults (mean age = 73 ± 7 years, BMI = 27.2 ± 5 kg m2, male = 23) were randomly assigned to complete a control or exercise task prior to administration of the seasonal influenza vaccine. The exercise group performed resistance exercises using upper and lower body muscle groups at an intensity of 60-percent one repetition maximum. Antigen-specific serum antibody titres were measured at baseline and one-month and six-months post-vaccination. Exercise task elicited expected changes in inflammatory markers, but for all three viral strains of the influenza vaccine, changes in antibody titre from baseline to one-month and six-months post vaccination were similar between groups who exercised prior to vaccination and those who rested. Control participants suffered a higher rate of systemic adverse events in the 48 h following vaccination. To our knowledge, this was the first randomised controlled trial (RCT) investigating the effects of resistance exercise on vaccine response in the older adult population, limitations include sample size and intensity of exercise task which may have contributed to the null finding.