A BS TRACT: Background: α-Synuclein (αSyn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic αSyn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar αSyn, making UB-312 a potential immunotherapeutic for synucleopathies. Objective: To investigate the safety, tolerability, and immunogenicity of UB-312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first-in-patient study. Methods: Fifty eligible healthy participants were enrolled in a 44-week, randomized, placebo-controlled, doubleblind study. Participants in seven cohorts were randomized to three intramuscular UB-312 or placebo injections at weeks 1, 5, and 13 (doses ranging between 40 and 2000 μg). Safety and tolerability were assessed by adverse events, clinical laboratory, vital signs, electrocardiograms, and neurological and physical examinations. Immunogenicity was assessed by measuring serum and cerebrospinal fluid (CSF) anti-αSyn antibody concentrations. Results: Twenty-three participants received all three vaccinations of UB-312. Most adverse events were mild, transient, and self-resolving. Common treatment-emergent adverse events included headache, nasopharyngitis, vaccination-site pain, lumbar puncture-site pain, and fatigue. UB-312 induced dose-and time-dependent antibody production. Antibodies were detectable in serum and CSF of all participants receiving the 300/300/300 μg UB-312 dose regimen. The average CSF/serum ratio was 0.2%. Conclusions: UB-312 was generally safe, well tolerated, and induced anti-αSyn antibodies in serum and CSF of healthy participants. The 100 and 300 μg doses are selected for further evaluation in participants with PD.

Intravenous immunoglobulin (IVIg) therapy has been suggested as a potential treatment option for hospitalised COVID‐19 patients. The aim of this systematic review and meta‐analysis was to investigate the potential impact of IVIg on mortality and length of hospitalisation in adult COVID‐19 patients. PubMed, Scopus, Web of Science and medRxiv were searched in the week of 20.12.2021 for English language, prospective trials, and retrospective studies with control groups, reporting on the use of intravenous immunoglobulin therapy in adult hospitalised COVID‐19 patients. Exclusion criteria were: studies evaluating the use of IVIg in paediatric COVID‐19 cases, trials using convalescent anti‐SARS‐CoV‐2 plasma or immunoglobulins derived from convalescent anti‐SARS‐CoV‐2 plasma. A random effects meta‐analysis with subgroup analyses regarding study design and patient disease severity according to WHO criteria was also performed. A total of 13 studies were included, of which 6 were prospective, on a total of 2313 (IVIg = 1104, control = 1209) patient outcomes. Meta‐analysis results indicated that IVIg therapy had no statistically significant effect on mortality (RR 0.91 [0.59; 1.39], p = 0.65, I 2 = 69% [46%; 83%]) or length of hospital stay (MD 0.51 [−2.80; 3.81], p = 0.76, I 2 = 96% [94%; 98%]). Subgroup analyses indicated no statistically significant impact on either outcome, but prospective studies' results suggested that IVIg may increase the length of hospitalisation in the severe COVID‐19 patient group (MD 2.66 [1.43; 3.90], p < 0.01, I 2 = 0% [0%; >90%]). The results of this meta‐analysis do not support use of IVIg in hospitalised adult COVID‐19 patients.

No abstract

AimTraditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new opportunities for studies in healthy volunteers, which are conducted faster and are less susceptible to confounders. Aim of this study was to investigate to what extent this approach is utilized and whether pharmacodynamic endpoints are evaluated in these early phase trials. We conducted a comprehensive review of clinical trials with healthy volunteers using immunotherapies potentially relevant for oncology.MethodsLiterature searches according to PRISMA guidelines and after registration in PROSPERO were conducted in PubMed, Embase, Web of Science and Cochrane databases with the cut-off date 20 October 2020, using search terms of relevant targets in immuno-oncology. Articles describing clinical trials with immunotherapeutics in healthy volunteers with a mechanism relevant for oncology were included. “Immunotherapeutic” was defined as compounds exhibiting effects through immunological targets. Data including study design and endpoints were extracted, with specific attention to pharmacodynamic endpoints and safety.ResultsIn total, we found 38 relevant immunotherapeutic compounds tested in HVs, with 86% of studies investigating safety, 82% investigating the pharmacokinetics (PK) and 57% including at least one pharmacodynamic (PD) endpoint. Most of the observed adverse events (AEs) were Grade 1 and 2, consisting mostly of gastrointestinal, cutaneous and flu-like symptoms. Severe AEs were leukopenia, asthenia, syncope, headache, flu-like reaction and liver enzymes increase. PD endpoints investigated comprised of cytokines, immune and inflammatory biomarkers, cell counts, phenotyping circulating immune cells and ex vivo challenge assays.DiscussionHealthy volunteer studies with immuno-oncology compounds have been performed, although not to a large extent. The integration of healthy volunteers in well-designed proof-of-mechanism oriented drug development programs has advantages and could be pursued more in the future, since integrative clinical trial protocols may facilitate early dose selection and prevent cancer patients to be exposed to non-therapeutic dosing regimens.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=210861, identifier CRD42020210861