Dataset Information

Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial.

ABSTRACT: Treatment of chronic hepatitis B (CHB) typically requires life-long administration of drugs. Cohort and pre-clinical studies have established the link between a functional T-cell-mounted immunity and resolution of infection. TG1050 is an adenovirus 5-based vaccine that expresses HBV polymerase and domains of core and surface antigen and has shown immunogenicity and antiviral effects in mice. We performed a phase 1 clinical trial to assess safety and explore immunogenicity and early efficacy of TG1050 in CHB patients. This randomized, double blind, placebo-controlled study included two sequential phases: one single dose cohort (SD, n = 12) and one multiple (3) doses cohort (MD, n = 36). Patients, virally suppressed under nucleoside(d)tide analog NUC therapy, were randomized 1:1:1 across 3 dose levels (DL) and assigned to receive 10⁹, 10¹⁰, 10¹¹ virus particles (vp) of TG1050 and then randomized within each DL to placebo (3:1 and 9:3 vaccines/placebo in each DL, respectively, for the SD and MD cohorts). Cellular (ELISPOT) and antibody responses (anti-Adenovirus), as well as evolution of circulating HBsAg and HBcrAg, were monitored. All doses were well tolerated in both cohorts, without severe adverse event. TG1050 was capable to induce IFN-γ producing T-cells targeting 1 to 3 encoded antigens, in particular at the 10¹⁰vp dose. Overall, minor decreases of HBsAg were observed while a number of vaccinees reached unquantifiable HBcrAg by end of the study. In CHB patients under NUC, TG1050 exhibited a good safety profile and was capable to induce HBV-specific cellular immune response. These data support further clinical evaluation, especially in combination studies.

SUBMITTER: Zoulim F

PROVIDER: S-EPMC7158919 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial.

Zoulim Fabien F Fournier Claire C Habersetzer François F Sprinzl Martin M Pol Stanislas S Coffin Carla S CS Leroy Vincent V Ma Mang M Wedemeyer Heiner H Lohse Ansgar W AW Thimme Robert R Lugardon Karine K Martin Perrine P Bastien Bérangère B Sansas Benoit B Adda Nathalie N Halluard Celine C Bendjama Kaïdre K Brandely Maud M Inchauspé Geneviève G

Human vaccines & immunotherapeutics 20191004 2

Treatment of chronic hepatitis B (CHB) typically requires life-long administration of drugs. Cohort and pre-clinical studies have established the link between a functional T-cell-mounted immunity and resolution of infection. TG1050 is an adenovirus 5-based vaccine that expresses HBV polymerase and domains of core and surface antigen and has shown immunogenicity and antiviral effects in mice. We performed a phase 1 clinical trial to assess safety and explore immunogenicity and early efficacy of T ...[more]

PMID: 31373537

Similar Datasets

Project description:BackgroundIn animal models, immunity to mosquito salivary proteins protects animals against mosquito-borne disease. These findings provide a rationale to vaccinate against mosquito saliva instead of the pathogen itself. To our knowledge, no vector salivary protein-based vaccine has been tested for safety and immunogenicity in humans. We aimed to assess the safety and immunogenicity of Anopheles gambiae saliva vaccine (AGS-v), a peptide-based vaccine derived from four A gambiae salivary proteins, in humans.MethodsIn this randomised, placebo-controlled, double-blind, phase 1 trial, participants were enrolled at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Participants were eligible if they were healthy adults, aged 18-50 years with no history of severe allergic reactions to mosquito bites. Participants were randomly assigned (1:1:1), using block randomisation and a computer-generated randomisation sequence, to treatment with either 200 nmol of AGS-v vaccine alone, 200 nmol of AGS-v with adjuvant (Montanide ISA 51), or sterile water as placebo. Participants and clinicians were masked to treatment assignment. Participants were given a subcutaneous injection of their allocated treatment at day 0 and day 21, followed by exposure to feeding by an uninfected Aedes aegypti mosquito at day 42 to assess subsequent risk to mosquito bites in a controlled setting. The primary endpoints were safety and immunogenicity at day 42 after the first immunisation. Participants who were given at least one dose of assigned treatment were assessed for the primary endpoints and analysis was by intention to treat. The trial was registered with ClinicalTrials.gov, NCT03055000, and is closed for accrual.FindingsBetween Feb 15 and Sept 10, 2017, we enrolled and randomly assigned 49 healthy adult participants to the adjuvanted vaccine (n=17), vaccine alone (n=16), or placebo group (n=16). Five participants did not complete the two-injection regimen with mosquito feeding at day 42, but were included in the safety analyses. No systemic safety concerns were identified; however, one participant in the adjuvanted vaccine group developed a grade 3 erythematous rash at the injection site. Pain, swelling, erythema, and itching were the most commonly reported local symptoms and were significantly increased in the adjuvanted vaccine group compared with both other treatment groups (nine [53%] of 17 participants in the adjuvanted vaccine group, two [13%] of 16 in the vaccine only group, and one [6%] of 16 in the placebo group; p=0·004). By day 42, participants who were given the adjuvanted vaccine had a significant increase in vaccine-specific total IgG antibodies compared with at baseline than did participants who were give vaccine only (absolute difference of log10-fold change of 0·64 [95% CI 0·39 to 0·89]; p=0·0002) and who were given placebo (0·62 [0·34 to 0·91]; p=0·0001). We saw a significant increase in IFN-γ production by peripheral blood mononuclear cells at day 42 in the adjuvanted vaccine group compared with in the placebo group (absolute difference of log10 ratio of vaccine peptide-stimulated vs negative control 0·17 [95% CI 0·061 to 0·27]; p=0·009) but we saw no difference between the IFN-γ production in the vaccine only group compared with the placebo group (0·022 [-0·072 to 0·116]; p=0·63).InterpretationAGS-v was well tolerated, and, when adjuvanted, immunogenic. These findings suggest that vector-targeted vaccine administration in humans is safe and could be a viable option for the increasing burden of vector-borne disease.FundingOffice of the Director and the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, and National Institutes of Health.

Project description:BackgroundVLA1553 is a live-attenuated vaccine candidate for active immunisation and prevention of disease caused by chikungunya virus. We report safety and immunogenicity data up to day 180 after vaccination with VLA1553.MethodsThis double-blind, multicentre, randomised, phase 3 trial was done in 43 professional vaccine trial sites in the USA. Eligible participants were healthy volunteers aged 18 years and older. Patients were excluded if they had history of chikungunya virus infection or immune-mediated or chronic arthritis or arthralgia, known or suspected defect of the immune system, any inactivated vaccine received within 2 weeks before vaccination with VLA1553, or any live vaccine received within 4 weeks before vaccination with VLA1553. Participants were randomised (3:1) to receive VLA1553 or placebo. The primary endpoint was the proportion of baseline negative participants with a seroprotective chikungunya virus antibody level defined as 50% plaque reduction in a micro plaque reduction neutralisation test (μPRNT) with a μPRNT50 titre of at least 150, 28 days after vaccination. The safety analysis included all individuals who received vaccination. Immunogenicity analyses were done in a subset of participants at 12 pre-selected study sites. These participants were required to have no major protocol deviations to be included in the per-protocol population for immunogenicity analyses. This trial is registered at ClinicalTrials.gov, NCT04546724.FindingsBetween Sept 17, 2020 and April 10, 2021, 6100 people were screened for eligibility. 1972 people were excluded and 4128 participants were enrolled and randomised (3093 to VLA1553 and 1035 to placebo). 358 participants in the VLA1553 group and 133 participants in the placebo group discontinued before trial end. The per-protocol population for immunogenicity analysis comprised 362 participants (266 in the VLA1553 group and 96 in the placebo group). After a single vaccination, VLA1553 induced seroprotective chikungunya virus neutralising antibody levels in 263 (98·9%) of 266 participants in the VLA1553 group (95% CI 96·7-99·8; p<0·0001) 28 days post-vaccination, independent of age. VLA1553 was generally safe with an adverse event profile similar to other licensed vaccines and equally well tolerated in younger and older adults. Serious adverse events were reported in 46 (1·5%) of 3082 participants exposed to VLA1553 and eight (0·8%) of 1033 participants in the placebo arm. Only two serious adverse events were considered related to VLA1553 treatment (one mild myalgia and one syndrome of inappropriate antidiuretic hormone secretion). Both participants recovered fully.InterpretationThe strong immune response and the generation of seroprotective titres in almost all vaccinated participants suggests that VLA1553 is an excellent candidate for the prevention of disease caused by chikungunya virus.FundingValneva, Coalition for Epidemic Preparedness Innovation, and EU Horizon 2020.

Project description:IntroductionReCOV is a recombinant protein vaccine that aims to induce cross-neutralization against SARS-CoV-2 variants. The phase I and phase II studies were conducted in New Zealand and the Philippines, respectively, for ReCOV primary series.MethodsBoth studies were randomized, double-blind, placebo-controlled designed among COVID-19 vaccine-naïve healthy adults who received two doses of study vaccination with a 21-day interval. In phase I, 100 younger (15-55 years) and older (56-80 years) subjects were 4:1 randomized to receive ReCOV (20 µg or 40 µg) or placebo. In the phase II study, 347 subjects (≥ 18 years) were 2:1 randomized to receive 40 µg ReCOV or placebo. Subjects that received ReCOV were followed up for 6 months after the second dosing. The safety outcomes included solicited and unsolicited AEs, SAEs, and AESIs. The immunogenicity outcomes were live-virus neutralizing antibody (NAb) against prototype, while pseudovirus NAbs against several SARS-CoV-2 variants were included in phase II as well.ResultsNo related SAE, AESI, or AE leading to early discontinuation were reported. The AE incidences were higher in ReCOV groups than placebo group in phase I while they were similar between study groups in phase II. The majority of solicited AEs were mild or moderate with median duration of 1.0-4.0 days. The common (≥ 10%) solicited AEs in phase I were injection site reactions, headache, pyrexia, fatigue, and myalgia, and common reported (≥ 5%) ones in phase II included injection site pain, headache, and pyrexia. Robust neutralizing activities against the prototype were observed in ReCOV groups, peaking at 14 days post the second dosing: in phase I, the GMTs for 20 μg and 40 μg ReCOV groups were 1643.2 IU/mL (95% CI 1188.5, 2271.9) and 1289.2 IU/mL (95% CI 868.3, 1914.1) in younger adults, and 1122.3 IU/mL (95% CI 722.6, 1743.1) and 680.3 IU/mL (95% CI 440.2, 1051.4) in older adults, respectively, while in the ReCOV group of phase II, the GMTs for subjects with seronegative and seropositive status at baseline were 3741.0 IU/mL (95% CI 3113.4, 4495.0) and 6138.3 IU/mL (95% CI 5255.1, 7169.9), respectively. In phase II, substantial levels of pseudovirus NAbs against SARS-CoV-2 variants were demonstrated; the peak GMTs for prototype, Omicron BA.2, and BA.4/5 were 8857, 4441, and 2644, and 15,667.3, 7334.3, and 4478.8 among seronegative and seropositive subjects, respectively. The neutralization persisted till 6 months post the second dosing, with only 2.5- to 5.2-fold declines for Omicron variants.ConclusionsTwo doses of 20 µg and 40 µg ReCOV are safe and immunogenic against SARS-CoV-2 prototype. The cross-neutralizing activities against Omicron variants support ReCOV advance to late-stage clinical trials.Trial registrationPhase I study, clinicaltrials.gov NCT04818801; phase II study, clinicaltrials.gov NCT05084989.

Dataset Information

Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial.

Publications

Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets