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Clinical Trial
. 2020;16(2):388-399.
doi: 10.1080/21645515.2019.1651141. Epub 2019 Oct 4.

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

Fabien Zoulim  1 , Claire Fournier  2 , François Habersetzer  3 , Martin Sprinzl  4 , Stanislas Pol  5 , Carla S Coffin  6 , Vincent Leroy  7 , Mang Ma  8 , Heiner Wedemeyer  9 , Ansgar W Lohse  10 , Robert Thimme  11 , Karine Lugardon  12 , Perrine Martin  13 , Bérangère Bastien  12 , Benoit Sansas  12 , Nathalie Adda  12 , Celine Halluard  12 , Kaïdre Bendjama  12 , Maud Brandely  12 , Geneviève Inchauspé  13
Affiliations
Clinical Trial

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

Fabien Zoulim et al. Hum Vaccin Immunother. 2020.

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.

Keywords: Hepatitis B; chronicity; immuno-therapy; immunogenicity; safety; vaccine.

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Figures

Figure 1.
Figure 1.
(a) Schematic representation of study design and conduct. Duration (52–54 weeks), vaccine administration (1 or 3, syringes) and blood samplings (black arrows) are indicated together with the number of patient’s visits (13 and 15 for SD and MD cohorts, respectively). Week 12 (W12) represents time of interim analysis. (b) Consort flow diagram.
Figure 2.
Figure 2.
Longitudinal titration of serum HBsAg in SD and MD cohorts. Data are represented as changes from baseline. Each colored line represents an individual patient. Dots represent HBsAg delta from baseline measured for a given time point (from time of vaccine administration (0) till week 52/54 (last time point). The four groups of patients from SD (Figure 2(a)) and MD (Figure 2(b)) cohorts are indicated (Placebo and 109, 1010, 1011 vp – injected groups). For MD cohort, the two patients displaying 0.4 logs decrease are outlined.
Figure 3.
Figure 3.
Individual HBcrAg evolution over time in MD cohort. Only patients displaying a baseline HBcrAg level > LoQ are represented. Data are presented as changes from baseline. Each colored line represents an individual patient. Dots represent HBcrAg values measured for a given time point (from time of vaccine administration (0) till week 52/54 (last time point). The four groups of patients are indicated (Placebo and 109, 1010, 1011 vp – injected groups).
Figure 4.
Figure 4.
TG1050 induced – HBV-specific T-cell responses. Blood samples were taken at 4 time points (at baseline, week 2, week 4 and week 12 for SD cohort and at baseline, week 4, week 6 and week 12 for MD cohort) post-initial vaccine administration and ELISPOT assays performed using purified PBMCs as described in Materials and Methods. Data are reported as number of spots changes from baseline for 2 × 105 cells/ml. For each cohort, the four groups of patients are indicated (Placebo and 109, 1010, 1011 vp – injected groups). Stimulation with the various peptide pools covering whole polymerase (3 pools, Figure 4(a)), the Core (1 pool, Figure 4(b)) and Env (1 pool, Figure 4(c)) were added for each antigen; change from baseline was normalized by the number of peptide pools tested for each patient (i.e., for some patients, only 1 or 2 Pol peptide pools were tested). Dotted line indicates the threshold of positivity (100 spots) as defined in Materials and Methods.
Figure 5.
Figure 5.
Number of antigens targeted following TG1050 administration. Percentage of patients displaying Pol and/or Core and/or Env- ELISPOT-specific responses following TG1050 administration is shown (at least one, two or three antigens targeted) over the course of analysis. Data are shown for SD and MD cohorts and for all four groups tested (Placebo and 109, 1010, 1011 vp – injected groups).
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