Lignin nanoparticles as a novel carrier for efficacious delivery of toll like receptor 7/8 agonist: Physicochemical and in-vitro evaluation

Background BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6 μg) formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 μg and 6 μg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28. Methods We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12–65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 μg with Algel-IMDG or 6 μg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT 50 ) and the microneutralisation test (MNT 50 ). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov , NCT04471519. Findings Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 μg with Algel-IMDG group (n=190) or 6 μg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT 50 ) at day 56 were significantly higher in the 6 μg with Algel-IMDG group (197·0 [95% CI 155·6–249·4]) than the 3 μg with Algel-IMDG group (100·9 [74·1–137·4]; p=0·0041). Seroconversion based on PRNT 50 at day 56 was reported in 171 (92·9% [95% CI 88·2–96·2] of 184 participants in the 3 μg with Algel-IMDG group and 174 (98·3% [95·1–99·6]) of 177 participants in the 6 μg with Algel-IMDG group. GMTs (MNT 50 ) at day 56 were 92·5 (95% CI 77·7–110·2) in the 3 μg with Algel-IMDG group and 160·1 (135·8–188·8) in the 6 μg with Algel-IMDG group. Seroconversion based on MNT 50 at day 56 was reported in 162 (88·0% [95% CI 82·4–92·3]) of 184 participants in the 3 μg with Algel-IMDG group and 171 (96·6% [92·8–98·8]) of 177 participants in the 6 μg with Algel-IMDG group. The 3 μg with Algel-IMDG and 6 μg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 μg with Algel-IMDG group (38 [20·0%; 95% CI 14·7–26·5] of 190) and the 6 μg with Algel-IMDG group (40 [21·1%; 15·5–27·5] of 190) was observed on days 0–7 and days 28–35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT 50 ) were 39·9 (95% CI 32·0–49·9) in the 3μg with Algel-IMDG group, 69·5 (53·7–89·9) in the 6 μg with Algel-IMDG group, 53·3 (40·1–71·0) in the 6 μg with Algel group, and 20·7 (14·5–29·5) in the Algel alone group. Interpretation In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 μg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial. Funding Bharat Biotech International. Translation For the Hindi translation of the abstract see Supplementary Materials section.

Multi-scale ordering of materials is central for the application of molecular systems in macroscopic devices. Self-assembly based on selective control of non-covalent interactions provides a powerful tool for the creation of structured systems at a molecular level, and application of this methodology to macromolecular systems provides a means for extending such structures to macroscopic length scale. Monolayer-functionalized nanoparticles can be made with a wide variety of metallic and non-metallic cores, providing a versatile building block for such approaches. Here we present a polymer-mediated 'bricks and mortar' strategy for the ordering of nanoparticles into structured assemblies. This methodology allows monolayer-protected gold particles to self-assemble into structured aggregates while thermally controlling their size and morphology. Using 2-nm gold particles as building blocks, we show that spherical aggregates of size 97 +/- 17 nm can be produced at 23 degrees C, and that 0.5-1 microm spherical assemblies with (5-40) x 10(5) individual subunits form at -20 degrees C. Intriguingly, extended networks of approximately 50-nm subunits are formed at 10 degrees C, illustrating the potential of our approach for the formation of diverse structural motifs such as wires and rods. These findings demonstrate that the assembly process provides control over the resulting aggregates, while the modularity of the 'bricks and mortar' approach allows combinatorial control over the constituents, providing a versatile route to new materials systems.

Previous findings from our group based on Monte Carlo simulations indicated that Fickian drug release from Euclidian or fractal matrices can be described with the Weibull function. In this study, the entire drug release kinetics of various published data and experimental data from commercial or prepared controlled release formulations of diltiazem and diclofenac are analyzed using the Weibull function. The exponent of time b of the Weibull function is linearly related to the exponent n of the power law derived from the analysis of the first 60% of the release curves. The value of the exponent b is an indicator of the mechanism of transport of a drug through the polymer matrix. Estimates for b< or =0.75 indicate Fickian diffusion in either fractal or Euclidian spaces while a combined mechanism (Fickian diffusion and Case II transport) is associated with b values in the range 0.75