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  HIV-1 TAT VACCINES: SECOND GENERATION
Tat + Microparticles (code T1-beta)
T1-beta vaccine formulation T1-beta is a vaccine formulation in which biologically active Tat molecules are adsorbed on innovative polymeric biocompatible core-shell microparticles which reversibly bind Tat on their surface without the need of surfactants and/or detergents.
T1-beta has been specifically designed for use in developing countries, where cold storage is a problem. In pre-clinical studies, this formulation has been proven to be stable and efficacious after room temperature storage .

Rationale

Soluble antigens (peptides and proteins) delivered by the parenteral (typically by injection) and mucosal routes typically have low immunogenicity due to their poor intracellular uptake and stability. However, their administration together with proper delivery systems, such as physical particles, greatly enhances antigenic stability and immunogenicity, thus reducing the antigen dose required.

Among delivery systems, biodegradable microparticles (e.g., poly-lactide- co-glycolide, known as PLGA) have been used to deliver vaccines. The drawback of these systems is that the antigens are damaged during encapsulation, leading to a significant reduction in vaccine activity.

Another approach is based on adsorbing charged molecules to the surface of the particles where functional groups interact with DNA or proteins/peptides. The drawback of these systems is that the use of chlorinated solvents, surfactants and/or detergents during particle preparation interferes with the reproducibility of particle size and size distribution and, in turn, this leads to variability in the formulations.
To overcome these problems, a novel biopharmaceuticals delivery platform has been developed in collaboration with scientists at the University of Piemonte Orientale (Laus M., Sparnacci K.) and the University of Padua (Caputo A.) and Centro Nazionale Ricerche (Tondelli L.). It is based on innovative polymeric particles, nanoparticles (50-1000 nm) and microparticles (1-5 µm), which are capable to reversibly bind biologically active macromolecules on their surface. Process development for the nanoparticle and microparticles is being carried out by a spin-off of the University of Piemonte Orientale.
This technology is innovative because the antigen is absorbed on the shell of the particles ensuring the reversible relase of the antigen, while protecting it from depredation by edongenous enzymes.
The procedure for synthesis of particles is suitable for simple and inexpensive scaling-up processes according to EMEA/FDA regulations. This procedure generates reproducible, homogeneously-sized and endotoxin-free particles. Manufactured particles are stable at room temperature in solution or in lyophilized form for at least 5 years. The particles can be sterilized by simple autoclavation without affecting their morphology or surface binding and release properties.
 
These particles can bind a large amount of antigen. They particles effectively bind proteins with different surface isoelectric points, including HIV-1 Tat. Preliminary studies indicate that Tat bound to particles is stable at room temperature for several weeks both in solution and in powder form.
 
Pre-clinical studies in mice indicate that Tat bound to particles is not toxic, even after multiple administrations of high doses (up to 1 mg) of the antigen.

These studies also show an increase in breadth of both humoral and cellular immunity against Tat. Similar results were obtained in monkeys using HIV-1 Tat protein formulated with a selected microparticle. Together, the data indicate that these nano- and micro-particles have important immunomodulatory and adjuvant functions. In addition, they can be used as vectors for delivering HIV proteins/DNA, including Tat, in candidate vaccines.
 
 

 

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