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Particle-Based Delivery of HIV Env Immunogens

Description:

 

Particle-Based Delivery of HIV Env Immunogens

Fast Track proposals will be accepted Number of anticipated awards: 3-4 Budget (total costs, per award): Phase I: up to $300,000/year for up to 2 years; Phase II: up to $1,000,000 per year up to 3 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Background

A major focus of HIV vaccine research has been the development of immunogens that elicit broadly neutralizing antibody responses targeting the envelope protein (Env). While the field has predominantly focused on immunogen design and soluble antigens, the targeted and controlled delivery of antigens has not received much attention and is a gap in the HIV field that needs to be addressed. Lipid- and polymer-based nanoparticle platforms have been shown to induce HIV-specific antibody and cellular immune responses in animal studies. HIV immunogens delivered via particle-based modalities may elicit better humoral and cellular immune responses. Specifically, multivalent/repetitive antigenic display on particle-based carriers may allow for higher avidity interactions and stimulate a diverse set of B cells. Consequently, such multivalent antigen display may mediate efficient engagement and activation of B cells, promoting stimulation of lower avidity cells from the germline antibody repertoire thereby enhancing affinity maturation resulting in superior antibody responses characterized by improved breadth, potency, and durability. Additionally, the ability of nanoparticles to target specific cells and release antigens in a controlled and sustained manner without the complications of viral vector toxicity and anti-vector immune responses makes nanoparticles a promising alternative to viral vectors. Altogether, for elicitation of potent, protective and durable immune responses, HIV immunogen design and particulate delivery of antigens should remain mutually inclusive and should converge for the development of HIV vaccine candidates capable of effectively inducing B/T-cell activation.

Project Goals

Tailored immunogens (such as Envs, monomers, native and/or native-like trimers, nucleic acids/RNA) combined with effective multivalent antigenic display on nanoparticles for delivery may provide a strategy to promote strong and long-lived neutralizing antibody responses against HIV and direct affinity maturation toward HIV neutralizing antibodies.

Phase I activities may include:

Engineering, fabricating nanoparticle platforms/systems and approaches (such as synthetic and/or self-assembling and/or covalent chemical attachment of an antigen to a nanoparticle) for delivering existing and/or novel HIV immunogens (such as Envs, monomers, native and/or native-like trimers, nucleic acids/RNA) that can augment HIV vaccine development by way of enhanced presentation, trafficking and targeting the antigen presentation pathway(s) for the induction of broad humoral and cellular immune responses

Evaluating particulate systems (such as synthetic and/or self-assembling and/or covalent chemical attachment of an antigen to a nanoparticle) that can facilitate co-delivery and/or co-formulation of HIV antigens (such as Envs, monomers, native and/or native-like trimers, nucleic acids/RNA) with licensed or novel adjuvants/TLR agonists

• Developing optimal parameters/conditions for incorporation of HIV antigen(s) in nanoparticulate formulation

• Assessing the effects of modulating particle size, shape, surface properties, composition and modulus/elastic properties of particulate delivery system components on immune responses

• Conducting pre-formulation/formulation studies on particulate antigen combinations to understand the interactions and compatibility of components (excipients, buffers, pH) and effect on antigen epitope integrity and its performance

• Developing assays and test methods to analyze and characterize the particulate-antigen formulations through in vitro (biophysical, physicochemical, binding assays) and/or in vivo testing (small animal studies)

• Developing assays to quantify encapsulation efficiency, immunogen release and expression

• Studying conditions for controlling particle size and size distribution, charge, composition, and aggregation

• Conducting short term stability studies (generate baseline data) on particulated HIV antigen formulations

• Evaluating particulated formulation technologies for fabrication and development of HIV vaccine development;

• Testing for batch-to-batch reproducibility and consistency of particulate formulations for manufacturing, impact of changes in scale, size of the batches

• Conducting studies to evaluate the sterile filterability of particulated formulations and assess the composition of components post sterilization

Developing an efficient process for early stage/pre-clinical studies, which could be adapted to scale-up studies which can subsequently lead to the production of clinical grade material in conformance with current good manufacturing practices (cGMP)

• Evaluating the immunogenicity and effectiveness of particle-based HIV protein and nucleic acid/RNA vaccine candidates using different co-delivery strategies such as, but not limited to, co-administration, colocalization, encapsulation, surface adsorption of antigens (vs. soluble antigen) in animal models

• Investigating the influence of heterologous prime-boost vaccination strategies on targeting germline B cell activation and maturation

• Investigating the effects of route of immunization, dose, dosage form and dose-sparing capacity of particulate formulations on the particle distribution and kinetics of immunogen immune response

Phase II activities may include:

Developing lead nanoparticle antigen formulation into an efficient, stable and reproducible process

• Generating a pilot lot and/or scale-up studies based on optimized conditions that can subsequently lead to the production of clinical grade material in conformance with current Good Manufacturing Practices (cGMP)

• Developing cGMP manufacturing processes for developing nanoparticle formulations

• Translating into in vitro studies to proof of concept studies in NHPs, as warranted

• Developing methods to evaluate compositional quality on critical components in nanoparticles. For example, but not limited to, quality, manufacturability and stability/degradation of lipids and related components

• Evaluating the performance, effectiveness, and toxicity of particulated HIV vaccine candidates vs. soluble antigen in small animal models

• Establishing quality assurance and quality control, methodology and development protocols for generation of HIV antigen-adjuvanted formulations for codelivery

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