HIV RNA vaccines
Inventors
Lusso, Paolo • Zhang, Peng • Narayanan, Elisabeth • Elbashir, Sayda Mahgoub
Assignees
ModernaTx Inc • US Department of Health and Human Services
Publication Number
US-12070495-B2
Publication Date
2024-08-27
Expiration Date
2040-03-13
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Abstract
Provided herein are methods and compositions for inducing in a subject abroad neutralizing antibody response to human immunodeficiency virus (HIV) infection.
Core Innovation
The invention provides mRNA-based immunogenic compositions and methods that induce a broadly neutralizing antibody response against multiple strains of human immunodeficiency virus (HIV). The compositions include mRNA encoding HIV envelope (Env) proteins and lentivirus group-specific antigen (Gag) proteins formulated in lipid nanoparticles. This co-formulation enables in vivo production of extracellular virus-like particles (VLPs), mimicking natural infection and facilitating persistent expression of endogenous proteins similar to those found in nature.
The immunization methods involve administering an initial dose and multiple autologous boosts comprising mRNA encoding Env and Gag, followed by multiple heterologous booster doses comprising mRNA encoding Env and Gag from different HIV clades. This intensive immunization mimics continuous, high-level antigenic exposure, focusing the antibody response on broadly neutralizing epitopes common across multiple HIV strains while excluding strain-specific epitopes. Additional mRNA encoding viral protease and furin enzymes may be included to enhance proteolytic processing and VLP formation, yielding properly formed particles that present native conformations of Env proteins.
Claims Coverage
The patent contains multiple independent claims focusing on methods of inducing immune responses to HIV using mRNA-based vaccines and on immunogenic compositions thereof. Main inventive features include vaccine formulation, dosing regimens, and molecular design of antigens and delivery systems.
Method of inducing broadly neutralizing antibody response using sequential autologous and heterologous mRNA doses formulated in lipid nanoparticles
A method comprising administering during a first period an initial and multiple autologous booster doses of a first composition with mRNA encoding HIV Env and lentivirus Gag protein in lipid nanoparticles, then during a second period multiple heterologous booster doses of a second composition with mRNA encoding HIV Env and Gag also in lipid nanoparticles, resulting in broadly neutralizing antibodies against multiple HIV strains.
Inclusion of mRNA encoding viral protease and furin for enhanced processing and VLP production
The first and/or second compositions may further comprise mRNA encoding HIV protease and/or furin to enable efficient proteolytic processing of Gag and Env proteins, thus promoting the production and release of properly formed virus-like particles.
Use of HIV Env proteins from different Group M clades with specific mutations and membrane-bound forms
The HIV Env proteins encoded may be from differing Group M Clades A-K and can comprise SOSIP.664 mutations or exist as membrane-bound proteins such as gp150 or gp160, possibly with cytosolic truncations, disulfide bridges, and modifications to glycans and epitopes to engage unmutated common ancestor antibodies.
Immunogenic compositions comprising lipid nanoparticles with specific lipid components and mRNA ratios
Compositions including lipid nanoparticles containing an ionizable cationic lipid, non-cationic lipid, sterol, and PEG-modified lipid formulated with mRNA encoding membrane-bound HIV Env and HIV Gag proteins, with controlled ratios of mRNA Env to Gag designed to optimize immune response.
The claims cover methods of sequential immunization with mRNA vaccines encoding HIV Env and Gag from multiple clades, formulations including protease and furin mRNA, and designed lipid nanoparticle vaccine compositions that induce broad neutralizing antibodies against HIV.
Stated Advantages
Persistent in vivo expression of native-like endogenous proteins enhances immune response durability.
Co-formulation of mRNA encoding Env and Gag proteins enables formation of virus-like particles that mimic natural infection.
Sequential autologous and heterologous boosting focuses antibody responses on broadly neutralizing epitopes, avoiding strain-specific responses.
Inclusion of mRNA encoding protease and furin improves processing and quality of virus-like particles.
Immunization protocols result in cross-clade heterologous broadly neutralizing antibodies and protection or delayed infection in a preclinical model.
Documented Applications
Inducing a broad and potent neutralizing antibody response to multiple strains of HIV, including tier-2 heterologous isolates, in human subjects.
Preventive vaccination against HIV infection by eliciting sterilizing immunity or durable protection.
Use of lipid nanoparticle-formulated mRNA vaccines encoding HIV Env and Gag proteins to generate virus-like particles in vivo.
Vaccination regimens employing multiple doses with defined intervals for effective boosting and induction of broad immunity.
Potential application in treatment or prevention of HIV-1 infections across diverse global viral clades.
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