Zika viral antigen constructs
Inventors
DOWD, Kimberly • Graham, Barney S. • Ko, Sung-Youl • Kong, Wing-pui • Mascola, John • Pierson, Theodore • SHARMA, Mayuri • Yu, Dong
Assignees
GlaxoSmithKline Biologicals SA • US Department of Health and Human Services
Publication Number
US-11780885-B2
Publication Date
2023-10-10
Expiration Date
2037-11-15
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Compounds useful as components of immunogenic compositions for the induction of an immunogenic response in a subject against viral infection, methods for their use in treatment, and processes for their manufacture are provided herein. The compounds comprise a nucleic acid construct comprising a sequence which encodes a Zika virus antigen.
Core Innovation
The invention provides nucleic acid constructs encoding Zika virus antigens, specifically nucleic acid-based vaccine constructs encoding a polypeptide comprising a full-length Zika virus pre-M-E antigen (prME) or an immunogenic fragment thereof. These constructs can be delivered as vectors or self-replicating RNA molecules, such as self-amplifying mRNA (SAM), and formulated in compositions that include cationic oil-in-water emulsions to induce an immune response against Zika virus infection. Methods for use in treatment and manufacturing processes for these constructs and compositions are also provided.
The problem addressed arises from the urgent need for effective immunogenic components or vaccines against Zika virus due to repeated outbreaks causing symptoms ranging from mild illness to severe fetal malformations such as microcephaly and neurological disorders including Guillain-Barré syndrome. Existing approaches like DNA vaccines, alphavirus RNA vectors, and mRNA vaccines have shown immunogenicity but there is a continuing necessity for improved vaccine constructs capable of inducing robust and protective immune responses.
Claims Coverage
The patent claims include one primary independent claim directed to a self-replicating RNA molecule encoding a Zika virus prME antigen with a JEV signal sequence, and independent claims directed to a DNA molecule encoding such RNA molecule, compositions comprising the RNA molecule, methods of inducing immune responses, and processes for producing RNA-based vaccines. Main inventive features from these independent claims encompass the RNA molecule structure, delivery formulations, methods of use, and manufacturing processes.
Self-replicating RNA molecule encoding a Zika prME antigen with JEV signal sequence
A self-replicating RNA molecule encoding (i) a polypeptide comprising a Zika virus prME antigen comprising amino acids 21-692 of SEQ ID NO:2 or a variant with at least 90% identity or an immunogenic fragment thereof and (ii) a Japanese Encephalitis Virus (JEV) signal sequence comprising SEQ ID NO:5 or a sequence with at least 90% sequence identity thereto.
Nucleic acid sequences encoding the self-replicating RNA molecule
Nucleic acid sequences comprising (a) sequences encoding polypeptides with amino acid sequences SEQ ID NO:19 or SEQ ID NO:24; (b) RNA sequences of SEQ ID NO:39 or SEQ ID NO:40; and (c) RNA sequences of SEQ ID NO:36 or SEQ ID NO:37.
DNA molecule encoding the self-replicating RNA molecule
A DNA molecule encoding the self-replicating RNA molecule as defined in the first inventive feature.
Compositions comprising the self-replicating RNA molecule
Compositions comprising an immunologically effective amount of the self-replicating RNA molecule, including formulations with non-viral delivery materials such as submicron cationic oil-in-water emulsions, liposomes, or biodegradable polymeric microparticle delivery systems.
Use of non-viral delivery systems with RNA compositions
Compositions where the non-viral delivery system includes components such as an oil core, cationic lipid, and surfactant, specifically formulations like cationic nano-emulsions (CNE).
Methods for inducing immune response against Zika virus infection
Methods comprising administering to a subject an immunologically effective amount of the self-replicating RNA molecule or the composition formulated with a non-viral delivery system to induce an immune response against Zika virus infection, particularly in humans.
Processes for producing RNA-based vaccines
Processes comprising in vitro transcription of DNA encoding the self-replicating RNA molecule to produce the RNA, followed optionally by formulation with a non-viral delivery system (submicron cationic oil-in-water emulsion, liposome, or biodegradable microparticle) and combination with an adjuvant including immunostimulants.
Composition inducing sterilizing immunity and specific neutralizing titers in Rhesus macaques
Compositions that induce sterilizing immunity and produce specific neutralizing antibody responses characterized by a 4-fold change in neutralizing titers when inoculated into Rhesus macaques.
The claims cover a self-replicating RNA vaccine encoding a Zika prME antigen linked with a JEV signal sequence, corresponding encoding DNA molecules, vaccine compositions with non-viral delivery systems, methods of inducing protective immune responses, and manufacturing processes, highlighting the vaccine's immunogenic efficacy and potential sterilizing immunity in primate models.
Stated Advantages
The vaccine achieves significant neutralizing antibody responses after a single immunization, with further enhancement after a booster dose.
The SAM construct #5283 uses lower doses to elicit immunity comparable to or better than higher dose DNA vaccines, indicating dose-sparing advantages.
The RNA vaccine induces sterilizing immunity in non-human primates, preventing detectable viremia post Zika virus challenge.
Formulation with a cationic oil-in-water emulsion enhances delivery efficiency and immune response without the risk of genomic integration or anti-vector immunity issues.
Documented Applications
Prevention of Zika virus infection in human subjects through nucleic acid-based vaccination using self-replicating RNA constructs encoding Zika virus prME antigens.
Therapeutic treatment of Zika virus infection by inducing humoral and cellular immune responses in subjects at risk or infected with Zika virus.
Reducing or preventing vertical transmission of Zika virus infection to fetuses across the placental barrier by vaccination of women.
Interested in licensing this patent?