Gene optimized hantaan virus M segment DNA vaccine for hemorrhagic fever with renal syndrome
Inventors
Assignees
United States Department of the Army
Publication Number
US-9968669-B2
Publication Date
2018-05-15
Expiration Date
2033-03-28
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Abstract
A synthetic, codon-optimized Hantaan virus (HTNV) full-length M gene open reading frame that consists of a unique nucleotide sequence encoding HTNV proteins. This synthetic gene was cloned into a plasmid to form the first optimized HTNV full-length M gene that elicits neutralizing antibodies in animals when delivered in combination with a similarly optimized Puumala virus (PUUV) DNA vaccine. The invention obviates the need for an extraneous gene sequence that was previously required for expression of the non-optimized HTNV gene. The synthetic gene is engineered into a molecular vaccine system to prevent hemorrhagic fever with renal syndrome (HFRS) caused by infection with HTNV, SEOV, or DOBV. Alternatively, it can be combined with the optimized PUUV DNA vaccine to protect against HFRS caused by any hantavirus.
Core Innovation
The invention is a synthetic, codon-optimized Hantaan virus (HTNV) full-length M gene open reading frame (ORF) DNA vaccine immunogen that encodes HTNV proteins. This synthetic gene was cloned into a plasmid creating an optimized HTNV full-length M gene vaccine that elicits neutralizing antibodies in animals, even when delivered in combination with a similarly optimized Puumala virus (PUUV) DNA vaccine. The synthetic gene eliminates the need for an extraneous gene sequence previously required for expression of non-optimized HTNV genes and is engineered as a molecular vaccine system designed to prevent hemorrhagic fever with renal syndrome (HFRS) caused by infections with HTNV, Seoul virus (SEOV), Dobrava virus (DOBV), or PUUV.
The problem being solved is the interference observed in bivalent hantavirus vaccines where prior non-optimized HTNV DNA vaccines, when mixed with PUUV DNA vaccines, resulted in an immune response predominantly against PUUV but not HTNV, preventing the creation of a comprehensive vaccine for HFRS covering multiple hantaviruses. Existing vaccines have not fully addressed this issue of immune interference within combination vaccines, and prior HTNV vaccines required extraneous nucleotides for expression, complicating vaccine development.
The inventive solution involves optimizing the HTNV M segment DNA vaccine by modifying its gene to maximize mammalian codon usage, increasing guanine-cytosine (GC) content to improve mRNA stability, and removing negative cis-acting motifs that compromise expression. This optimized HTNV vaccine overcomes the interference problem, allowing it to be combined with an optimized PUUV DNA vaccine without reduction in immunogenicity or protective efficacy. The vaccine can be safely delivered by various methods including intramuscular or intradermal electroporation and is manufactured using current Good Manufacturing Practice (cGMP) techniques to ensure quality and safety.
Claims Coverage
The patent contains three independent claims focused on the bivalent hantavirus vaccine that protects against hemorrhagic fever with renal syndrome (HFRS).
A bivalent vaccine composition for HTNV and PUUV
The vaccine comprises a synthetic codon-optimized HTNV full-length M gene open reading frame segment according to SEQ ID NO. 1 combined with a Puumala virus (PUUV) DNA vaccine specifically protecting against HFRS caused by HTNV infection.
Delivery methods for the vaccine
The immunogenic amounts of the HTNV synthetic codon-optimized open reading frame segment and the PUUV DNA vaccine are administered using intramuscular or intradermal delivery devices.
Dose and delivery schedule optimization for PUUV DNA
The PUUV DNA component of the bivalent vaccine is optimized in terms of dose and delivery schedule to enhance immunogenic efficacy.
The claims cover a bivalent DNA vaccine combining optimized HTNV and PUUV genes formulated for protection against HFRS, with specific delivery methods and dose optimizations to ensure immunogenicity and effective protection.
Stated Advantages
The vaccine overcomes immune interference seen in previous combination vaccines allowing co-administration of HTNV and PUUV DNA vaccines without reduction in immune responses to either virus.
The synthetic, optimized HTNV DNA vaccine does not require extraneous nucleotide sequences for expression, improving the molecular construct's efficiency and simplifying vaccine formulation.
The vaccine provides a broadly protective, safe, economical, and flexible platform that covers multiple hantaviruses causing HFRS including HTNV, SEOV, DOBV, and PUUV.
The use of electroporation delivery methods enhances immune responses, allowing reduced DNA dose and accelerated, strong neutralizing antibody responses.
The vaccine is suitable for large scale production using cGMP manufacturing, has long term stability, and is applicable for mass vaccination efforts.
Documented Applications
Prevention and protection of humans from hemorrhagic fever with renal syndrome (HFRS) caused by hantavirus infections including Hantaan virus (HTNV), Seoul virus (SEOV), Dobrava virus (DOBV), and Puumala virus (PUUV).
Use as a bivalent DNA vaccine for simultaneous immunization against HTNV and PUUV hantaviruses.
Delivery by intramuscular or intradermal electroporation for efficient DNA uptake and immune response induction.
Potential vaccine platform for mass immunization against hantavirus-caused HFRS in geographic regions where multiple hantaviruses co-circulate, such as Asia and Europe.
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