Stable live attenuated recombinant dengue vaccine
Inventors
Jain, Rajesh • Singh, Sukhjeet • Jambu, Lavit
Assignees
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Publication Number
US-11123420-B2
Publication Date
2021-09-21
Expiration Date
Abstract
The present invention relates to field of live attenuated recombinant tetravalent dengue vaccines and methods of producing stable compositions. Present invention specifically relates to a stable composition and methods of using such a stable composition comprising live attenuated recombinant dengue virus, stabilizer, bulking agent and optionally buffering agents, wherein the live attenuated dengue virus is generated from Δ 30 and or Δ 31 deleted or mutated dengue strains. More specifically, the present invention relates to stabilizers for freeze-dried live attenuated immunogenic and/or vaccine compositions that may comprise, inter alia, dengue virus(es). The invention further relates to stabilized, freeze-dried live attenuated immunogenic and/or vaccine compositions of, dengue virus(es), which may contain these stabilizers. Other aspects of the invention are described in or are evident from the following disclosure, and are within the ambit of the invention.
Core Innovation
The invention provides a vaccine composition comprising a tetravalent live attenuated recombinant dengue virus candidate including (rDEN1Δ30), (rDEN2/4Δ30), (rDEN3Δ30/31), and (rDEN4Δ30). The recombinant dengue virus candidate is combined as a vaccine composition with human serum albumin and/or gelatin or hydrolyzed gelatin and/or collagen or hydrolyzed collagen.
The problem addressed is deterioration of dengue virus titre during lyophilization and during storage after lyophilization. The invention is focused on reducing titre loss associated with freeze-drying and subsequent storage under refrigerated and elevated temperature conditions.
The core approach is the formulation of the tetravalent live attenuated recombinant dengue virus candidate with protein stabilizers, namely human serum albumin and/or gelatin (including hydrolyzed gelatin) and/or collagen (including hydrolyzed collagen). Optional additional excipients include sugar bulking agents and buffering agents to set a final pH in the range of about 7.0±0.5, together with lyophilization-stabilized compositions that show reduced titre loss.
Claims Coverage
The document includes at least one independent claim. The claims cover a tetravalent live attenuated recombinant dengue vaccine composition defined by specific recombinant dengue virus candidates together with defined protein stabilizers, with dependent claims further specifying quantitative dosing and formulation parameters.
Tetravalent live attenuated recombinant dengue virus candidate with specified deletions
A vaccine composition comprising a tetravalent live attenuated recombinant dengue virus candidate including (rDEN1Δ30), (rDEN2/4Δ30), (rDEN3Δ30/31) and (rDEN4Δ30).
Protein stabilizers selected from human serum albumin and gelatins/collagens (including hydrolyzed forms)
Human serum albumin and/or gelatin or hydrolyzed gelatin and/or collagen or hydrolyzed collagen.
Minimum dengue virus dose per administration volume
Dengue viruses present at a dose of at least 3.0 log10 PFU per 0.5 ml.
Quantified amounts of albumin and/or gelatin and collagen stabilizers
Human serum albumin and/or gelatin or hydrolyzed gelatin at 1–30 mg per 0.5 ml and/or collagen or hydrolyzed collagen at 1–30 mg per 0.5 ml.
Final pH range for the vaccine composition
A final pH of about 6 to 7.
Temperature-sensitive phenotype in specified cell systems
Dengue strains having a temperature-sensitive phenotype in Vero cells or the human liver cell line HuH-7.
Overall, claim coverage centers on a tetravalent live attenuated recombinant dengue virus vaccine composition with specific recombinant dengue constructs and the use of protein stabilizers. Dependent claims further constrain quantitative dose levels, stabilizer amounts, final pH, and a temperature-sensitive phenotype in specified cell lines.
Stated Advantages
Reduced titre loss during lyophilization and during storage under refrigerated and elevated temperature conditions.
Documented Applications
A freeze-dried (lyophilized) tetravalent live attenuated recombinant dengue vaccine composition suitable for storage and evaluation of stability after lyophilization under refrigerated and elevated temperature conditions.
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