Altering the immundominance hierarchy using a DNA vaccine expressing conserved regions
Inventors
Pavlakis, George • Felber, Barbara • Mullins, James
Assignees
University of Washington Center for Commercialization • US Department of Health and Human Services
Publication Number
US-11167025-B2
Publication Date
2021-11-09
Expiration Date
2034-03-04
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Abstract
The invention provides methods and compositions for eliciting broad immune responses. The methods employ nucleic acid vaccines that encodes highly conserved elements from a virus.
Core Innovation
The invention provides methods and compositions for eliciting broad immune responses by employing nucleic acid vaccines encoding highly conserved elements from a virus, particularly HIV-1 p24gag. It focuses on generating immune responses to nearly invariable proteome segments that are essential for virus function, while avoiding immunodominant or variable regions that can mutate to escape immune responses but retain viral function. This approach aims to induce immune responses able to prevent virus acquisition or propagation by excluding variable segments and potential immunodominant decoy epitopes.
The problem being solved is the difficulty in HIV vaccine design caused by the high variability of HIV-1 strains and the presence of immunodominant epitopes that may hinder effective universal vaccine responses. The vaccine approach addresses the challenge of viral diversity and immunodominance by focusing on conserved elements within viral proteins, such as Gag, and employing DNA vaccines expressing these conserved elements in conjunction with DNA encoding the full-length protein. This strategy overcomes diversity and broadens T cell and humoral immunity to HIV.
Claims Coverage
The patent claims encompass inventive features covering nucleic acid constructs encoding fusion polypeptides of conserved elements of HIV-1 p24gag, expression vectors encoding these polypeptides, and combinations thereof, including variant conserved elements and signal peptide fusions.
Nucleic acid encoding fusion polypeptides of conserved HIV p24gag elements
A nucleic acid encoding a fusion polypeptide comprising the conserved element amino acid sequences SEQ ID NOS: 1-7, separated by alanine-containing peptide linker sequences. This includes constructs encoding the specific amino acid sequence of SEQ ID NO:15 and potentially fused to a GM-CSF signal peptide.
Expression vectors encoding multiple conserved element fusion polypeptides
Expression vectors comprising nucleic acid sequences encoding first and second fusion polypeptides, the first polypeptide including conserved elements SEQ ID NOS: 1-7 and the second including conserved elements SEQ ID NOS: 8-14, separated by alanine-containing linkers. Variants include polypeptides with GM-CSF signal peptides and specific sequences such as SEQ ID NOS:16, 19, 21, or 29.
Nucleic acid constructs comprising multiple conserved element encoding sequences
Nucleic acid constructs comprising nucleic acids encoding fusion polypeptides of conserved elements sets (SEQ ID NOS:1-7 and SEQ ID NOS:8-14), optionally fused to signal peptides, wherein the nucleic acids may be DNA or RNA molecules, encoding full sequences such as SEQ ID NO:17.
The claims cover nucleic acid and expression vector constructs that encode fusion polypeptides of highly conserved HIV p24gag elements separated by alanine linkers, including variants with signal peptides, to elicit broad immune responses. The claims encompass nucleotide constructs encoding such polypeptides individually or in combination, including DNA and RNA forms.
Stated Advantages
Induction of broad and cross-clade reactive cellular and humoral immune responses to conserved viral elements.
Enhanced stability and presentation of conserved element antigens leading to improved immunogenicity compared to full-length proteins.
Ability to overcome immunodominance by variable epitopes that can function as decoys, focusing immune responses on conserved, functionally critical viral regions.
Generation of multifunctional CD4+ and CD8+ T cell responses with cytotoxic potential.
Priming with conserved element DNA vaccines followed by full-length protein boost enhances immune breadth and magnitude to conserved regions.
Documented Applications
Use as a DNA vaccine platform for inducing broad immune responses to conserved elements of HIV-1 p24gag proteins.
Administration of nucleic acid vaccines encoding conserved viral protein elements in mammals, including humans and non-human primates, for prophylactic or therapeutic purposes.
Use of fusion polypeptides comprising conserved elements with signal peptides or lysosomal targeting sequences to optimize antigen presentation and immune response.
Heterologous prime-boost vaccination strategies employing conserved element DNA vaccines followed by full-length protein DNA vaccines to achieve enhanced immune responses.
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