Altering the immundominance hierarchy using a DNA vaccine expressing conserved regions
Inventors
Pavlakis, George • Felber, Barbara • Mullins, James
Assignees
Washngton Through Its Center For Commercialization, University of • University of Washington Center for Commercialization • US Department of Health and Human Services
Publication Number
US-10426830-B2
Publication Date
2019-10-01
Expiration Date
2033-03-04
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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, such as HIV. This approach involves a DNA vaccine expressing conserved elements (CE) of viral proteins, specifically HIV-1 p24gag, arranged collinearly and connected by linkers to induce immune responses directed to nearly invariable proteome segments essential for viral function, while excluding variable and potentially immunodominant decoy epitopes.
The problem addressed is the challenge in HIV vaccine design due to the virus's high sequence diversity and the presence of immunodominant epitopes that may obstruct effective universal vaccine responses. Variable sequences within viral proteins mutate to escape immune responses and may contain immunodominant T cell epitopes acting as 'decoys', thus impeding the induction of protective immune responses against conserved regions associated with viral control.
The invention offers a vaccination strategy where nucleic acid constructs encoding conserved elements are administered, either sequentially or concurrently, with nucleic acid constructs encoding the full-length or substantially full-length protein from which the conserved elements are derived. This strategy broadens the immune response, overcoming diversity by generating cross-clade specific T cell and humoral immunity, and enhances responses to protective conserved regions of HIV.
Claims Coverage
The patent contains multiple independent claims focused on methods of inducing immune responses by administering nucleic acid constructs encoding conserved elements and full-length protein sequences.
Method of inducing immune response using sequential administration of nucleic acids encoding conserved elements and full-length protein
Administering a first nucleic acid encoding a polypeptide comprising at least six conserved elements from an HIV protein, joined by linkers and each less than 50 amino acids in length; administering a second nucleic acid encoding a variant polypeptide differing by 1-3 amino acids in corresponding conserved elements; followed by administration of a nucleic acid encoding the full-length or substantially full-length HIV protein at least two weeks later, with these sequences operably linked to a promoter in a plasmid.
Selection and variant design of conserved elements
The first and second conserved element polypeptides comprise specific conserved elements from HIV Gag (e.g., p24gag) with amino acid sequences set forth in SEQ ID NOS:1-7, 32, 33 for the first polypeptide and SEQ ID NOS:8-14, 40, 41 for the second, with variants having at least 80% amino acid identity to the originals.
Modes of administration and expression vectors
The conserved element nucleic acids encoding the polypeptides can be administered sequentially or concurrently, contained within the same or different vectors, and the nucleic acid constructs encoding the conserved element polypeptides and the full-length proteins can be administered intramuscularly by in vivo electroporation.
Together, the independent claims cover the method of inducing broad immune responses to HIV by administering nucleic acid constructs encoding conserved elements and their variants, followed by nucleic acid encoding full-length HIV proteins, emphasizing specific sequences, administration timing, and vector constructs.
Stated Advantages
The conserved element vaccine approach induces broader and more potent cellular and humoral immune responses than full-length protein vaccines alone.
It overcomes the problem of viral sequence diversity by focusing immune responses on conserved viral regions essential for viral function.
The method avoids immunodominant decoy epitopes that divert the immune response, thereby enhancing the quality and breadth of protective immunity.
Administration of conserved element vaccines prior to full-length protein vaccination enhances immune response magnitude, breadth, polyfunctionality, and cytotoxic potential.
Documented Applications
Development of universal or broad HIV vaccines capable of eliciting immune responses against most or all circulating HIV strains by targeting conserved proteome segments.
Use of DNA vaccines encoding conserved viral protein elements, either alone or in combination with full-length protein vaccines, to induce cellular and humoral immunity in mammalian hosts including humans and non-human primates.
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