Recombinant MVA viruses expressing clade A/G, clade B, and clade C modified HIV env, gag and pol genes
Inventors
Moss, Bernard • Wyatt, Linda • Robinson, Harriet L.
Assignees
Emory University • National Institutes of Health NIH
Publication Number
US-9453239-B2
Publication Date
2016-09-27
Expiration Date
2025-08-29
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Abstract
The invention provides modified vaccinia Ankara (MVA), a replication-deficient strain of vaccinia virus, expressing human immunodeficiency virus (HIV) env, gag, and pol genes.
Core Innovation
The invention provides modified vaccinia Ankara (MVA), a replication-deficient strain of vaccinia virus, expressing human immunodeficiency virus (HIV) env, gag, and pol genes. The HIV env gene is modified to encode an HIV Env protein composed of gp120 and the membrane-spanning and ectodomain of gp41 but lacking part or all of the cytoplasmic domain of gp41. The invention includes recombinant MVA viruses containing HIV env, gag, and pol genes or modified genes thereof from clade A/G, clade B, or clade C, with specific sequences (SEQ ID NOs) provided and sequences having high identity thereto, and methods of making and using these recombinant MVA viruses for production of HIV Env, Gag, and Pol antigens.
The problem being solved concerns the development of an effective HIV vaccine that induces strong cell-mediated immunity and broadly reactive anti-envelope antibodies. Existing approaches may lack multi-protein responses crucial for protection, and there is a need for safe and immunogenic recombinant viral vectors capable of boosting CD8+ T cell responses and eliciting antibody responses. The invention addresses issues with viral vector immunity and immunogen expression levels by providing recombinant MVA viruses expressing modified HIV Env, Gag, and Pol sequences, designed to be immunogenic and stable.
Claims Coverage
The patent includes multiple independent claims covering recombinant MVA viruses expressing HIV Env, Gag, and Pol antigens with specific genetic configurations. The main inventive features relate to the design and composition of the recombinant MVA viruses and methods of use in immune response boosting.
Recombinant MVA virus composition with HIV antigen insertion at MVA deletion sites
A recombinant MVA virus comprises a sequence encoding an HIV Env antigen inserted into deletion site II and a sequence encoding HIV Gag and Pol antigens inserted into deletion site III of the MVA genome, with transcription controlled by separate promoters and a defined non-coding sequence between the first promoter and the initiation codon of the env gene (SEQ ID NO:8).
Use of specific HIV clade B sequences encoding Env, Gag, and Pol antigens
The recombinant MVA virus includes sequences encoding HIV Env (SEQ ID NO:3) and Gag and Pol (SEQ ID NO:4) antigens, with tacit emphasis on clade B sequences, employed in the virus inserted at deletion sites II and III of MVA, including constructs where sequences consist of the indicated SEQ IDs.
Control of transcription by first and second promoters
Both the sequence encoding the HIV Env antigen and the sequence encoding the HIV Gag and Pol antigens are transcribed under the control of separate promoters, typically the mH5 vaccinia promoter, facilitating expression of these antigens in the recombinant MVA.
Pharmaceutical compositions comprising recombinant MVA with HIV antigens
Pharmaceutical compositions comprising the described recombinant MVA virus and a pharmaceutically acceptable carrier, formulated for various administration routes including intravenous, intramuscular, intradermal, mucosal, and others, optionally including pharmaceutically acceptable excipients, carriers, buffers, or stabilizers.
Methods of boosting and inducing CD8+ T cell and antibody immune responses
Methods comprising administering the recombinant MVA virus composition to primates, including humans, to boost CD8+ T cell or antibody immune responses previously primed by nucleic acid molecules encoding HIV Env, Gag, or Pol antigens, or to induce such immune responses by priming with nucleic acid molecules followed by boosting with recombinant MVA.
The inventions claimed define recombinant MVA viruses incorporating defined HIV Env, Gag, and Pol sequences inserted at specific MVA genome deletion sites, with controlled expression by separate promoters, pharmaceutical compositions containing these constructs, and methods employing these compositions to prime and boost HIV-specific CD8+ T cell and antibody responses in primates.
Stated Advantages
MVA vectors are highly attenuated and safe, with an excellent safety record in humans including immunosuppressed individuals.
Recombinant MVA allows high-level expression of HIV antigens even in non-permissive cells, making it an efficient and exceptionally safe gene expression vector.
The use of modified HIV env genes truncated in the gp41 cytoplasmic tail and mutated gag and pol genes improves antigen expression and immunogenicity.
The recombinant MVA virus can boost CD8+ T cell responses primed by DNA vaccines or other viral vectors and also elicit antibody responses.
Vaccination regimes involving DNA prime and MVA boost are predicted to provide effective protection against intramucosal challenge with live HIV.
Formulations of recombinant MVA vaccines allow for storage and administration advantages, including potential use of needleless injection devices and freeze-dried powders.
Documented Applications
Use as prophylactic or therapeutic vaccination against HIV/AIDS to induce CD8+ T cell and antibody immune responses.
Administration of recombinant MVA vaccines in immunization regimes including DNA priming followed by MVA boosting to protect primates against HIV infection.
Use in experimental contexts in nonhuman mammals for investigation of immune responses and protection mechanisms against HIV or AIDS.
Formulation of recombinant MVA vaccines suited for intradermal, intramuscular, or mucosal administration routes in humans or other mammals.
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