Nucleic acids encoding human immunodeficiency virus type 1 (HIV-1) N-terminal deleted gp120 immunogens and methods of use
Inventors
Kim, Jerome • Harrison, Stephen • Haynes, Barton F. • Tomaras, Georgia D. • Michael, Nelson
Assignees
Boston Childrens Hospital • Duke University • United States Department of the Army
Publication Number
US-11053285-B2
Publication Date
2021-07-06
Expiration Date
2032-07-05
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Abstract
The present invention relates, in general, to human immunodeficiency virus (HIV), and in particular to a vaccine for HIV-1 and to methods of making and using same.
Core Innovation
The invention relates to an HIV-1 vaccine based on nucleic acids encoding recombinant proteins comprising gp120 or gp140 envelope glycoproteins wherein the original 4 to 25 consecutive amino acids at the N-terminus immediately after the envelope signal peptide are deleted, and an N-terminal Herpes Simplex gD tag is not substituted. This N-terminal deletion, particularly around 11 amino acids, results in gp120 monomers that exhibit enhanced antigenicity and improved scalability for vaccine production.
The problem addressed by the invention arises from previous HIV-1 vaccine design challenges, including the presence of disulfide-linked gp120 dimers in recombinant Env preparations that occlude neutralizing epitopes, poor immunogenicity of certain Env regions, and difficulties in producing stable monomeric gp120 at scale. The deletion of the N-terminal residues eliminates aberrant disulfide-linked dimers, stabilizes neutralizing epitopes in the V1V2 and V2V3 regions, enhances expression of the C1 A32-like ADCC epitope, and thus improves both the antigenicity and manufacturability of Env immunogens.
The invention provides a general design strategy applicable to multiple Env sequences, including transmitted founder viruses and consensus sequences. The truncated gp120 or gp140 sequences can be formulated as DNAs, protein boosts, or vectored inserts with adjuvants. The immunogens induce improved immune responses correlated with protection signals seen in the RV144 clinical trial, confirming that the N-terminal deletion is the key modification enhancing Env immunogenicity rather than the previously used HSV gD tag.
Claims Coverage
The patent claims include independent claims directed to nucleic acids encoding HIV-1 Env proteins with specific N-terminal deletions, compositions including such nucleic acids, and methods of inducing immune responses. The coverage involves the extent of N-terminal deletions, specific Env variants, and vaccine formulation aspects.
Nucleic acid encoding HIV-1 Env with N-terminal deletion
A nucleic acid encoding a recombinant HIV-1 envelope gp120 or gp140 protein having a deletion of 4 to 25 consecutive amino acids at the N-terminus immediately following the signal peptide, with no substitution of an N-terminal Herpes Simplex gD tag.
Preferred N-terminal deletion length
Deletions of 5 to 11 consecutive amino acids at the N-terminus, with specific embodiments of 7 or 11 amino acid deletions.
Inclusion of multiple HIV-1 Env variants
Application of the N-terminal deletion design to various HIV-1 Env strains including A244, 1086.C, 089.C, 63521.B, CONS, 6240.B, 040.B, and A1C recombinant Env 707-01-069-2.
Vaccine compositions with deleted Env nucleic acids and adjuvants
Compositions comprising nucleic acids encoding HIV-1 Env gp120 with the specified N-terminal deletions formulated with carriers or adjuvants for vaccination.
Methods of immune response induction
Methods involving administering the compositions or nucleic acids encoding N-terminally deleted Env gp120 to subjects to induce immune responses.
Vectors comprising nucleic acids with N-terminally deleted Env
Recombinant vectors such as rAdenovirus, recombinant mycobacteria, or recombinant vaccinia vectors carrying the nucleic acid encoding the N-terminally deleted Env gp120 or gp140 proteins.
The claims collectively cover nucleic acids encoding HIV-1 Env proteins with defined N-terminal deletions without using a gD tag, compositions and vaccine formulations comprising these nucleic acids, methods of immune induction using these compositions or nucleic acids, and recombinant vectors carrying the deleted Env sequences, emphasizing deletions of about 4 to 25 residues particularly 5 to 11 amino acids in multiple Env variants.
Stated Advantages
Deletion of the N-terminal 4 to 25 amino acids results in primarily monomeric gp120 expression, thus solving protein production and scalability issues.
The Delta 11 deletion enhances the antigenicity of conformational neutralizing epitopes in the V1V2, V2V3, and C1 regions, improving antibody binding affinity and immune responses.
Enhanced binding to antibodies from RV144 vaccinees was shown, indicating improved immunogenicity relevant to clinical vaccine efficacy.
The design removes detrimental disulfide-linked dimers and likely improves correct folding and stability of Env immunogens.
Documented Applications
Use of nucleic acids encoding N-terminally deleted HIV-1 gp120 or gp140 as immunogens in vaccines for prophylactic or therapeutic induction of immune responses against HIV-1 infection.
Formulation of N-terminal truncated Env proteins or nucleic acids in various vaccine platforms including DNA vaccines, recombinant viral vectors (rAdenovirus, recombinant mycobacteria, vaccinia vectors), or protein boosts with adjuvants such as MF59 and AS01B.
Use of these immunogens or compositions via multiple administration routes including intramuscular, subcutaneous, intranasal, intrarectal, intravaginal, and other mucosal delivery methods to induce protective immunity.
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