Human immunodeficiency virus type 1 (HIV-1) N-terminal deleted GP120 immunogens
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 • US Army Medical Research and Development Command
Publication Number
US-10040826-B2
Publication Date
2018-08-07
Expiration Date
2032-07-05
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 development of an HIV-1 vaccine and methods of making and using immunogens derived from the HIV-1 envelope gp120 or gp140 proteins with specific N-terminal deletions. It addresses challenges associated with producing monomeric gp120 envelopes that express neutralizing epitopes reflective of the native viral envelope, ensuring proper antigenicity and enabling scalable vaccine production.
The problem being solved includes the difficulty in producing monomeric envelopes that are not disulfide linked and occluded in important epitopes, and the poor immunogenicity of many regions of the HIV Env protein. Disulfide-linked Env dimers hinder antibody binding, while some immunogenic responses are subdominant or down regulated. The invention's design strategy involves deletion, preferably of about 11 amino acids, at the N-terminus of gp120 leading to stabilization of neutralizing epitopes and predominantly monomeric expression, overcoming issues in antigenicity and scalable production of Env proteins for vaccine use.
Claims Coverage
The patent includes multiple independent claims covering recombinant HIV-1 Env proteins with specific N-terminal deletions and methods of their use in immunogenic compositions and immune response induction. There are several inventive features relating to these deletions, protein types, and uses.
N-terminal deletion of HIV-1 Env gp120 or gp140 without gD substitution
A recombinant HIV-1 envelope protein (gp120 or gp140) comprising deletion of about 4 to 25 consecutive amino acids immediately after the envelope signal peptide at the N-terminus, with no substitution of a Herpes Simplex virus gD tag in place of these amino acids.
Preferred length of N-terminal deletion
Deletions specifically comprising 5 to 11 consecutive amino acids, including embodiments with exactly eleven (11) or seven (7) amino acid deletions at the N-terminus immediately after the signal peptide.
Applicability to various HIV-1 Env sequences
The N-terminal deletion design applied to multiple HIV-1 Env variants, including A244, 1086.C, 089.C, 63521.B, CONS, 6240.B, 040.B, and A1C recombinant Env 707-01-069-2.
Immunogenic compositions comprising N-terminal deleted recombinant protein and adjuvant
Compositions comprising the recombinant N-terminally deleted HIV-1 Env gp120 protein combined with an adjuvant for use as immunogens.
Methods of inducing immune response using N-terminal deleted immunogens
Methods of eliciting an immune response by administering the immunogenic composition or recombinant protein comprising the specified N-terminal deletion of the HIV-1 Env gp120 to subjects.
The independent claims focus on recombinant HIV-1 Env proteins with defined N-terminal deletions without gD tag substitution, their compositions with carriers or adjuvants, and methods for inducing immune responses using such immunogens. The inventive features highlight the specific deletion ranges, application to various Env strains, and use in vaccine formulations and immunization methods.
Stated Advantages
Deletion of about 11 amino acids at the N-terminus stabilizes important HIV-1 gp120 epitopes (V1V2 conformational neutralizing epitopes, V2,V3 quaternary neutralizing epitopes, and C1 A32-like ADCC epitope) enhancing antigenicity and immunogenicity.
The N-terminal deletion leads to predominantly monomeric gp120 expression rather than dimers, solving the production and scalability issues of gp120 Env vaccine production.
Enhanced binding of relevant neutralizing and ADCC-mediating antibodies to the deleted gp120 Env forms, including higher affinity for antibodies corresponding to epitopes correlated with protection in the RV144 trial.
The deletion improves folding reliability of gp120 expressed in mammalian cells, reducing misfolding and aberrant disulfide-linked dimers, contributing to conformational homogeneity of the immunogen.
Documented Applications
Use of the N-terminally deleted gp120 or gp140 recombinant proteins as HIV-1 vaccine immunogens administered as proteins, DNA vaccines, or inserted into viral/bacterial vectors such as rAdenovirus, recombinant mycobacteria, and recombinant vaccinia vectors.
Formulation of these HIV-1 Env constructs with adjuvants such as MF59, AS01B, polyI, polyC or alum for administration via subcutaneous, intramuscular, intranasal, or other mucosal routes to induce an immune response.
Use of these immunogens to induce antibodies targeting specific neutralizing and ADCC epitopes against HIV-1 in prophylactic vaccination or in infected individuals to potentially reduce viral load.
Interested in licensing this patent?