Biochemically stabilized HIV-1 ENV trimer vaccine
Inventors
Harrison, Stephen C. • Chen, Bing • Barouch, Dan C. • Nkolola, Joseph P. • Seaman, Michael Scott
Assignees
Boston Childrens Hospital • Howard Hughes Medical Institute • Beth Israel Deaconess Medical Center Inc • National Institutes of Health NIH
Publication Number
US-9707289-B2
Publication Date
2017-07-18
Expiration Date
2029-10-13
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Abstract
Stabilized trimers of a clade A strain and a clade C strain of HIV-1 are provided. Broadly neutralizing antisera against HIV-1, methods of making broadly neutralizing antisera against HIV-1, broadly neutralizing vaccines against HIV-1, as well as methods of treating subjects infected with HIV, preventing HIV infection, and inhibiting HIV-mediated activities are also provided.
Core Innovation
The invention provides stabilized trimers of HIV-1 envelope glycoproteins from clade A and clade C strains that are capable of eliciting a broadly neutralizing antibody response in vivo. These stabilized trimers include gp140 polypeptides derived from primary isolates CZA97.012 (clade C) and 92UG037.8 (clade A) fused to oligomerization domains such as the T4 fibritin foldon trimerization domain to increase biochemical stability and conformational homogeneity. Such stabilized trimers elicit neutralizing antisera that can neutralize multiple HIV-1 clades.
The problem addressed by the invention is the difficulty in producing biochemically stable, immunogenic, trimeric HIV-1 envelope (Env) immunogens that mimic the native trimeric structure of Env on HIV-1 virions. This native-like trimer structure is important because it is the target of broadly neutralizing antibodies that can prevent infection or viral spread. Previous Env immunogens, including monomeric gp120, failed to elicit broadly neutralizing antibodies effectively, and existing trimeric preparations often lacked stability or homogeneity.
The invention further addresses therapeutic and prophylactic applications by providing methods of treating HIV-infected subjects, preventing HIV infection, and inhibiting HIV-mediated activities. These methods involve administering the stabilized Env gp140 trimer immunogens to subjects to induce production of broadly neutralizing antisera that can neutralize multiple clades of HIV-1, decrease viral titer, and inhibit activities such as viral spread and fusion.
Claims Coverage
The claims include multiple independent claims directed to immunogenic compositions comprising stabilized gp140 trimers, methods of therapeutic treatment using these compositions, and methods of inhibiting HIV-mediated activity. The main inventive features focus on the specific stabilized gp140 trimer sequences, inclusion of an oligomerization domain, and their ability to elicit broadly neutralizing antisera.
Immunogenic composition comprising stabilized gp140 trimer
An immunogenic composition comprising an isolated, antigenic, stabilized trimer of gp140. The trimer comprises three identical polypeptide sequences, each at least 98% identical to residues 30-708 of SEQ ID NO: 2 including SEQ ID NO: 8, and includes a T4 fibritin trimerization domain. The composition elicits production of neutralizing antisera against HIV after injection into a subject.
Immunogenic composition including stabilized gp140 trimer with oligomerization domain
An immunogenic composition comprising a stabilized trimer with an isolated gp140 polypeptide at least 98% identical to residues 30-708 of SEQ ID NO: 2, which includes SEQ ID NO: 8 and an oligomerization domain. The composition elicits neutralizing antisera against HIV after injection.
Isolated, antigenic, stabilized trimer of gp140 with oligomerization domain
An isolated, antigenic stabilized trimer of gp140 comprising a gp140 polypeptide at least 98% identical to residues 30-708 of SEQ ID NO: 2. The trimer includes an oligomerization domain and elicits production of neutralizing antisera against HIV after injection into a subject.
Method of therapeutically treating HIV-infected subject using stabilized gp140 trimer composition
A method of treating a subject infected with HIV by contacting the subject with the specified immunogenic composition comprising a stabilized gp140 trimer, resulting in production of neutralizing anti-HIV antisera to therapeutically treat the subject.
Method of inhibiting HIV-mediated activity by administering stabilized gp140 trimer composition
A method of inhibiting an HIV-mediated activity in a subject by administering the specified immunogenic composition with stabilized gp140 trimers, thereby producing neutralizing anti-HIV antisera that inhibit the HIV-mediated activity such as viral spread and decrease HIV titer.
The claims focus on immunogenic compositions containing stabilized HIV-1 gp140 trimers with defined sequences and oligomerization domains, methods of inducing broadly neutralizing antisera, and methods of treating or preventing HIV infection or inhibiting HIV-mediated activities.
Stated Advantages
The stabilized trimers elicit broadly neutralizing antibodies against multiple HIV-1 clades.
The immunogens are biochemically stable and conformationally homogeneous, increasing their immunogenicity and reproducibility.
The stabilized trimers can reduce HIV-1 viral titer and inhibit HIV-mediated activities such as viral spread.
The disclosed immunogens and regimens provide a systematic tiered approach to evaluate neutralizing antibody responses across diverse HIV-1 isolates.
Documented Applications
Therapeutic treatment of subjects infected with HIV by administering stabilized gp140 trimers to produce neutralizing antisera.
Prevention of HIV infection by inducing immunity through administration of stabilized gp140 trimers.
Inhibition of HIV-mediated activities such as viral spread, fusion, and viral entry in infected subjects.
Use as immunogens in vaccines to elicit broadly neutralizing antibodies against HIV-1 clades, including clade A, B, and C.
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