Antibody evolution immunogens
Inventors
Haynes, Barton F. • Liao, Hua-Xin • Lynch, Rebecca M. • Zhou, Tongqing • Gao, Feng • Boyd, Scott • Shaw, George M. • Hahn, Beatrice H. • Kepler, Thomas B. • Korber, Bette T. • Kwong, Peter • Mascola, John
Assignees
Boston University • University of Pennsylvania Penn • Los Alamos National Security LLC • Duke University • Leland Stanford Junior University • US Department of Health and Human Services • Office of Technology Transfer
Publication Number
US-10004800-B2
Publication Date
2018-06-26
Expiration Date
2033-09-12
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Abstract
The present invention relates, in general, to HIV-1 and, in particular, to broadly neutralizing HIV-1 antibodies, and to HIV-1 immunogens and to methods of using such immunogens to induce the production of broadly neutralizing HIV-1 antibodies in a subject (e.g., a human).
Core Innovation
The invention relates to HIV-1 and broadly neutralizing HIV-1 antibodies (BnAbs), specifically to HIV-1 immunogens and methods for inducing broadly neutralizing HIV-1 antibodies in a subject. It involves compositions comprising recombinant HIV-1 envelope proteins and their use in vaccine strategies to elicit BnAbs through interaction with unmutated common ancestors (UCAs) and intermediate antibodies of BnAb clonal lineages.
The background identifies the problem that induction of HIV-1 envelope broadly neutralizing antibodies has been a key and challenging goal in HIV-1 vaccine development. Mature BnAbs typically require substantial somatic mutation and many possess unusual features, imposing substantial barriers to their elicitation. In particular, it has been difficult to find envelope proteins that bind with high affinity to BnAb UCAs, especially for CD4 binding site (CD4bs) BnAb lineages. Prior to this invention, heterologous Envs that bind the UCAs of CD4bs BnAb lineages had not been identified, and the co-evolutionary pathways from transmitted/founder (T/F) virus through BnAb development were unknown.
This invention addresses the difficulty in inducing BnAbs by elucidating the interplay between virus evolution and BnAb maturation, based on longitudinal study in an HIV-1 infected subject (CH505). The invention identifies that the transmitted founder virus envelope binds with high affinity to a UCA B cell receptor of a broadly neutralizing clonal lineage (CH103), initiating antibody lineages that mature into BnAbs. The invention includes HIV-1 immunogens comprising transmitted/founder and sequentially evolved envelope variants to guide B cell maturation pathways for BnAb induction. It also provides vaccine strategies involving sequential administration of selected Envs or Env subunits that bind to UCA and intermediate antibodies to induce BnAbs.
Claims Coverage
The patent includes 24 claims comprising 2 main independent claims covering compositions of recombinant HIV-1 envelope proteins and methods of inducing immune responses using these compositions. They define the core inventive features relating to the HIV-1 envelope proteins and their use in immunization.
Composition comprising recombinant HIV-1 envelope protein
A composition comprising a recombinant HIV-1 envelope protein consisting of all consecutive amino acids immediately after the signal peptide in SEQ ID NO: 879 or SEQ ID NO: 861, optionally purified as gp120 or gp140, combined with a carrier and optionally an adjuvant.
Method of inducing an immune response by administering HIV-1 envelope protein composition
A method of inducing an immune response in a mammal by administering the composition comprising the recombinant HIV-1 envelope protein as defined above in an amount sufficient to induce broadly neutralizing antibodies against HIV-1, including modes of administration such as injection, intrarectally or vaginally, and optionally as a prime in a prime/boost immunization regimen.
The claims focus on compositions of recombinant HIV-1 envelope proteins derived from specific sequence identifiers and their use to induce broadly neutralizing antibody responses in subjects by immunization. The claims cover both protein compositions and corresponding immunization methods including prime/boost strategies.
Stated Advantages
Use of transmitted founder virus envelope that binds BnAb unmutated common ancestors to initiate B cell lineages that develop broadly neutralizing antibodies, lowering the barrier of somatic mutations needed.
Sequential immunization strategies with selected Env variants that mimic natural viral evolution guiding affinity maturation towards breadth and potency in antibody responses.
Identification of HIV-1 Env immunogens capable of high affinity binding to BnAb lineage UCAs and intermediates, overcoming previous difficulties with lack of suitable immunogens.
Potential to induce broadly neutralizing antibodies more efficiently by targeting vaccine immunogens to facilitate favorable antibody maturation pathways.
Documented Applications
Use in vaccine design to induce broadly neutralizing HIV-1 antibodies by administration of recombinant viral envelope proteins derived from transmitted/founder virus and evolved viral variants in sequential or combination immunization regimens.
Immunization of subjects, including humans, with compositions comprising HIV-1 envelope proteins or encoding nucleic acid sequences to generate broadly neutralizing antibodies prophylactically or therapeutically.
Formulation of immunogens as gp120 or gp140 proteins or subunits thereof and delivery via injections, including intramuscular, subcutaneous, intrarectal, or vaginal routes.
Use of nucleic acid-based vaccines encoding the envelope proteins for in vivo expression to elicit an immune response.
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