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 R.
Assignees
Boston University • University of Pennsylvania Penn • Duke University • Triad National Security LLC • Leland Stanford Junior University • US Department of Health and Human Services
Publication Number
US-10849970-B2
Publication Date
2020-12-01
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 broadly neutralizing antibodies (BnAbs), specifically to HIV-1 immunogens and methods of using such immunogens to induce the production of broadly neutralizing HIV-1 antibodies in a subject such as a human. The immunogens comprise HIV-1 envelope proteins or subunits, particularly those including the gp120 CD4 binding site loop region, in compositions with a carrier and optionally an adjuvant. The invention further includes constructs comprising nucleotide sequences encoding these envelope proteins present in vectors, including viral or mycobacterial vectors, and methods of administering these compositions or constructs to induce an immune response.
The problem addressed is the difficulty in inducing broadly neutralizing antibodies against HIV-1, particularly those targeting the CD4 binding site (CD4bs), due to the complex maturation pathways and high levels of somatic mutation required. Prior efforts have been hampered by the lack of Envs that bind with high affinity to BnAb germline or unmutated common ancestors (UCAs). The invention arises from studies isolating the CH103 CD4bs BnAb clonal lineage from a patient followed from acute HIV-1 infection through BnAb development, demonstrating that a transmitted/founder (T/F) Env bound the UCA and that sequential evolution of viral Env variants drove affinity maturation and neutralization breadth.
The invention provides immunization strategies including sequential immunizations with Env constructs derived from the CH505 transmitted/founder virus and its evolved variants to mimic natural virus-antibody co-evolution and drive BnAb development. These immunogens may be administered as proteins, nucleic acids, or via viral vectors to a subject. The method involves priming with the T/F Env or subunits and boosting with representatives of evolved Env variants in combination or series, intending to activate naïve B cells and stimulate affinity maturation pathways resulting in broadly neutralizing CD4bs antibodies.
Claims Coverage
The patent contains multiple claims with independent claims directed to compositions comprising recombinant HIV-1 envelope proteins, recombinant HIV-1 envelope proteins themselves, and methods of inducing an immune response by administering these compositions or proteins.
Compositions comprising specific recombinant HIV-1 envelope proteins
Compositions contain recombinant HIV-1 envelope proteins comprising all consecutive amino acids immediately after the signal peptide in specific SEQ ID NOS (884 or 866) together with a carrier, optionally comprising purified gp120 or gp140 proteins and an adjuvant.
Recombinant HIV-1 envelope proteins as immunogens
Isolated recombinant HIV-1 envelope proteins consisting of specific sequences (immediately after the signal peptide in SEQ ID NO: 884 or 866) suitable for use as immunogens.
Methods for inducing immune responses with compositions or proteins
Administering compositions or recombinant HIV-1 envelope proteins comprising sequences immediately after the signal peptide in SEQ ID NOS 884 or 866 to mammals, including humans, in amounts sufficient to induce an immune response, including prime-boost regimens where these proteins are administered as boost or prime immunogens.
Use of nucleic acid encoding CH505 transmitted/founder HIV-1 envelope as prime
Methods comprising administering nucleic acid encoding the CH505 transmitted/founder HIV-1 envelope as a prime in a prime/boost immunization regimen.
The claims cover compositions of specific recombinant HIV-1 envelope proteins, their use in inducing immune responses in mammals via administration of compositions or proteins, and include prime/boost methods with protein or nucleic acid immunogens. The claimed inventive features focus on the sequences immediately after the signal peptide in specific SEQ ID NOS and their use in vaccines to induce broadly neutralizing antibodies.
Stated Advantages
The CH103 BnAb lineage requires fewer somatic mutations compared to other CD4bs broadly neutralizing antibodies, potentially simplifying vaccine-induced antibody maturation.
The transmitted/founder HIV-1 envelope binds effectively to unmutated common ancestors of BnAb lineages, providing a logical and rational starting point for vaccine immunization strategies.
Sequential immunization with evolving Env variants mimics natural virus-antibody co-evolution, promoting the induction of broadly neutralizing antibodies with neutralization breadth.
Compositions and immunogens can be delivered using multiple formats including proteins, nucleic acids, and viral vectors, providing versatility in vaccination approaches.
Antibody polyreactivity arises during affinity maturation coincident with broad neutralizing activity, suggesting polyreactivity may be beneficial for neutralization breadth.
Sequential immunization with selected Env variants induces higher levels of CD4 binding site antibodies than single immunogen administration, demonstrating immunization strategy efficacy.
Documented Applications
The immunogens and compositions are intended for use in prophylactic vaccination to induce broadly neutralizing HIV-1 antibodies in humans and other mammals.
The immunogens may also be administered to HIV-1 infected individuals to potentially reduce viral load.
The nucleic acid sequences encoding the immunogens can be administered to express Env proteins in vivo and induce antibody responses.
Vaccination regimens include sequential or prime-boost administration of transmitted/founder and evolved HIV-1 Env proteins or constructs in compositions suitable for injection or mucosal administration (intrarectally or vaginally).
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