Search

US-20260124290-A1 - HIV Immunogens, Vaccines, and Methods Related Thereto

US20260124290A1US 20260124290 A1US20260124290 A1US 20260124290A1US-20260124290-A1

Abstract

This disclosure relates to modified HIV envelope proteins or envelope protein fragments, or trimeric complexes thereof which have uses in vaccination methods or therapeutic strategies. In certain embodiments, this disclosure relates to modified HIV envelope proteins or envelope protein fragments, or trimeric complexes thereof, comprising an arginine (R) at position 166, glutamine (Q) at position 170, and an amino acid histidine (H) at position 173. In certain embodiments, this disclosure relates to nucleic acids and recombinant vectors encoding said proteins.

Inventors

  • Rama Rao Amara
  • Sailaja Gangadhara
  • Anusmita SAHOO
  • Tiffany Turner-Styles

Assignees

  • EMORY UNIVERSITY

Dates

Publication Date
20260507
Application Date
20251219

Claims (20)

  1. 1 . A pharmaceutical composition comprising an HIV envelope protein comprising the amino acid sequence of MEGSWVTVYYGVPVWKEAKTTLFCASDAKAYEKKVHNVWATHACVPTDPNPQEMVL ANVTENFNMWKNDMVEQMHEDIISLWDESLKPCVKLTPLCVTLNCTNVKGNESDTSEV MKNCSFNATTELRDKKQKVHALFYKLDVVPLNGNSSSSGEYRLINCNTSAITQACPKVS FDPIPLHYCAPAGFAILKCNNKTFNGTGPCRNVSTVQCTHGIKPVVSTQLLLNGSLAEEEI IIRSENLTNNAKTIIVHLNESVNIVCTRPNNNTRKSIRIGPGQWFYATGDIIGNIRQAHCNIS ESKWNNTLQKVGEELAKHFPSKTIKFEPSSGGDLEITTHSFNCRGEFFYCNTSDLFNGTY RNGTYNHTGRSSNGTITLQCKIKQIINMWQEVGRPIYAPPIEGEITCNSNITGLLLLRDGG QSNETNDTETFRPGGGDMRDNWRSELYKYKVVEIKPLGVAPTEAKRRVVEGGGGSGG GGSAVGIGAVFLGFLGAAGSTMGAASMTLTVQARQLLSGNPDWLPDMTVWGIKQLQA RVLAIERYLKDQQLLGMWGCSGKLICTTAVPWNSSWSNKSQNEIWGNMTWMQWDREI NNYTNTIYRLLEDSQNQQEKNEKDLLALD (SEQ ID NO: 3), or variant having greater than 80% sequence identity, and a pharmaceutically acceptable excipient.
  2. 2 . The pharmaceutical composition of claim 1 , wherein the protein comprises the amino acid sequence of RDKKQKVH (SEQ ID NO: 2).
  3. 3 . The pharmaceutical composition of claim 1 , wherein the protein comprises the amino acid arginine (R) at position 127, glutamine (Q) at position 131 and histidine (H) at position 134 relative to SEQ ID NO: 3, wherein the N-terminal methionine (M) is position 39.
  4. 4 . The pharmaceutical composition of claim 1 , further comprising another therapeutic ingredient.
  5. 5 . The pharmaceutical composition of claim 1 , further comprising a bacteriostatic, antibiotic, or antiviral agent.
  6. 6 . The pharmaceutical composition of claim 5 , wherein the antiviral agent is nucleoside reverse transcriptase inhibitor, abacavir, azidothymidine, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine, a non-nucleoside reverse transcriptase inhibitor, delavirdine, efavirenz, nevirapine, a protease inhibitor, amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, fosamprenavir, ritonavir, saquinavir, tipranavir, a fusion protein inhibitor or enfuvirtide.
  7. 7 . The pharmaceutical composition of claim 1 in the form of an injectable fluid comprising a buffering agent, tonicity adjusting agent, salt solution, physiological saline, aqueous dextrose, or glycerol.
  8. 8 . The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipient is mannitol, lactose, starch, or magnesium stearate.
  9. 9 . The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable excipients sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate, sodium acetate or sorbitan monolaurate.
  10. 10 . The pharmaceutical composition of claim 1 , further comprising aluminum hydroxide, lecithin, or IL-12.
  11. 11 . A pharmaceutical composition comprising a nucleic acid, or recombinant vector in operable combination with a heterologous promoter, encoding a protein comprising the amino acid sequence of MEGSWVTVYYGVPVWKEAKTTLFCASDAKAYEKKVHNVWATHACVPTDPNPQEMVL ANVTENFNMWKNDMVEQMHEDIISLWDESLKPCVKLTPLCVTLNCTNVKGNESDTSEV MKNCSFNATTELRDKKQKVHALFYKLDVVPLNGNSSSSGEYRLINCNTSAITQACPKVS FDPIPLHYCAPAGFAILKCNNKTFNGTGPCRNVSTVQCTHGIKPVVSTQLLLNGSLAEEEI IIRSENLTNNAKTIIVHLNESVNIVCTRPNNNTRKSIRIGPGQWFYATGDIIGNIRQAHCNIS ESKWNNTLQKVGEELAKHFPSKTIKFEPSSGGDLEITTHSFNCRGEFFYCNTSDLFNGTY RNGTYNHTGRSSNGTITLQCKIKQIINMWQEVGRPIYAPPIEGEITCNSNITGLLLLRDGG QSNETNDTETFRPGGGDMRDNWRSELYKYKVVEIKPLGVAPTEAKRRVVEGGGGSGG GGSAVGIGAVFLGFLGAAGSTMGAASMTLTVQARQLLSGNPDWLPDMTVWGIKQLQA RVLAIERYLKDQQLLGMWGCSGKLICTTAVPWNSSWSNKSQNEIWGNMTWMQWDREI NNYTNTIYRLLEDSQNQQEKNEKDLLALD (SEQ ID NO: 3), or variant having greater than 80% sequence identity, and a pharmaceutically acceptable excipient.
  12. 12 . The pharmaceutical composition of claim 11 , wherein the protein comprises the amino acid sequence of RDKKQKVH (SEQ ID NO: 2).
  13. 13 . The pharmaceutical composition of claim 11 , wherein the protein comprises the amino acid arginine (R) at position 127, glutamine (Q) at position 131 and histidine (H) at position 134 relative to SEQ ID NO: 3, wherein the N-terminal methionine (M) is position 39.
  14. 14 . The pharmaceutical composition of claim 11 , further comprising another therapeutic ingredient.
  15. 15 . The pharmaceutical composition of claim 11 , further comprising a bacteriostatic, antibiotic, or antiviral agent.
  16. 16 . The pharmaceutical composition of claim 15 , wherein the antiviral agent is nucleoside reverse transcriptase inhibitor, abacavir, azidothymidine, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine, a non-nucleoside reverse transcriptase inhibitor, delavirdine, efavirenz, nevirapine, a protease inhibitor, amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, fosamprenavir, ritonavir, saquinavir, tipranavir, a fusion protein inhibitor or enfuvirtide.
  17. 17 . The pharmaceutical composition of claim 11 in the form of an injectable fluid comprising a buffering agent, tonicity adjusting agent, salt solution, physiological saline, aqueous dextrose, or glycerol.
  18. 18 . The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable excipient is mannitol, lactose, starch, or magnesium stearate.
  19. 19 . The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable excipients sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, and triethanolamine oleate, sodium acetate or sorbitan monolaurate.
  20. 20 . The pharmaceutical composition of claim 11 , further comprising aluminum hydroxide, lecithin, or IL-12.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 17/776,896 filed May 13, 2022, which is the National Stage of International Application No. PCT/US2020/060472 filed Nov. 13, 2020, which claims the benefit of U.S. Provisional Application No. 62/935,142 filed Nov. 14, 2019. The entirety of each of these applications is hereby incorporated by reference for all purposes. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under AI109633 awarded by the National Institutes for Health. The government has certain rights in this invention. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED AS AN XML FILE VIA THE OFFICE ELECTRONIC FILING SYSTEM The Sequence Listing associated with this application is provided in XML format and is hereby incorporated by reference into the specification. The name of the XML file containing the Sequence Listing is 20038USCON.xml. The XML file is 13,238 bytes, was created on Dec. 18, 2025, and is being submitted electronically via the USPTO Patent Center. BACKGROUND There are millions of humans living with HIV/AIDS. Combination antiretroviral therapy (cART) treatment regimens have successfully prolonged the lives of infected individuals. However, there is a need to develop a safe and effective HIV vaccine to reduce the spread of HIV infections. Developing vaccines for HIV has been challenging. Stopping combination antiretroviral therapy (cART) leads to the re-emergence. Immune privileged areas are able to shield HIV from the immune system. See Churchill et al., Nat Rev Microbiol. 2016, 14:55-60. HIV-1 has surface spikes made up of trimeric viral envelope glycoprotein (Env) proteins containing a membrane-anchored subunit gp41 and surface subunit gp120. Subunit gp120 undergoes conformational changes upon interaction with CD4. Further binding of gp120 to CCR5 and/or CXCR4 in target cell membranes leads to invasion of HIV into the cells by the fusion of the viral and cellular membranes. Initial HIV vaccines candidates consisted of gp120 subunits. These vaccines elicited antibody responses in all of vaccinated participants, but it was ineffective in preventing HIV-1 infection. More recently, a clinical trial for HIV vaccination, referred to as RV144, involved using a recombinant canarypox HIV vector (ALVAC-HIV) plus two recombinant gp120 boosts (AIDSVAX B/E). ALVAC-HIV is a live recombinant canarypox vector vaccine that expresses HIV-1 gag, protease, and gp120 linked to the transmembrane anchoring portion of gp41. A post hoc analysis in vaccine efficacy revealed an early peak in vaccine efficacy in the first year, which declined thereafter. See Robb et al. Lancet Infect Dis. 2012, 12:531-537. It is reported that viral evolution was a response to the RV144 HIV vaccination suggesting immune pressure is exerted on the HIV virus. See Gao et al, Viruses, 2018, 10(4), pii: E167. The generation of an antibody response capable of neutralizing a broad range of clinical isolates remains a major challenge in human immunodeficiency virus type 1 (HIV-1) vaccine development. Thus, there is a need to identify improved therapeutic or preventative strategies. Sanders et al. report cleaved, soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. PLoS Pathog, 2012, 9(9): e1003618.Sharma et al. report cleavage-independent HIV-1 env trimers engineered as soluble native spike mimetics for vaccine design. Cell Reports, 2015, 11, 539-550.Kong et al. report uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability. Nat Commun, 2016, 7:12040-12040. See also US Patent App. Publ. Nos. 2020/0230229 and 2020/0165303. References cited herein are not an admission of prior art. SUMMARY This disclosure relates to modified HIV envelope proteins or envelope protein fragments, or trimeric complexes thereof which have uses in vaccination methods or therapeutic strategies. In certain embodiments, this disclosure relates to modified HIV envelope proteins or envelope protein fragments, or trimeric complexes thereof, comprising an arginine (R) at position 166, glutamine (Q) at position 170, and an amino acid histidine (H) at position 173. In certain embodiments, this disclosure relates to nucleic acids and recombinant vectors encoding said proteins. In certain embodiments, the modified HIV envelope protein is non-naturally occurring. In certain embodiments, the gp120 domain or fragment thereof is conjugated to the gp41 domain or fragment thereof. In certain embodiments, the envelope protein or envelope protein fragment contains one or more amino acids substituted with cysteine (C) or the envelope protein or envelope protein fragment contains a flexible linker comprising the amino acids glycine or serine, such as a flexible linker comprising polyglycine or poly(glycine-serine) or a polyglycine and serin