Vaccine compositions of herpesvirus envelope protein combinations to induce immune response
Inventors
Cui, Xinle • Snapper, Clifford M.
Assignees
Uniformed Services University of Health Sciences • Henry M Jackson Foundation for Advancedment of Military Medicine Inc
Publication Number
US-11572389-B2
Publication Date
2023-02-07
Expiration Date
2038-01-26
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Abstract
Provided are antigenic compositions and uses thereof that include at least two human herpesvirus (HHV) polypeptides involved in mediating HHV binding, fusion, and entry into host cells, such as gp350, gH, gL, and gB, or nucleic acids encoding the polypeptides. The two HHV polypeptides comprise any combination of: a gB polypeptide; a gp350 polypeptide; a gL polypeptide; and a gH polypeptide, and optionally any one or more of the following polypeptides: gp42, gM, gN, gl, gC, gE, gD, ORF68, BMRF-2, BDLF2, UL128, UL130, UL131A, and gpK8.1. Also disclosed are methods of inducing an immune response or treating or preventing an HHV infection in a subject by administering to the subject at least two of the HHV polypeptides or nucleic acid(s) encoding the same. Methods of passively transferring immunity using high-titer anti-HHV antibodies or immune cells are also disclosed.
Core Innovation
Human herpes viruses (HHV) are enveloped DNA viruses that cause significant morbidity and mortality worldwide. There are eight known HHV types, including HSV-1, HSV-2, VZV, EBV, HCMV, HHV-6, HHV-7, and KSHV, each associated with different diseases. Viral entry into host cells involves envelope proteins mediating binding, fusion, and entry, principally glycoprotein B (gB), glycoprotein H (gH), and glycoprotein L (gL), with gH and gL forming a heterodimeric complex.
Existing vaccines, such as recombinant monomeric gp350 for EBV or live-attenuated or subunit gB vaccines for HCMV, have shown limited efficacy. Prior art identified multimerization of HHV antigens to enhance immunogenicity, but combining multiple antigens is often problematic due to vaccine or immune interference, resulting in diminished antibody responses.
This invention provides antigenic compositions comprising at least two HHV fusion and host cell entry polypeptides, notably combinations of gp350, gB, gH, and gL, which, when administered, induce additive or synergistic antibody responses in subjects. Unexpectedly, combining monomeric and/or multimeric forms of these proteins counteracts the commonly observed immune interference and elicits high-titer, neutralizing antibodies that block multiple steps of the virus-host cell fusion process, thereby improving protection against HHV infection.
The disclosed compositions include recombinant or native proteins, optionally truncated, multimerized, or fused, and may be administered as proteins, nucleic acid vaccines (DNA, RNA, viral vectors), or virus-like particles. Additionally, the invention discloses passive immunization methods using high-titer anti-HHV antibodies or immune cells derived from immunized or highly seropositive donors to passively transfer immunity to at-risk or immunocompromised subjects.
Claims Coverage
The claims define several inventive features focusing on antigenic compositions comprising combinations of specific EBV polypeptides and methods of their administration for inducing immunity or treating infections.
Combination of monomeric or multimeric EBV gp350 with monomeric or multimeric EBV gB and/or gH/gL heterodimer
An antigenic composition comprising at least two EBV polypeptides not fused into a fusion protein: a first polypeptide comprising monomeric or multimeric gp350 extracellular domain; and a second polypeptide comprising monomeric or multimeric gB extracellular domain with the furin cleavage site replaced and/or a monomeric or multimeric gH/gL heterodimer with extracellular domains. The composition excludes fusion with polypeptides assembling into nanoparticles.
Inclusion of intracellular domains and specific peptide linkers
The polypeptides may further include corresponding intracellular domains connected to extracellular domains via polypeptide linkers of about 6 to 70 amino acids, such as a 15 amino acid linker.
Specific multimeric states of EBV polypeptides
Compositions specifying the gp350 polypeptide in monomeric, dimeric, trimeric, or tetrameric form, and the gB polypeptide in monomeric, dimeric, or trimeric form; and compositions with monomeric gp350 paired with monomeric or trimeric gH/gL, or tetrameric gp350 paired with trimeric gH/gL.
Triadic combinations of gp350, gB, and gH/gL polypeptides
Compositions comprising monomeric gp350, trimeric gB, and monomeric gH/gL heterodimer; or tetrameric gp350, trimeric gB, and trimeric gH/gL heterodimer.
Optional addition of EBV gp42, BDLF2, and BMRF-2 polypeptides
Compositions may further include these accessory EBV polypeptides.
Pharmaceutical compositions and adjuvants
Compositions may further include pharmaceutically acceptable excipients and/or adjuvants appropriate for vaccine formulation.
Methods for prevention, treatment, and induction of immunity against EBV
Methods include administering a therapeutically effective amount of the compositions, either sequentially or concurrently, to subjects at risk or with EBV infection.
Nucleic acid compositions and expression vectors
Compositions comprising nucleic acids encoding the EBV polypeptides, optionally within viral vectors, enabling expression of the components.
Structural independence of polypeptides
The first and second EBV polypeptides are not fused together or bound via oligomerization domains to each other.
The claims cover antigenic compositions of specific EBV envelope protein combinations and their use in immunization, encompassing monomeric and multimeric forms, with or without intracellular domains, linked by peptide linkers but not forming fusion proteins or nanoparticles. The claims also cover nucleic acid-based vaccines encoding these proteins and methods of administering them to prevent or treat EBV infection.
Stated Advantages
Induction of additive or synergistic high-titer neutralizing antibody responses to multiple HHV proteins.
Improved protection against HHV infection due to blocking multiple steps of virus-host cell fusion.
Overcoming vaccine or immune interference commonly observed with multicomponent vaccines.
Ability to passively transfer immunity via high-titer antibodies or immune cells from immunized subjects.
Documented Applications
Preventing or treating infections caused by human herpesviruses, including Epstein-Barr Virus (EBV), Human Cytomegalovirus (HCMV), Herpes Simplex Virus types 1 and 2 (HSV-1, HSV-2), Varicella-Zoster Virus (VZV), Human Herpesvirus 6 and 7 (HHV-6, HHV-7), and Kaposi's Sarcoma-Associated Herpesvirus (KSHV).
Immunization of individuals at risk of or suffering from diseases associated with HHV infections, including post-transplant lymphoproliferative disorder (PTLD), nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin lymphoma, infectious mononucleosis, congenital HCMV infection, shingles, and Kaposi's sarcoma.
Passive immunotherapy by administration of high-titer anti-HHV antibodies or immune cells to immunocompromised or at-risk subjects.
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