Middle east respiratory syndrome coronavirus immunogens, antibodies, and their use
Inventors
Graham, Barney • Kong, Wing-pui • Modjarrad, Kayvon • Wang, Lingshu • Shi, Wei • Joyce, Michael Gordon • Kanekiyo, Masaru • Mascola, John
Assignees
US Department of Health and Human Services
Publication Number
US-10759846-B2
Publication Date
2020-09-01
Expiration Date
2036-02-24
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Abstract
Methods of inducing an immune response in a subject to the Middle East respiratory syndrome coronavirus (MERS-CoV) are provided. In several embodiments, the immune response is a protective immune response that inhibits or prevents MERS-CoV infection in the subject. Recombinant MERS-CoV polypeptides and nucleic acid molecules encoding same are also provided. Additionally, neutralizing antibodies that specifically bind to MERS-CoV S protein and antigen binding fragments thereof are disclosed. The antibodies and antigen binding fragments are useful, for example, in methods of detecting MERS-CoV S protein in a sample or in a subject, as well as methods of preventing and treating a MERS-CoV infection in a subject.
Core Innovation
The invention provides methods of inducing an immune response in a subject to the Middle East respiratory syndrome coronavirus (MERS-CoV). Specifically, the immune response is often a protective response that inhibits or prevents MERS-CoV infection. The invention includes recombinant MERS-CoV polypeptides and nucleic acid molecules encoding the same. Neutralizing antibodies that specifically bind to the MERS-CoV Spike (S) protein, including antigen binding fragments thereof, are also disclosed.
The problem being solved is the urgent need for an effective vaccine and related therapeutic agents against MERS-CoV, a highly fatal virus causing severe acute respiratory infection. There are thousands of infections and hundreds of deaths attributed to MERS-CoV, with human-to-human transmission not being sustained, suggesting a large zoonotic reservoir as a principal source for transmission events. The high case fatality rate, vaguely defined epidemiology, and absence of prophylactic or therapeutic measures for MERS-CoV make vaccine development critical.
The invention describes a new immunization strategy based on the MERS-CoV Spike glycoprotein, including a prime-boost vaccination comprising administering a nucleic acid molecule encoding full-length MERS-CoV S protein followed by administration of a polypeptide consisting of the S1 subunit of the MERS-CoV S protein. This approach elicits a broad and potent neutralizing antibody response that can prevent or treat MERS-CoV infection. Additionally, the invention provides novel immunogens such as the MERS-CoV S protein or fragments like the receptor binding domain (RBD) linked to protein nanoparticles, enhancing immunogenicity.
Claims Coverage
The patent claims focus on isolated nucleic acid molecules encoding monoclonal antibodies or antigen binding fragments thereof that specifically bind to MERS-CoV S protein, comprising various variable heavy and light chain regions.
Isolated nucleic acid molecules encoding monoclonal antibodies or antigen binding fragments
Isolated nucleic acids encoding antibodies or antigen binding fragments comprising heavy chain variable regions (VH) and light chain variable regions (VL), each with complementarity determining regions (CDRs), corresponding to specific sequences including JC57-13, JC57-11, JC57-14, C2, C5, A2, A10, FIB_B2, FIB_H1, G2, G4, D12, and F11, which specifically bind to MERS-CoV S protein.
Inclusion of CDR sequences defining antibody specificity
The nucleic acid encodes antibodies wherein the heavy and light chain complementarity determining regions (HCDR1, HCDR2, HCDR3; LCDR1, LCDR2, LCDR3) comprise the amino acid sequences set forth in the patent for the defined antibodies, conferring specificity for binding MERS-CoV S protein.
Nucleic acids encoding full heavy and light chain variable regions
Nucleic acid molecules encoding the full amino acid sequences of VH and VL variable regions of the listed antibodies that specifically bind MERS-CoV S protein, including variants corresponding to the sequences set forth as SEQ ID NOs in the patent.
Human framework and constant region inclusion
Nucleic acid molecules encoding antibodies comprising human framework regions, including humanized antibodies with human constant domains, optionally with modifications to increase antibody half-life via enhanced neonatal Fc receptor binding.
Encoding antigen binding fragments and expression vectors
Nucleic acids encoding antigen binding fragments such as Fv, Fab, F(ab’)2, scFv, or scFv dimers, operably linked to promoters in vectors, and cells comprising such nucleic acids for expression of the antibodies or fragments that specifically bind MERS-CoV S protein.
Pharmaceutical compositions and kits
Pharmaceutical compositions comprising the nucleic acid molecules or vectors and pharmaceutically acceptable carriers, in sterile unit dosage forms, optionally including multiple nucleic acid molecules encoding different antibodies for combinatorial immunization, and kits containing nucleic acids with instructions for use.
The claims cover isolated nucleic acid molecules encoding monoclonal antibodies and antigen binding fragments with defined variable regions and CDRs specific for MERS-CoV S protein, including humanized forms, expression systems, pharmaceutical compositions, and methods of producing such antibodies by expression in host cells.
Stated Advantages
The prime-boost vaccination strategy elicits a broad repertoire of neutralizing antibodies targeting multiple epitopes on the MERS-CoV spike protein, both within and outside the receptor binding domain (RBD).
DNA prime and protein boost immunization induces a Th1-biased immune response associated with effective viral control, which is an improvement over protein-only regimens that induce a Th2-biased response.
Neutralizing antibodies generated have potency and breadth, being able to neutralize multiple MERS-CoV strains, including strains with mutations that confer resistance to particular antibodies.
The DNA prime/protein boost regimen provides greater and earlier protection in non-human primates, reducing lung disease after MERS-CoV challenge compared to protein-only or DNA-only immunizations.
Documented Applications
Inducing an immune response to MERS-CoV S protein to prevent or treat Middle East respiratory syndrome coronavirus infection in subjects.
Use of isolated monoclonal antibodies or antigen binding fragments specific for MERS-CoV S protein for diagnostic purposes to detect MERS-CoV infection in biological samples or subjects.
Therapeutic use of the antibodies and antigen binding fragments to treat or prevent MERS-CoV infection by neutralizing the virus.
Use of recombinant MERS-CoV polypeptides, nucleic acids, protein nanoparticles, viral vectors and immunogens in vaccine formulations and prime-boost regimens to protect against MERS-CoV infection.
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