Multivalent vaccines for rabies virus and coronaviruses
Inventors
Johnson, Reed F. • Schnell, Matthias • Hensley, Lisa E. • Wirblich, Christoph • COLEMAN, Christopher M. • Frieman, Matthew S.
Assignees
Thomas Jefferson University • University of Maryland Baltimore • US Department of Health and Human Services
Publication Number
US-12269155-B2
Publication Date
2025-04-08
Expiration Date
2037-03-31
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Abstract
The present disclosure provides methods and compositions for inducing an immune response that confers dual protection against infections by either or both of a rabies virus and a coronavirus, and/or which can be used therapeutically for an existing infection with rabies virus and/or a coronavirus to treat at least one symptom thereof and/or to neutralize or clear the infecting agents. In particular, the present disclosure provides a recombinant rabies virus vector comprising a nucleotide sequence encoding at least one coronavirus immunogenic glycoprotein fragment, as well as pharmaceutical compositions comprising the vaccine vectors.
Core Innovation
The invention provides recombinant rabies virus vectors that are genetically modified to express at least one immunogenic glycoprotein fragment from a coronavirus, such as MERS-CoV or SARS-CoV. Specifically, the recombinant vectors comprise a nucleotide sequence encoding at least one coronavirus glycoprotein or fragment thereof, including spike protein truncations or chimeric proteins. These constructs are capable of inducing immune responses to both the rabies virus and coronaviruses through a single vaccine platform.
This technology addresses the need for effective vaccines against coronaviruses, notably MERS-CoV and SARS-CoV, for which no approved vaccines exist despite ongoing global threats. Prior vaccine platforms (such as adenovirus, modified vaccinia Ankara, and recombinant proteins) each present limitations like pre-existing immunity, reduced immunogenicity, or the need for multiple doses. The background discusses the challenges faced, including safety, immunogenicity, ease of production, and residual pathogenicity, especially for immunocompromised individuals.
The present disclosure enables the development of bivalent (or multivalent) vaccines that provide dual and simultaneous immune protection against both rabies virus and one or more coronaviruses. The platform supports various forms, including live-attenuated, chemically inactivated, and replication-deficient vaccines, and utilizes effective attenuation strategies (e.g., SAD B19 RABV derivatives). These constructs are suitable for both prophylactic and therapeutic administration, providing the means to induce humoral and/or cellular immune responses to prevent infection or treat existing infections.
Claims Coverage
The patent covers several inventive features in its independent claims, focusing on recombinant rabies virus vectors, multivalent vaccines, compositions, and methods for immune response and treatment.
Recombinant rabies virus vector with coronavirus spike protein truncation
A recombinant rabies virus vector comprising a nucleotide sequence encoding at least one immunogenic glycoprotein fragment of a coronavirus, in which the fragment is a C-terminal truncation of a spike protein from Middle East Respiratory Coronavirus (MERS-CoV) or Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). Key features: - The truncation includes deletion of from about 15 to about 35 amino acids, or specifically about 19 amino acids from the C-terminus of the spike protein. - The immunogenic glycoprotein fragment may include the S1 domain of a spike protein. - The immunogenic glycoprotein fragment may be a chimeric protein including a membrane anchor from a virus other than a coronavirus (such as RABV glycoprotein), which can include ectodomain, transmembrane, and cytoplasmic domains of the RABV glycoprotein. - The rabies virus genome may be attenuated or derived from the live attenuated SAD B19 RABV vaccine.
Multivalent vaccine for rabies and coronavirus
A multivalent vaccine effective to induce an immune response against both rabies and at least one coronavirus, comprising the recombinant rabies virus vector described above.
Vaccine composition containing the multivalent vaccine
A vaccine composition comprising one or more of the multivalent vaccine and a pharmaceutically acceptable carrier. The composition may further include at least one additional therapeutic agent, such as an anti-viral drug, anti-viral antibody, immunostimulatory agent, adjuvant, or combinations thereof.
Methods of inducing immune response using the multivalent vaccine
A method of inducing an immune response against a coronavirus or a rabies virus, or both, in a subject, comprising administering a therapeutically effective amount of the multivalent vaccine.
Methods of inducing neutralizing antibodies and treating infections
A method of inducing neutralizing antibodies against coronavirus or rabies virus in a subject infected with or exposed to these viruses by administering a therapeutically effective amount of the multivalent vaccine. Furthermore, a method of treating a subject infected with a coronavirus or rabies virus by administering a therapeutically effective amount of the multivalent vaccine to induce an immune response.
Live, replication-competent or replication-deficient rabies virus vectors expressing coronavirus spike truncations
A live, replication-competent or replication-deficient rabies virus based vector expressing at least one immunogenic glycoprotein fragment comprising a C-terminal truncation of a spike protein from MERS-CoV or SARS-CoV. The vector can have specific nucleotide sequences as defined in SEQ ID NO: 21, 23, or 24.
The inventive features provide a recombinant rabies virus platform for expressing coronavirus spike protein truncations, enabling multivalent vaccine use, compositions containing these vaccines, and various prophylactic and therapeutic methods for inducing immune responses or treating infections.
Stated Advantages
The vaccine induces dual protection against rabies virus and at least one coronavirus, enabling simultaneous immune responses against both pathogens with a single construct.
Recombinant vaccines based on attenuated RABV vectors are safe, with neurovirulence eliminated or substantially mitigated, reducing the risk of neurological damage.
The platform accommodates various forms, including live-attenuated, chemically inactivated, and replication-deficient vaccines, increasing flexibility and potential safety.
The vaccine constructs can be used both prophylactically to prevent infection and therapeutically to treat existing infections by inducing humoral and/or cellular immune responses.
RABV-based vaccine constructs are capable of inducing strong immune responses against both their vector and the expressed immunogen, conferring effective neutralization and protection.
The existing RABV platform has a strong safety and production record, enhancing the feasibility of clinical development and public health use.
Documented Applications
Immunization and therapy in humans and animals against infections caused by either or both rabies virus and coronavirus (including MERS-CoV and SARS-CoV).
Use as a vaccine for wildlife (e.g., oral vaccination in Europe), and potential use in camels and humans in areas with endemic MERS-CoV infections.
Treatment of subjects infected with either or both rabies virus and coronavirus to induce immune responses, treat symptoms, or clear infecting agents.
Use in laboratory diagnostics to evaluate the presence of antibodies against rabies and/or coronavirus in a sample.
Applications in vaccine composition for preventative and therapeutic administration via various delivery routes (e.g., parenteral injection, subcutaneous, intramuscular, intranasal, oral, or topical application).
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