Multivalent vaccines for rabies virus and filoviruses
Inventors
Blaney, Joseph E. • Paragas, Jason • Jahrling, Peter • Johnson, Reed • Schnell, Matthias
Assignees
Thomas Jefferson University • Cisco Technology Inc • US Department of Health and Human Services
Publication Number
US-10849975-B2
Publication Date
2020-12-01
Expiration Date
2032-02-02
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Abstract
The present invention 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 filovirus, and/or which can be used therapeutically for an existing infection with rabies virus and/or a filovirus to treat at least one symptom thereof and/or to neutralize or clear the infecting agents. In particular, the present invention provides a recombinant rabies virus vector comprising a nucleotide sequence encoding at least one filovirus glycoprotein or an immunogenic fragment thereof, as well as pharmaceutical compositions comprising the vaccine vectors.
Core Innovation
The present invention provides methods and compositions for inducing an immune response that confers dual protection against infections by either or both a rabies virus and a filovirus, and/or which can be used therapeutically for an existing infection with rabies virus and/or a filovirus to treat at least one symptom thereof and/or to neutralize or clear the infecting agents. It specifically provides a recombinant rabies virus vector comprising a nucleotide sequence encoding at least one filovirus glycoprotein or an immunogenic fragment thereof, and pharmaceutical compositions comprising the vaccine vectors.
The invention relates to novel recombinant vaccine constructs based on genetically modifying an attenuated rabies virus vaccine vector to express one or more filovirus immunogenic polypeptides, such as an Ebolavirus or Marburgvirus glycoprotein (GP), thereby inducing humoral and/or cellular immune responses against infection by rabies virus and/or filoviruses upon administering the vaccine construct or recombinant virion. The vaccine constructs may be bivalent or multivalent as a single agent capable of simultaneous immune response induction against two or more viral pathogens, used prophylactically to protect against infections or therapeutically to aid neutralization or clearing of preexisting infections.
The problem being solved is the lack of available vaccines or effective therapeutic treatments for filovirus infections, which cause highly lethal hemorrhagic fever with high mortality rates and no currently safe and effective vaccines. Multiple vaccination strategies against EBOV have faced obstacles including safety concerns, pre-existing vector immunity, and challenges related to manufacturing, dosage, or schedule. Therefore, there is a great need for additional vaccine candidates for prophylactic or therapeutic use against filoviruses such as Ebolavirus or Marburgvirus.
Claims Coverage
The patent claims include multiple independent claims covering compositions and methods related to recombinant multivalent rabies virus vectors expressing filovirus glycoproteins and their pharmaceutical formulations, protective immune responses, and related therapeutic methods.
Recombinant multivalent rabies virus vector composition
A composition comprising a therapeutically effective amount of a recombinant multivalent rabies virus vector encoding at least one filovirus glycoprotein incorporated into the rabies virus virion, where the rabies virus genome is attenuated, and which induces protective immune responses including neutralizing antibodies against rabies virus and filovirus infections.
Filovirus glycoprotein specificity and sequences
The filovirus glycoprotein encoded is from Ebolavirus or Marburgvirus, including Zaire, Sudan, Cote d'Ivoire, Reston, Bundibugyo Ebolavirus species or Marburgvirus, with amino acid sequences as set forth in SEQ ID NOS: 1-6.
Rabies virus vector derivation and additional filovirus proteins
The rabies virus vector is derived from the live attenuated SAD B19 RABV vaccine, optionally further expressing additional filovirus proteins selected from nucleoprotein (NP), VP40, VP35, VP30, VP24, and RNA-dependent RNA polymerase (L) of Ebolavirus or Marburgvirus.
Multivalent immunogenic composition
A therapeutically effective amount of recombinant rabies virus vector expressing at least one filovirus glycoprotein incorporated into the attenuated rabies virion, inducing immune responses protective against rabies virus and filovirus including neutralizing antibodies.
Pharmaceutical compositions and combination therapies
Pharmaceutical compositions comprising the recombinant rabies virus vector compositions with pharmaceutically acceptable carriers, optionally combined with additional therapeutic agents such as anti-viral drugs, antibodies, immunostimulatory agents, or adjuvants.
Methods of treatment and immune response induction
Methods of treating subjects infected with filovirus and/or rabies virus by administering therapeutically effective amounts of the claimed compositions; methods of inducing protective immune responses and neutralizing antibodies against filovirus and rabies virus infections via administration of the compositions.
The claims cover recombinant attenuated rabies virus vectors expressing filovirus glycoproteins incorporated into virions, pharmaceutical compositions thereof, methods of inducing immune responses and treating infections, and inclusion of additional filovirus proteins and therapeutic agents, with specific embodiments based on known glycoprotein sequences and vaccine strains.
Stated Advantages
Bivalent (multivalent) vaccine capable of simultaneous induction of immune responses against both rabies and filoviruses as a single therapeutic/immunization agent.
Utilizes an attenuated rabies virus vaccine vector with a good safety record, including derivatives with greatly reduced neurovirulence.
Vaccine constructs induce both humoral and cellular immunity against rabies virus and filoviruses.
The recombinant vectors can be live attenuated, replication-deficient, or chemically inactivated, allowing for flexibility in vaccine design with potential for rapid development and enhanced safety.
Inactivated vaccine formulations incorporate filovirus glycoproteins into rabies virions, enabling traditional killed vaccines with a strong safety profile.
The platform enables combination with other vaccine antigens for multivalent immunization without loss of immune response.
Pre-existing immunity to rabies virus does not substantially interfere with induction of filovirus-specific immune responses.
Potential for cost-effective production and distribution leveraging existing rabies vaccine manufacturing and safety knowledge.
Documented Applications
Prophylactic vaccination to induce protective humoral and cellular immune responses against subsequent infections by rabies virus and/or filoviruses such as Ebolavirus and Marburgvirus.
Therapeutic use to treat existing infections with rabies virus and/or filoviruses, neutralizing or clearing infecting agents and ameliorating symptoms.
Development of multivalent vaccines for use in humans, nonhuman primates, and animals.
Use in wildlife vaccination for endangered nonhuman primates as a conservation measure against filovirus outbreaks.
Development of diagnostic kits and methods utilizing vaccine antigens to detect the presence of antibodies raised against rabies and/or filoviruses in samples.
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