Patent classifications
C12N2770/32621
RECOMBINANT ENTEROVIRUSES AND USES THEREOF
The present disclosure generally relates to, inter alia, to nucleic acid constructs encoding a modified enterovirus genome that is devoid of partial or complete nucleic acid sequences encoding viral structural proteins. The disclosure also provides compositions and methods useful for producing defective interfering particles (DIPs) of enteroviruses, and for the prevention and/or treatment of various health conditions such as immune diseases and viral infections.
NEWCASTLE DISEASE VIRUS-BASED VECTORED VACCINE
Provided are compositions and methods for vaccinating against picornaviruses. The compositions include modified Newcastle Disease viruses (NDVs) that are sufficient to produce virus-like particles (VLPs) in a host recipient. The modified NDVs contain a single stranded negative sense RNA polynucleotide having nucleotide sequences configured in a 3′-5′ direction encoding sequentially NDV nucleocapsid protein (NP), phosphoprotein (P), matrix protein (M), fusion protein (F), hemagglutinin-neuraminidase (HN) and RNA-dependent RNA polymerase (L) protein. A first nucleotide sequence encoding a picornavirus capsid polyprotein precursor is positioned between the between P and M nucleotide sequences. A second nucleotide sequence encoding a picornavirus protease that is capable of processing the capsid polyprotein precursor is positioned between the HN and L nucleotide sequences. Purified, infectious non-pathogenic NDV particles are included, as are methods for using such particles for vaccination against any infectious picornavirus. Kits and articles of manufacture containing and/or for making the NDV particles are also provided.
ATTENUATED VIRUSES USEFUL FOR VACCINES
This invention provides an attenuated virus which comprises a modified viral genome containing nucleotide substitutions engineered in multiple locations in the genome, wherein the substitutions introduce synonymous deoptimized codons into the genome. The instant attenuated virus may be used in a vaccine composition for inducing a protective immune response in a subject. The invention also provides a method of synthesizing the instant attenuated virus. Further, this invention further provides a method for preventing a subject from becoming afflicted with a virus-associated disease comprising administering to the subject a prophylactically effective dose of a vaccine composition comprising the instant attenuated virus.
NEOADJUVANT CANCER TREATMENT
Provided is a method of treating a tumor in an individual by neoadjuvant therapy, wherein the individual has not previously undergone treatment to effectively reduce tumor burden, the method comprising administering an oncolytic chimeric poliovirus construct, or an oncolytic chimeric poliovirus construct and an immune checkpoint inhibitor, followed by reduction of the tumor. The method may further comprise administration of immune checkpoint inhibitor or oncolytic chimeric poliovirus construct following reduction of tumor. Kits for performing the methods are also provided.
Combination Treatment
Human clinical use of a chimeric poliovirus construct has demonstrated excellent anti-tumor effect. Combination with immune checkpoint inhibitors increases the anti-tumor effect. Tumors of different types are susceptible to the combination treatment, including but not limited to melanoma, glioglastoma, renal cell carcinoma, prostate cancer, breast cancer, lung cancer, medulloblastoma, and colorectal cancer.
Combination treatment
Human clinical use of a chimeric poliovirus construct has demonstrated excellent anti-tumor effect. Combination with immune checkpoint inhibitors increases the anti-tumor effect. Tumors of different types are susceptible to the combination treatment, including but not limited to melanoma, glioglastoma, renal cell carcinoma, prostate cancer, breast cancer, lung cancer, medulloblastoma, and colorectal cancer.
METHODS FOR ENTEROVIRUS INACTIVATION, ADJUVANT ADSORPTION AND DOSE REDUCED VACCINE COMPOSITIONS OBTAINED THEREOF
The present invention is directed to improved methods of Enterovirus inactivation by formaldehyde in presence of tromethamine buffer resulting in maximum recovery of D-antigen. Subsequent adsorption of said sIPV on aluminium hydroxide provides significantly dose reduced sIPV compositions.
NEWCASTLE DISEASE VIRUS-BASED VECTORED VACCINE
Provided are compositions and methods for vaccinating against picornaviruses. The compositions include modified Newcastle Disease viruses (NDVs) that are sufficient to produce virus-like particles (VLPs) in a host recipient. The modified NDVs contain a single stranded negative sense RNA polynucleotide having nucleotide sequences configured in a 3-5 direction encoding sequentially NDV nucleocapsid protein (NP), phosphoprotein (P), matrix protein (M), fusion protein (F), hemagglutinin-neuraminidase (HN) and RNA-dependent RNA polymerase (L) protein. A first nucleotide sequence encoding a picornavirus capsid polyprotein precursor is positioned between the between P and M nucleotide sequences. A second nucleotide sequence encoding a picornavirus protease that is capable of processing the capsid polyprotein precursor is positioned between the HN and L nucleotide sequences. Purified, infectious non-pathogenic NDV particles are included, as are methods for using such particles for vaccination against any infectious picornavirus. Kits and articles of manufacture containing and/or for making the NDV particles are also provided.
MODIFIED PROTEIN ENCODING SEQUENCES HAVING INCREASED RARE HEXAMER CONTENT
This invention provides a modified protein encoding sequence containing nucleotide substitutions at multiple locations in the protein encoding sequence, wherein the substitutions introduce rare hexamers. These hexamers may be Frame Dependent, or depleted in only the reading frame, or Frame Independent, or depleted in all three frames. Modified protein encoding se quences of the present invention may include modified viruses useful for vaccines.
Cold-adapted-viral-attenuation (CAVA) and novel attenuated poliovirus strains
A poliovirus (PV) strain was attenuated by a novel method of Cold-Adapted-Viral-Attenuation (CAVA). The resulting recombinant attenuated PV, CAVA-PV, shows wild-type replication at 30 C., but no substantial replication at 37 C. The inability to replicate at 37 C. is defined by an inability to quantify virus during infection at this temperature by titration (infectious units), qPCR (viral RNA) or Electron Microscopy (visual signs of infection). CAVA-PV is genetically stable under production conditions and shows utility for use as the backbone to produce attenuated strains with the same antigenic profile as conventional vaccines by replacing the sequence coding for the capsid of CAVA-PV with sequences coding for capsids of different PV strains. Furthermore, mutations identified in CAVA-PV can be engineered into different, even wild-type and neurovirulent poliovirus background strains to obtain additional CAVA-PV strains.