Compositions and Methods for Generating an Immune Response to a Flavivirus

Abstract

The compositions and methods are described for generating an immune response to a flavivirus such as Zika virus. The compositions and methods described herein relate to a modified vaccinia Ankara (MVA) vector encoding one or more viral antigens for generating a protective immune response to a member of genus Flavivirus (such as a member of species Zika virus), in the subject to which the vector is administered. The compositions and methods of the present invention are useful both prophylactically and therapeutically and may be used to prevent and/or treat an infection caused by Flavivirus.

1 . A recombinant modified vaccinia Ankara (MVA) vector comprising at least one nucleic acid sequence encoding at least one  Flavivirus  protein, wherein the at least one nucleic acid sequence is inserted into the MVA vector under the control of at least one promoter compatible with poxvirus expression systems. 
     
     
         2 . The recombinant MVA vector of  claim 1  wherein the recombinant modified vaccinia Ankara (MVA) vector comprises a first nucleic acid sequence encoding a  Flavivirus  structural protein and a second nucleic acid sequence encoding a  Flavivirus  nonstructural (NS) protein, wherein both the first nucleic acid sequence and the second nucleic acid sequence are inserted into the MVA vector under the control of promoters compatible with poxvirus expression systems. 
     
     
         3 . The recombinant MVA vector of  claim 2 , wherein the  Flavivirus  structural protein selected from premembrane-E (PrM-E), soluble E without a transmembrane domain, E protein domain I, E protein domain II, or E protein domain, III, PrM, and fragments thereof. 
     
     
         4 . The recombinant MVA vector of  claim 2 , wherein the  Flavivirus  non-structural protein selected from NS1, NS2A, NS2B, NS3, NS4A, NS4B or NS5. 
     
     
         5 . The recombinant MVA vector of  claim 2 , wherein the  Flavivirus  non-structural protein is t NS1. 
     
     
         6 . The recombinant MVA vector of  claim 2 , wherein the  Flavivirus  structural protein is premembrane-E sequence and the first nucleic acid sequence is inserted into a deletion site selected from I, II, III, IV, V or VI; and wherein the second nucleic acid sequence is inserted into a deletion site selected from I, II, III, IV, V or VI. 
     
     
         7 . The recombinant MVA vector of  claim 2 , wherein the  Flavivirus  structural protein is premembrane-E sequence and the first nucleic acid sequence is inserted between two essential and highly conserved MVA genes; and wherein the second nucleic acid sequence is inserted into a restructured and modified deletion III. 
     
     
         8 . The recombinant MVA vector of  claim 2 , wherein the  Flavivirus  structural protein is premembrane-E protein sequence, and the first nucleic acid sequence is inserted between MVA genes, I8R and G1L. 
     
     
         9 . The recombinant MVA vector of  claim 1 , wherein the at least one promoter is selected from the group consisting of Pm2H5, Psyn II, and mH5 promoters or combinations thereof. 
     
     
         10 . The recombinant MVA vector of  claim 2 , wherein the  Flavivirus  protein structural protein sequence is a premembrane-E sequence and both the premembrane E-sequence and the non-structural protein sequence are from a  flavivirus  species. 
     
     
         11 . A pharmaceutical composition comprising a recombinant MVA vector comprising a first nucleic acid sequence encoding a  Flavivirus  structural protein and a second nucleic acid sequence encoding a  Flavivirus  non-structural (NS) protein, wherein both the first and second nucleic acid sequences are inserted into the MVA vector under the control of promoters compatible with poxvirus expression systems. 
     
     
         12 . The pharmaceutical composition of  claim 10 , wherein the recombinant MVA vector is formulated for intraperitoneal, intramuscular, intradermal, epidermal, mucosal or intravenous administration. 
     
     
         13 . A method of inducing an immune response in a subject in need thereof, said method comprising administering to the subject an amount of a recombinant MVA vector effective to induce an immune response, wherein the recombinant MVA vector comprises a first nucleic acid sequence encoding a  Flavivirus  structural protein and a second nucleic acid sequence encoding a  Flavivirus  nonstructural (NS) protein, and
 wherein both the first and second nucleic acid sequences are inserted into the MVA vector under the control of promoters compatible with poxvirus expression systems.   
     
     
         14 . The method of  claim 12 , wherein the immune response is a humoral immune response, a cellular immune response or a combination thereof. 
     
     
         15 . The method of  claim 12 , wherein the immune response comprises production of binding antibodies against the  flavivirus.    
     
     
         16 . The method of  claim 12 , wherein the immune response comprises production of neutralizing antibodies against the  flavivirus.    
     
     
         17 . The method of  claim 12 , wherein the immune response comprises production of a cell-mediated immune response against the  flavivirus.    
     
     
         18 . A method of treating a Flaviviridae virus infection in a subject in need thereof, said method comprising administering to the subject an amount of a recombinant MVA vector effective to induce an immune response, wherein the recombinant MVA vector comprises a first nucleic acid sequence encoding a  Flavivirus  structural protein and a second nucleic acid sequence encoding a  Flavivirus  nonstructural (NS) protein sequence, and
 wherein both the first and second nucleic acid sequences are inserted into the MVA vector under the control of promoters compatible with poxvirus expression systems.   
     
     
         19 . The method of  claim 17 , wherein the Flaviviridae virus infection is caused by a Zika virus. 
     
     
         20 . The method of  claim 17 , wherein the subject is exposed to Flaviviridae virus, but not yet symptomatic of Flaviviridae virus infection. 
     
     
         21 . (canceled)