Recombinant subunit dengue virus vaccine
The present invention provides dengue virus vaccines and immunogenic compositions for administration to human subjects. The vaccine compositions of the present invention comprise recombinantly produced monomeric and/or dimeric forms of truncated dengue virus envelope glycoprotein that, when formulated together with an adjuvant and a pharmaceutically acceptable carrier, induce balanced tetravalent immune responses. In preferred embodiments of the compositions described herein, the DEN4 protein component is a dimeric form of DEN4. The compositions are designed to be acceptable for use in the general population, including immunosuppressed, immunocompromised, and immunosenescent individuals. Also provided herein are methods of inducing a protective immune response in a human patient population by administering the compositions described herein to the patients.
1. A method for raising an immune response in a human patient, the method comprising administering a therapeutically effect amount of an immunogenic composition to the patient, wherein the immunogenic composition comprises an effective amount of purified dengue virus envelope (“E”) protein monomers of serotype DEN-1, DEN-2, DEN-3, and DEN-4, a pharmaceutically acceptable excipient, and an effective amount of adjuvant; wherein the E proteins each constitute approximately 80% of the length of wild type E starting from amino acid residue 1 at its N-terminus, such that said E protein is secretable into growth medium when expressed recombinantly in a host cell; wherein the amount of DEN4 E protein is about 1.5 to about 3 times the individual amounts of DEN1, DEN2, and DEN3 E proteins, and wherein the composition induces the production of neutralizing antibodies in human subjects.
2. A method of producing neutralizing antibodies in a human subject against all four dengue serotypes comprising administering to the subject an effective amount of an immunogenic composition, wherein the immunogenic composition comprises an effective amount of purified dengue virus envelope (“E”) protein monomers of serotype DEN-1, DEN-2, DEN-3, and DEN-4, a pharmaceutically acceptable excipient, and an effective amount of adjuvant; wherein the E proteins each constitute approximately 80% of the length of wild type E starting from amino acid residue 1 at its N-terminus, such that said E protein is secretable into growth medium when expressed recombinantly in a host cell; wherein the amount of DEN4 E protein is about 1.5 to about 3 times the individual amounts of DEN1, DEN2, and DEN3 E proteins, and wherein the composition induces the production of neutralizing antibodies the human subject against all four dengue serotypes.
3. The method of claim 1 , wherein the amount of DEN4 protein is about twice the individual amount of DEN1, DEN2, and DEN3 proteins in the composition.
4. The method of claim 3 , wherein the composition is administered via an intramuscular, subcutaneous or intradermal route of administration.
5. The method of claim 2 , wherein the amount of DEN4 protein is about twice the individual amount of DEN1, DEN2, and DEN3 proteins in the composition.
6. The method of claim 5 , wherein the composition is administered via an intramuscular, subcutaneous or intradermal route of administration.
7. The method of claim 1 , wherein the composition induces the production of neutralizing antibodies in human subjects against DEN1, DEN2, DEN3, and DEN4 serotypes.
8. The method of claim 7 , wherein the composition induces the production of balanced specific neutralizing antibodies in human subjects against DEN1, DEN2, DEN3, and DEN4 serotypes.
9. The method of claim 2 , wherein the composition induces the production of balanced specific neutralizing antibodies in human subjects against DEN1, DEN2, DEN3, and DEN4 serotypes.