Dengue vaccine unit dose and administration thereof

Abstract

The invention relates to a unit dose of a dengue vaccine composition and methods and uses for preventing dengue disease and methods for stimulating an immune response to all four dengue virus serotypes in a subject or subject population. The unit dose of a dengue vaccine composition includes constructs of each dengue serotype, such as TDV-1, TDV-2, TDV-3 and TDV-4, at various concentrations in order to improve protection from dengue infection.

1 . (canceled) 
     
     
         2 . A method for vaccinating against dengue disease in a subject or a subject population, the method comprising administering to the subject or subject population a dengue virus composition that results in a vaccine efficacy of at least 60% against dengue serotype 2 which is represented by at least 60% reduction in dengue disease occurrence attributed to dengue serotype 2 in vaccinated subjects compared to unvaccinated subjects. 
     
     
         3 . The method according to  claim 2 , wherein the dengue virus composition comprises
 a non-chimeric dengue serotype 2 virus comprising a nucleotide sequence operable to encode an amino acid sequence of SEQ ID NO: 4.   
     
     
         4 . The method according to  claim 3 , wherein the dengue virus composition comprises a non-chimeric dengue serotype 2 virus derived from the wild type virus strain DEN-2 16681 and differs in at least three nucleotides from the wild type as follows:
 a) 5′-noncoding region (NCR)-57,   b) NS1-53 Gly-to-Asp, and   c) NS3-250 Glu-to-Val.   
     
     
         5 . The method according to  claim 2 , wherein the dengue virus composition comprises a non-chimeric dengue serotype 2 virus comprising the structural proteins provided in the amino acid sequence of SEQ ID NO: 4. 
     
     
         6 . The method according to  claim 2 , wherein the dengue virus composition comprises a non-chimeric dengue serotype 2 virus comprising a nucleotide sequence according to SEQ ID NO: 3 
     
     
         7 . The method according to  claim 2 , wherein the dengue virus composition comprises four live attenuated dengue virus serotypes defined by a dengue serotype 1 virus strain, a non-chimeric dengue serotype 2 virus strain, a dengue serotype 3 virus strain, and a dengue serotype 4 virus strain, wherein each of the serotypes 1, 3 and 4 are each independently a non-chimeric or chimeric dengue virus. 
     
     
         8 . The method according to  claim 7 , wherein the dengue virus composition is lyophilized and upon reconstitution with 0.5 mL of at least one pharmaceutically acceptable diluent comprises:
 (i) the dengue serotype 1 virus strain having a concentration of 3.3 log 10 pfu/0.5 mL to 5.0 log 10 pfu/0.5 mL,   (ii) the non-chimeric dengue serotype 2 virus strain having a concentration of 2.7 log 10 pfu/0.5 mL to 4.9 log 10 pfu/0.5 mL,   (iii) the dengue serotype 3 virus strain having a concentration of 4.0 log 10 pfu/0.5 mL to 5.7 log 10 pfu/0.5 mL, and   (iv) the dengue serotype 4 virus strain having a concentration of 4.5 log 10 pfu/0.5 mL to 6.2 log 10 pfu/0.5 mL.   
     
     
         9 . The method according to  claim 7 , wherein the dengue virus composition is lyophilized and upon reconstitution with 0.5 mL of at least one pharmaceutically acceptable diluent, the dengue virus composition comprises:
 (i) the dengue serotype 1 virus strain having a concentration of at least 3.3 log 10 pfu/0.5 mL,   (ii) the non-chimeric dengue serotype 2 virus strain having a concentration of at least 2.7 log 10 pfu/0.5 mL,   (iii) the dengue serotype 3 virus strain having a concentration of at least 4.0 log 10 pfu/0.5 mL, and   (iv) the dengue serotype 4 virus strain having a concentration of at least 4.5 log 10 pfu/0.5 mL.   
     
     
         10 . The method according to  claim 7 , wherein the four live attenuated dengue virus serotypes are defined by at least one of the following:
 (1) the non-chimeric dengue serotype 2 virus strain is derived from the wild type virus strain DEN-2 16681 and differs in at least three nucleotides from the wild type as follows:
 a) 5′-noncoding region (NCR)-57, 
 b) NS1-53 Gly-to-Asp, and 
 c) NS3-250 Glu-to-Val; and 
 three chimeric dengue virus strains are derived from the dengue serotype 2 virus strain by replacing the structural proteins prM and E from the dengue serotype 2 virus strain with the corresponding structural proteins from the other dengue serotypes, resulting in the following chimeric dengue virus strains: 
 a chimeric dengue serotype 2/1 virus strain, 
 a chimeric dengue serotype 2/3 virus strain, and 
 a chimeric dengue serotype 2/4 virus strain; 
   (2) the dengue serotype 1 virus strain is a chimeric dengue serotype 2/1 virus strain, the dengue serotype 3 virus strain is a chimeric dengue serotype 2/3 virus strain, and the dengue serotype 4 virus strain is a chimeric dengue serotype 2/4 virus strain; wherein
 the chimeric dengue serotype 2/1 virus strain comprises a nucleotide sequence according to SEQ ID NO: 1, 
 the non-chimeric dengue serotype 2 virus strain comprises a nucleotide sequence according to SEQ ID NO: 3, 
 the chimeric dengue serotype 2/3 virus strain comprises a nucleotide sequence according to SEQ ID NO: 5, and 
 the chimeric dengue serotype 2/4 virus strain comprises a nucleotide sequence according to SEQ ID NO: 7; 
   (3) the dengue serotype 1 virus strain is a chimeric dengue serotype 2/1 virus strain, the dengue serotype 3 virus strain is a chimeric dengue serotype 2/3 virus strain, and the dengue serotype 4 virus strain is a chimeric dengue serotype 2/4 virus strain; wherein
 the chimeric dengue serotype 2/1 virus strain comprises the structural proteins provided in the amino acid sequence of SEQ ID NO: 2, 
 the non-chimeric dengue serotype 2 virus strain comprises the structural proteins provided in the amino acid sequence of SEQ ID NO: 4, 
 the chimeric dengue serotype 2/3 virus strain comprises the structural proteins provided in the amino acid sequence of SEQ ID NO: 6, and 
 the chimeric dengue serotype 2/4 s virus train comprises the structural proteins provided in the amino acid sequence of SEQ ID NO: 8, and 
   (4) the dengue serotype 1 virus strain is a chimeric dengue serotype 2/1 virus strain, the dengue serotype 3 virus strain is a chimeric dengue serotype 2/3 virus strain, and the dengue serotype 4 virus strain is a chimeric dengue serotype 2/4 virus strain; wherein
 the chimeric dengue serotype 2/1 virus strain comprises a nucleotide sequence encoding the amino acid sequence SEQ ID NO: 2, 
 the non-chimeric dengue serotype 2 virus strain comprises a nucleotide sequence encoding the amino acid sequence SEQ ID NO: 4, 
 the chimeric dengue serotype 2/3 virus strain comprises a nucleotide sequence encoding the amino acid sequence SEQ ID NO: 6, and 
 the chimeric dengue serotype 2/4 virus strain comprises a nucleotide sequence encoding the amino acid sequence SEQ ID NO: 8. 
   
     
     
         11 . The method according to  claim 10 , wherein the dengue virus composition is lyophilized and upon reconstitution with 0.5 mL of at least one pharmaceutically acceptable diluent, (i), (ii), (iii), and (iv) provide a total concentration of pfu/0.5 ml and based on said total concentration of pfu/0.5 ml, the concentration of (i) in pfu/0.5 ml is at least 1%, the concentration of (ii) in pfu/0.5 ml is less than 10%, the concentration of (iii) in pfu/0.5 ml is at least 10%, and the concentration of (iv) in pfu/0.5 ml is at least 50%. 
     
     
         12 . The method according to  claim 11 , wherein based on said total concentration of pfu/0.5 mL, the concentration of (iii) in pfu/0.5 ml is at least 12%, or at least 14%, or at least 16%, or at least 18%. 
     
     
         13 . The method according to  claim 11 , wherein the dengue virus composition comprises:
 (i) the chimeric dengue serotype 2/1 strain in a concentration of at least 3.3 log 10 pfu/0.5 mL to 3.8 log 10 pfu/0.5 mL,   (ii) the non-chimeric dengue serotype 2 strain in a concentration of at least 2.7 log 10 pfu/0.5 mL,   (iii) the chimeric dengue serotype 2/3 strain in a concentration of at least 4.0 log 10 pfu/0.5 mL, and   (iv) the chimeric dengue serotype 2/4 strain in a concentration of at least 4.5 log 10 pfu/0.5 mL or at least 4.6 log 10 pfu/0.5 mL to optionally 6.2 log 10 pfu/0.5 mL.   
     
     
         14 . The method according to  claim 2 , wherein the dengue virus composition comprises a non-reducing sugar, a surfactant, a protein, and an inorganic salt. 
     
     
         15 . The method according to  claim 14 , wherein the dengue virus composition comprises trehalose, poloxamer 407, human serum albumin, and sodium chloride. 
     
     
         16 . The method according to  claim 15 , wherein the dengue virus composition comprises from about 143 mg/mL to about 185 mg/mL α,α-trehalose dihydrate or an equimolar amount of other forms of α,α-trehalose, from about 9.1 mg/mL to about 12.4 mg/mL poloxamer 407, from about 0.88 mg/mL to about 1.32 mg/mL human serum albumin, and from about 70 mM to 140 mM sodium chloride, when measured in 0.5 mL. 
     
     
         17 . The method according to  claim 2 , wherein the method further comprises a second administration of the dengue virus composition to the subject or the subject population, wherein the second administration is within 3 months of, and at least 4 weeks following, the administration of the dengue virus composition. 
     
     
         18 . The method according to  claim 2 , wherein the subject or subject population is between the ages of 2 months and 60 years of age. 
     
     
         19 . The method according to  claim 18 , wherein the subject or subject population is 4 to 60 years of age. 
     
     
         20 . The method according to  claim 2 , wherein the subject or subject population is from a dengue endemic region. 
     
     
         21 . The method of  claim 2 , wherein the subject or subject population is from a dengue non-endemic region. 
     
     
         22 . A method for vaccinating against dengue disease in a subject or a subject population in each of seropositive subjects and seronegative subjects, the method comprising administering to the subject or subject population, a dengue virus composition that results in a vaccine efficacy of at least 60% against dengue serotype 2, wherein the dengue virus composition comprises a non-chimeric dengue serotype 2 comprising a nucleotide sequence operable to encode an amino acid sequence of SEQ ID NO: 4. 
     
     
         23 . The method according to  claim 22 , wherein administering to a subject at least one dose of the dengue virus composition comprises administering a first dose of the dengue virus composition to the subject and administering a second dose of the dengue virus composition to the subject within 3 months of the administration of the first dose, wherein the subject is a human subject aged between 4 years and 60 years of age. 
     
     
         24 . The method according to  claim 23 , wherein the dengue virus composition comprises four live attenuated dengue virus serotypes:
 (i) a chimeric dengue serotype 2/1 strain,   (ii) the non-chimeric dengue serotype 2 strain,   (iii) a chimeric dengue serotype 2/3 strain, and   (iv) a chimeric dengue serotype 2/4 strain.   
     
     
         25 . The method according to  claim 24 , wherein the method provides a combined vaccine efficacy of at least 60% against dengue serotype 2 in each of seropositive subjects and seronegative subjects, for at least 12 months after a second unit dose administration, by administering to a subject population of seropositive subjects, seronegative subjects, or a combination thereof a dengue virus composition, wherein the four live attenuated dengue virus serotypes comprise:
 (1) the non-chimeric dengue serotype 2 virus strain which is derived from the wild type virus strain DEN-2 16681 and differs in at least three nucleotides from the wild type as follows:
 a) 5′-noncoding region (NCR)-57, 
 b) NS1-53 Gly-to-Asp, and 
 c) NS3-250 Glu-to-Val; and 
 wherein the three chimeric dengue virus strains are derived from the non-chimeric dengue serotype 2 virus strain by replacing the structural proteins prM and E from the non-chimeric dengue serotype 2 virus strain with the corresponding structural proteins from the other dengue serotypes, resulting in the following chimeric dengue virus strains: 
 the chimeric dengue serotype 2/1 virus strain, 
 the chimeric dengue serotype 2/3 virus strain, and 
 the chimeric dengue serotype 2/4 virus strain; 
   (2) the chimeric dengue serotype 2/1 virus strain comprises a nucleotide sequence according to SEQ ID NO: 1,
 the non-chimeric dengue serotype 2 virus strain comprises a nucleotide sequence according to SEQ ID NO: 3, 
 the chimeric dengue serotype 2/3 virus strain comprises a nucleotide sequence according to SEQ ID NO: 5, and 
 the chimeric dengue serotype 2/4 virus strain comprises a nucleotide sequence according to SEQ ID NO: 7; 
   (3) the chimeric dengue serotype 2/1 virus strain comprises the structural proteins provided in the amino acid sequence of SEQ ID NO: 2,
 the non-chimeric dengue serotype 2 virus strain comprises the structural proteins provided in the amino acid sequence of SEQ ID NO: 4, 
 the chimeric dengue serotype 2/3 virus strain comprises the structural proteins provided in the amino acid sequence of SEQ ID NO: 6, and 
 the chimeric dengue serotype 2/4 s virus strain comprises the structural proteins provided in the amino acid sequence of SEQ ID NO: 8, and 
   (4) the chimeric dengue serotype 2/1 virus strain comprises a nucleotide sequence encoding the amino acid sequence SEQ ID NO: 2,
 the non-chimeric dengue serotype 2 virus strain comprises a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 4, 
 the chimeric dengue serotype 2/3 virus strain comprises a nucleotide sequence encoding the amino acid sequence SEQ ID NO: 6, and 
 the chimeric dengue serotype 2/4 virus strain comprises a nucleotide sequence encoding the amino acid sequence SEQ ID NO: 8. 
   
     
     
         26 . The method according to  claim 25 , wherein the dengue virus composition is lyophilized and upon reconstitution with 0.5 mL of at least one pharmaceutically acceptable diluent, (i), (ii), (iii), and (iv) provide a total concentration of pfu/0.5 ml and based on said total concentration of pfu/0.5 ml, the concentration of (i) in pfu/0.5 ml is at least 1%, the concentration of (ii) in pfu/0.5 ml is less than 10%, the concentration of (iii) in pfu/0.5 ml is at least 10%, and the concentration of (iv) in pfu/0.5 ml is at least 50%. 
     
     
         27 . The method according to  claim 26 , wherein based on said total concentration of pfu/0.5 mL, the concentration of (iii) in pfu/0.5 ml is at least 12%, or at least 14%, or at least 16%, or at least 18%. 
     
     
         28 . The method according to  claim 26 , wherein the dengue virus composition comprises:
 (i) the chimeric dengue serotype 2/1 strain in a concentration of at least 3.3 log 10 pfu/0.5 mL to 3.8 log 10 pfu/0.5 mL,   (ii) the non-chimeric dengue serotype 2 strain in a concentration of at least 2.7 log 10 pfu/0.5 mL,   (iii) the chimeric dengue serotype 2/3 strain in a concentration of at least 4.0 log 10 pfu/0.5 mL, and   (iv) the chimeric dengue serotype 2/4 strain in a concentration of at least 4.5 log 10 pfu/0.5 mL or at least 4.6 log 10 pfu/0.5 mL to optionally 6.2 log 10 pfu/0.5 mL.   
     
     
         29 . The method according to  claim 21 , wherein the dengue virus composition comprises a non-reducing sugar, a surfactant, a protein, and an inorganic salt. 
     
     
         30 . The method according to  claim 29 , wherein the dengue virus composition comprises trehalose, poloxamer 407, human serum albumin, and sodium chloride. 
     
     
         31 . The method according to  claim 30 , wherein the dengue virus composition comprises from about 143 mg/mL to about 185 mg/mL α,α-trehalose dihydrate or an equimolar amount of other forms of α,α-trehalose, from about 9.1 mg/mL to about 12.4 mg/mL poloxamer 407, from about 0.88 mg/mL to about 1.32 mg/mL human serum albumin, and from about 70 mM to 140 mM sodium chloride, when measured in 0.5 mL. 
     
     
         32 . The method according to  claim 22 , wherein the method further comprises administering a second unit dose of the dengue virus composition to the subject or the subject population, wherein the second unit dose is administered within 3 months of, and at least 4 weeks following the administration of the dengue vaccine composition. 
     
     
         33 . The method according to  claim 22 , wherein the subject or subject population is between the ages of 2 months and 60 years of age. 
     
     
         34 . The method according to  claim 32 , wherein the subject or subject population is 4 to 60 years of age. 
     
     
         35 . The method according to  claim 22 , wherein the subject or subject population is from a dengue endemic region. 
     
     
         36 . The method of  claim 22 , wherein the subject or subject population is from a dengue non-endemic region.