Compositions and methods of vaccination against dengue virus in children and young adults

Abstract

Embodiments herein concern compositions, methods, and uses for inducing an immune response to all four dengue virus serotypes in a child or young adult from about 1 year to about 20 years of age. Some embodiments concern compositions that can include dengue virus chimeras that, either alone or in combination with other constructs, can be used in vaccine compositions against all four dengue virus serotypes. Compositions can include constructs of more than one serotypes of dengue virus, such as dengue-1 (DEN-1) virus, dengue-2 (DEN-2) virus, dengue-3 (DEN-3) virus and/or dengue-4 (DEN-4) virus, at various concentrations or ratios to improve protection from infection in children and young adults. In certain embodiments, viruses of the formulations are limited to dengue virus serotypes. Other embodiments concern methods of administering immunogenic compositions against dengue virus that can include chimeric dengue constructs and live, attenuated dengue viruses using single, dual or other regimens.

1 - 32 . (canceled) 
     
     
         33 . A method for inducing immune seropositivity against two or more dengue virus serotypes in a plurality of human dengue naïve subjects or a plurality of human dengue immune subjects, each subject being from 1 year of age to less than 18 years of age, the method comprising:
 obtaining or preparing a tetravalent dengue vaccine composition ready for administration to the subject, wherein the composition includes all four dengue virus serotypes, including a dengue-2 virus serotype comprising a live, attenuated dengue-2 virus, a dengue-2/1 chimera,
 a dengue-2/3 chimera, and 
 a dengue-2/4 chimera, and 
 
 administering the composition subcutaneously to the subjects, 
 wherein administering the composition consists of administering a first dose of the composition on day 0, and administering a second dose of a same composition against dengue virus about 3 months after the first administration, 
 wherein the composition comprises a concentration of the live attenuated dengue-2 virus serotype being at least one half of a log plaque forming unit (PFU) lower than the log PFU of more than one of the other dengue virus serotypes, or a concentration of the dengue-2/3 chimera or dengue 2/4 chimera that is at least one half log greater than the log PFU of the dengue-2 virus serotype in the tetravalent dengue formulation, 
 wherein the dengue-2 virus serotype is in the form of the DENV-2 16681 derived DEN-2 PDK-53 variant, with a triple mutation at NS1-53, at 5′NC-57 and at NS3-250 such that an amino acid position 250 of the NS3 protein contains a valine residue, 
 wherein each of the dengue-2/1, dengue-2/3, and dengue-2/4 chimeras have said dengue-2 virus serotype as viral backbone and one or more structural protein genes encoding capsid, premembrane/membrane or envelope of said dengue-2 virus serotype or combinations thereof replaced with one or more corresponding structural protein genes from DEN-1, DEN-3 or DEN-4, respectively; and 
 wherein the administered tetravalent dengue vaccine composition in the human subjects provides a seropositivity rate of at least 50% against all four dengue serotypes at about day 30 after a single dose and wherein a seropositive subject is a subject having an MNT 50  titer≥10. 
 
     
     
         34 . The method according to  claim 33 , wherein the tetravalent dengue vaccine composition provides a seropositivity rate of at least 80% at day 28 after one dose against three dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11 years of age. 
     
     
         35 . The method according to  claim 33 , wherein the tetravalent dengue vaccine composition provides a seropositivity rate of at least 95% at day 28 after one dose against two dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11 years of age. 
     
     
         36 . The method according to  claim 33 , wherein the tetravalent dengue vaccine composition provides a seropositivity rate of at least 80% at day 120 after a second dose at day 90 against all four dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11 years of age. 
     
     
         37 . The method according to  claim 33 , wherein the tetravalent dengue vaccine composition provides a seropositivity rate of at least 90% at day 120 after a second dose at day 90 against three dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11 years of age. 
     
     
         38 . The method according to  claim 33 , wherein the tetravalent dengue vaccine composition provides a seropositivity rate of at least 95% at day 120 after a second dose at day 90 against two dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11 years of age. 
     
     
         39 . The method according to  claim 33 , wherein the tetravalent dengue vaccine composition comprises:
 a dengue-2/1 chimera having a concentration from about 1.0×10 3  to about 5×10 5  PFU;   a live, attenuated dengue-2 virus serotype having a concentration from about 1.0×10 3  to about 5×10 5  PFU   a dengue-2/3 chimera having a concentration from about 5.0×10 3  to about 5×10 5  PFU; and   a dengue-2/4 chimera having a concentration from about 1.0×10 4  to about 5×10 6  PFU.   
     
     
         40 . A tetravalent dengue vaccine composition comprising:
 (i) a live, attenuated dengue-2 virus serotype having the following mutations relative to the DENV-2 16681 derived DEN-2 PDK-53 variant: a triple mutation at NS1-53, a single mutation at 5′NC and a single mutation at NS3-250, such that the amino acid position 250 of the NS3 protein contains a valine residue; and at least one further mutation selected from the group consisting of:   a glutamic acid residue at position 52 of the prM protein; and   a valine residue at position 412 of the NS5 protein;   (ii) three chimera dengue strains, DENV-2/1 chimera, DENV-2/3 chimera, and DENV-2/4 chimera, wherein the DENV 2/1, DENV 2/3 and DENV 2/4 chimeras have a backbone derived from said live attenuated dengue-2 virus, wherein one or more of the structural protein genes encoding capsid, premembrane(prM) and envelope (E) of said live attenuated dengue-2 virus is replaced with one or more of the structural protein genes encoding capsid, premembrane (prM) and envelope (E) protein from dengue virus serotype 1; dengue virus serotype 3; or dengue virus serotype 4 respectively,   wherein the composition comprises a concentration of the live attenuated dengue-2 virus serotype being at least one half of a log plaque forming unit (PFU) lower than the log PFU of more than one of the other dengue virus serotypes, or a concentration of the dengue-2/3 chimera or dengue 2/4 chimera that is at least one half log greater than the log PFU of the dengue-2 virus serotype in the tetravalent dengue formulation;   and wherein the tetravalent dengue virus vaccine composition when administered to a plurality of human dengue naïve subjects or plurality of human dengue immune subjects, provides the subjects with a combined seropositivity rate of at least 50% against all four dengue serotypes at about day 30 after a single dose and wherein a seropositive subject is a subject having an MNT 50  titer≥10.   
     
     
         41 . The tetravalent dengue vaccine composition of  claim 40 , wherein the tetravalent dengue composition provides a seropositivity rate of at least 80% at day 28 after one dose against three dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11. 
     
     
         42 . The tetravalent dengue vaccine composition of  claim 40 , wherein the tetravalent dengue composition provides a seropositivity rate of at least 95% at day 28 after one dose against two dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 
     
     
         11 . 
     
     
         43 . The tetravalent dengue vaccine composition of  claim 40 , wherein the tetravalent dengue composition provides a seropositivity rate of at least 80% at day 120 after a second dose at day 90 against all four dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11. 
     
     
         44 . The tetravalent dengue vaccine composition of  claim 40 , wherein the tetravalent dengue composition provides a seropositivity rate of at least 90% at day 120 after a second dose at day 90 against three dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11. 
     
     
         45 . The tetravalent dengue vaccine composition of  claim 40 , wherein the tetravalent dengue composition provides a seropositivity rate of at least 95% at day 120 after a second dose at day 90 against two dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11. 
     
     
         46 . The tetravalent dengue vaccine composition of  claim 40 , comprising:
 a dengue-2/1 chimera having a concentration from about 1.0×10 3  to about 5×10 5  PFU;   a live, attenuated dengue-2 virus serotype having a concentration from about 1.0×10 3  to about 5×10 5  PFU   a dengue-2/3 chimera having a concentration from about 5.0×10 3  to about 5×10 5  PFU; and   a dengue-2/4 chimera having a concentration from about 1.0×10 4  to about 5×10 6  PFU.   
     
     
         47 . A method for inducing an immunogenic response against two or more dengue virus serotypes in a plurality of human dengue naïve subjects or plurality of human dengue immune subjects, each subject being from 1 year of age to less than 18 years of age, the method comprising:
 obtaining or preparing a tetravalent dengue vaccine composition ready for administration to the subject, wherein the composition includes all four dengue virus serotypes, 
 administering a first dose of the composition subcutaneously on day 0 to one or more of the subjects, 
 wherein administering the composition consists of: 
 administering the first dose of the composition, and administering a second dose of the composition about 3 months after the first administration, wherein the administered tetravalent dengue vaccine composition in the plurality of human dengue naïve subjects or the plurality of human dengue immune subjects provides a seropositivity rate of at least 50% against all four dengue serotypes at about day 180 after the first dose in vaccinated subjects compared to unvaccinated subjects, and wherein a seropositive subject is a subject having an MNT 50  titer≥10; 
 the tetravalent dengue virus composition comprising four dengue virus strains representing serotype 1, serotype 2, serotype 3 and serotype 4, represented by a chimeric dengue serotype 2/1 strain, a dengue serotype 2 strain, a chimeric dengue serotype 2/3 strain, and a chimeric dengue serotype 2/4 strain, the dengue serotype 2 strain being derived from the wild type virus strain DEN-2 16681 and differing in at least three nucleotides from the wild type as follows: 
 a) 5′-noncoding region (NCR)-57 (nt-57 C-to-T) 
 b) NS1-53 Gly-to-Asp (nt-2579 G-to-A) 
 c) NS3-250 Glu-to-Val (nt-5270 A-to-T); and 
 the three chimeric dengue strains being derived from the serotype 2 strain by replacing the structural proteins prM and E from serotype 2 strain with the corresponding structural proteins from the other dengue serotypes, resulting in the following chimeric dengue strains:
 a DENV-2/1 chimera, 
 a DENV-2/3 chimera and 
 a DENV-2/4 chimera; and 
 
 wherein the composition comprises a concentration of the live attenuated dengue-2 virus serotype being at least one half of a log plaque forming unit (PFU) lower than the log PFU of more than one of the other dengue virus serotypes, or a concentration of the dengue-2/3 chimera or dengue 2/4 chimera that is at least one half log greater than the log PFU of the dengue-2 virus serotype in the tetravalent dengue formulation. 
 
     
     
         48 . The method according to  claim 47 , wherein a concentration of the dengue-2/3 chimera is at least one-half a log greater in terms of PFUs than the dengue-2 virus serotype in the tetravalent vaccine formulation. 
     
     
         49 . The method according to  claim 47 , wherein the tetravalent dengue vaccine composition provides a seropositivity rate of at least 80% at day 28 after one dose against three dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11 years of age. 
     
     
         50 . The method according to  claim 47 , wherein the tetravalent dengue vaccine composition provides a seropositivity rate of at least 95% at day 28 after one dose against two dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11 years of age. 
     
     
         51 . The method according to  claim 50 , wherein the tetravalent dengue vaccine composition provides a seropositivity rate of at least 80% at day 120 after a second dose at day 90 against all four dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11 years of age. 
     
     
         52 . The method according to  claim 51 , wherein the tetravalent dengue vaccine composition provides a seropositivity rate of at least 90% at day 120 after a second dose at day 90 against three dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11 years of age. 
     
     
         53 . The method according to  claim 52 , wherein the tetravalent dengue vaccine composition provides a seropositivity rate of at least 95% at day 120 after a second dose at day 90 against two dengue serotypes when administered to dengue naïve or dengue immune subject aged 1.5 to 11 years of age. 
     
     
         54 . The method according to  claim 47 , wherein the tetravalent dengue vaccine composition comprises:
 a dengue-2/1 chimera having a concentration from about 1.0×10 3  to about 5×10 5  PFU;   a live, attenuated dengue-2 virus serotype having a concentration from about 1.0×10 3  to about 5×10 5  PFU   a dengue-2/3 chimera having a concentration from about 5.0×10 3  to about 5×10 5  PFU; and   a dengue-2/4 chimera having a concentration from about 1.0×10 4  to about 5×10 6  PFU.