Human Cytomegalovirus Immunogenic Composition

Abstract

The invention relates to an immunogenic composition comprising an HCMV gH/gL/UL128/UL130/UL131 pentameric complex antigen and a TH1-inducing adjuvant. It further relates to the immunogenic composition for use as an HCMV vaccine.

1 . An immunogenic composition comprising:
 an HCMV gB antigen;   an HCMV gH/gL/UL128/UL130/UL131 pentameric complex antigen; and   a Th1-inducing adjuvant comprising a TLR-4 agonist;   wherein said HCMV gB antigen is a full length gB polypeptide lacking at least a portion of a transmembrane domain of the gB polypeptide, a full length gB polypeptide lacking at least 80% of the amino acid sequence of the transmembrane domain or a full length gB polypeptide lacking at least 80% of the amino acid sequences of both the transmembrane domain and the intracellular domain and   wherein, in said HCMV gH/gL/UL128/UL130/UL131 pentameric complex antigen, the gH antigen lacks at least a portion of a transmembrane domain of the full length gH.   
     
     
         2 . The immunogenic composition according to  claim 1 , wherein said Th1-inducing adjuvant induces in mice a lower IgG1:IgG2a,c ratio, and/or a higher INF-y level, and/or a lower IL-5 level than MF59 in a composition comprising the same HCMV gB antigen and the same HCMV gH/gL/UL128/UL130/UL131 pentameric complex antigen. 
     
     
         3 . (canceled) 
     
     
         4 . The immunogenic composition according to  claim 1 , wherein said TLR-4 agonist is selected from the group consisting of a lipopolysaccharide, a monophosphoryl lipid A (MPL), a 3-de-O-acylated monophosphoryl lipid A (3D-MPL), a glucopyranosyl lipid adjuvant (GLA), a second-generation Lipid Adjuvant (SLA), a phospholipid dimer connected by a noncarbohydrate backbone and an aminoalkyl glucosaminide phosphate, or a derivative thereof. 
     
     
         5 . (canceled) 
     
     
         6 . The immunogenic composition according to  claim 1 , wherein said TLR4 agonist is in combination with a delivery system such as aqueous nanosuspension, calcium phosphate, liposomes, virosomes, ISCOMs, micro- and nanoparticles, or emulsions. 
     
     
         7 . The immunogenic composition according to  claim 6 , wherein said delivery system is an oil-in-water emulsion. 
     
     
         8 . The immunogenic composition according to  claim 1 , wherein said TLR-4 agonist is chosen from E6020 (CAS number: 287180-63-6) and a GLA (CAS Number 1246928-63-4) TLR-4 agonist. 
     
     
         9 . An immunogenic composition comprising:
 an HCMV gB antigen:   an HCMV gH/gL/UL128/UL130/UL131 pentameric complex antigen, and   a Th1-inducing adjuvant, wherein said Th-1 inducing adjuvant comprises a linear or branched polyacrylic acid polymer salt with a weight average molecular weight Mw in the range of 350 to 650 kDa, and   wherein said HCMV gB antigen is a full length gB polypeptide lacking at least a portion of a transmembrane domain of the gB polypeptide, a full length gB polypeptide lacking at least 80% of the amino acid sequence of the transmembrane domain or a full length gB polypeptide lacking at least 80% of the amino acid sequences of both the transmembrane domain and the intracellular domain and   wherein, in said HCMV gH/gL/UL128/UL130/UL131 pentameric complex antigen, the gH antigen lacks at least a portion of a transmembrane domain of the full length gH.   
     
     
         10 . The immunogenic composition according to  claim 9 , wherein said linear or branched polyacrylic acid polymer salt is PAA225000. 
     
     
         11 . The immunogenic composition according to  claim 1 , wherein said HCMV gB antigen comprises one or several mutations at the endoproteolytic cleavage site. 
     
     
         12 . (canceled) 
     
     
         13 . The immunogenic composition according to  claim 1 , wherein said HCMV gB antigen is gBdTm. 
     
     
         14 . The immunogenic composition according to  claim 1 , wherein in the said HCMV gH/gL/UL128/UL130/UL131 pentameric complex antigen, the gH antigen lacks all at least 80% of the amino acid sequence of the transmembrane domain. 
     
     
         15 . The immunogenic composition according to  claim 14 , wherein said gH comprises the ectodomain of the full length gH encoded by UL75 gene. 
     
     
         16 . The immunogenic composition according to  claim 1 , wherein the HCMV gB and the HCMV gH/gL/UL128/UL130/UL131 pentameric complex are the sole HCMV antigens. 
     
     
         17 . A HCMV vaccine comprising the immunogenic composition according to  claim 1 . 
     
     
         18 . The HCMV vaccine according to  claim 17 , wherein said vaccine increases neutralizing antibody levels and/or persistence. 
     
     
         19 . The immunogenic composition according to  claim 6 , wherein TLR-4 agonist in combination with a delivery system is AS01 or AS02. 
     
     
         20 . A method for preventing HCMV infection in a patient in need thereof, comprising the administration of an immunologically effective amount of the immunogenic composition according to  claim 1 . 
     
     
         21 . The immunogenic composition according to  claim 6 , wherein said delivery system is liposomes. 
     
     
         22 . A kit comprising:
 (i) a first kit component comprising an HCMV gB antigen and an HCMV gH/gL/UL128/UL130/UL131 pentameric complex antigen,   wherein said HCMV gB antigen is a full length gB polypeptide lacking at least a portion of a transmembrane domain of the gB polypeptide, a full length gB polypeptide lacking at least 80% of the amino acid sequence of the transmembrane domain or a full length gB polypeptide lacking at least 80% of the amino acid sequences of both the transmembrane domain and the intracellular domain and   wherein, in said HCMV gH/gL/UL128/UL130/UL131 pentameric complex antigen, the gH antigen lacks at least a portion of a transmembrane domain of the full length gH; and   (ii) a second kit component comprising a Th-1 inducing adjuvant, wherein the Th-1 inducing adjuvant comprises a TLR-4 agonist.   
     
     
         23 . A method of treating a subject in need thereof comprising administering a therapeutically effective amount of the immunogenic composition of  claim 1  to the subject.