PRIME-BOOST REGIMENS INVOLVING ADMINISTRATION OF AT LEAST ONE mRNA CONSTRUCT

Abstract

The present invention relates to novel prime-boost regimens that involve the administration of at least one mRNA construct, such as the use of such constructs in “boost” administration subsequently to “prime” administration of certain other antigenic composition(s). Such inventive regimens may, in particular, be useful for the induction of an immune response in a subject, and/or the vaccination of such subject against infection from one or more pathogens, and/or the treatment or prevention of one or more diseases or conditions, including a tumour or cancer, allergy or autoimmune conditions, and/or a disease or condition associated with infection from a pathogen. The present invention further describes methods, uses, vaccination compositions, kits and packaged vaccine components related to or useful for one or more of such regimens

1 . A second antigenic composition that comprises
 at least one mRNA construct that encodes at least one immunogenic peptide or polypeptide,   for use as a vaccine, wherein at least once an effective amount of the second antigenic composition is administered to a subject in need thereof subsequently to administration to the subject at least once of an effective amount of a first antigenic composition that comprises at least one immunogenic peptide or polypeptide and/or that comprises at least one nucleic acid construct that encodes at least one immunogenic peptide or polypeptide,   wherein:   the nucleic acid construct, if comprised in the first antigenic composition, is not an mRNA construct; and   at least one epitope of the immunogenic peptide or polypeptide comprised in, or encoded by the nucleic acid construct comprised in, the first antigenic composition is identical to or at least 70%, 75%, 80%, 85%, 90%, 95% or at least 98% identical to at least one epitope of the immunogenic peptide or polypeptide encoded by the mRNA construct of the second antigenic composition.   
     
     
         2 . A first antigenic composition that comprises
 at least one immunogenic peptide or polypeptide and/or that comprises   at least one nucleic acid construct that encodes at least one immunogenic peptide or polypeptide,   for use as a vaccine, wherein at least once an effective amount of the first antigenic composition is administered to a subject in need thereof prior to administration to the subject at least once an effective amount of a second antigenic composition that comprises at least one mRNA construct that encodes at least one immunogenic peptide or polypeptide,   wherein:   the nucleic acid construct, if comprised in the first antigenic composition, is not an mRNA construct; and   at least one epitope of the immunogenic peptide or polypeptide comprised in, or encoded by the nucleic acid construct comprised in, the first antigenic composition is identical to or at least 70%, 75%, 80%, 85%, 90%, 95% or at least 98% identical to at least one epitope of the immunogenic peptide or polypeptide encoded by the mRNA construct of the second antigenic composition.   
     
     
         3 . A first antigenic composition that comprises
 at least one immunogenic peptide or polypeptide and/or that comprises   at least one nucleic acid construct that encodes at least one immunogenic peptide or polypeptide,   and   a second antigenic composition that comprises   at least one mRNA construct that encodes at least one immunogenic peptide or polypeptide,   wherein   the nucleic acid construct, if comprised in the first antigenic composition, is not an mRNA construct; and   at least one epitope of the immunogenic peptide or polypeptide comprised in, or encoded by the nucleic acid construct comprised in, the first antigenic composition is identical to or at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or at least 99% identical to at least one epitope of the immunogenic peptide or polypeptide encoded by the mRNA construct of the second antigenic composition,   for use as a vaccine, wherein an effective amount of the second antigenic composition is administered at least once to a subject in need thereof   subsequently to administration to the subject at least once of an effective amount of a first antigenic composition.   
     
     
         4 . The second antigenic composition for use according to  claim 1 , the first antigenic composition for use according to  claim 2 , or the first antigenic composition and the second antigenic composition for use according to  claim 3 , wherein the vaccine is used as a medicament for inducing an immune response. 
     
     
         5 . The second antigenic composition for use according to  claim 1  or  4 , the first antigenic composition for use according to  claim 2  or  4 , or the first antigenic composition and the second antigenic composition for use according to  claim 3  or  4 , wherein the first antigenic composition and the second antigenic composition are administered to the subject in need thereof, respectively, in a prime-boost immunisation regimen. 
     
     
         6 . The second antigenic composition for use according to  claim 1 ,  4  or  5 , the first antigenic composition for use according to  claim 2 ,  4  or  5 , or the first antigenic composition and the second antigenic composition for use according to  claim 3 ,  4  or  5 , wherein the first antigenic composition and the second antigenic composition are not administered concurrently. 
     
     
         7 . The second antigenic composition for use according to any one of  claims 1  or  4  to  6 , the first antigenic composition for use according to any one of  claims 2  or  4  to  6 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  6 , wherein the second antigenic composition is subsequently administered within about 28, 14 or 7 days of administration of the first antigenic composition, preferably about 27, 24, 21, 18, 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 day(s) after administration of the first antigenic composition. 
     
     
         8 . The second antigenic composition for use according to any one of  claims 1  or  4  to  7 , the first antigenic composition for use according to any one of  claims 2  or  4  to  7 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  7 , wherein:
 the first antigenic composition is administered in two or more doses prior to the administration of the second antigenic composition, and/or 
 the second antigenic composition is administered in two or more doses subsequently to the administration of the first antigenic composition, 
 preferably, wherein the first antigenic composition and/or the second antigenic composition is administered in a number of doses selected from the list of consisting of: 2, 3, 4, 5, 6, 7, 8, 9 and 10 times. 
 
     
     
         9 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 8 , wherein the interval between the administration of one or more pairs of consecutive doses is from about 5 to 120 days. 
     
     
         10 . The second antigenic composition for use according to any one of  claims 1  or  4  to  9 , the first antigenic composition for use according to any one of  claims 2  or  4  to  9 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  9 , wherein the first antigenic composition and/or the second antigenic composition is administered by subcutaneous, intramuscular and/or intradermal injection. 
     
     
         11 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 10 , wherein the injection is carried out using jet injection. 
     
     
         12 . The second antigenic composition for use according to any one of  claims 1  or  4  to  11 , the first antigenic composition for use according to any one of  claims 2  or  4  to  11 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  11 , wherein the G/C content of the region of the mRNA construct encoding at least one epitope of the immunogenic peptide or polypeptide is increased compared with the G/C content of the region of the wild type mRNA that encodes the epitope of the immunogenic peptide or polypeptide, preferably wherein the amino acid sequence of the epitope of the immunogenic peptide or polypeptide encoded by the G/C-enriched mRNA is not modified compared with the amino acid sequence of the epitope of the immunogenic peptide or polypeptide encoded by the wild type mRNA. 
     
     
         13 . The second antigenic composition for use according to any one of  claims 1  or  4  to  12 , the first antigenic composition for use according to any one of  claims 2  or  4  to  12 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  12 , wherein the mRNA construct comprises additionally:
 (a) a 5′-CAP structure; 
 (b) a poly(A) sequence; and 
 (c) optionally a poly (C) sequence. 
 
     
     
         14 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 13 , wherein the poly(A) sequence comprises a sequence of about 25 to about 400 adenosine nucleotides, preferably a sequence of about 50 to about 400 adenosine nucleotides, more preferably a sequence of about 50 to about 300 adenosine nucleotides, even more preferably a sequence of about 50 to about 250 adenosine nucleotides, most preferably a sequence of about 60 to about 250 adenosine nucleotides. 
     
     
         15 . The second antigenic composition for use according to any one of  claims 1  or  4  to  14 , the first antigenic composition for use according to any one of  claims 2  or  4  to  14 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  14 , wherein the mRNA construct comprises additionally at least one histone stem-loop, preferably comprising the corresponding RNA sequence to the nucleic acid sequence according to SEQ ID NO. 1, or a homolog, a fragment or a variant thereof. 
     
     
         16 . The second antigenic composition for use according to any one of  claims 1  or  4  to  15 , the first antigenic composition for use according to any one of  claims 2  or  4  to  15 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  15 , wherein the mRNA construct comprises additionally a 3′-UTR element. 
     
     
         17 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 16 , wherein the 3′-UTR element comprises or consists of a nucleic acid sequence which is derived from a 3′-UTR of a gene providing a stable mRNA or from a homolog, a fragment or a variant thereof. 
     
     
         18 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 17 , wherein the 3′-UTR element comprises or consists of a nucleic acid sequence derived from a 3′-UTR of a gene selected from the group consisting of an albumin gene, an alpha-globin gene, a beta-globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen alpha gene; or from a homolog, a fragment or a variant thereof. 
     
     
         19 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 17  or  18 , wherein the 3′-UTR element is derived from a nucleic acid sequence according to SEQ ID NO. 3 or SEQ ID NO. 4, or from a corresponding RNA sequence, a homolog, a fragment or a variant thereof. 
     
     
         20 . The second antigenic composition for use according to any one of  claims 1  or  4  to  19 , the first antigenic composition for use according to any one of  claims 2  or  4  to  19 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  19 , wherein the mRNA construct comprises, preferably in 5′—to 3′-direction:
 (a) a 5′-CAP structure, preferably m7GpppN; 
 (b) a coding region encoding at least one immunogenic peptide or polypeptide; 
 (c) a 3′-UTR element comprising or consisting of a nucleic acid sequence which is derived from an alpha-globin gene, preferably comprising the corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO. 4; or a homolog, a fragment or a variant thereof; 
 (d) optionally a poly(A) sequence, preferably comprising about 64 adenosines; 
 (e) optionally a poly(C) sequence, preferably comprising about 30 cytosines; and 
 (f) optionally a histone-stem-loop, preferably comprising the corresponding RNA sequence to the nucleic acid sequence according to SEQ ID NO. 1, or a homolog, a fragment or a variant thereof. 
 
     
     
         21 . The second antigenic composition for use according to any one of  claims 1  or  4  to  20 , the first antigenic composition for use according to any one of  claims 2  or  4  to  20 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  20 , wherein the mRNA construct comprises additionally a 5′-UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5′-UTR of a TOP gene, or from a corresponding RNA sequence, a homolog, a fragment, or a variant thereof, preferably lacking the 5′TOP motif. 
     
     
         22 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 21 , wherein the 5′-UTR element comprises or consists of a nucleic acid sequence which is derived from a 5′-UTR of a TOP gene encoding a ribosomal protein, or from a corresponding RNA sequence or from a homolog, a fragment or a variant thereof, preferably lacking the 5′TOP motif. 
     
     
         23 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 22 , wherein the 5′-UTR element comprises or consists of a nucleic acid sequence which is derived from a 5′-UTR of a TOP gene encoding a ribosomal Large protein (RPL) or from a homolog, a fragment or variant thereof, preferably lacking the 5′TOP motif and more preferably comprising or consisting of a corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO. 5, or a homolog, a fragment or a variant thereof. 
     
     
         24 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 23 , wherein the mRNA construct comprises, preferably in 5′—to 3′-direction:
 (a) a 5′-CAP structure, preferably m7GpppN; 
 (b) a 5′-UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5′-UTR of a TOP gene, preferably comprising or consisting of the corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO. 5, or a homolog, a fragment or a variant thereof; 
 (c) a coding region encoding at least one immunogenic peptide or polypeptide; 
 (d) a 3′-UTR element comprising or consisting of a nucleic acid sequence which is derived from a gene providing a stable mRNA, preferably comprising or consisting of the corresponding RNA sequence of a nucleic acid sequence according to SEQ ID NO. 3, or a homolog, a fragment or a variant thereof; 
 (e) a poly(A) sequence preferably comprising about 64 adenosines; 
 (f) a poly(C) sequence, preferably comprising about 30 cytosines; and 
 (g) a histone-stem-loop, preferably comprising the corresponding RNA sequence of the nucleic acid sequence according to SEQ ID NO. 1, or a homolog, a fragment or a variant thereof. 
 
     
     
         25 . The second antigenic composition for use according to any one of  claims 1  or  4  to  24 , the first antigenic composition for use according to any one of  claims 2  or  4  to  24 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  24 , wherein the mRNA construct is associated with or complexed with a cationic or polycationic compound or a polymeric carrier, preferably in a weight ratio selected from a range of about 6:1 (w/w) to about 0.25:1 (w/w), more preferably from about 5:1 (w/w) to about 0.5:1 (w/w), even more preferably of about 4:1 (w/w) to about 1:1 (w:w) or of about 3:1 (w/w) to about 1:1 (w/w), and most preferably a ratio of about 3:1 (w/w) to about 2:1 (w/w) of mRNA to cationic or polycationic compound and/or with a polymeric carrier; or optionally in a nitrogen/phosphate ratio of mRNA to cationic or polycationic compound and/or polymeric carrier in the range of about 0.1-10, preferably in a range of about 0.3-4 or 0.3-1, more preferably in a range of about 0.5-1 or 0.7-1, and most preferably in a range of about 0.3-0.9 or 0.5-0.9. 
     
     
         26 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 25 , wherein the mRNA construct is associated or complexed with a cationic protein or peptide, preferably protamine. 
     
     
         27 . The second antigenic composition for use according to any one of  claims 1  or  4  to  26 , the first antigenic composition for use according to any one of  claims 2  or  4  to  26 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  26 , wherein the second antigenic composition comprises a plurality or more than one mRNA construct, each as set forth in any one of  claims 1  to  26 . 
     
     
         28 . The second antigenic composition for use according to any one of  claims 1  or  4  to  27 , the first antigenic composition for use according to any one of  claims 2  or  4  to  27 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  27 , wherein the mRNA construct is complexed at least partially with a cationic or polycationic compound and/or a polymeric carrier, preferably cationic proteins or peptides and most preferably protamine. 
     
     
         29 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 28 , wherein the ratio of complexed mRNA to free mRNA is selected from a range of about 5:1 (w/w) to about 1:10 (w/w), preferably from a range of about 4:1 (w/w) to about 1:8 (w/w), more preferably from a range of about 3:1 (w/w) to about 1:5 (w/w) or 1:3 (w/w), and most preferably the ratio of complexed mRNA to free mRNA is from a ratio of about 2:1 (w/w) to about 1:2 (w/w) such as about 1:1 (w/w). 
     
     
         30 . The second antigenic composition for use according to any one of  claims 1  or  4  to  29 , the first antigenic composition for use according to any one of  claims 2  or  4  to  29 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  29 , wherein the first antigenic composition comprises at least one immunogenic peptide or polypeptide, preferably an immunogenic protein or an immunogenic peptide. 
     
     
         31 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 30 , wherein the first antigenic composition comprises a solution of at least one immunogenic peptide or polypeptide, preferably comprises a solution of at least one immunogenic protein and/or at least one immunogenic peptide. 
     
     
         32 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 30  or  31 , wherein the first antigenic composition comprises at least one preparation comprising at least one immunogenic peptide or polypeptide, preferably wherein the preparation is selected from the list consisting of: a virus preparation, a cell preparation and a bacteria preparation. 
     
     
         33 . The second antigenic composition for use according to any one of  claims 1  or  4  to  32 , the first antigenic composition for use according to any one of  claims 2  or  4  to  32 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  32 , wherein the first antigenic composition comprises at least one nucleic acid construct that encodes at least one immunogenic peptide or polypeptide, preferably wherein the nucleic acid construct is a DNA construct. 
     
     
         34 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 33 , wherein said nucleic acid construct is a viral vector. 
     
     
         35 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 34 , wherein the viral vector is one derived from a virus selected from the list consisting of: poxvirus, adenovirus, adeno-associated virus (AAV), alphavirus, herpesvirus, retrovirus, lentivirus, cytomegalovirus, sendai virus, flavivirus, parvovirus. 
     
     
         36 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 35 , wherein the viral vector is one derived from a poxvirus selected from the list consisting of: smallpox virus (variola), vaccinia virus, cowpox virus, monkeypox virus. 
     
     
         37 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 36 , wherein the viral vector is one derived from a vaccinia virus selected from the list consisting of: New York Attenuated Vaccinia Virus (NYVAC), ALVAC, TROVAC and Modified Vaccinia Ankara (MVA). 
     
     
         38 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 37 , wherein the viral vector is one derived from MVA. 
     
     
         39 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 38 , wherein the viral vector is derived from the virus seed batch 460 MG obtained from the 571th passage of vaccina virus in chick embryo fibroblast cells or wherein the viral vector is derived from the virus seed batch MVA 476 MG/14/78. 
     
     
         40 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 38  or  39 , wherein the viral vector is derived or produced prior to 31 Dec. 1978. 
     
     
         41 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to any one of  claims 37  to  40 , wherein the viral vector is free from prion contamination. 
     
     
         42 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 33 , wherein said nucleic acid construct is a self-replicating RNA molecule. 
     
     
         43 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 33 , wherein said nucleic acid construct is not a viral vector and/or is not a self-replicating RNA molecule. 
     
     
         44 . The second antigenic composition for use according to any one of  claims 1  or  4  to  43 , the first antigenic composition for use according to any one of  claims 2  or  4  to  43 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  43 , wherein the amino acid sequence of the immunogenic peptide or polypeptide comprised in the first antigenic composition, or encoded by the nucleic acid construct comprised in the first antigenic composition, is identical to or at least 70%, 75%, 80%, 85%, 90%, 95% or at least 98% identical to the amino acid sequence of the immunogenic peptide or polypeptide encoded by the mRNA construct comprised in the second antigenic composition. 
     
     
         45 . The second antigenic composition for use according to any one of  claims 1  or  4  to  44 , the first antigenic composition for use according to any one of  claims 2  or  4  to  44 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  44 , in the treatment or prophylaxis of a condition, disorder or disease. 
     
     
         46 . The second antigenic composition for use according to any one of  claims 1  or  4  to  45 , the first antigenic composition for use according to any one of  claims 2  or  4  to  45 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  45 , wherein the amino acid sequence of at least the epitope is from a pathogen, or a homolog, a fragment or a variant thereof, preferably wherein the immunogenic peptide or polypeptide comprised in the first antigenic composition, or encoded by the nucleic acid construct comprised in the first antigenic composition, and the immunogenic peptide or polypeptide encoded by the mRNA construct comprised in the second antigenic composition is from a pathogen, or a homolog, a fragment or a variant thereof. 
     
     
         47 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 46 , wherein the pathogen is one selected from the list consisting of: a virus, a bacterium, a fungus and a protozoan. 
     
     
         48 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 46  or  47 , in the treatment or prophylaxis of infection from the pathogen, or of a condition, disorder or disease associated therewith. 
     
     
         49 . The second antigenic composition for use according to any one of  claims 1  or  4  to  45 , the first antigenic composition for use according to any one of  claims 2  or  4  to  45 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  45 , wherein the amino acid sequence of at least the epitope is from a tumour or cancer cell, or a homolog, a fragment or a variant thereof, preferably wherein the immunogenic peptide or polypeptide comprised in the first antigenic composition, or encoded by the nucleic acid construct comprised in the first antigenic composition, and the immunogenic peptide or polypeptide encoded by the mRNA construct comprised in the second antigenic composition is from a tumour or cancer cell, or a homolog, a fragment or a variant thereof. 
     
     
         50 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 49 , wherein the tumour or cancer cell is a cell from a tumour or cancer selected from the list consisting of: prostate cancer, lung cancer, breast cancer, brain cancer, colon cancer, stomach cancer, liver cancer, pancreas cancer, ovary cancer, lymphoma, leukemia, and myeloma. 
     
     
         51 . The second antigenic composition, the first antigenic composition, or the first and second antigenic composition for use according to  claim 49  or  50 , in the treatment or prophylaxis of the tumour or cancer, or of a condition, disorder or disease associated therewith. 
     
     
         52 . The second antigenic composition for use according to any one of  claims 1  or  4  to  51 , the first antigenic composition for use according to any one of  claims 2  or  4  to  51 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  51 , wherein the first and/or the second antigenic composition comprises additionally an adjuvant. 
     
     
         53 . The second antigenic composition for use according to any one of  claims 1  or  4  to  52 , the first antigenic composition for use according to any one of  claims 2  or  4  to  52 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  52 , wherein the first antigenic composition and/or the second antigenic composition is a pharmaceutical composition, optionally comprising additionally a pharmaceutically acceptable carrier. 
     
     
         54 . A vaccine combination comprising:
 a first antigenic composition as set forth in any one of  claims 1  or  4  to  53 ; and   a second antigenic composition as set forth in any one of  claims 1  or  4  to  53 .   
     
     
         55 . A kit, preferably for inducing an immune response in a subject; the kit comprising a plurality of separate containers, the contents of at least two containers differing from each other in whole or in part,
 the first of such containers containing:   a first antigenic composition as set forth in any one of  claims 1  or  4  to  53 ; and   the second of such containers containing:   a second antigenic composition as set forth in any one of  claims 1  or  4  to  53 .   
     
     
         56 . The kit of  claim 55 , comprising additionally instructions to:
 (a) administer to a subject, preferably one in need thereof, at least once an effective amount of the first antigenic composition; and   (b) subsequently administer to the subject at least once an effective amount of the second antigenic composition.   
     
     
         57 . A packaged vaccine comprising:
 a first antigenic composition as set forth in any one of  claims 1  or  4  to  53 ; and/or   a second antigenic composition as set forth in any one of  claims 1  or  4  to  53 , the package comprising additionally instructions to:   (a) administer to a subject, preferably one in need thereof, at least once an effective amount of the first antigenic composition; and   (b) subsequently administer to the subject at least once an effective amount of the second antigenic composition.   
     
     
         58 . The second antigenic composition for use according to any one of  claims 1  or  4  to  53 , the first antigenic composition for use according to any one of  claims 2  or  4  to  53 , or the first antigenic composition and the second antigenic composition for use according to any one of  claims 3  to  53 , the vaccine combination of  claim 54 , the kit of  claim 55  or  56  or the packaged vaccine of  claim 57 , for use in a prime-boost vaccination regimen. 
     
     
         59 . The kit of  claim 55 ,  56  or  58  or the packaged vaccine of  claim 57  or  58 , comprising additional instructions to administer the second antigenic composition as defined in any one of  claims 1  or  4  to  53 , the first antigenic composition as defined in any one of  claims 2  or  4  to  53 , or the first antigenic composition and the second antigenic composition as defined in any one of  claims 3  to  53 . 
     
     
         60 . A method for inducing an immune response in a subject, the method comprising the steps:
 (a) administering to a subject in need thereof at least once an effective amount of a first antigenic composition; and   (b) subsequently administering to the subject at least once an effective amount of a second antigenic composition,   wherein the first antigenic composition, the second antigenic composition and the administration is as set forth in any one of  claims 1  to  53 .