Vaccination in elderly patients

Abstract

The present invention relates to vaccines comprising at least one mRNA encoding at least one antigen for use in the treatment of a disease in an elderly patient preferably exhibiting an age of at least 50 years, more preferably of at least 55 years, 60 years, 65 years, 70 years, or older, wherein the treatment comprises vaccination of the patient and eliciting an immune response in said patient. The present invention is furthermore directed to kits and kits of parts comprising such a vaccine and/or its components and to methods applying such a vaccine or kit.

1 . A method for stimulating an immune response in a patient comprising selecting an elderly human patient exhibiting an age of at least 50 years and administering to the subject a composition comprising at least one mRNA encoding at least one antigen for the prophylaxis and/or treatment of a disease. 
     
     
         2 . The method of  claim 1 , wherein the immune response is a Th1 immune response. 
     
     
         3 . The method of  claim 1 , wherein the elderly patient is male or female and/or exhibits an age of at least 55 years, 60 years, 65 years, 70 years, or older. 
     
     
         4 . The method of  claim 1 , wherein the disease is selected from infectious diseases, viral, bacterial or protozoological infectious diseases, autoimmune diseases, allergies or allergic diseases or cancer or tumour diseases. 
     
     
         5 . The method of  claim 1 , wherein the antigen is selected from protein and peptide antigens, tumour antigens, self-antigens or auto-antigens, autoimmune self-antigens, pathogenic antigens, viral antigens, bacterial antigens, fungal antigens, protozoological antigens, animal antigens, allergy antigens. 
     
     
         6 . The method of  claim 1 , wherein the vaccine is to be administered parenterally, orally, nasally, pulmonary, by inhalation, topically, rectally, buccally, vaginally, or via an implanted reservoir. 
     
     
         7 . The method of  claim 1 , wherein the at least one mRNA encoding at least one antigen is to be administered in its naked form or is associated with or complexed with a cationic or polycationic compound. 
     
     
         8 . The method of  claim 1 , wherein the at least one mRNA encoding at least one antigen is complexed with a polymeric carrier formed by disulfide-crosslinked cationic components selected from
 an oligopeptide having following sum formula (I):
   {(Arg) l ;(Lys) m ;(His) n ;(Orn) 0 ;(Xaa) x };  (formula (I)
 
   
       Wherein l+m+n+o+x=3-100, and l, m, n or o independently of each other is any number selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90 and 91-100 provided that the overall content of Arg (Arginine), Lys (Lysine), His (Histidine) and Orn (Ornithine) represents at least 10% of all amino acids of the oligopeptide of formula (V); and Xaa is any amino acid selected from native (=naturally occurring) or non-native amino acids except of Arg, Lys, His or Orn; and x is any number selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, provided, that the overall content of Xaa does not exceed 90% of all amino acids of the oligopeptide of formula (I),
 or from a disulfide-crosslinked cationic component comprising as a repeat unit an oligopeptide having following subformula (Ia):
   {(Arg) l ;(Lys) m ;(His) n ;(Orn) o ;(Xaa′) x (Cys) y };  formula (Ia)
 
 
 
       wherein (Arg) l ;(Lys) m ;(His) n ;(Orn) 0 ; and x is preferably are as defined above for formula (I), Xaa′ is any amino acid selected from native (=naturally occurring) or non-native amino acids except of Arg, Lys, His, Orn or Cys and y is any number selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80 and 81-90, provided that the overall content of Arg (Arginine), Lys (Lysine), His (Histidine) and Orn (Ornithine) represents at least 10% of all amino acids of the oligopeptide.
 or from a disulfide-crosslinked cationic component comprising as a repeat unit an oligopeptide having following subformula (Ib):
   Cys 1 {(Arg) l ;(Lys) m ;(His) n ;(Orn) 0 ;(Xaa) x }Cys 2 ;  (formula (Ib))
 
 
 
       wherein component {(Arg) l ;(Lys) m ;(His) n ;(Orn) 0 ;(Xaa) x } (formula (I)) within formula (Ib) is as defined herein and forms a core of subformula (Ib), and wherein Cys 1  and Cys 2  are Cysteines proximal to, or terminal to (Arg) l ;(Lys) m ;(His) n ;(Orn) o ;(Xaa) x . 
     
     
         9 . The method of  claim 1 , wherein the at least one mRNA encoding at least one antigen is complexed with a polymeric carrier according to generic formula (VI):
   L-P 1 -S-[S-P 2 -S] n -S-P 3 -L   
       wherein,
 P 1  and P 3  
 are different or identical to each other and represent a linear or branched hydrophilic polymer chain, each P 1  and P 3  exhibiting at least one —SH-moiety, capable to form a disulfide linkage upon condensation with component P 2 , the linear or branched hydrophilic polymer chain selected independent from each other from polyethylene glycol (PEG), poly-N-(2-hydroxypropyl)methacrylamide, poly-2-(methacryloyloxy)ethyl phosphorylcholines, poly(hydroxyalkyl L-asparagine), poly(2-(methacryloyloxy)ethyl phosphorylcholine), hydroxyethylstarch or poly(hydroxyalkyl L-glutamine), wherein the hydrophilic polymer chain exhibits a molecular weight of about 1 kDa to about 100 kDa, 
 
 P 2  is a cationic or polycationic peptide or protein, having a length of about 3 to about 100 amino acids, or
 is a cationic or polycationic polymer, having a molecular weight of about 0.5 kda to about 30 kda, 
 each P 2  exhibiting at least two —SH-moieties, capable to form a disulfide linkage upon condensation with further components P 2  or component(s) P 1  and/or P 3 ; 
 
 —S—S— is a (reversible) disulfide bond; 
 L is an optional ligand, which may be present or not, and may be selected independent from the other from RGD, Transferrin, Folate, a signal peptide or signal sequence, a localization signal or sequence, a nuclear localization signal or sequence (NLS), an antibody, a cell penetrating peptide (CPP), TAT, KALA, a ligand of a receptor, cytokines, hormones, growth factors, small molecules, carbohydrates, mannose, galactose, synthetic ligands, small molecule agonists, inhibitors or antagonists of receptors, or RGD peptidomimetic analogues; and 
 n is an integer, selected from a range of about 1 to 50, preferably in a range of about 1, 2, 3, 4, or 5 to 10, more preferably in a range of about 1, 2, 3, or 4 to 9. 
 
     
     
         10 . The method of  claim 9 , wherein the at least one mRNA encoding at least one antigen is complexed with a polymeric carrier molecule according to formula (VIa)
   L-P 1 -S-{[S-P 2 -S] a [S-(AA) x -S] b }-S-P 3 -L,   
       wherein S, L, P 1 , P 2  and P 3  are preferably as defined above for formula (VI), a and b are integers, wherein a+b=n and n is an integer as defined above for formula (VI),
 x is an integer selected from a range of about 1 to 100, and 
 (AA) is selected from an aromatic, a hydrophilic, a lipophilic, or a weak basic amino acid or peptide, or is a signal peptide or signal sequence, a localization signal or sequence, a nuclear localization signal or sequence (NLS), an antibody, a cell penetrating peptide (CPPp), or is selected from therapeutically active proteins or peptides, from antigens, tumour antigens, pathogenic antigens, animal antigens, viral antigens, protozoan antigens, bacterial antigens, allergic antigens, autoimmune antigens, from allergens, from antibodies, from immunostimulatory proteins or peptides, or from antigen-specific T-cell receptors. 
 
     
     
         11 . The method of  claim 1 , wherein the vaccine is formulated to comprise a) an (adjuvant) component, comprising or consisting of at least one (m)RNA, complexed with a cationic or polycationic compound and/or with a polymeric carrier, and b) at least one free mRNA encoding an antigen. 
     
     
         12 . The method of  claim 11 , wherein the (m)RNA is an mRNA, an immunostimulatory nucleic acid, a CpG nucleic acid, a CpG-RNA, a CpG-DNA, or an immunostimulatory RNA (isRNA). 
     
     
         13 . The method  claim 1 , wherein the vaccine furthermore comprises a pharmaceutically acceptable carrier and or vehicle. 
     
     
         14 . The method of  claim 1 , wherein the vaccine furthermore comprises at least one adjuvant, an auxiliary substance selected from lipopolysaccharides, TNF-alpha, CD40 ligand, or cytokines, monokines, lymphokines, interleukins or chemokines, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IFN-alpha, IFN-beta, IFN-gamma, GM-CSF, G-CSF, M-CSF, LT-beta, TNF-alpha, growth factors, and hGH, a ligand of human Toll-like receptor TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, a ligand of murine Toll-like receptor TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 OR TLR13, a ligand of a NOD-like receptor, a ligand of a RIG-I like receptor, an immunostimulatory nucleic acid, an immunostimulatory RNA (isRNA), a CpG-DNA, an antibacterial agent, or an anti-viral agent. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the vaccine is formulated to comprise a) an (adjuvant) component, comprising or consisting of at least one (m)RNA, complexed with a cationic or polycationic compound and/or with a polymeric carrier, and b) at least one free mRNA encoding an antigen. 
     
     
         17 . The method of  claim 1 , wherein the vaccine is formulated to comprise a) an (adjuvant) component, comprising or consisting of at least one (m)RNA, complexed with a cationic or polycationic compound and/or with a polymeric carrier, and b) at least one free mRNA encoding an antigen. 
     
     
         18 . The method of  claim 1 , wherein the vaccine is formulated to comprise a) an (adjuvant) component, comprising or consisting of at least one (m)RNA, complexed with a cationic or polycationic compound and/or with a polymeric carrier, and b) at least one free mRNA encoding an antigen. 
     
     
         19 . The method of  claim 11 , wherein the (m)RNA is an mRNA, an immunostimulatory nucleic acid, a CpG nucleic acid, a CpG-RNA, a CpG-DNA, or an immunostimulatory RNA (isRNA). 
     
     
         20 . The method of  claim 1 , wherein the patient exhibits an age of at least 85 years. 
     
     
         21 . The method of  claim 1 , wherein the vaccine is administered intradermally. 
     
     
         22 . The method of  claim 1 , wherein the vaccine is administered at least a second time. 
     
     
         23 . The method of  claim 1 , wherein the antigen is an infectious disease antigen and the wherein the method provides a protective immune response. 
     
     
         24 . The method of  claim 1 , wherein the antigen is a prostate cancer antigen and the patient has prostate cancer.