JP5632404B2 - プラスモジウム抗原を含むワクチン - Google Patents
プラスモジウム抗原を含むワクチン Download PDFInfo
- Publication number
- JP5632404B2 JP5632404B2 JP2012014815A JP2012014815A JP5632404B2 JP 5632404 B2 JP5632404 B2 JP 5632404B2 JP 2012014815 A JP2012014815 A JP 2012014815A JP 2012014815 A JP2012014815 A JP 2012014815A JP 5632404 B2 JP5632404 B2 JP 5632404B2
- Authority
- JP
- Japan
- Prior art keywords
- malaria
- vaccine
- rts
- children
- antigen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229960005486 vaccine Drugs 0.000 title claims description 78
- 239000000427 antigen Substances 0.000 title claims description 46
- 102000036639 antigens Human genes 0.000 title claims description 46
- 108091007433 antigens Proteins 0.000 title claims description 46
- 241000224016 Plasmodium Species 0.000 title claims description 6
- 201000004792 malaria Diseases 0.000 claims description 78
- 239000002671 adjuvant Substances 0.000 claims description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 11
- 239000002502 liposome Substances 0.000 claims description 8
- 239000007764 o/w emulsion Substances 0.000 claims description 7
- 108090000623 proteins and genes Proteins 0.000 description 41
- 235000018102 proteins Nutrition 0.000 description 38
- 102000004169 proteins and genes Human genes 0.000 description 38
- 208000015181 infectious disease Diseases 0.000 description 26
- 241000223960 Plasmodium falciparum Species 0.000 description 25
- 230000036541 health Effects 0.000 description 20
- 201000010099 disease Diseases 0.000 description 18
- 238000002255 vaccination Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 16
- 244000045947 parasite Species 0.000 description 15
- 230000004044 response Effects 0.000 description 15
- 239000002158 endotoxin Substances 0.000 description 12
- 230000028993 immune response Effects 0.000 description 12
- 230000003308 immunostimulating effect Effects 0.000 description 12
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 12
- 210000003046 sporozoite Anatomy 0.000 description 12
- 108091029430 CpG site Proteins 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- 229920006008 lipopolysaccharide Polymers 0.000 description 11
- 208000030852 Parasitic disease Diseases 0.000 description 10
- 230000002411 adverse Effects 0.000 description 10
- 150000001413 amino acids Chemical group 0.000 description 10
- 208000007502 anemia Diseases 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 238000012544 monitoring process Methods 0.000 description 10
- 229930182490 saponin Natural products 0.000 description 10
- 150000007949 saponins Chemical class 0.000 description 10
- 235000017709 saponins Nutrition 0.000 description 10
- 208000009182 Parasitemia Diseases 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 230000009885 systemic effect Effects 0.000 description 9
- 102000004127 Cytokines Human genes 0.000 description 8
- 108090000695 Cytokines Proteins 0.000 description 8
- 229960000074 biopharmaceutical Drugs 0.000 description 7
- 230000034994 death Effects 0.000 description 7
- 231100000517 death Toxicity 0.000 description 7
- 230000002163 immunogen Effects 0.000 description 7
- 210000004185 liver Anatomy 0.000 description 7
- 239000002773 nucleotide Substances 0.000 description 7
- 125000003729 nucleotide group Chemical group 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 229940031999 pneumococcal conjugate vaccine Drugs 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 241000255925 Diptera Species 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 210000003743 erythrocyte Anatomy 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 101710117490 Circumsporozoite protein Proteins 0.000 description 5
- 108091034117 Oligonucleotide Proteins 0.000 description 5
- 206010037660 Pyrexia Diseases 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 230000036755 cellular response Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000005534 hematocrit Methods 0.000 description 5
- 208000002672 hepatitis B Diseases 0.000 description 5
- 230000003053 immunization Effects 0.000 description 5
- 238000002649 immunization Methods 0.000 description 5
- 230000005847 immunogenicity Effects 0.000 description 5
- 229940124735 malaria vaccine Drugs 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 206010010904 Convulsion Diseases 0.000 description 4
- 102100031673 Corneodesmosin Human genes 0.000 description 4
- 101710139375 Corneodesmosin Proteins 0.000 description 4
- 101710137302 Surface antigen S Proteins 0.000 description 4
- 230000036760 body temperature Effects 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 230000000925 erythroid effect Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 229960001438 immunostimulant agent Drugs 0.000 description 4
- 239000003022 immunostimulating agent Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- LUBUTTBEBGYNJN-UHFFFAOYSA-N 4-amino-n-(5,6-dimethoxypyrimidin-4-yl)benzenesulfonamide;5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1.COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC LUBUTTBEBGYNJN-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 101710104031 Thrombospondin-related anonymous protein Proteins 0.000 description 3
- UZQJVUCHXGYFLQ-AYDHOLPZSA-N [(2s,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-4-[(2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hy Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2[C@@]1(C=O)C)C)(C)CC(O)[C@]1(CCC(CC14)(C)C)C(=O)O[C@H]1[C@@H]([C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O[C@H]4[C@@H]([C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)[C@H](O)[C@@H](CO)O4)O)[C@H](O)[C@@H](CO)O3)O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UZQJVUCHXGYFLQ-AYDHOLPZSA-N 0.000 description 3
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 3
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 3
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000007123 defense Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002489 hematologic effect Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 210000003936 merozoite Anatomy 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 208000010444 Acidosis Diseases 0.000 description 2
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 2
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical compound C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 description 2
- 101710145634 Antigen 1 Proteins 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- 206010063094 Cerebral malaria Diseases 0.000 description 2
- 206010009192 Circulatory collapse Diseases 0.000 description 2
- 206010010071 Coma Diseases 0.000 description 2
- 241000305071 Enterobacterales Species 0.000 description 2
- 208000002476 Falciparum Malaria Diseases 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 102000004895 Lipoproteins Human genes 0.000 description 2
- 108090001030 Lipoproteins Proteins 0.000 description 2
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 2
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 2
- 206010035500 Plasmodium falciparum infection Diseases 0.000 description 2
- 201000011336 Plasmodium falciparum malaria Diseases 0.000 description 2
- 230000024932 T cell mediated immunity Effects 0.000 description 2
- 230000007950 acidosis Effects 0.000 description 2
- 208000026545 acidosis disease Diseases 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 229940037003 alum Drugs 0.000 description 2
- 229960001444 amodiaquine Drugs 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 230000028996 humoral immune response Effects 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 230000002969 morbid Effects 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 206010040560 shock Diseases 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000012646 vaccine adjuvant Substances 0.000 description 2
- 229940124931 vaccine adjuvant Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 101150090724 3 gene Proteins 0.000 description 1
- KQPKMEYBZUPZGK-UHFFFAOYSA-N 4-[(4-azido-2-nitroanilino)methyl]-5-(hydroxymethyl)-2-methylpyridin-3-ol Chemical compound CC1=NC=C(CO)C(CNC=2C(=CC(=CC=2)N=[N+]=[N-])[N+]([O-])=O)=C1O KQPKMEYBZUPZGK-UHFFFAOYSA-N 0.000 description 1
- -1 AMA-1 Proteins 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 241000878022 Anopheles funestus Species 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000759568 Corixa Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229940124884 Engerix-B Drugs 0.000 description 1
- 101000993654 Escherichia coli (strain K12) Pantothenate kinase Proteins 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 108700020122 Hiberix Proteins 0.000 description 1
- 229940124885 Hiberix Drugs 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001111984 Homo sapiens N-acylneuraminate-9-phosphatase Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010022086 Injection site pain Diseases 0.000 description 1
- 206010053425 Injection site swelling Diseases 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 102000000743 Interleukin-5 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- ULNXMMYXQKGNPG-LPEHRKFASA-N Met-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCSC)N ULNXMMYXQKGNPG-LPEHRKFASA-N 0.000 description 1
- 241001092142 Molina Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 102100023906 N-acylneuraminate-9-phosphatase Human genes 0.000 description 1
- 241001644525 Nastus productus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108091081548 Palindromic sequence Proteins 0.000 description 1
- 241001505483 Plasmodium falciparum 3D7 Species 0.000 description 1
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 1
- 108700005482 Protozoan circumsporozoite Proteins 0.000 description 1
- 241001454523 Quillaja saponaria Species 0.000 description 1
- 235000009001 Quillaja saponaria Nutrition 0.000 description 1
- 241000607149 Salmonella sp. Species 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 101710152205 Sporozoite antigen Proteins 0.000 description 1
- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical compound COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 description 1
- 210000000447 Th1 cell Anatomy 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 238000001793 Wilcoxon signed-rank test Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000008350 antigen-specific antibody response Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000011246 composite particle Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000600 disaccharide group Chemical group 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000011985 exploratory data analysis Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- SPSXSWRZQFPVTJ-ZQQKUFEYSA-N hepatitis b vaccine Chemical compound C([C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC1N=CN=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)OC(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@@H](N)CCCNC(N)=N)C1=CC=CC=C1 SPSXSWRZQFPVTJ-ZQQKUFEYSA-N 0.000 description 1
- 229940124736 hepatitis-B vaccine Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 231100001079 no serious adverse effect Toxicity 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229940047091 other immunostimulants in atc Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000011519 second-line treatment Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- 229960004673 sulfadoxine Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/002—Protozoa antigens
- A61K39/015—Hemosporidia antigens, e.g. Plasmodium antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6075—Viral proteins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Tropical Medicine & Parasitology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
Description
そのようなワクチンの好ましい標的集団は小児、特に5歳未満の小児、特に1〜4歳の小児である。
該抗原は、スポロゾイト上または該寄生生物の他の前赤血球段階(例えば、肝臓段階)で発現される任意の抗原から選ばれうる。好ましくは、該抗原は、サーカムスポロゾイト(CS)タンパク質、肝臓段階抗原1(LSA-1)、肝臓段階抗原3(LSA-3)、トロンボスポンジン関連無名タンパク質(TRAP)、および(赤血球段階に加えて)肝臓段階に存在することが最近示された尖端メレゾイト抗原1(AMA-1)から選ばれる。これらの抗原のすべては当分野でよく知られている。該抗原は全タンパク質またはその免疫原性断片でありうる。マラリア抗原の免疫原性断片(例えば、AMA-1由来のエクトドメイン)はよく知られている。
本発明での使用のための好ましい抗原はサーカムスポロゾイト(CS)タンパク質から誘導され、好ましくは、HBsAgとのハイブリッドタンパク質の形態である。該抗原は全CSタンパク質またはその一部(互いに融合していることが可能なCSタンパク質の断片を含む)でありうる。
・Sacchromyes cerevisiae TDH3遺伝子配列から誘導されるヌクレオチド1059-1061によりコードされるメチオニン残基(Musti A.m.ら Gene 1983 25 133-143)、
・該ハイブリッド遺伝子を構築するために用いるクローニング法により得られるヌクレオチド配列(1062-1070)から誘導される3アミノ酸Met Ala Pro、
・Plasmodium falciparum株3D7(Caspersら, 前掲)のサーカムスポロゾイトタンパク質(CSP)のアミノ酸207-395に相当するヌクレオチド1071-1637によりコードされる189アミノ酸のストレッチ、
・該ハイブリッド遺伝子を構築するために用いるクローニング法により得られるヌクレオチド1638-1640によりコードされるアミノ酸(Gly)、
・B型肝炎ウイルス(adw血清型)プレS2タンパク質(Nature 280: 815-819, 1979)の4個のカルボキシ末端残基に相当する、ヌクレオチド1641-1652によりコードされる4アミノ酸Pro Val Thr Asn、
・ヌクレオチド1653-2330によりコードされB型肝炎ウイルス(adw血清型)のSタンパク質を特定する226アミノ酸のストレッチ。
好ましいRTS,S構築物は、同時に合成され精製中に自発的に複合粒子構造体(RTS,S)を形成する2つのポリペプチドRTSおよびSを含む。
好ましくは、本発明は更に、水中油型エマルションまたはリポソームを使用する。
1.3D-MPL、QS21および水中油型エマルション、
2.リポソーム製剤中の3D-MPLおよびQS21、
3.リポソーム製剤中の3D-MPL、QS21およびCpG。
研究地域
治験はモザンビーク南部のManhica地方(Maputo Province)のCentro de Investigacao em Saude da Manhica [CISM] (Manhica Health Research Centre)で2003年4月〜2004年5月に行われた。この地域の特徴は他の文献に詳細に記載されている9。気候は、11月〜4月の温暖な雨季と1年の残りの時期の一般には冷涼な乾季との2つの異なる季節を有する亜熱帯気候である。2003年の年間降水量は1286mmであった。顕著な季節性を伴う永続的マラリア伝染は大部分はP. falciparumによるものである。Anopheles funestusが主要ベクターであり、2002年の推定昆虫接種率(entomologic inoculation rate)(EIR)は38であった。アモジアキンとスルファドキシン-ピリメタミン(SP)とに基づく併用療法が単純性マラリアに対する第一線(ファーストライン)の治療であり、医療施設で容易に利用可能である。CISMに隣接して、ベッド数110の委託医療施設であるManhica Health Centerがある。この地域の医療ネットワークは他の8つの周辺診療所および1つの地方病院よりなる。
この研究は、GSK Biologicals' RTS,S/AS02Aマラリアワクチンの安全性、免疫原性および効力を評価するための第IIb相二重盲検ランダム化およびコントロール化治験であった。主要目的は、初回ワクチン接種時に1〜4歳の小児において、第3用量投与の14日後から開始する6ヶ月の監視期間にわたり、P. falciparumマラリアの臨床エピソードに対する効力を評価することであった。
CISMは該研究地域における人口統計調査システムを運営している10。この人口調査から、潜在的に適格性を有する居住小児の一覧を作成した。彼らの自宅を訪問し、親または保護者に説明書を読み聞かせ、募集基準を照査した。これらは、EPIワクチンでの完全な免疫化および該研究地域における居住の確認を含むものであった。関心を持った親/保護者をManhica Health CentreまたはIlha Josina Health Postに招いた。初回訪問時に、特別に訓練されたスタッフが、親/保護者のグループに、再び該説明書を読み聞かせ、説明した。この説明の理解を確認するための個別の口頭での理解度試験に彼らが合格した後で初めて、個別の同意を求めた。ついで、インフォームドコンセント用紙に署名(あるいは読み書きできない場合には拇印)するよう彼らに求めた。該コミュニティの一員が、公平な立会人としての役割を果たし、該コンセント用紙(同意書)に連署した。スクリーニングは簡単な病歴確認および検査、血液学的指穿刺による採血ならびに生化学的検査を含むものであった。
1〜4歳の2022名の小児を募集し、Manhica Health CenterまたはIlha Josina Health Postにおいて3用量のRTS,S/AS02A候補マラリアワクチンまたは対照ワクチン接種計画を受けるようにランダム化した。該ランダム化は、ブロック法(1:1の比、ブロックサイズ = 6)を用いて、GSK Biologicalsにおいて行った。
各ワクチン接種後、研究参加者を少なくとも1時間観察した。訓練された現場担当者が小児の自宅をその後の3日間毎日訪問して、有害事象がある場合にはそれを記録した。自発的(solicited)局所性および全身性の有害事象をこの期間にわたり実証した12。非自発的(unsolicited)有害事象を、各用量の投与後の30日間にわたり、病院罹患監視システムを介して記録した。重篤有害事象(SAE)を同様にして検出し、該研究の全体にわたって記録した。第3用量の投与の60日後から、研究参加小児の自宅を1ヶ月に1回訪問した。該訪問中に、居住状況を確認し、未報告のSAEを実証した。以下の血液学的および生化学的パラメーターを全参加者についてモニターした:第3用量投与の1ヶ月後の全血球数ならびに第3用量投与の1および6.5ヵ月後のクレアチニン、アラニンアミノトランスフェラーゼ[ALT]およびビリルビン。
第1用量投与前に全参加者においてB型表面抗原(HBsAg)の状態を測定した。コホート1においては第1用量投与前ならびに第3用量投与の30日後および6.5ヶ月後に抗CS抗体を測定し、コホート2においてはこれらの同時点で抗HBs抗体を測定した。スクリーニング時に両コホートにおいて間接蛍光抗体試験(IFAT)を行った。
1997年から、医療施設に基づく罹患監視システムが機能しており13、現在ではManhica Health CenterならびにMaragraおよびIlha Josinaの診療所(Health Posts)において確立されている。個人IDカードにより研究参加者を特定し、標準化された実証および適当な医療処置を確保するために、3つ全ての施設において、プロジェクト医療スタッフが1日24時間待機している。
寄生生物の存在およびP. falciparum無性段階の密度を測定するために、標準的な品質管理法に従いギムザ染色血液スライドを読み取った14。Hospital Clinic of Barcelonaにおいて、外的な妥当性評価を行った。乾燥生化学的光度計VITROS DT II(Orto Clinical Diagnostics, Johnson & Johnson Company, USA)を使用して、生化学的パラメーターを測定した。Sysmex KX-21N細胞計数器(Sysmex Corporation Kobe, Japan)を使用して、血液学的試験を行った。マイクロヘマトクリット遠心機での遠心分離の後、Hawksleyヘマトクリット測定器を使用してヘパリン化微毛細管内でヘマトクリット(PCV)を測定した。
コホート1において評価した一次エンドポイントは症候性P. falciparumマラリアの最初の臨床エピソードまでの時間であった。臨床エピソードは、37.5℃以上の腋窩体温および2500/μlを超えるP. falciparum無性寄生虫血症の存在を医療施設に示した小児として定義された。このケース定義は91%特異的で95%感受性であると推定されている15。二次および三次エンドポイントは、異なる臨床マラリア定義に関するワクチン効力の評価および複数のエピソードの検査を含むものであった。
コホート1および2に関する治験プロファイルを図2aおよび2bに示す。各コホート内で、ランダム化は、比較可能な小児群を与えた(表1)。すべての指標は、マラリア伝染強度が、コホート2の研究地域においては、コホート1の研究地域より高かったことを示唆している。
RTS,S/AS02Aおよび対照ワクチンは安全であり、十分に許容されるものであり、どちらの群においても被験者の92%以上が全3用量の投与を受けた。局所性および全身性の自発的(solicited)有害事象は短い持続時間のものであり、ほとんどは強度において軽度または中等度であった。等級3の局所性または全身性有害事象は稀であり、短い持続時間のものであった。RTS,S/AS02Aおよび対照群においては、腕の運動を制限する局所注射部位疼痛が、それぞれ7(0.2%)および1(0.03%)用量の投与後に生じ、20mmを超える注射部位腫脹が、それぞれ224(7.7%)および14(0.5%)用量の投与後に生じた。通常の活動を妨げる、全身性の自発的有害事象(発熱、被刺激性、眠気、食欲不振)が、RTS,S/AS02Aおよび対照群においてそれぞれ55(1.9%)および23(0.8%)の用量の投与後に生じた。少なくとも1つの非自発的(unsolicited)有害事象がRTS,S/AS02A群の653名(64.5%)の被験者および対照群の597名(59.1%)の被験者により報告された。安全検査値は該治験の経過にわたりベースラインから実質的に不変のままであった。
ワクチン接種前の抗CS抗体価は被検小児においては低かった。該ワクチンは免疫原性であり、第3用量の投与後に高い抗体レベルを誘導し、6ヶ月で初期レベルの約1/4に低下したが、依然としてベースライン値を十分に上回っていた。対照群の抗体レベルは追跡期間の全体にわたり低いままであった。該ワクチンは(97%血清防御を超える)高レベルの抗HBsAg抗体をも誘導した(表2)。CSおよびHBsAgの両方に関して、該ワクチンの免疫原性は、24月齢未満の小児においては、より高かった。
コホート1において行ったATP解析においては、282名の小児が、一次ケースの定義を満たす最初の又は唯一の臨床エピソードを示し(RTS,S/AS02A群では123名および対照群では159名)、26.9%(95% CI: 7.4%〜42.2%; p = 0.009)の粗ワクチン効力推定値および29.9%(95% CI: 11%〜44.8%; p = 0.004)の調整推定値を与えた(図3aおよび表3)。臨床マラリアの最初のエピソードを有する小児における無性段階寄生生物の密度はワクチン接種によっては影響されなかった。なぜなら、提示時の幾何平均密度はRTS,S/AS02Aおよび対照群においてそれぞれ43 522/μLおよび41 867/μLであったからである(p = 0.915)。
RTS,S/AS02Aは、P. falciparumにより引き起こされる感染および或るスペクトルの臨床疾患の両方に対して若いアフリカ人小児において防御をもたらす最初のサブユニットワクチンである。結果は、感染に対して部分的防御を誘導する単一の前赤血球抗原に基づくワクチンが、血液段階成分の非存在下であっても、罹患率を減少させうることを示している。
1. Hay SI, Guerra CA, Tatem AJ, Noor AM, Snow RW. The global distribution and population at risk of malaria: past, present, and future. The Lancet Infectious Diseases 2004;4(6):327-336.
2. Breman JG, Alilio MS, Mills A. The intolerable burden of malaria: what's new, what's needed. Am J Trop Med Hyg 2004;71(2_suppl):0-i-.
3. Klausner R, Alonso P. An attack on all fronts. Nature 2004;430(7002):930-1.
4. Ballou WR, Arevalo-Herrera M, Carucci D, Richie TL, Corradin G, Diggs C, et al. Update on the clinical development of candidate malaria vaccines. Am J Trop Med Hyg 2004;71(2_suppl):239-247.
5. Stoute J, Slaoui M, Heppner D, Momin P, Kester K, Desmons P, et al. A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS,S Malaria Vaccine Evaluation Group. N Engl J Med 1997;336(2):86-91.
6. Bojang KA, Milligan PJM, Pinder M, Vigneron L, Alloueche A, Kester KE, et al. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. The Lancet 2001;358(9297):1927-1934.
7. Bojang KA,, Olodude F, Pinder M, Ofori-Anyinam O, Vigneron L, Fitzpatrick S, Njie F, Kassanga A, Leach A, Milman J, Rabinovich R, McAdam KPWJ, Kester KE, Heppner DG, Cohen JD, Tornieporth N, and Milligan PJM. Safety and immunogenicity of RTS,S/AS02A candidate malaria vaccine in Gambian children. Vaccine submitted.
8. Macete E, Aponte JJ, Guinovart C, Sacarlal J, Mandomando I, Espasa M, et al. Safety, reactogenicity and immunogenicty of the RTS,S/AS02A candidate malaria vaccine in children aged 1 to 4 years in Mozambique. Vaccine submitted.
9. Alonso P, Saute F, Aponte J, Gomez-Olive F, Nhacolo A, Thomson R, et al. Manhica DSS, Mozambique. In: INDEPTH, ed. Population and Health in Developing Countries. Ottawa: International Development Research Centre, 2001: 189-195.
10. Dame JB, Williams JL, McCutchan TF, Weber JL, Wirtz RA, Hockmeyer WT, Maloy WL, Haynes JD, Schneider I, Roberts D, et al. Structure of the gene encoding the immunodominant surface antigen on the sporozoite of the human malaria parasite Plasmodium falciparum. Science. 1984;225:593-9.
11. Young JF, Hockmeyer WT, Gross M, Ballou WR, Wirtz RA, Trosper JH, Beaudoin RL, Hollingdale MR, Miller LH, Diggs CL, et al. Expression of Plasmodium falciparum circumsporozoite proteins in Escherichia coli for potential use in a human malaria vaccine. Science 1985;228:958-62.
12. Doherty J, Pinder M, Tornieporth N, Carton C, Vigneron L, Milligan P, et al. A phase I safety and immunogenicity trial with the candidate malaria vaccine RTS,S/SBAS2 in semi-immune adults in The Gambia. Am J Trop Med Hyg 1999;61(6):865-868.
13. Loscertales MP, Roca A, Ventura P, Abascassamo F, Dos Santos F, Sitaube M, et al. Epidemiology and clinical presentation of respiratory syncytial virus infection in a rural area of southern Mozambique. Pediatr Infect Dis J 2002;21:148-155.
14. Alonso P, Smith T, Schellenberg J, Masanja H, Mwankusye S, Urassa H, et al. Randomised trial of efficacy of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania. The Lancet 1994;344:1175-81.
15. Saute F, Aponte J, Almeda J, Ascaso C, Abellana R, Vaz N, et al. Malaria in southern Mozambique: malariometric indicators and malaria case definition in Manhica district. in press.
16. World Health Organization. Management of severe malaria, a practical handbook. Second edition, 2000. http://mosquito.who.int/docs/hbsm.pdf
17. Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York: Springer, 2000.
18. Hess KR. Graphical methods for assessing violations of the proportional hazards assumption in Cox regression. Stat Med 1995;14(15):1707-23.
19. Cytel Software Corporation. StatXact PROCs for SAS Users (version 6). Cambridge, MA, USA.
20. SAS Institue Inc. SAS software (version 8). Cary, NC, USA.
21. Stata Corporation. Stata Statistical Software (Release 8.0). College Station, TX, USA 2003.
22. Sun P, Schwenk R, White K, Stoute JA, Cohen J, Ballou WR, Voss G, Kester KE, Heppner DG, Krzych U. Protective immunity induced with malaria vaccine, RTS,S, is linked to Plasmodium falciparum circumsporozoite protein-specific CD4(+) and CD8(+) T cells producing IFN-gamma. J Immunol. 2003 Dec 15; 171(12): 6961-7.
23. Stoute, JA, Kester KE, Krzych U, Wellde BT, Hall T, White K, Glenn G, Ockenhouse CF, Garcon N, Schwenk R, Lanar DE, Momin P, Golenda C, Slaoui M, Wortmann G, Cohen J, Ballou WR. Long Term Efficacy and Immune Responses Following Immunization with the RTS,S Malaria Vaccine. J Infect Dis 178:1139-44, 1998.
Claims (3)
- 前赤血球段階で発現されるPlasmodium抗原、および製薬上許容されるアジュバントを含む、24ヶ月未満の小児における重篤マラリア疾患に対するワクチン組成物であって、Plasmodium抗原が25μg/用量のRTS,Sであり、アジュバントがそれぞれ25μg/用量の3D-MPLとQS21との組合せを含む、上記組成物。
- 該アジュバントが水中油型エマルションを更に含む、請求項1記載の組成物。
- 該アジュバントがリポソームを更に含む、請求項1記載の組成物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0420634A GB0420634D0 (en) | 2004-09-16 | 2004-09-16 | Vaccines |
GB0420634.8 | 2004-09-16 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007531693A Division JP5670611B2 (ja) | 2004-09-16 | 2005-09-14 | プラスモジウム抗原を含むワクチン |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2012116849A JP2012116849A (ja) | 2012-06-21 |
JP5632404B2 true JP5632404B2 (ja) | 2014-11-26 |
Family
ID=33306702
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007531693A Expired - Fee Related JP5670611B2 (ja) | 2004-09-16 | 2005-09-14 | プラスモジウム抗原を含むワクチン |
JP2012014815A Expired - Fee Related JP5632404B2 (ja) | 2004-09-16 | 2012-01-27 | プラスモジウム抗原を含むワクチン |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007531693A Expired - Fee Related JP5670611B2 (ja) | 2004-09-16 | 2005-09-14 | プラスモジウム抗原を含むワクチン |
Country Status (18)
Country | Link |
---|---|
US (1) | US20080102091A1 (ja) |
EP (1) | EP1791558A2 (ja) |
JP (2) | JP5670611B2 (ja) |
KR (1) | KR101362097B1 (ja) |
CN (2) | CN101056653A (ja) |
AR (1) | AR051023A1 (ja) |
AU (1) | AU2005284223B2 (ja) |
BR (1) | BRPI0515334A (ja) |
CA (1) | CA2579527C (ja) |
GB (1) | GB0420634D0 (ja) |
IL (1) | IL181733A0 (ja) |
MA (1) | MA28885B1 (ja) |
MX (1) | MX2007003160A (ja) |
NO (1) | NO20071523L (ja) |
RU (1) | RU2423994C2 (ja) |
SG (2) | SG159520A1 (ja) |
TW (1) | TW200621287A (ja) |
WO (1) | WO2006029887A2 (ja) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050002958A1 (en) * | 1999-06-29 | 2005-01-06 | Smithkline Beecham Biologicals Sa | Vaccines |
GB0513421D0 (en) | 2005-06-30 | 2005-08-03 | Glaxosmithkline Biolog Sa | Vaccines |
SG173377A1 (en) | 2006-07-18 | 2011-08-29 | Glaxosmithkline Biolog Sa | Vaccines for malaria |
PL2066344T3 (pl) | 2006-09-07 | 2011-10-31 | Glaxosmithkline Biologicals Sa | Skojarzona szczepionka zawierająca inaktywowany wirus polio |
PL2137210T3 (pl) * | 2007-03-02 | 2017-06-30 | Glaxosmithkline Biologicals Sa | Nowy sposób i kompozycje |
UY31285A1 (es) * | 2007-08-13 | 2009-03-31 | Vacunas | |
WO2010108177A2 (en) * | 2009-03-20 | 2010-09-23 | University Of South Florida | A method and composition using a dual specificity protein tyrosine phosphatase as an antimalarial drug target |
US20120244178A1 (en) * | 2011-03-25 | 2012-09-27 | Denise Doolan | Plasmodium falciparum antigens |
US9241988B2 (en) * | 2012-04-12 | 2016-01-26 | Avanti Polar Lipids, Inc. | Disaccharide synthetic lipid compounds and uses thereof |
US9169304B2 (en) | 2012-05-01 | 2015-10-27 | Pfenex Inc. | Process for purifying recombinant Plasmodium falciparum circumsporozoite protein |
UY35418A (es) | 2013-03-15 | 2014-10-31 | Glaxosmithkline Biolog Sa | Vacuna que proporciona protección frente a diferentes Picornavirus humanos. |
GB201416773D0 (en) * | 2014-09-23 | 2014-11-05 | Glaxosmithkline Biolog S A And Chancellor Masters And Scolars Of The The University Of Oxford | Novel Methods For Including An Imune Response |
WO2016184784A1 (en) | 2015-05-15 | 2016-11-24 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Peptides including binding domain of plasmodium falciparum proteins (cbp1 and cbp2) to chemokine cx3cl1 |
CA2998540C (en) * | 2015-09-16 | 2024-04-02 | Artificial Cell Technologies, Inc. | Anti-malaria compositions and methods |
JP2022526334A (ja) | 2019-03-25 | 2022-05-24 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 新たなタウ種を標的化することによるタウオパチー障害の処置の方法 |
WO2020221451A1 (en) * | 2019-04-30 | 2020-11-05 | Humabs Biomed Sa | Antibodies binding to plasmodium circumsporozoite protein and uses thereof |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69228698T2 (de) | 1991-11-16 | 1999-09-16 | Smithkline Beecham Biologicals S.A., Rixensart | HYBRIDES PROTEIN ZWISCHEN CS AUS PLASMODIUM UND HBsAG |
JP3755890B2 (ja) * | 1992-06-25 | 2006-03-15 | スミスクライン・ビーチャム・バイオロジカルス(ソシエテ・アノニム) | アジュバント含有ワクチン組成物 |
UA56132C2 (uk) * | 1995-04-25 | 2003-05-15 | Смітклайн Бічем Байолоджікалс С.А. | Композиція вакцини (варіанти), спосіб стабілізації qs21 відносно гідролізу (варіанти), спосіб приготування композиції вакцини |
EP1201250A1 (en) * | 2000-10-25 | 2002-05-02 | SMITHKLINE BEECHAM BIOLOGICALS s.a. | Immunogenic compositions comprising liver stage malarial antigens |
EP1423405A4 (en) * | 2001-03-26 | 2005-01-05 | Us Army | AMA-1 PROTEIN OF PLASMODIUM FALCIPARUM AND ITS APPLICATIONS |
US7550275B2 (en) * | 2002-11-12 | 2009-06-23 | The United States Of America As Represented By The Secretary Of The Navy | Expression, purification and uses of a Plasmodium falciparum liver stage antigen 1 polypeptide |
ATE553200T1 (de) * | 2003-08-15 | 2012-04-15 | Commw Scient Ind Res Org | Verfahren und mittel zur veränderung der fasereigenschaften in faserproduzierenden pflanzen |
-
2004
- 2004-09-16 GB GB0420634A patent/GB0420634D0/en not_active Ceased
-
2005
- 2005-09-14 EP EP05786962A patent/EP1791558A2/en not_active Withdrawn
- 2005-09-14 BR BRPI0515334-4A patent/BRPI0515334A/pt not_active Application Discontinuation
- 2005-09-14 SG SG201000764-9A patent/SG159520A1/en unknown
- 2005-09-14 TW TW094131758A patent/TW200621287A/zh unknown
- 2005-09-14 CN CNA2005800380226A patent/CN101056653A/zh active Pending
- 2005-09-14 AU AU2005284223A patent/AU2005284223B2/en not_active Ceased
- 2005-09-14 WO PCT/EP2005/009995 patent/WO2006029887A2/en active Application Filing
- 2005-09-14 SG SG2013057559A patent/SG193159A1/en unknown
- 2005-09-14 US US11/575,414 patent/US20080102091A1/en not_active Abandoned
- 2005-09-14 CN CN201410301031.0A patent/CN104027795A/zh active Pending
- 2005-09-14 CA CA2579527A patent/CA2579527C/en not_active Expired - Fee Related
- 2005-09-14 RU RU2007109608/15A patent/RU2423994C2/ru not_active IP Right Cessation
- 2005-09-14 KR KR1020077007679A patent/KR101362097B1/ko not_active IP Right Cessation
- 2005-09-14 JP JP2007531693A patent/JP5670611B2/ja not_active Expired - Fee Related
- 2005-09-14 MX MX2007003160A patent/MX2007003160A/es active IP Right Grant
- 2005-09-14 AR ARP050103838A patent/AR051023A1/es not_active Application Discontinuation
-
2007
- 2007-03-06 IL IL181733A patent/IL181733A0/en unknown
- 2007-03-23 NO NO20071523A patent/NO20071523L/no not_active Application Discontinuation
- 2007-03-30 MA MA29790A patent/MA28885B1/fr unknown
-
2012
- 2012-01-27 JP JP2012014815A patent/JP5632404B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
AR051023A1 (es) | 2006-12-13 |
AU2005284223B2 (en) | 2011-12-15 |
MX2007003160A (es) | 2007-10-23 |
RU2423994C2 (ru) | 2011-07-20 |
SG193159A1 (en) | 2013-09-30 |
WO2006029887A2 (en) | 2006-03-23 |
CA2579527C (en) | 2016-06-21 |
MA28885B1 (fr) | 2007-09-03 |
JP2008513400A (ja) | 2008-05-01 |
KR101362097B1 (ko) | 2014-02-21 |
TW200621287A (en) | 2006-07-01 |
CN101056653A (zh) | 2007-10-17 |
JP5670611B2 (ja) | 2015-02-18 |
EP1791558A2 (en) | 2007-06-06 |
JP2012116849A (ja) | 2012-06-21 |
BRPI0515334A (pt) | 2008-07-22 |
WO2006029887A3 (en) | 2006-05-11 |
AU2005284223A1 (en) | 2006-03-23 |
CA2579527A1 (en) | 2006-03-23 |
US20080102091A1 (en) | 2008-05-01 |
RU2007109608A (ru) | 2008-10-27 |
SG159520A1 (en) | 2010-03-30 |
GB0420634D0 (en) | 2004-10-20 |
NO20071523L (no) | 2007-03-28 |
KR20070052342A (ko) | 2007-05-21 |
CN104027795A (zh) | 2014-09-10 |
IL181733A0 (en) | 2007-07-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5632404B2 (ja) | プラスモジウム抗原を含むワクチン | |
JP5508266B2 (ja) | ワクチン | |
EP1896060B1 (en) | Anti-malaria vaccine | |
CN101820901B (zh) | 疫苗 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130730 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20131024 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20131029 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140130 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20140408 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140808 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20140825 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20140924 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20141009 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5632404 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |