CN115443148A - 鼻内mRNA疫苗 - Google Patents
鼻内mRNA疫苗 Download PDFInfo
- Publication number
- CN115443148A CN115443148A CN202180009112.1A CN202180009112A CN115443148A CN 115443148 A CN115443148 A CN 115443148A CN 202180009112 A CN202180009112 A CN 202180009112A CN 115443148 A CN115443148 A CN 115443148A
- Authority
- CN
- China
- Prior art keywords
- mrna
- combination
- antigen
- vaccine
- infection
- 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.)
- Pending
Links
- 108700021021 mRNA Vaccine Proteins 0.000 title abstract description 9
- 229940126582 mRNA vaccine Drugs 0.000 title abstract description 9
- 108020004999 messenger RNA Proteins 0.000 claims abstract description 86
- 229960005486 vaccine Drugs 0.000 claims abstract description 53
- 239000000427 antigen Substances 0.000 claims abstract description 46
- 108091007433 antigens Proteins 0.000 claims abstract description 46
- 102000036639 antigens Human genes 0.000 claims abstract description 46
- 239000000203 mixture Substances 0.000 claims abstract description 27
- 230000003308 immunostimulating effect Effects 0.000 claims abstract description 22
- 230000001717 pathogenic effect Effects 0.000 claims abstract description 18
- 108010029697 CD40 Ligand Proteins 0.000 claims abstract description 17
- 102100032937 CD40 ligand Human genes 0.000 claims abstract description 17
- 230000003612 virological effect Effects 0.000 claims abstract description 14
- 102100025221 CD70 antigen Human genes 0.000 claims abstract description 8
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 claims abstract description 8
- 230000001580 bacterial effect Effects 0.000 claims abstract description 8
- 230000002538 fungal effect Effects 0.000 claims abstract description 7
- 150000002632 lipids Chemical class 0.000 claims description 23
- 208000015181 infectious disease Diseases 0.000 claims description 21
- 102000004169 proteins and genes Human genes 0.000 claims description 21
- 108090000623 proteins and genes Proteins 0.000 claims description 21
- 239000002105 nanoparticle Substances 0.000 claims description 19
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 17
- 241000711573 Coronaviridae Species 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 244000052769 pathogen Species 0.000 claims description 11
- 238000009472 formulation Methods 0.000 claims description 9
- 230000000241 respiratory effect Effects 0.000 claims description 8
- 230000005875 antibody response Effects 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- UVBYMVOUBXYSFV-XUTVFYLZSA-N 1-methylpseudouridine Chemical compound O=C1NC(=O)N(C)C=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 UVBYMVOUBXYSFV-XUTVFYLZSA-N 0.000 claims description 5
- 208000035473 Communicable disease Diseases 0.000 claims description 5
- 229920002873 Polyethylenimine Polymers 0.000 claims description 5
- 239000002479 lipoplex Substances 0.000 claims description 5
- 239000011159 matrix material Substances 0.000 claims description 5
- 230000004936 stimulating effect Effects 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 239000000412 dendrimer Substances 0.000 claims description 2
- 229920000736 dendritic polymer Polymers 0.000 claims description 2
- 101000956368 Trittame loki CRISP/Allergen/PR-1 Proteins 0.000 claims 1
- 125000003835 nucleoside group Chemical group 0.000 claims 1
- 238000011161 development Methods 0.000 abstract description 12
- 230000004044 response Effects 0.000 abstract description 10
- 210000000612 antigen-presenting cell Anatomy 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 241001465754 Metazoa Species 0.000 description 20
- 108020004414 DNA Proteins 0.000 description 18
- 210000004072 lung Anatomy 0.000 description 14
- 238000001727 in vivo Methods 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- ZKVLEFBKBNUQHK-UHFFFAOYSA-N helium;molecular nitrogen;molecular oxygen Chemical compound [He].N#N.O=O ZKVLEFBKBNUQHK-UHFFFAOYSA-N 0.000 description 11
- 241000700605 Viruses Species 0.000 description 10
- 238000013459 approach Methods 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000002255 vaccination Methods 0.000 description 10
- 102000053602 DNA Human genes 0.000 description 9
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 239000002777 nucleoside Substances 0.000 description 9
- 150000003833 nucleoside derivatives Chemical class 0.000 description 9
- 230000006698 induction Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 241000315672 SARS coronavirus Species 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 6
- 125000003729 nucleotide group Chemical group 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 208000025721 COVID-19 Diseases 0.000 description 5
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 5
- 230000036039 immunity Effects 0.000 description 5
- 230000003053 immunization Effects 0.000 description 5
- 238000002649 immunization Methods 0.000 description 5
- 206010022000 influenza Diseases 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 244000309467 Human Coronavirus Species 0.000 description 4
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 208000036142 Viral infection Diseases 0.000 description 4
- 230000007969 cellular immunity Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 239000007922 nasal spray Substances 0.000 description 4
- 229940097496 nasal spray Drugs 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 210000002345 respiratory system Anatomy 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- BVLGKOVALHRKNM-XUTVFYLZSA-N 2-Thio-1-methylpseudouridine Chemical compound CN1C=C(C(=O)NC1=S)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O BVLGKOVALHRKNM-XUTVFYLZSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 208000035143 Bacterial infection Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 206010057190 Respiratory tract infections Diseases 0.000 description 3
- 101710198474 Spike protein Proteins 0.000 description 3
- 101710172711 Structural protein Proteins 0.000 description 3
- 230000005867 T cell response Effects 0.000 description 3
- 102000002689 Toll-like receptor Human genes 0.000 description 3
- 108020000411 Toll-like receptor Proteins 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000002941 microtiter virus yield reduction assay Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 210000004877 mucosa Anatomy 0.000 description 3
- 201000009240 nasopharyngitis Diseases 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 210000001331 nose Anatomy 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 229940096913 pseudoisocytidine Drugs 0.000 description 3
- 208000023504 respiratory system disease Diseases 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 230000029812 viral genome replication Effects 0.000 description 3
- 206010048282 zoonosis Diseases 0.000 description 3
- WEYNBWVKOYCCQT-UHFFFAOYSA-N 1-(3-chloro-4-methylphenyl)-3-{2-[({5-[(dimethylamino)methyl]-2-furyl}methyl)thio]ethyl}urea Chemical group O1C(CN(C)C)=CC=C1CSCCNC(=O)NC1=CC=C(C)C(Cl)=C1 WEYNBWVKOYCCQT-UHFFFAOYSA-N 0.000 description 2
- OYTVCAGSWWRUII-DWJKKKFUSA-N 1-Methyl-1-deazapseudouridine Chemical compound CC1C=C(C(=O)NC1=O)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O OYTVCAGSWWRUII-DWJKKKFUSA-N 0.000 description 2
- CWXIOHYALLRNSZ-JWMKEVCDSA-N 2-Thiodihydropseudouridine Chemical compound C1C(C(=O)NC(=S)N1)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O CWXIOHYALLRNSZ-JWMKEVCDSA-N 0.000 description 2
- NUBJGTNGKODGGX-YYNOVJQHSA-N 2-[5-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2,4-dioxopyrimidin-1-yl]acetic acid Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CN(CC(O)=O)C(=O)NC1=O NUBJGTNGKODGGX-YYNOVJQHSA-N 0.000 description 2
- HOCJTJWYMOSXMU-XUTVFYLZSA-N 4-Methoxypseudouridine Chemical compound COC1=C(C=NC(=O)N1)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O HOCJTJWYMOSXMU-XUTVFYLZSA-N 0.000 description 2
- VTGBLFNEDHVUQA-XUTVFYLZSA-N 4-Thio-1-methyl-pseudouridine Chemical compound S=C1NC(=O)N(C)C=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 VTGBLFNEDHVUQA-XUTVFYLZSA-N 0.000 description 2
- ITGWEVGJUSMCEA-KYXWUPHJSA-N 5-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1-prop-1-ynylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)N(C#CC)C=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 ITGWEVGJUSMCEA-KYXWUPHJSA-N 0.000 description 2
- DDHOXEOVAJVODV-GBNDHIKLSA-N 5-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-sulfanylidene-1h-pyrimidin-4-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=S)NC1=O DDHOXEOVAJVODV-GBNDHIKLSA-N 0.000 description 2
- BNAWMJKJLNJZFU-GBNDHIKLSA-N 5-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-sulfanylidene-1h-pyrimidin-2-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=S BNAWMJKJLNJZFU-GBNDHIKLSA-N 0.000 description 2
- QXDXBKZJFLRLCM-UAKXSSHOSA-N 5-hydroxyuridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(O)=C1 QXDXBKZJFLRLCM-UAKXSSHOSA-N 0.000 description 2
- PEHVGBZKEYRQSX-UHFFFAOYSA-N 7-deaza-adenine Chemical compound NC1=NC=NC2=C1C=CN2 PEHVGBZKEYRQSX-UHFFFAOYSA-N 0.000 description 2
- HCGHYQLFMPXSDU-UHFFFAOYSA-N 7-methyladenine Chemical compound C1=NC(N)=C2N(C)C=NC2=N1 HCGHYQLFMPXSDU-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000037384 Clostridium Infections Diseases 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- 208000001528 Coronaviridae Infections Diseases 0.000 description 2
- 206010048768 Dermatosis Diseases 0.000 description 2
- YKWUPFSEFXSGRT-JWMKEVCDSA-N Dihydropseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1C(=O)NC(=O)NC1 YKWUPFSEFXSGRT-JWMKEVCDSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 208000009889 Herpes Simplex Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 2
- 201000009906 Meningitis Diseases 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 208000000474 Poliomyelitis Diseases 0.000 description 2
- 229930185560 Pseudouridine Natural products 0.000 description 2
- PTJWIQPHWPFNBW-UHFFFAOYSA-N Pseudouridine C Natural products OC1C(O)C(CO)OC1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-UHFFFAOYSA-N 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 208000035056 Tick-Borne disease Diseases 0.000 description 2
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 108010067390 Viral Proteins Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- WGDUUQDYDIIBKT-UHFFFAOYSA-N beta-Pseudouridine Natural products OC1OC(CN2C=CC(=O)NC2=O)C(O)C1O WGDUUQDYDIIBKT-UHFFFAOYSA-N 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 229940030156 cell vaccine Drugs 0.000 description 2
- 235000013330 chicken meat Nutrition 0.000 description 2
- 238000010668 complexation reaction Methods 0.000 description 2
- 230000009260 cross reactivity Effects 0.000 description 2
- 231100000676 disease causative agent Toxicity 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 208000024386 fungal infectious disease Diseases 0.000 description 2
- 230000035931 haemagglutination Effects 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 239000012678 infectious agent Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- -1 mannosyl Lipid Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005399 mechanical ventilation Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 210000003928 nasal cavity Anatomy 0.000 description 2
- 210000002850 nasal mucosa Anatomy 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- PTJWIQPHWPFNBW-GBNDHIKLSA-N pseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-GBNDHIKLSA-N 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- YZSZLBRBVWAXFW-LNYQSQCFSA-N (2R,3R,4S,5R)-2-(2-amino-6-hydroxy-6-methoxy-3H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound COC1(O)NC(N)=NC2=C1N=CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YZSZLBRBVWAXFW-LNYQSQCFSA-N 0.000 description 1
- MIXBUOXRHTZHKR-XUTVFYLZSA-N 1-Methylpseudoisocytidine Chemical compound CN1C=C(C(=O)N=C1N)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O MIXBUOXRHTZHKR-XUTVFYLZSA-N 0.000 description 1
- KYEKLQMDNZPEFU-KVTDHHQDSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3,5-triazine-2,4-dione Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)N=C1 KYEKLQMDNZPEFU-KVTDHHQDSA-N 0.000 description 1
- UTQUILVPBZEHTK-ZOQUXTDFSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-3-methylpyrimidine-2,4-dione Chemical compound O=C1N(C)C(=O)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 UTQUILVPBZEHTK-ZOQUXTDFSA-N 0.000 description 1
- QLOCVMVCRJOTTM-TURQNECASA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-prop-1-ynylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C#CC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 QLOCVMVCRJOTTM-TURQNECASA-N 0.000 description 1
- GFYLSDSUCHVORB-IOSLPCCCSA-N 1-methyladenosine Chemical compound C1=NC=2C(=N)N(C)C=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O GFYLSDSUCHVORB-IOSLPCCCSA-N 0.000 description 1
- UTAIYTHAJQNQDW-KQYNXXCUSA-N 1-methylguanosine Chemical compound C1=NC=2C(=O)N(C)C(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O UTAIYTHAJQNQDW-KQYNXXCUSA-N 0.000 description 1
- WJNGQIYEQLPJMN-IOSLPCCCSA-N 1-methylinosine Chemical compound C1=NC=2C(=O)N(C)C=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O WJNGQIYEQLPJMN-IOSLPCCCSA-N 0.000 description 1
- JCNGYIGHEUKAHK-DWJKKKFUSA-N 2-Thio-1-methyl-1-deazapseudouridine Chemical compound CC1C=C(C(=O)NC1=S)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O JCNGYIGHEUKAHK-DWJKKKFUSA-N 0.000 description 1
- MPDKOGQMQLSNOF-GBNDHIKLSA-N 2-amino-5-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1h-pyrimidin-6-one Chemical compound O=C1NC(N)=NC=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 MPDKOGQMQLSNOF-GBNDHIKLSA-N 0.000 description 1
- JRYMOPZHXMVHTA-DAGMQNCNSA-N 2-amino-7-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1h-pyrrolo[2,3-d]pyrimidin-4-one Chemical compound C1=CC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O JRYMOPZHXMVHTA-DAGMQNCNSA-N 0.000 description 1
- IBKZHHCJWDWGAJ-FJGDRVTGSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1-methylpurine-6-thione Chemical compound C1=NC=2C(=S)N(C)C(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O IBKZHHCJWDWGAJ-FJGDRVTGSA-N 0.000 description 1
- HPKQEMIXSLRGJU-UUOKFMHZSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-methyl-3h-purine-6,8-dione Chemical compound O=C1N(C)C(C(NC(N)=N2)=O)=C2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O HPKQEMIXSLRGJU-UUOKFMHZSA-N 0.000 description 1
- PBFLIOAJBULBHI-JJNLEZRASA-N 2-amino-n-[[9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-6-yl]carbamoyl]acetamide Chemical compound C1=NC=2C(NC(=O)NC(=O)CN)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O PBFLIOAJBULBHI-JJNLEZRASA-N 0.000 description 1
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 description 1
- QCPQCJVQJKOKMS-VLSMUFELSA-N 2-methoxy-5-methyl-cytidine Chemical compound CC(C(N)=N1)=CN([C@@H]([C@@H]2O)O[C@H](CO)[C@H]2O)C1OC QCPQCJVQJKOKMS-VLSMUFELSA-N 0.000 description 1
- TUDKBZAMOFJOSO-UHFFFAOYSA-N 2-methoxy-7h-purin-6-amine Chemical compound COC1=NC(N)=C2NC=NC2=N1 TUDKBZAMOFJOSO-UHFFFAOYSA-N 0.000 description 1
- STISOQJGVFEOFJ-MEVVYUPBSA-N 2-methoxy-cytidine Chemical compound COC(N([C@@H]([C@@H]1O)O[C@H](CO)[C@H]1O)C=C1)N=C1N STISOQJGVFEOFJ-MEVVYUPBSA-N 0.000 description 1
- WBVPJIKOWUQTSD-ZOQUXTDFSA-N 2-methoxyuridine Chemical compound COC1=NC(=O)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 WBVPJIKOWUQTSD-ZOQUXTDFSA-N 0.000 description 1
- FXGXEFXCWDTSQK-UHFFFAOYSA-N 2-methylsulfanyl-7h-purin-6-amine Chemical compound CSC1=NC(N)=C2NC=NC2=N1 FXGXEFXCWDTSQK-UHFFFAOYSA-N 0.000 description 1
- QEWSGVMSLPHELX-UHFFFAOYSA-N 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine Chemical compound C12=NC(SC)=NC(NCC=C(C)CO)=C2N=CN1C1OC(CO)C(O)C1O QEWSGVMSLPHELX-UHFFFAOYSA-N 0.000 description 1
- JUMHLCXWYQVTLL-KVTDHHQDSA-N 2-thio-5-aza-uridine Chemical compound [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=S)NC(=O)N=C1 JUMHLCXWYQVTLL-KVTDHHQDSA-N 0.000 description 1
- RHFUOMFWUGWKKO-XVFCMESISA-N 2-thiocytidine Chemical compound S=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RHFUOMFWUGWKKO-XVFCMESISA-N 0.000 description 1
- GJTBSTBJLVYKAU-XVFCMESISA-N 2-thiouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=S)NC(=O)C=C1 GJTBSTBJLVYKAU-XVFCMESISA-N 0.000 description 1
- RDPUKVRQKWBSPK-UHFFFAOYSA-N 3-Methylcytidine Natural products O=C1N(C)C(=N)C=CN1C1C(O)C(O)C(CO)O1 RDPUKVRQKWBSPK-UHFFFAOYSA-N 0.000 description 1
- UTQUILVPBZEHTK-UHFFFAOYSA-N 3-Methyluridine Natural products O=C1N(C)C(=O)C=CN1C1C(O)C(O)C(CO)O1 UTQUILVPBZEHTK-UHFFFAOYSA-N 0.000 description 1
- RDPUKVRQKWBSPK-ZOQUXTDFSA-N 3-methylcytidine Chemical compound O=C1N(C)C(=N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RDPUKVRQKWBSPK-ZOQUXTDFSA-N 0.000 description 1
- ZSIINYPBPQCZKU-BQNZPOLKSA-O 4-Methoxy-1-methylpseudoisocytidine Chemical compound C[N+](CC1[C@H]([C@H]2O)O[C@@H](CO)[C@@H]2O)=C(N)N=C1OC ZSIINYPBPQCZKU-BQNZPOLKSA-O 0.000 description 1
- FGFVODMBKZRMMW-XUTVFYLZSA-N 4-Methoxy-2-thiopseudouridine Chemical compound COC1=C(C=NC(=S)N1)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O FGFVODMBKZRMMW-XUTVFYLZSA-N 0.000 description 1
- OCMSXKMNYAHJMU-JXOAFFINSA-N 4-amino-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidine-5-carbaldehyde Chemical compound C1=C(C=O)C(N)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 OCMSXKMNYAHJMU-JXOAFFINSA-N 0.000 description 1
- OZHIJZYBTCTDQC-JXOAFFINSA-N 4-amino-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2-thione Chemical compound S=C1N=C(N)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 OZHIJZYBTCTDQC-JXOAFFINSA-N 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- LOICBOXHPCURMU-UHFFFAOYSA-N 4-methoxy-pseudoisocytidine Chemical compound COC1NC(N)=NC=C1C(C1O)OC(CO)C1O LOICBOXHPCURMU-UHFFFAOYSA-N 0.000 description 1
- HFQQYIUTYJVYFZ-UHFFFAOYSA-N 4-methylpentyl 2-cyanoprop-2-enoate Chemical compound CC(C)CCCOC(=O)C(=C)C#N HFQQYIUTYJVYFZ-UHFFFAOYSA-N 0.000 description 1
- SJVVKUMXGIKAAI-UHFFFAOYSA-N 4-thio-pseudoisocytidine Chemical compound NC(N1)=NC=C(C(C2O)OC(CO)C2O)C1=S SJVVKUMXGIKAAI-UHFFFAOYSA-N 0.000 description 1
- FAWQJBLSWXIJLA-VPCXQMTMSA-N 5-(carboxymethyl)uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(CC(O)=O)=C1 FAWQJBLSWXIJLA-VPCXQMTMSA-N 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- NFEXJLMYXXIWPI-JXOAFFINSA-N 5-Hydroxymethylcytidine Chemical compound C1=C(CO)C(N)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NFEXJLMYXXIWPI-JXOAFFINSA-N 0.000 description 1
- ZAYHVCMSTBRABG-UHFFFAOYSA-N 5-Methylcytidine Natural products O=C1N=C(N)C(C)=CN1C1C(O)C(O)C(CO)O1 ZAYHVCMSTBRABG-UHFFFAOYSA-N 0.000 description 1
- XUNBIDXYAUXNKD-DBRKOABJSA-N 5-aza-2-thio-zebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=S)N=CN=C1 XUNBIDXYAUXNKD-DBRKOABJSA-N 0.000 description 1
- OSLBPVOJTCDNEF-DBRKOABJSA-N 5-aza-zebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=CN=C1 OSLBPVOJTCDNEF-DBRKOABJSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- STRZQWQNZQMHQR-UAKXSSHOSA-N 5-fluorocytidine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 STRZQWQNZQMHQR-UAKXSSHOSA-N 0.000 description 1
- ZXIATBNUWJBBGT-JXOAFFINSA-N 5-methoxyuridine Chemical compound O=C1NC(=O)C(OC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 ZXIATBNUWJBBGT-JXOAFFINSA-N 0.000 description 1
- RPQQZHJQUBDHHG-FNCVBFRFSA-N 5-methyl-zebularine Chemical compound C1=C(C)C=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RPQQZHJQUBDHHG-FNCVBFRFSA-N 0.000 description 1
- ZAYHVCMSTBRABG-JXOAFFINSA-N 5-methylcytidine Chemical compound O=C1N=C(N)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 ZAYHVCMSTBRABG-JXOAFFINSA-N 0.000 description 1
- USVMJSALORZVDV-UHFFFAOYSA-N 6-(gamma,gamma-dimethylallylamino)purine riboside Natural products C1=NC=2C(NCC=C(C)C)=NC=NC=2N1C1OC(CO)C(O)C1O USVMJSALORZVDV-UHFFFAOYSA-N 0.000 description 1
- OZTOEARQSSIFOG-MWKIOEHESA-N 6-Thio-7-deaza-8-azaguanosine Chemical compound Nc1nc(=S)c2cnn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1 OZTOEARQSSIFOG-MWKIOEHESA-N 0.000 description 1
- RFHIWBUKNJIBSE-KQYNXXCUSA-O 6-thio-7-methyl-guanosine Chemical compound C1=2NC(N)=NC(=S)C=2N(C)C=[N+]1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O RFHIWBUKNJIBSE-KQYNXXCUSA-O 0.000 description 1
- MJJUWOIBPREHRU-MWKIOEHESA-N 7-Deaza-8-azaguanosine Chemical compound NC=1NC(C2=C(N=1)N(N=C2)[C@H]1[C@H](O)[C@H](O)[C@H](O1)CO)=O MJJUWOIBPREHRU-MWKIOEHESA-N 0.000 description 1
- ISSMDAFGDCTNDV-UHFFFAOYSA-N 7-deaza-2,6-diaminopurine Chemical compound NC1=NC(N)=C2NC=CC2=N1 ISSMDAFGDCTNDV-UHFFFAOYSA-N 0.000 description 1
- YVVMIGRXQRPSIY-UHFFFAOYSA-N 7-deaza-2-aminopurine Chemical compound N1C(N)=NC=C2C=CN=C21 YVVMIGRXQRPSIY-UHFFFAOYSA-N 0.000 description 1
- ZTAWTRPFJHKMRU-UHFFFAOYSA-N 7-deaza-8-aza-2,6-diaminopurine Chemical compound NC1=NC(N)=C2NN=CC2=N1 ZTAWTRPFJHKMRU-UHFFFAOYSA-N 0.000 description 1
- SMXRCJBCWRHDJE-UHFFFAOYSA-N 7-deaza-8-aza-2-aminopurine Chemical compound NC1=NC=C2C=NNC2=N1 SMXRCJBCWRHDJE-UHFFFAOYSA-N 0.000 description 1
- LHCPRYRLDOSKHK-UHFFFAOYSA-N 7-deaza-8-aza-adenine Chemical compound NC1=NC=NC2=C1C=NN2 LHCPRYRLDOSKHK-UHFFFAOYSA-N 0.000 description 1
- OGHAROSJZRTIOK-KQYNXXCUSA-O 7-methylguanosine Chemical compound C1=2N=C(N)NC(=O)C=2[N+](C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OGHAROSJZRTIOK-KQYNXXCUSA-O 0.000 description 1
- VJNXUFOTKNTNPG-IOSLPCCCSA-O 7-methylinosine Chemical compound C1=2NC=NC(=O)C=2N(C)C=[N+]1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VJNXUFOTKNTNPG-IOSLPCCCSA-O 0.000 description 1
- HCAJQHYUCKICQH-VPENINKCSA-N 8-Oxo-7,8-dihydro-2'-deoxyguanosine Chemical compound C1=2NC(N)=NC(=O)C=2NC(=O)N1[C@H]1C[C@H](O)[C@@H](CO)O1 HCAJQHYUCKICQH-VPENINKCSA-N 0.000 description 1
- ABXGJJVKZAAEDH-IOSLPCCCSA-N 9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-(dimethylamino)-3h-purine-6-thione Chemical compound C1=NC=2C(=S)NC(N(C)C)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O ABXGJJVKZAAEDH-IOSLPCCCSA-N 0.000 description 1
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 208000010370 Adenoviridae Infections Diseases 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 208000007887 Alphavirus Infections Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
- 101710185050 Angiotensin-converting enzyme Proteins 0.000 description 1
- 206010059313 Anogenital warts Diseases 0.000 description 1
- 208000006400 Arbovirus Encephalitis Diseases 0.000 description 1
- 208000009828 Arbovirus Infections Diseases 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 206010003757 Atypical pneumonia Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000031729 Bacteremia Diseases 0.000 description 1
- 206010044583 Bartonella Infections Diseases 0.000 description 1
- 208000006373 Bell palsy Diseases 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 241000008904 Betacoronavirus Species 0.000 description 1
- 208000024956 Borna Disease Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003508 Botulism Diseases 0.000 description 1
- 208000004020 Brain Abscess Diseases 0.000 description 1
- 206010006500 Brucellosis Diseases 0.000 description 1
- 208000008371 Bunyaviridae Infections Diseases 0.000 description 1
- 206010073031 Burkholderia infection Diseases 0.000 description 1
- 206010069748 Burkholderia pseudomallei infection Diseases 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- 208000006339 Caliciviridae Infections Diseases 0.000 description 1
- 206010051226 Campylobacter infection Diseases 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000003732 Cat-scratch disease Diseases 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 208000014912 Central Nervous System Infections Diseases 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 208000007190 Chlamydia Infections Diseases 0.000 description 1
- 208000019442 Chlamydiaceae Infections Diseases 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000002077 Coxsackievirus Infections Diseases 0.000 description 1
- 206010011409 Cross infection Diseases 0.000 description 1
- 201000007336 Cryptococcosis Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 108010041986 DNA Vaccines Proteins 0.000 description 1
- 208000004449 DNA Virus Infections Diseases 0.000 description 1
- 229940021995 DNA vaccine Drugs 0.000 description 1
- XULFJDKZVHTRLG-JDVCJPALSA-N DOSPA trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)CCNC(=O)C(CCCNCCCN)NCCCN)OCCCCCCCC\C=C/CCCCCCCC XULFJDKZVHTRLG-JDVCJPALSA-N 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- 206010012310 Dengue fever Diseases 0.000 description 1
- 208000007163 Dermatomycoses Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010014568 Empyema Diseases 0.000 description 1
- 206010015108 Epstein-Barr virus infection Diseases 0.000 description 1
- 201000000297 Erysipelas Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 206010061126 Escherichia infection Diseases 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 206010016228 Fasciitis Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010017553 Furuncle Diseases 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- 201000000628 Gas Gangrene Diseases 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 206010061192 Haemorrhagic fever Diseases 0.000 description 1
- 208000008913 Hantavirus Infections Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 208000004898 Herpes Labialis Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 201000002563 Histoplasmosis Diseases 0.000 description 1
- 101000929928 Homo sapiens Angiotensin-converting enzyme 2 Proteins 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 241000711467 Human coronavirus 229E Species 0.000 description 1
- 241001428935 Human coronavirus OC43 Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 206010061259 Klebsiella infection Diseases 0.000 description 1
- 206010023927 Lassa fever Diseases 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 206010024238 Leptospirosis Diseases 0.000 description 1
- 206010024641 Listeriosis Diseases 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 206010025102 Lung infiltration Diseases 0.000 description 1
- 208000016604 Lyme disease Diseases 0.000 description 1
- 208000035719 Maculopathy Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 208000005647 Mumps Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 208000031998 Mycobacterium Infections Diseases 0.000 description 1
- 206010028470 Mycoplasma infections Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 208000003926 Myelitis Diseases 0.000 description 1
- RSPURTUNRHNVGF-IOSLPCCCSA-N N(2),N(2)-dimethylguanosine Chemical compound C1=NC=2C(=O)NC(N(C)C)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O RSPURTUNRHNVGF-IOSLPCCCSA-N 0.000 description 1
- NIDVTARKFBZMOT-PEBGCTIMSA-N N(4)-acetylcytidine Chemical compound O=C1N=C(NC(=O)C)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NIDVTARKFBZMOT-PEBGCTIMSA-N 0.000 description 1
- WVGPGNPCZPYCLK-WOUKDFQISA-N N(6),N(6)-dimethyladenosine Chemical compound C1=NC=2C(N(C)C)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O WVGPGNPCZPYCLK-WOUKDFQISA-N 0.000 description 1
- USVMJSALORZVDV-SDBHATRESA-N N(6)-(Delta(2)-isopentenyl)adenosine Chemical compound C1=NC=2C(NCC=C(C)C)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O USVMJSALORZVDV-SDBHATRESA-N 0.000 description 1
- VQAYFKKCNSOZKM-IOSLPCCCSA-N N(6)-methyladenosine Chemical compound C1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VQAYFKKCNSOZKM-IOSLPCCCSA-N 0.000 description 1
- WVGPGNPCZPYCLK-UHFFFAOYSA-N N-Dimethyladenosine Natural products C1=NC=2C(N(C)C)=NC=NC=2N1C1OC(CO)C(O)C1O WVGPGNPCZPYCLK-UHFFFAOYSA-N 0.000 description 1
- LZCNWAXLJWBRJE-ZOQUXTDFSA-N N4-Methylcytidine Chemical compound O=C1N=C(NC)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 LZCNWAXLJWBRJE-ZOQUXTDFSA-N 0.000 description 1
- GOSWTRUMMSCNCW-UHFFFAOYSA-N N6-(cis-hydroxyisopentenyl)adenosine Chemical compound C1=NC=2C(NCC=C(CO)C)=NC=NC=2N1C1OC(CO)C(O)C1O GOSWTRUMMSCNCW-UHFFFAOYSA-N 0.000 description 1
- VQAYFKKCNSOZKM-UHFFFAOYSA-N NSC 29409 Natural products C1=NC=2C(NC)=NC=NC=2N1C1OC(CO)C(O)C1O VQAYFKKCNSOZKM-UHFFFAOYSA-N 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 206010029443 Nocardia Infections Diseases 0.000 description 1
- 206010029444 Nocardiosis Diseases 0.000 description 1
- 206010029803 Nosocomial infection Diseases 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- 206010067152 Oral herpes Diseases 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 208000009608 Papillomavirus Infections Diseases 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- 206010067781 Pharyngeal abscess Diseases 0.000 description 1
- 229920002730 Poly(butyl cyanoacrylate) Polymers 0.000 description 1
- 229920002724 Poly(ethyl cyanoacrylate) Polymers 0.000 description 1
- 208000001676 Polyomavirus Infections Diseases 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 238000012356 Product development Methods 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 229940096437 Protein S Drugs 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 208000032536 Pseudomonas Infections Diseases 0.000 description 1
- 206010037151 Psittacosis Diseases 0.000 description 1
- 208000020264 Puerperal Infection Diseases 0.000 description 1
- 206010037688 Q fever Diseases 0.000 description 1
- 208000009341 RNA Virus Infections Diseases 0.000 description 1
- 206010037742 Rabies Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 description 1
- 208000003801 Retropharyngeal Abscess Diseases 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 208000034712 Rickettsia Infections Diseases 0.000 description 1
- 206010061495 Rickettsiosis Diseases 0.000 description 1
- 208000000705 Rift Valley Fever Diseases 0.000 description 1
- 206010039438 Salmonella Infections Diseases 0.000 description 1
- 241001678561 Sarbecovirus Species 0.000 description 1
- 206010039587 Scarlet Fever Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 208000019802 Sexually transmitted disease Diseases 0.000 description 1
- 101710167605 Spike glycoprotein Proteins 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 229930182558 Sterol Chemical class 0.000 description 1
- 206010061372 Streptococcal infection Diseases 0.000 description 1
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 description 1
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 208000007712 Tinea Versicolor Diseases 0.000 description 1
- 206010056131 Tinea versicolour Diseases 0.000 description 1
- 208000034784 Tularaemia Diseases 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 208000036826 VIIth nerve paralysis Diseases 0.000 description 1
- 206010047400 Vibrio infections Diseases 0.000 description 1
- 102100029469 WD repeat and HMG-box DNA-binding protein 1 Human genes 0.000 description 1
- 101710097421 WD repeat and HMG-box DNA-binding protein 1 Proteins 0.000 description 1
- 201000006449 West Nile encephalitis Diseases 0.000 description 1
- 206010057293 West Nile viral infection Diseases 0.000 description 1
- 208000027207 Whipple disease Diseases 0.000 description 1
- 208000003152 Yellow Fever Diseases 0.000 description 1
- 206010048249 Yersinia infections Diseases 0.000 description 1
- 208000035472 Zoonoses Diseases 0.000 description 1
- 206010061418 Zygomycosis Diseases 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 201000007691 actinomycosis Diseases 0.000 description 1
- 230000004518 activated T cell apoptosis Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 210000001552 airway epithelial cell Anatomy 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 208000006730 anaplasmosis Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 206010004145 bartonellosis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004159 blood analysis Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000004308 chancroid Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 201000003486 coccidioidomycosis Diseases 0.000 description 1
- 238000012777 commercial manufacturing Methods 0.000 description 1
- 201000007717 corneal ulcer Diseases 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- 201000003929 dermatomycosis Diseases 0.000 description 1
- UMGXUWVIJIQANV-UHFFFAOYSA-M didecyl(dimethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)CCCCCCCCCC UMGXUWVIJIQANV-UHFFFAOYSA-M 0.000 description 1
- ZPTBLXKRQACLCR-XVFCMESISA-N dihydrouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)CC1 ZPTBLXKRQACLCR-XVFCMESISA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 201000010582 ecthyma Diseases 0.000 description 1
- 208000000292 ehrlichiosis Diseases 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 206010014801 endophthalmitis Diseases 0.000 description 1
- 208000010227 enterocolitis Diseases 0.000 description 1
- 244000309457 enveloped RNA virus Species 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 208000020612 escherichia coli infection Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 208000003512 furunculosis Diseases 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 208000027096 gram-negative bacterial infections Diseases 0.000 description 1
- 208000029629 hantavirus infectious disease Diseases 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 201000007162 hidradenitis suppurativa Diseases 0.000 description 1
- 208000008025 hordeolum Diseases 0.000 description 1
- 230000005745 host immune response Effects 0.000 description 1
- 102000048657 human ACE2 Human genes 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000009851 immunogenic response Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 201000001371 inclusion conjunctivitis Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 201000006747 infectious mononucleosis Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- QRWOVIRDHQJFDB-UHFFFAOYSA-N isobutyl cyanoacrylate Chemical compound CC(C)COC(=O)C(=C)C#N QRWOVIRDHQJFDB-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000030500 lower respiratory tract disease Diseases 0.000 description 1
- 201000003453 lung abscess Diseases 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 238000012083 mass cytometry Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 201000004015 melioidosis Diseases 0.000 description 1
- 210000001806 memory b lymphocyte Anatomy 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000005871 monkeypox Diseases 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 201000007524 mucormycosis Diseases 0.000 description 1
- 208000010805 mumps infectious disease Diseases 0.000 description 1
- 208000027531 mycobacterial infectious disease Diseases 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000000901 ornithosis Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000009340 pathogen transmission Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012910 preclinical development Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 208000010563 rat-bite fever Diseases 0.000 description 1
- 208000030925 respiratory syncytial virus infectious disease Diseases 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 208000009146 rhinoscleroma Diseases 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- DWRXFEITVBNRMK-JXOAFFINSA-N ribothymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 DWRXFEITVBNRMK-JXOAFFINSA-N 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- RHFUOMFWUGWKKO-UHFFFAOYSA-N s2C Natural products S=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 RHFUOMFWUGWKKO-UHFFFAOYSA-N 0.000 description 1
- 206010039447 salmonellosis Diseases 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 229940022511 therapeutic cancer vaccine Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 230000007485 viral shedding Effects 0.000 description 1
- 210000000605 viral structure Anatomy 0.000 description 1
- RPQZTTQVRYEKCR-WCTZXXKLSA-N zebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=CC=C1 RPQZTTQVRYEKCR-WCTZXXKLSA-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
- A61K39/12—Viral antigens
-
- 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
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001129—Molecules with a "CD" designation not provided for elsewhere
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001136—Cytokines
- A61K39/001138—Tumor necrosis factors [TNF] or CD70
-
- 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
- A61K39/12—Viral antigens
- A61K39/215—Coronaviridae, e.g. avian infectious bronchitis virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5156—Animal cells expressing foreign proteins
-
- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
-
- 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
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
- A61K2039/541—Mucosal route
- A61K2039/543—Mucosal route intranasal
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/20011—Coronaviridae
- C12N2770/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Abstract
本发明一般性涉及鼻内mRNA疫苗,更具体而言,包含一种或多种免疫刺激分子、一种或多种致病性抗原和专门设计的递送系统。具体而言,所述免疫刺激分子和致病性抗原以编码这些分子和抗原的mRNA分子的形式提供;更具体而言,编码CD40L、caTLR4和/或CD70的mRNA分子与一种或多种编码细菌、病毒或真菌抗原的mRNA分子组合。具体而言,递送是允许疫苗保护和沉积并靶向鼻子中的抗原呈递细胞的化学化合物的混合物。具体而言,本发明非常适合在爆发环境中开发快速应答疫苗。
Description
发明领域
本发明一般性涉及鼻内mRNA疫苗,更具体而言,包含一种或多种免疫刺激分子、一种或多种致病性抗原和专门设计的递送系统。具体而言,所述免疫刺激分子和致病性抗原以编码这些分子和抗原的mRNA分子的形式提供;更具体而言,编码CD40L、caTLR4和/或CD70的mRNA分子与一种或多种编码细菌、病毒或真菌抗原的mRNA分子组合。具体而言,递送是允许疫苗保护和沉积并靶向鼻子中的抗原呈递细胞的化学化合物的混合物。具体而言,本发明非常适合在爆发环境中开发快速应答疫苗。
发明背景
过去围绕SARS和MERS等暴发传染病疫苗所做的努力影响有限,因为疫苗是在流行高峰之后发生的,并且所使用的技术不允许更广泛的覆盖范围和在后续的暴发中重复使用。当前对COVID-19(nCoV-2019)疫苗设计的努力利用了诱导高水平全身中和抗体的技术。然而,据报道,从SARS或MERS感染中恢复的患者的抗体应答本质上是短暂的,并且对相关毒株的交叉反应性有限。相比之下,T细胞对冠状病毒的应答似乎是持久的并且具有显著的交叉反应性。
黏膜、特别是鼻内的T细胞免疫已成为预防下呼吸道感染和几种空气传播病毒病原体疾病的关键工具。已经在非常特殊的情况下在小鼠中显示了mRNA的鼻内施用以诱导如此强的免疫力。使用T细胞免疫作为主要防御使该方法对体液免疫应答所针对的病毒蛋白的已知变异性更加稳健,并为保护免受毒株漂变甚至未来的冠状病毒变体的侵害带来希望。用mRNA进行鼻内疫苗接种有可能诱导这种黏膜的T细胞应答。此外,鼻内递送是一种经过验证的疫苗技术,其中已在市场上销售。
TriMix是一种编码免疫刺激蛋白CD40L、CD70和组成型活性形式的TLR4(caTLR4)的三种mRNA的混合物,其已被证明可增强T细胞在皮内、静脉内和结内mRNA疫苗施用治疗癌症疫苗的情况下对共同递送的mRNA编码抗原的应答的幅度和质量。在此,我们证明了TriMix mRNA与抗原编码mRNA的共同施用能够增强针对呼吸道病毒的鼻内疫苗接种的功效。
长期以来,会导致原本健康的人患上“普通感冒”的人冠状病毒(HCoV)一直被认为是无关紧要的病原体。然而,在21世纪,2种高致病性HCoV——严重急性呼吸综合征冠状病毒(SARS-CoV)、中东呼吸综合征冠状病毒(MERS-CoV)——从动物传染源(reservoir)中出现而导致全球流行病,其发病率和死亡率令人恐惧。
冠状病毒是有包膜的RNA病毒,其广泛分布于人、其他哺乳动物和鸟类中并可引起呼吸道、肠、肝和神经系统疾病。已知六种冠状病毒物种会导致人疾病。四种病毒——229E、OC43、NL63和HKU1——很普遍并通常会在免疫活性个体中引起普通感冒症状。其它两种毒株——严重急性呼吸综合征冠状病毒(SARS-CoV)和中东呼吸综合征冠状病毒(MERS-CoV)——起源于人畜共患病并有时与致命疾病有关。SARS-CoV是2002年和2003年在中国广东省爆发的严重急性呼吸综合征的病原体。MERS-CoV是2012年在中东地区爆发的严重呼吸疾病的病原体。
SARS的常见症状包括发烧、咳嗽、呼吸困难,并且偶尔还有水样腹泻。在受感染的患者中,20%至30%需要机械通气,10%死亡,老年患者和有内科合并症的患者死亡率更高。已经记录了人与人之间的传播,主要是在医疗保健环境中。这种医院内传播可以用基本的病毒学来解释:SARS S糖蛋白的主要人受体(人血管紧张素转换酶2(ACE2))主要存在于下呼吸道,而不是上气道。受体分布可能解释了上呼吸道症状的缺乏以及当个体已经住院时病毒脱落高峰发生在疾病晚期(约10天)的发现。SARS护理通常需要产生气溶胶的手术,例如插管,这也可能造成突出的医院内传播。
MERS与SARS有许多共同的临床特征,例如严重的非典型肺炎,但关键差异是明显的。MERS患者有突出的胃肠道症状,并且经常出现急性肾功能衰竭,这可用MERS-CoV S糖蛋白与存在于下气道以及肾和胃肠道中的二肽基肽酶4(DPP4)结合来解释。MERS需要对50%至89%的患者进行机械通气,并且病死率为36%。
2019年12月,出现一群不明原因肺炎患者。通过对肺炎患者样品进行无偏测序,发现了一种以前未知的β冠状病毒。人气道上皮细胞被用于分离一种名为COVID-19的新型冠状病毒,它在sarbecovirus亚属orthocoronavirinae亚科中形成了另一个分支(clade)。与MERS-CoV和SARS-CoV不同,COVID-19是感染人的冠状病毒家族的第七个成员。
没有针对冠状病毒的人疫苗被注册,甚至没有比I期开发更进一步的针对冠状病毒的人疫苗。确实存在许多(减毒活)兽用冠状病毒疫苗(犬、猫)。
在每次爆发时,都会启动加速的疫苗开发。然而,由于开发时间长,当候选疫苗通过I期时,发病率(以及因此测试疫苗效力的可能性)已经下降到低水平。后续的爆发属于不同的病毒亚型,因此之前的努力就白费了。
基于SARS的爆发,许多美国、欧盟和亚洲的疫苗开发商将候选疫苗转移到临床前开发阶段,并且少数实际上进行了I期测试(Roper&Rehm,2009)。到2003年,所采用的疫苗技术包括几种减毒活病毒、少数亚单位疫苗、一些基于腺病毒的疫苗和一些DNA疫苗。
数据表明,诱导强烈的全身抗体应答(例如针对刺突蛋白)并不能保证中和。Roper等人,2009提出,鼻内疫苗接种很可能是通过诱导强IgA应答来预防传播的选择途径。
为了在呼吸疾病爆发时为新疫苗的这些漫长的开发过程提供答案,我们现在开发了一个新的疫苗平台,其包含:一种或多种mRNA分子,其编码选自包括CD40L、caTLR4和CD70的列表的功能性免疫刺激蛋白;和一种或多种mRNA分子,其编码细菌、病毒或真菌抗原;以鼻内制剂的形式。这种平台方法非常适合在新的甚至现有的呼吸病原体爆发时快速开发疫苗。
发明概述
在第一方面,本发明提供一种组合,其包含:
-一种或多种mRNA分子,其编码选自包括CD40L、caTLR4和CD70的列表的功能性免疫刺激蛋白;和
-一种或多种mRNA分子,其编码细菌、病毒或真菌抗原或被设计成包含T细胞刺激性表位并抑制T调节性表位的人工抗原。
其中所述组合是鼻内制剂的形式。
在具体实施方案中,所述一种或多种mRNA分子编码所有所述功能性免疫刺激蛋白CD40L、caTLR4和CD70。
在又一个实施方案中,所述抗原是来自呼吸道病原体、例如冠状病毒的抗原。
在另一个具体实施方案中,所述抗原是M(基质)、N(核壳)、S(刺突)抗原或病毒编码的非结构蛋白(NSP);特别是M(基质)、N(核壳)、S(刺突)抗原。
在另一个具体实施方案中,所述抗原是由来自病原体基因组的几个表位组成的人工组成的免疫原。
在本发明的又一个实施方案中,所述mRNA分子被配制成基于脂质或聚合物的纳米颗粒的形式,包括基于脂质的纳米颗粒,或树枝状聚合物、多聚复合物(polyplex)、脂质复合物(lipoplex)、混合脂质多聚复合物(lipopolyplex)或多聚脂质复合物(polylipoplex)制剂;例如基于脂质的纳米颗粒或脂质复合物或多聚脂质复合物制剂。
在另一方面,本发明还提供了包含如本文所定义的组合的疫苗。
整个发明包括与适当的递送装置和使用方案的组合,以最大限度地递送和暴露于鼻子并且最小化肺暴露。
此外,本发明提供如本文所定义的组合或疫苗,其用于人或兽药;具体而言,其用于预防和/或治疗传染病。
发明详述
如上文已详述的,本发明提供一种组合,其包含:
-一种或多种mRNA分子,其编码选自包括CD40L、caTLR4和CD70的列表的功能性免疫刺激蛋白;和
-一种或多种mRNA分子,其编码细菌、病毒或真菌抗原,特别是被设计成用于诱导抗体应答的mRNA分子;或者被设计成包含T细胞刺激性表位并抑制T调节性表位的人工抗原;
其中所述组合是鼻内制剂的形式。
在具体实施方案中,所述组合包含TriMix,即编码所有所述CD40L、caTLR4和CD70免疫刺激蛋白的mRNA分子。
在整个发明中,术语“TriMix”代表编码CD40L、CD70和caTLR4免疫刺激蛋白的mRNA分子的混合物。正如通过添加可溶性CD40L和LPS连接CD40和TLR4所显示的那样,使用CD40L和caTLR4的组合产生成熟的、分泌细胞因子/趋化因子的DC。将CD70引入DC通过抑制活化的T细胞凋亡和通过支持T细胞增殖为CD27+幼稚T细胞提供共刺激信号。作为caTLR4的替代物,可以使用其他Toll样受体(TLR)。对于每种TLR,组成型活性形式是已知的,并且可能被引入DC中以引发宿主免疫应答。然而,在我们看来,caTLR4是最有效的激活分子并因此是优选的。
在整个说明书中使用的术语“靶”不限于本文可能描述的具体实例。任何传染原,例如病毒、细菌或真菌都可以被靶向。
在整个说明书中使用的术语“靶特异性抗原”不限于本文可能描述的具体实例。本领域技术人员将清楚本发明涉及在APC中诱导免疫刺激,而与呈递的靶特异性抗原无关。待呈递的抗原将取决于人们打算在受试者中引发免疫诱导的靶的类型。靶特异性抗原的典型实例是对细菌和真菌细胞或对具体病毒蛋白或病毒结构具有特异性的表达或分泌标记。
靶特异性抗原优选选自致病性基因组中相当稳定的区域,即在其中观察到相同致病性物种的不同毒株之间几乎没有变化。对于短期解决方案,即为已经感染或具有感染的高风险的受试者开发疫苗,最佳靶抗原可能是“M”(基质)和/或“N”(核衣壳)蛋白和非结构蛋白。对于旨在用于预防在高风险区域和密切接触个体中传播的围栏紧急疫苗,一种有趣的组合是通过鼻内递送的含有S(刺突)和M/N靶的mRNA疫苗。对于预防性疫苗接种等长期解决方案,最佳解决方案是一种“通用”疫苗,其能够在下一次事件发生时迅速部署。刺突蛋白的高度可变性、使用的不同受体以及对中和潜力的怀疑使得基于抗体的通用疫苗不太可能。在那种情况下,针对主要致病性毒株的保守区域的基于T细胞的疫苗则要可行得多。在一个具体实施方案中,由来自病原体基因组的强T细胞刺激性表位组成并且去除任何T抑制表位的人工构建的免疫原,将提供如此强大和广泛的保护。或者,可以设计抗原以在受试者中诱导抗体应答。
在整个说明书中使用的术语“传染病”或“感染”并不旨在限于本文可能已经举例说明的感染类型。因此,该术语涵盖接种疫苗对受试者有益的所有传染原。非限制性实例是以下病毒引起的感染或病症:获得性免疫缺陷综合征-腺病毒科感染-甲病毒感染-虫媒病毒感染-贝尔麻痹-博尔纳病-布尼亚病毒科感染-杯状病毒科感染-水痘-普通感冒-尖锐湿疣-冠状病毒科感染-柯萨奇病毒感染-巨细胞病毒感染-登革热-DNA病毒感染-传染性臁疮-脑炎-脑炎,虫媒病毒-脑炎,单纯疱疹-EB病毒感染-传染性红斑-幼儿急疹-疲劳综合征,慢性-汉坦病毒感染-出血热,病毒性-肝炎,病毒性,人-唇疱疹-单纯疱疹-带状疱疹-耳带状疱疹-疱疹病毒科感染-HIV感染-禽类传染性单核细胞增多症-流感-流感,人-拉沙热-麻疹-脑膜炎,病毒性-传染性软疣-猴痘-腮腺炎-脊髓炎-乳头状瘤病毒感染-副粘病毒科感染-白蛉热-脊髓灰质炎-多瘤病毒感染-脊髓灰质炎后综合征-狂犬病-呼吸道合胞病毒感染-裂谷热-RNA病毒感染-风疹-严重急性呼吸道综合征-慢病毒性疾病-天花-亚急性硬化性全脑炎-蜱传播疾病-肿瘤病毒感染-疣目-西尼罗河热-病毒病-黄热病-人畜共患病-等。病毒的特异性抗原可以是HIV-gag、-tat、-rev或-nef,或丙型肝炎抗原;特别优选的病毒引起的感染或病症是冠状病毒科感染,例如由冠状病毒229E、冠状病毒OC43、SARS-CoV、HCoV NL63、HKU1、MERS-CoV或COVID-19引起的感染。
其他非限制性实例是以下由细菌或真菌引起的感染或病症:脓肿-放线菌病-无形体病-炭疽-关节炎,反应性-曲霉病-菌血症-细菌感染和真菌病-巴尔通体感染-肉毒中毒-脑脓肿-布鲁氏菌病-伯克霍尔德菌感染-弯曲杆菌感染-念珠菌病-念珠菌病,外阴阴道性-猫抓病-蜂窝织炎-中枢神经系统感染-软下疳-衣原体感染-衣原体科感染-霍乱-梭菌感染-球孢子菌病-角膜溃疡-交叉感染-隐球菌病-皮肤真菌病-白喉-埃立克体病-脓胸,胸膜性-心内膜炎,细菌性-眼内炎-小肠结肠炎,假膜性-丹毒-大肠杆菌感染-筋膜炎,坏死性-富尼埃坏疽-疖病-梭形杆菌感染-气性坏疽-淋病-革兰氏阴性细菌感染-革兰氏阳性细菌感染结节-腹股沟肉芽肿-化脓性汗腺炎-组织胞浆菌病-睑腺炎-脓疱病-克雷伯菌感染-军团病-麻风-钩端螺旋体病-李斯特菌感染-脓性颌下炎-肺脓肿-莱姆病-性病性淋巴肉芽肿-马杜拉菌病-类鼻疽-脑膜炎,细菌性-分枝杆菌感染-支原体感染-真菌病-诺卡菌感染-甲癣-骨髓炎-甲沟炎-盆腔炎-鼠疫-肺炎球菌感染-假单胞菌感染-鹦鹉热-产褥感染-Q热-鼠咬热-回归热-呼吸道感染-咽后脓肿-风湿热-鼻硬结病-立克次体感染-落基山斑疹热-沙门菌感染-猩红热-恙虫病-脓毒症-性传播疾病,细菌性-性传播疾病,细菌性-休克,脓毒性-皮肤病,细菌性-皮肤病,传染性-葡萄球菌感染-链球菌感染-梅毒-梅毒,先天性-破伤风-蜱媒传疾病-癣-花斑癣-沙眼-结核病-结核病,脊柱性-兔热病-伤寒-伤寒,流行性虱传播-尿路感染-惠普尔病-百日咳-弧菌感染-雅司病-耶尔森菌感染-人畜共患病-接合菌病-等。
在本发明疫苗的一个优选实施方案中,mRNA或DNA分子编码CD40L和CD70免疫刺激蛋白。在本发明疫苗的一个特别优选的实施方案中,mRNA或DNA分子编码CD40L、CD70和caTLR4免疫刺激蛋白。
所述编码免疫刺激蛋白的mRNA或DNA分子可以是单一的mRNA或DNA分子的一部分。优选地,所述单一的mRNA或DNA分子能够同时表达两种或更多种蛋白质。在进一步的实施方案中,编码免疫刺激蛋白的两种或更多种mRNA或DNA分子是单一的mRNA或DNA分子的一部分。该单一的mRNA或DNA分子优选能够独立地表达两种或更多种蛋白质。在一个优选的实施方案中,编码免疫刺激蛋白的两种或更多种mRNA或DNA分子通过内部核糖体进入位点(IRES)连接在单一的mRNA或DNA分子中,从而能够将两种或更多种mRNA序列中的每一个分开翻译成氨基酸序列。或者,在不同免疫刺激因子的编码序列之间并入自切割2a肽编码序列。这样,两种或更多种因子可以由一个单一的mRNA或DNA分子编码。连接有IRES序列或自切割2a肽的编码CD40L和CD70的mRNA对细胞进行电穿孔的初步数据表明,这种方法确实是可行的。
因此,本发明进一步提供了编码两种或更多种免疫刺激因子的mRNA分子,其中通过在两种或更多种编码序列之间使用IRES,两种或更多种免疫刺激因子与单一的mRNA分子分开翻译。或者,本发明提供了编码由自切割2a肽编码序列隔开的两种或更多种免疫刺激因子的mRNA分子,使得能够在翻译后切割两种蛋白质序列。
在任何实施方案中,所述靶特异性抗原选自:从一种或多种靶细胞分离的总mRNA、一种或多种特异性靶mRNA分子、一种或多种靶细胞的蛋白质裂解物、来自一种或多种靶细胞的特异性蛋白质、合成的靶特异性肽或蛋白质和合成的编码靶特异性抗原或其衍生肽的mRNA或DNA。所述靶可以是病毒、细菌或真菌、蛋白质或mRNA,特别是被设计成诱导抗体应答的mRNA分子。
本文使用或提及的mRNA或DNA可以是裸露的mRNA或DNA,或受保护的mRNA或DNA。保护DNA或mRNA增加了其稳定性,同时保留了将mRNA或DNA用于疫苗接种目的的能力。保护mRNA和DNA的非限制性实例可以是:脂质体包封、鱼精蛋白保护、(阳离子)脂质脂质复合(Lipid Lipoplexation)、脂质、阳离子或聚阳离子组合物、甘露糖基脂质复合、气泡脂质体化(Bubble Liposomation)、聚乙烯亚胺(PEI)保护、负载脂质体的微泡保护、脂质纳米颗粒等。
在一些优选的实施方案中,本发明方法中使用的mRNA具有5'帽结构,其具有所谓的CAP-1结构,意味着相对于帽核苷酸而言,倒数第二个核苷酸中核糖的2'羟基被甲基化。
在另一个具体实施方案中,所述mRNA分子是自扩增或反式扩增的mRNA分子。自扩增的mRNA分子通常编码抗原以及能够实现细胞内RNA扩增和丰富蛋白质表达的病毒复制机制。反式扩增的mRNA分子使用类似的原理,但是抗原和病毒复制机制是由不同的mRNA分子编码的。
在另一个具体实施方案中,本发明使用的两个、三个、四个、……或所有的mRNA分子具有5'帽结构,其具有所谓的CAP-1结构。
在进一步的实施方案中,本发明的一种或多种mRNA分子可以进一步包含至少一种修饰的核苷。在另一个具体实施方案中,本发明的两个、三个、四个、……或所有使用的mRNA分子具有至少一种修饰的核苷。
在本发明的另一个具体实施方案中,所述mRNA分子进一步包含至少一种修饰的核苷,例如选自包括假尿苷、5-甲氧基-尿苷、5-甲基-胞苷、2-硫代-尿苷和N6-甲基腺苷的列表。
在本发明的一个具体实施方案中,所述至少一种修饰的核苷可以是假尿苷,例如选自包括4-硫代-假尿苷、2-硫代-假尿苷、1-羧甲基-假尿苷、1-丙炔基-假尿苷、1-牛磺酸甲基-假尿苷、N1-甲基-假尿苷、4-硫代-1-甲基-假尿苷、2-硫代-1-甲基-假尿苷、1-甲基-1-脱氮-假尿苷、2-硫代-1-甲基-1-脱氮-假尿苷、二氢假尿苷、2-硫代-二氢假尿苷、4-甲氧基-假尿苷和4-甲氧基-2-硫代-假尿苷的列表。在一个非常具体的实施方案中,所述至少一种修饰的核苷是N1-甲基-假尿苷。
适用于本发明情况下的备选核苷修饰包括:吡啶-4-酮核糖核苷、5-氮杂-尿苷、2-硫代-5-氮杂-尿苷、4-硫代-假尿苷、2-硫代-假尿苷、5-羟基尿苷、3-甲基尿苷、5-羧甲基-尿苷、1-羧甲基-假尿苷、5-丙炔基-尿苷、1-丙炔基-假尿苷、5-牛磺酸甲基尿苷、1-牛磺酸甲基-假尿苷、5-牛磺酸甲基-2-硫代-尿苷、1-牛磺酸甲基-4-硫代-尿苷、5-甲基-尿苷、1-甲基-假尿苷、4-硫代-1-甲基-假尿苷、2-硫代-1-甲基-假尿苷、1-甲基-1-脱氮-假尿苷、2-硫代-1-甲基-1-脱氮-假尿苷、二氢尿苷、二氢假尿苷、2-硫代-二氢尿苷、2-硫代-二氢假尿苷、2-甲氧基尿苷、2-甲氧基-4-硫代-尿苷、4-甲氧基-假尿苷和4-甲氧基-2-硫代-假尿苷。在一些实施方案中,mRNA包含选自以下的至少一种核苷:5-氮杂-胞苷、假异胞苷、3-甲基-胞苷、N4-乙酰胞苷、5-甲酰基胞苷、N4-甲基胞苷、5-羟甲基胞苷、1-甲基-假异胞苷、吡咯并-胞苷、吡咯并-假异胞苷、2-硫代-胞苷、2-硫代-5-甲基-胞苷、4-硫代-假异胞苷、4-硫代-1-甲基-假异胞苷、4-硫代-1-甲基-1-脱氮-假异胞苷、1-甲基-1-脱氮-假异胞苷、zebularine、5-氮杂-zebularine、5-甲基-zebularine、5-氮杂-2-硫代-zebularine、2-硫代-zebularine、2-甲氧基-胞苷、2-甲氧基-5-甲基-胞苷、4-甲氧基-假异胞苷和4-甲氧基-1-甲基-假异胞苷。在一些实施方案中,mRNA包含选自以下的至少一种核苷:2-氨基嘌呤、2,6-二氨基嘌呤、7-脱氮-腺嘌呤、7-脱氮-8-氮杂-腺嘌呤、7-脱氮-2-氨基嘌呤、7-脱氮-8-氮杂-2-氨基嘌呤、7-脱氮-2,6-二氨基嘌呤、7-脱氮-8-氮杂-2,6-二氨基嘌呤、1-甲基腺苷、N6-异戊烯基腺苷、N6-(顺式-羟基异戊烯基)腺苷、2-甲硫基-N6-(顺式-羟基异戊烯基)腺苷、N6-甘氨酰氨基甲酰腺苷、N6-苏氨酰氨基甲酰腺苷、2-甲硫基-N6-苏氨酰氨基甲酰腺苷、N6,N6-二甲基腺苷、7-甲基腺嘌呤、2-甲硫基-腺嘌呤和2-甲氧基-腺嘌呤。在一些实施方案中,mRNA包含选自以下的至少一种核苷:肌苷、1-甲基肌苷、怀俄苷、怀丁苷、7-脱氮-鸟苷、7-脱氮-8-氮杂-鸟苷、6-硫代-鸟苷、6-硫代-7-脱氮-鸟苷、6-硫代-7-脱氮-8-氮杂-鸟苷、7-甲基-鸟苷、6-硫代-7-甲基-鸟苷、7-甲基肌苷、6-甲氧基-鸟苷、1-甲基鸟苷、N2-甲基鸟苷、N2,N2-二甲基鸟苷、8-氧代-鸟苷、7-甲基-8-氧代-鸟苷、1-甲基-6-硫代-鸟苷和N2,N2-二甲基-6-硫代-鸟苷。
用于本发明的mRNA分子可以含有一种或多种修饰的核苷酸,在具体实施方案中,至少10%、20%、30%、40%、50%、60%、70%、80%、90%或100%的特定类型的核苷酸可以被修饰的核苷酸替代。也不排除在相同的mRNA分子中包含不同的核苷酸修饰。在本发明的一个非常具体的实施方案中,所述mRNA分子中约100%的尿苷被N1-甲基-假尿苷替代。
在一个具体实施方案中,本发明的一种或多种所述mRNA分子可以进一步包含翻译增强子和/或核滞留元件。合适的翻译增强子和核保留元件是在WO2015071295中描述的翻译增强子和核保留元件。
本发明的组合和疫苗特别配制用于鼻内施用。
在本发明的情况下,术语“鼻施用”或“鼻内施用”是指将本发明的组合物/疫苗应用于鼻腔的施用途径。鼻粘膜可用于成分的非侵入性局部或全身施用。更具体地,在本发明的情况下,使用这种鼻内施用形式,本发明的mRNA分子可以与上呼吸道中的抗原呈递细胞直接接触并诱导几种保护性T细胞,如常驻记忆CD8+T细胞,从而诱导针对呼吸道感染的局部免疫力。这也降低了病原体传播到下呼吸道的风险,也降低了疾病病理。
允许这种鼻内施用的任何制剂都适用于本发明的情况下。具体而言,下文提供了一些具体的非限制性实例:
在非常容易的设置中,本发明的组合物/疫苗可以通过简单地将包含一种或多种mRNA分子的治疗上可接受的溶液注射在口鼻咽腔中来施用,例如以滴管的形式。或者,可以使用单位/双剂量系统,特别是在施用需要精确给药(dosing)的情况下。这些系统包含准备好以进行施用的一个或两个分开的半剂量。
优选选择用于鼻内施用的治疗上可接受的溶液,使得它们不影响其中包含的mRNA的稳定性。此外,此类溶液优选增加口鼻咽腔的抗原呈递细胞中的RNA摄取。因此,可以使用经典的RNA转染缓冲液/组分,例如或 转染剂是直链聚乙烯亚胺衍生物(特别是多聚复合物)。因此,在一个具体的实施方案中,鼻内施用可以在聚乙烯亚胺和/或其衍生物的存在下进行。
Lipofectamine由DOSPA(2,3-二油酰氧基-N-[2(精胺甲酰胺基)乙基]-N,N-二甲基-1-丙基三氟乙酸铵)和DOPE(1,2-二油酰-sn-甘油-3-磷酸乙醇胺)的3:1混合物组成。
或者,本发明的组合物/疫苗可被配制成气溶胶喷雾剂、鼻喷雾剂、多剂量喷雾泵……的形式。在多剂量喷雾泵中,可以将组合物/疫苗填充到由玻璃或塑料材料制成的瓶子中,这些瓶子通过附接包括浸管(dip tube)的鼻喷雾泵来封闭。鼻喷雾泵是容积式泵,当通过将致动器压向瓶子来致动泵时,活塞在计量室中向下移动。计量室底部的阀门机构将防止回流到浸管中。因此,活塞的向下移动将在计量室内产生压力,从而通过致动器迫使空气或液体向外并产生喷雾。当致动压力被移除时,弹簧将迫使活塞和致动器返回其初始位置。这会在计量室中产生负压,通过从计量室底部的浸管上方的球座上提起球,将液体从容器中拉出。计量室确保正确的给药,致动器尖端的开放式涡流室将雾化经计量的剂量。
对于大多数鼻喷雾泵,每次致动所分配的体积设置在50到150μl,对于成年人而言每个鼻孔的施用量约为100μl是最佳的,因为更大的体积容易流出来。因此,当两个鼻孔都被喷雾时,预期剂量最好适合约100–200μl的体积。
取决于预期目的,可以根据具体施用方案施用鼻内组合物,所述施用方案例如每天一次、两次或三次。或者,鼻内施用可以每两天、三天、四天、五天、六天或七天施用一次,例如每周一次或者备选地每两周一次。对于每次所述施用,给药也可以变化,例如在治疗开始时较高剂量,而在治疗结束时较低剂量。使用方案包含具体说明,以尽量减少肺部吸收,例如在施用后屏住呼吸或呼气。
本发明的组合物可以用作预防性组合物(例如在症状出现之前)或备选地用作治疗性组合物(例如当症状已经出现时)。
鉴于mRNA分子的不稳定性质,这些分子优选为如上文定义的受保护形式;更具体地,它们可以包括在例如脂质纳米颗粒中。因此,本发明还提供了如本文定义的组合或组合物;其中一种或多种所述mRNA分子包含在纳米颗粒中;例如基于脂质的纳米颗粒或多聚复合物、脂质复合物和脂质多聚复合物。
如本文所用,术语“纳米颗粒”是指这样的任何颗粒,其直径使得该颗粒适合于特别是通常具有小于1000纳米(nm)的直径的核酸的全身施用、特别是静脉内施用。
在本发明的一个具体实施方案中,纳米颗粒选自包含脂质纳米颗粒和聚合物纳米颗粒的列表。
脂质纳米颗粒(LNP)通常被称为由不同脂质的组合组成的纳米级颗粒。虽然许多不同类型的脂质可以包括在这样的LNP中,但是本发明的LNP可以例如由可电离脂质、磷脂、甾醇和PEG脂质的组合组成。
聚合物纳米颗粒通常可以是纳米球或纳米胶囊。两种主要策略用于制备聚合物纳米颗粒,即“自上而下”的方法和“自下而上”的方法。在自上而下的方法中,预制聚合物的分散体产生聚合物纳米颗粒,而在自下而上的方法中,单体的聚合导致聚合物纳米颗粒的形成。自上而下和自下而上的方法都使用合成聚合物/单体,如聚(d,l-丙交酯-共-乙交酯)、聚(氰基丙烯酸乙酯)、聚(氰基丙烯酸丁酯)、聚(氰基丙烯酸异丁酯)和聚(氰基丙烯酸异己酯);稳定剂,如聚(乙烯醇)和二癸基二甲基溴化铵;二氯甲烷和乙酸乙酯、苯甲醇、环己烷、乙腈、丙酮等有机溶剂。最近,科学界一直在尝试通过使用天然聚合物和毒性较小的溶剂的合成方法来寻找合成聚合物的替代品。
本发明还提供如本文所定义的组合和疫苗用于人或兽药,特别是用于治疗病原体感染,更特别是呼吸系统感染,例如病毒感染。
最后,本发明提供了一种治疗病原体感染的方法,包括向有需要的受试者施用本发明的组合或疫苗的步骤。
该组合物在兽医领域也可能有价值,其目的不仅包括预防和/或治疗动物疾病,而且还包括——对经济上重要的动物如牛、猪、羊、鸡、鱼等——提高动物的生长和/或体重和/或从动物获得的肉类或其他产品的数量和/或质量。
待治疗的受试者优选患有选自包含下组的疾病或病症:细菌、病毒或真菌感染。
如本文所用,术语“预防”旨在降低被感染的风险或减轻与致病性感染相关的症状。
实施例
实施例1:短期危机
在(不太可能的)危机真正导致全球大流行的情况下,紧急产品的门槛将迅速下降。谈到(迫在眉睫的)流感大流行,几种采用全新佐剂技术的疫苗有机会在这种情况下进行快速测试。
在这种情况下,可以遵循以下任何选项:
A)基于“杀伤”T细胞的疫苗——待被用于高风险污染或受感染个体。最好的靶可能是“M”(基质)和/或“N”(核衣壳)蛋白。
B)围栏紧急疫苗——待被用于防止在高风险区域和密切接触个体中的传播。在这种情况下,一种有趣的组合可能是通过鼻内递送的含有S(刺突)和M/N靶的mRNA疫苗。在小鼠肿瘤模型中获得了出乎意料的好结果(Phua,Leong,&Nair,2013;Phua,Staats,Leong,&Nair,2014),研究人员采用了来自Stemgent的转染试剂盒的鼻内递送方案。
实施例2:长期解决方案
针对所有可能的冠状病毒或其他类型病原体的大规模预防性疫苗接种似乎不太可能。不仅因为毒株的可变性,还因为侵袭时机和地点的不可预测性,因此确定谁处于危险之中是不可能完成的任务。
因此,最佳解决方案是一种“通用”疫苗,其能够在下一次事件发生时迅速部署。刺突蛋白的高度可变性、使用的不同受体以及对广泛中和潜力的怀疑使得基于抗体的通用疫苗不太可能。针对主要致病性毒株的保守区域的基于T细胞的疫苗似乎要可行得多。对致病家族的基因组成进行彻底分析,并使用表位预测和融合构建体进行智能设计,从而给出了最佳可能的候选者。
实施例3:开发概况
第1步:探索性小鼠实验(生物分布、概念和安全性):
·鼻内Fluc生物分布研究
·Trimix——模型抗原(例如E7)——鼻内——免疫读数和鼻/气道组织病理学。
研究级生产M、N和S mRNA,以及编码结构和非结构蛋白的mRNA
快速通道科学建议:Innovation办公室,sFDA
第2步:小鼠实现免疫和毒性:
·Trimix——M/S——鼻内——nCoV免疫读数和全毒组织病理学(full toxhistopath)。
根据需要调整StemFect并(以最低GMP质量)提供
用于攻击研究的研究级生产——M*和S*
M/S mRNA(和Trimix)的GMP级生产
临床试验提交
第3步:健康志愿者中I期进入II期试验:
·时间安排0d(任选7d)。I期25名受试者
·设置为最少250名受试者。
·安全参数和免疫读数(如果使用S,则包括IgA)。
动物攻击模型:
·Trimix——M*(+S*)——第0天(任选第7天)免疫,物种特异性冠状病毒株攻击——产生保护/免疫相关性(50只动物)
商业制造和一致性
紧急使用文件提交
实施例4:临床前产品开发方法
临床前程序由以下4个步骤组成:
1.呼吸道表达和分布评估。使用通过生物发光监测体内FLUC mRNA表达的独特可能性,在小鼠中进行的第一个实验评估了我们的2到3个潜在的鼻腔递送系统(裸mRNA、StemFect和内部LNP),并确认鼻腔中的递送和表达和在肺中表达不存在或低表达。基于其在该测定中的性能及其一般可制造性特性选择递送系统。
2.在第二个小鼠实验中评估T细胞免疫应答的诱导。在这里,在2种给药方案(0、8天和0、-22天)下施用我们拥有内部和已发表的经验和免疫学工具的2种模型抗原。对所有T细胞区室(粘膜、肺、淋巴结、全身)的全面评估以及对呼吸道和选定器官的安全性评估证实了该平台的免疫学假设和预期的安全性谱。
3.GLP重复剂量毒性研究使疫苗能够进展到临床应用。根据我们之前对mRNA疫苗的经验,我们更愿意选择单一物种。根据疫苗设计期间预测的应答,这项研究可以确认COVID-19靶对相关免疫应答的诱导。已经对用于肠胃外施用的TriMix+抗原mRNA进行了毒性评估。本次评估的关键重点是递送系统。此外,支持遗传毒性和药理学研究被添加到递送系统的选定成分的计划中。根据实验1中的发现,需要特别注意肺的继发作用。一些额外的研究可以与I期的开始同时进行。
4.动物的攻击和疾病预防研究。建议该步骤与临床研究同时进行。相关动物物种和病毒毒株的选择取决于冠状病毒疫苗工作贡献者网络内的合作。这项研究表明,该疫苗阻止了接种有我们的产品并在免疫后受到病毒攻击的动物发生下呼吸道疾病。免疫评估可以将这种保护与免疫应答相关联,然后可以进而将其与在人受试者中观察到的应答进行比较。使用动物攻击可以探索疫苗产生广泛应答的潜力,以保护免受毒株漂变或新的冠状病毒家族成员的侵害。
实施例5:临床开发方法
我们的临床开发方法是专注于安全性和免疫原性——并与动物攻击模型建立关联,以支持预期的功效。为了迎合作为紧急疫苗的使用,从I期到II期的流动转变允许以最快的速度生成所需的数据。出于同样的原因,我们选择了一个简短的诱导时间安排。与体液应答的诱导相反,如此短的施用时间安排确实导致T细胞免疫的良好结果。
通过3个步骤评估产品的安全性:
1.测量鼻粘膜T细胞免疫是一种相对较新的方法,仅发表在几篇论文中。如前所述(Jochems等人,2018和2019年),使用微创刮除术纵向收集来自接种疫苗个体的鼻腔样品。已建立的冷冻保存方案允许进行批量分析。这使我们能够平行测量i)通过表型分型对疫苗接种的体内应答和ii)抗原特异性应答。使用针对鼻免疫系统的小组进行大规模细胞计数(mass cytometry)深度表征体内T细胞,包括组织驻留的记忆T细胞、B细胞和DC应答。该测定现在在LUMC进行了小型化以用于分析鼻刮除术样品。通过将鼻细胞与疫苗激活的来自同一个体的PBMC的单核细胞衍生的树突细胞共培养来评估鼻子中抗原特异性免疫的建立。修改内部方案以使其能够评估粘膜应答。在上清液中测量细胞因子的产生(IFNγ、TNFα等),而通过流式细胞术对T细胞上的CD40L和CTLA-4诱导进行表型分型,以测量抗原特异性刺激。使用从人鼻粘膜收集的纵向微创样品同时表征细胞表型和功能具有快速预测疫苗成功的巨大潜力。这些方法对我们的具体方案的修改是与程序的临床前阶段平行进行的。
2.在健康人志愿者中进行的I期多次递增剂量研究。根据临床前结果,我们选择了本研究的起始和靶向剂量/时间安排。该研究的第一部分是从开始到主要评估安全性的靶方案的快速递升(例如,每步3名受试者)。本研究的终点是安全性(临床评估、患者报告和血液分析)、全身(PBMC)和粘膜(鼻采样)免疫评估。本研究包括大约40名受试者,其中至少25名接受了靶剂量/时间安排。在接种疫苗前(第-5天和第-1天)、接种疫苗后早期(第3天和第7天)和较长时间的随访(第2、3、4和8周)收集鼻样品。
3.同样在健康志愿者中,这个初始I期之后是扩展进入II期免疫原性研究。随着所选疫苗时间安排包括的受试者数量增加(n=100),它允许对诱导的免疫应答、其变异性、其长期动态及其与动物模型和保护的相关性进行稳健的评估。在相同的设置和网络中继续研究在数据生成的一致性和速度方面具有明显的优势。
实施例6:小鼠体内鼻内施用
材料与方法
小鼠
从Charles River获得总共48只小鼠(Mus musculus),并在研究开始前14天适应环境。在适应过程中,动物根据体重被分配到一组,并通过尾巴纹身来识别。
构建体设计
将流感NP蛋白(Influenza A/NL/18/94H3N2)的全长编码序列同框克隆到信号序列和DC lamp序列,以优化MHC复合体形式的加工和呈递。为了提高表达和减少对mRNA构建体的免疫原性应答,使用了N1甲基假尿苷修饰。
免疫原性构建体以固定的1:1比例结合TriMix mRNA使用。
施用
在第0天、第7天、第14天,根据如下详述的组归属(每组16只小鼠)鼻内进行候选和对照施用
在第42天,来自NP/TriMix mod(体内jetPEI)(第1组),NP-mod(体内jetPEI)(第2组)或PBS(第3组)的所有动物进行鼻内攻击(1LD50,10μl)。
在终末时间点(第48天),动物在安乐死前5分钟接受静脉注射的CD45.2-BV605抗体(Biolegend,Clone 104,3μg)。收集肺并使用肺浸润免疫(左叶)进行病毒滴定。
在第0天、第7天和第14天免疫:
在第0天,用微量移液器向所有动物鼻内施用30μL(每个鼻孔15μL)候选制剂(第1组和第2组)或PBS(第3组)。在第7天和第14天,用微量移液器鼻内施用30微升(30μL)(每个鼻孔15μL)候选制剂(第1组和第2组)或PBS(第3组)。在麻醉下对动物进行施用。
在第0天、第7天和第14天,用3.75μg/3.75μg NP/TriMix mod(体内jetPEI)(第1组)或7.5μg NP-mod(体内jetPEI)(第2组)进行鼻内免疫(每个鼻孔15μL)。
病毒感染:
在第42天,用NP/TriMix mod(体内jetPEI)(第1组)、NP-mod(体内jetPEI)(第2组)或媒介(第3组)处理的组中的所有动物都用甲型流感PR8鼻内攻击(1LD50,10ul)。
肺分离:
在终末时间(第48天),通过二氧化碳窒息对动物实施安乐死,并在收集器官之前进行大体尸检。
无菌收集肺(左叶),称重并置于4℃的Precellys管中的0.5mL收集培养基(补充有0.1% FBS(Gibco,Cat.26140-079)的49% DMEM(Gibco,Cat.11965-084)和49% Medium199(Gibco,Cat.11150-059))中。将Precellys管中的肺匀浆、等分并冷冻以进行病毒滴定。
肺组织样品中的流感病毒载量估计:(TCID50)
为病毒载量估计收集的肺样品(第48天)在5000rpm下以两个20秒的周期并且周期之间有5秒的停顿进行破裂。在将0.5ml DMEM/Medium-199、0.1% FBS添加到试管中之前和之后,将组织匀浆涡旋几秒钟。通过在3200 x g和4℃下离心10分钟,清除组织匀浆中的组织碎片。收集澄清的上清液并等分并冷冻以进行病毒滴定。
使用Spin-X管(Corning,Cat.8160)对肺样品进行过滤灭菌(在14000 x g和4℃下5分钟)。将过滤后的肺样品在无菌微量滴定聚丙烯管中在滴定培养基(补充有0.1% FBS(Gibco,Cat.26140-079)、1X GlutaMax(Gibco,Cat.35050-061)和0.1% Gentamicin(Gibco,Cat.15750-060)的49% DMEM(Gibco,Cat.11965-084)和49% Medium199(Gibco,Cat.11150-059))中进行10倍稀释,起始稀释度为1/2。胰蛋白酶化MDCK细胞、合并并以2.4x105个细胞/mL重悬于滴定培养基中。将50μL样品系列稀释液添加到96孔板的适当孔(一式八份)中,并将2.4x104个MDCK细胞(100μL)添加到所有孔中。将总体积为200μL的样品在37℃和5% CO2下孵育7天以允许病毒复制。
通过血细胞凝集评估TCID50,血细胞凝集是通过在V型底96孔板中混合50μL病毒上清液与50μL 0.5%鸡红细胞实现的。将板在室温下孵育1小时并读取血细胞凝集。
结果
肺样品中的病毒载量估计:
通过肺TCID50对流感病毒进行定量显示NP/Trimix mod(体内jetPEI)(第1组)中16只动物中有10只的病毒滴度低于定量限,用NP mod(体内jetPEI)处理(第2组)和未处理(第3组)的组中则只有4只动物低于定量限(图1)。
因此,当鼻内施用时,本发明的组合物能够降低受到攻击的小鼠中的病毒载量。
参考文献
Jochems SP,de Ruiter K,Solórzano C,Voskamp A,Mitsi E,Nikolaou E,Carniel BF,Pojar S,German EL,ReinéJ,Soares-Schanoski A,Hill H,Robinson R,Hyder-Wright AD,Weight CM,Durrenberger PF,Heyderman RS,Gordon SB,Smits HH,Urban BC,Rylance J,Collins AM,Wilkie MD,Lazarova L,Leong SC,Yazdanbakhsh M,Ferreira DM.Innate and adaptive nasal mucosal immune responses followingexperimental human pneumococcal colonization.J Clin Invest.2019Jul 30;130:4523-4538
Jochems SP,Marcon F,Carniel BF,Holloway M,Mitsi E,Smith E,GritzfeldJF,Solórzano C,ReinéJ,Pojar S,Nikolaou E,German EL,Hyder-Wright A,Hill H,Hales C,de Steenhuijsen Piters WAA,Bogaert D,Adler H,Zaidi S,Connor V,GordonSB,Rylance J,Nakaya HI,Ferreira DM.Inflammation induced by influenza virusimpairs human innate immune control of pneumococcus.Nat Immunol.2018Dec;19(12):1299-1308
Phua,K.K.L.,Leong,K.W.,&Nair,S.K.(2013).Transfection efficiency andtransgene expression kinetics of mRNA delivered in naked and nanoparticleformat.Journal of Controlled Release,166(3),227–233.https://doi.org/10.1016/j.jconrel.2012.12.029
Phua,K.K.L.,Staats,H.F.,Leong,K.W.,&Nair,S.K.(2014).Intranasal mRNAnanoparticle vaccination induces prophylactic and therapeutic anti-tumorimmunity.Scientific Reports,4,4–10.https://doi.org/10.1038/srep05128
Roper,R.L.,&Rehm,K.E.(2009).SARS vaccines:Where are we?Expert Reviewof Vaccines,8(7),887–898.https://doi.org/10.1586/erv.09.43
Claims (14)
1.一种组合,其包含:
-一种或多种mRNA分子,其编码选自包括CD40L、caTLR4和CD70的列表的功能性免疫刺激蛋白;和
-一种或多种mRNA分子,其编码细菌、病毒或真菌抗原;
其中所述组合是鼻内制剂的形式。
2.根据权利要求1所述的组合,其中所述一种或多种mRNA分子编码所有所述功能性免疫刺激蛋白CD40L、caTLR4和CD70。
3.根据权利要求1或2中任一项所述的组合,其中所述抗原是来自呼吸道病原体的抗原。
4.根据权利要求1至3中任一项所述的组合,其中所述抗原是M(基质)、N(核壳)、S(刺突)抗原,被设计成含有T细胞刺激性表位并抑制T调节性表位的人工抗原,或者是被设计成引发抗体应答的表面抗原。
5.根据权利要求3所述的组合,其中所述呼吸道病原体是冠状病毒。
6.根据权利要求1至5中任一项所述的组合,其中所述mRNA分子被配制成纳米颗粒、例如基于脂质的纳米颗粒的形式。
7.根据权利要求1至5中任一项所述的组合,其中所述mRNA分子被配制成脂质复合物(lipoplex)、树枝状聚合物、多聚复合物(polyplex)或混合脂质多聚复合物(lipopolyplex)的形式。
8.根据权利要求7所述的组合,其中所述mRNA分子被使用聚乙烯亚胺配制成多聚复合物的形式。
9.根据权利要求1至8中任一项所述的组合,其中所述mRNA分子中的一种或多种包含5’CAP-1结构。
10.根据权利要求1至9中任一项所述的组合,其中所述mRNA分子中的一种或多种包含一种或多种修饰核苷,特别是N1-甲基-假尿苷。
11.一种疫苗,其包含权利要求1至10中任一项所述的组合。
12.根据权利要求1至10中任一项所述的组合或根据权利要求11所述的疫苗,其用于人或兽药。
13.根据权利要求1至10中任一项所述的组合或根据权利要求11所述的疫苗,其用于预防和/或治疗传染病。
14.一种预防或治疗传染病的方法,所述方法包括向有需要的受试者施用权利要求1至10中任一项所述的组合或权利要求11所述的疫苗。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP20157300.3 | 2020-02-14 | ||
EP20157300 | 2020-02-14 | ||
PCT/EP2021/053633 WO2021160881A1 (en) | 2020-02-14 | 2021-02-15 | Intranasal mrna vaccines |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115443148A true CN115443148A (zh) | 2022-12-06 |
Family
ID=69593570
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180009112.1A Pending CN115443148A (zh) | 2020-02-14 | 2021-02-15 | 鼻内mRNA疫苗 |
Country Status (13)
Country | Link |
---|---|
US (1) | US20230071518A1 (zh) |
EP (1) | EP4103226A1 (zh) |
JP (1) | JP2023518340A (zh) |
KR (1) | KR20230004447A (zh) |
CN (1) | CN115443148A (zh) |
AU (1) | AU2021219304A1 (zh) |
BR (1) | BR112022015666A2 (zh) |
CA (1) | CA3170239A1 (zh) |
IL (1) | IL295507A (zh) |
MX (1) | MX2022009943A (zh) |
TW (1) | TW202144002A (zh) |
WO (1) | WO2021160881A1 (zh) |
ZA (1) | ZA202209779B (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11576966B2 (en) | 2020-02-04 | 2023-02-14 | CureVac SE | Coronavirus vaccine |
US11241493B2 (en) | 2020-02-04 | 2022-02-08 | Curevac Ag | Coronavirus vaccine |
KR20230164648A (ko) | 2020-12-22 | 2023-12-04 | 큐어백 에스이 | SARS-CoV-2 변이체에 대한 RNA 백신 |
WO2023037320A1 (en) * | 2021-09-10 | 2023-03-16 | Intron Biotechnology, Inc. | Mucosal messenger rna vaccine |
WO2023108076A1 (en) * | 2021-12-08 | 2023-06-15 | Yale University | Surface conjugation to poly(amine-co-ester) nanoparticles for targeting to cells and tissues |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015071295A1 (en) * | 2013-11-12 | 2015-05-21 | Vrije Universiteit Brussel | Rna transcription vector and uses thereof |
WO2015164674A1 (en) * | 2014-04-23 | 2015-10-29 | Moderna Therapeutics, Inc. | Nucleic acid vaccines |
EP3453754A1 (en) * | 2012-08-23 | 2019-03-13 | Vrije Universiteit Brussel | Enhancing the t-cells stimulatory capacity of human antigen presenting cells and their use in vaccination |
CN110352071A (zh) * | 2016-10-26 | 2019-10-18 | 库瑞瓦格股份公司 | 脂质纳米颗粒mRNA疫苗 |
-
2021
- 2021-02-15 IL IL295507A patent/IL295507A/en unknown
- 2021-02-15 WO PCT/EP2021/053633 patent/WO2021160881A1/en active Search and Examination
- 2021-02-15 CN CN202180009112.1A patent/CN115443148A/zh active Pending
- 2021-02-15 EP EP21705192.9A patent/EP4103226A1/en active Pending
- 2021-02-15 CA CA3170239A patent/CA3170239A1/en active Pending
- 2021-02-15 JP JP2022548838A patent/JP2023518340A/ja active Pending
- 2021-02-15 MX MX2022009943A patent/MX2022009943A/es unknown
- 2021-02-15 BR BR112022015666A patent/BR112022015666A2/pt unknown
- 2021-02-15 KR KR1020227031704A patent/KR20230004447A/ko unknown
- 2021-02-15 AU AU2021219304A patent/AU2021219304A1/en active Pending
- 2021-02-15 US US17/799,118 patent/US20230071518A1/en active Pending
- 2021-02-17 TW TW110105299A patent/TW202144002A/zh unknown
-
2022
- 2022-09-01 ZA ZA2022/09779A patent/ZA202209779B/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3453754A1 (en) * | 2012-08-23 | 2019-03-13 | Vrije Universiteit Brussel | Enhancing the t-cells stimulatory capacity of human antigen presenting cells and their use in vaccination |
WO2015071295A1 (en) * | 2013-11-12 | 2015-05-21 | Vrije Universiteit Brussel | Rna transcription vector and uses thereof |
WO2015164674A1 (en) * | 2014-04-23 | 2015-10-29 | Moderna Therapeutics, Inc. | Nucleic acid vaccines |
CN110352071A (zh) * | 2016-10-26 | 2019-10-18 | 库瑞瓦格股份公司 | 脂质纳米颗粒mRNA疫苗 |
Non-Patent Citations (2)
Title |
---|
ALBERTO C. GUARDO ET AL.: "Preclinical evaluation of an mRNA HIV vaccine combining rationally selected antigenic sequences and adjuvant signals (HTI-TriMix)" * |
LORNA LEAL ET AL.: "Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection" * |
Also Published As
Publication number | Publication date |
---|---|
BR112022015666A2 (pt) | 2022-09-27 |
WO2021160881A1 (en) | 2021-08-19 |
EP4103226A1 (en) | 2022-12-21 |
JP2023518340A (ja) | 2023-05-01 |
ZA202209779B (en) | 2024-01-31 |
TW202144002A (zh) | 2021-12-01 |
KR20230004447A (ko) | 2023-01-06 |
CA3170239A1 (en) | 2021-08-19 |
US20230071518A1 (en) | 2023-03-09 |
MX2022009943A (es) | 2022-10-18 |
IL295507A (en) | 2022-10-01 |
WO2021160881A9 (en) | 2022-11-10 |
AU2021219304A1 (en) | 2022-10-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN115443148A (zh) | 鼻内mRNA疫苗 | |
Flanagan et al. | Progress and pitfalls in the quest for effective SARS-CoV-2 (COVID-19) vaccines | |
JP2023002709A (ja) | RNA送達に有利なpKa値を有する脂質を含むリポソーム | |
Samsa et al. | Self-amplifying RNA vaccines for Venezuelan equine encephalitis virus induce robust protective immunogenicity in mice | |
JP2000516200A (ja) | ウシの呼吸病に対するポリヌクレオチドワクチン処方 | |
HU224833B1 (en) | Intradermal bovine polynucleotide vaccine | |
WO2022110099A1 (en) | Coronavirus vaccines and uses thereof | |
CN116390752A (zh) | 自扩增性sars-cov-2rna疫苗 | |
Larsen et al. | Effects of DNA dose, route of vaccination, and coadministration of porcine interleukin-6 DNA on results of DNA vaccination against influenza virus infection in pigs | |
Bai et al. | A single vaccination of nucleoside-modified Rabies mRNA vaccine induces prolonged highly protective immune responses in mice | |
Cox et al. | Non‐lethal viral challenge of influenza haemagglutinin and nucleoprotein DNA vaccinated mice results in reduced viral replication | |
JP2023551982A (ja) | マルチシストロン性rnaワクチン及びその使用 | |
EP2454374B1 (en) | Oral vaccines produced and administered using edible micro-organism | |
Wu et al. | RSV fusion (F) protein DNA vaccine provides partial protection against viral infection | |
US20230105376A1 (en) | Piv5-based coronavirus vaccines and methods of use thereof | |
US7601500B2 (en) | Prime-boost vaccine for the protection of equines against viral infection | |
US20220370600A1 (en) | Multigenic mva-sars-cov-2 vaccine | |
WO2023201881A1 (zh) | 香菇多糖在制备新型冠状病毒呼吸道粘膜疫苗中的应用 | |
US20230285542A1 (en) | Coronavirus Vaccine | |
WO2023091988A1 (en) | Expression of the spike s glycoprotein of sars-cov-2 from avian paramyxovirus type 3 (apmv3) | |
EP1987840A1 (en) | Prime-boost vaccine for the protection of equines against viral infection | |
TW202400800A (zh) | 用於預防和治療狂犬病毒感染的組合物和方法 | |
WO2023222757A1 (en) | Vaccine for preventing or treating cronavirus infection | |
WO2023154960A1 (en) | Pan-pneumovirus vaccine compositions and methods of use thereof | |
CN117815377A (zh) | mRNA的用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40085781 Country of ref document: HK |