92:. Cell-based antigen production offer a faster and more stable production of vaccines compared to embryonic chicken eggs, which produce 1-2 vaccine doses per chicken egg. Though host cells replicate well in chicken eggs, vaccine production with mammalian cells would not rely on an adequate supply of chicken eggs to produce each vaccine. In addition, cell-based vaccines may allow for multiple viral vaccines be produced in the same production platforms and facilities in a more sterile environment. In addition, some strains do not grow well on embryonic chicken eggs.
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in 2009, for use in countries affiliated with the
European Union. Optaflu is nearly identical to Flucelvax; it is also produced in Madin-Darby canine kidney cells and targets the same Influenza subtypes. The main differences are in release specifications for measuring vaccine lots' safety, efficacy,
95:
Cell lines grown in synthetic media avoid animal serum, which may pose a sterility problem, more specifically, preventing the spread of transmissible spongiform encephalopathies. Another benefit is the avoidance of egg-allergen. Lastly, cell-based vaccines may be more effective given that, with
47:
response to disease-causing agents. This immune response enables the immune system to act more quickly and effectively when exposed to that antigen again, and is the most effective tool to date to prevent the spread of infectious diseases.
80:. The candidate vaccine virus strain will replicate using the mammalian cells. Next, the virus is extracted from the cells in the liquid culture, purified, then tested or modified for the specific vaccine being produced.
96:
egg-based vaccines, there is a risk that the virus may mutate (antigenic drift) during its long growth phase in the chicken egg, thus causing the immune system to produce a different antibody than originally intended.
1134:
The main differences in manufacturing between
Flucelvax and Optaflu are limited to minor differences in release specifications and the methods used to calculate HA concentration.
801:
1107:
2346:
657:
464:
Vlecken DH, Pelgrim RP, Ruminski S, Bakker WA, van der Pol LA (October 2013). "Comparison of initial feasibility of host cell lines for viral vaccine production".
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Perdue ML, Arnold F, Li S, Donabedian A, Cioce V, Warf T, Huebner R (August 2011). "The future of cell culture-based influenza vaccine production".
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Zahoor MA, Khurshid M, Qureshi R, Naz A, Shahid M (July 2016). "Cell culture-based viral vaccines: current status and future prospects".
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1327:
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Flucelvax was approved for active immunization against influenza for use in adults 18 years of age and older on 20 November 2012.
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1973:
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61:
2031:
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1064:
Doroshenko A, Halperin SA (June 2009). "Trivalent MDCK cell culture-derived influenza vaccine
Optaflu (Novartis Vaccines)".
154:
viruses. The vaccine is approved for people over the age of three years. As of 2013, Flucelvax had shown similar levels of
1829:
1539:
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118:, for use in the United States. Developed by Protein Sciences Corporation, it is suitable for people with egg allergies.
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1114:
1039:
1004:
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954:
925:
895:
863:
829:
775:
115:
1173:
Toovey S (November 2007). "Preventing rabies with the
Verorab vaccine: 1985-2005 Twenty years of clinical experience".
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891:
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techniques in developing viral vaccines has been widely investigated in the 2000s as a complementary and alternative
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2001:
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The main benefit of cell-based vaccines is the ability to rapidly produce vaccine supplies during an impending
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and quality, mostly due to differences between U.S. and
European regulatory standards and tests.
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753:
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481:
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375:
318:
210:
Attenuvax is a vaccine approved in 2007, against measles developed using a primary cell line.
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60:, avian or insect tissue culture of cells with a finite lifespan. These cells are typically
34:
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1705:
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1574:
1504:
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1439:
1388:
951:"FDA approves first seasonal influenza vaccine manufactured using cell culture technology"
502:
195:
114:
In 2013, FluBlok, which is produced with insect cells, was approved by the United States
1221:
The virus in Ixiaro is grown in mammal cells ('Vero cells') under laboratory conditions.
2459:
2408:
2135:
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1986:
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722:"Current and emerging cell culture manufacturing technologies for influenza vaccines"
622:
605:
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69:
44:
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560:
330:
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2011:
1906:
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477:
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cell line. Specifically, Flucelvax targets four
Influenza sub-types which includes
30:
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691:
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2006:
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is a smallpox vaccine approved by the Food and Drug
Administration in 2007.
191:
187:
65:
22:
1272:
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1085:
757:
678:"Vaccine Production in Cells". Flu.gov. 2006-07-17. Retrieved 2013-09-24.^
631:
552:
485:
450:
379:
322:
1292:
Cellosaurus list of cell lines that are/can be used for vaccine production
738:
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432:
2172:
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2160:
2130:
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1822:
1817:
772:"FDA approves new seasonal influenza vaccine made using novel technology"
361:
218:
131:
126:
In 2012, the US FDA approved
Flucelvax as the first mammalian cell-based
89:
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43:
work to prepare an immune system to fight off disease by generating an
40:
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544:
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2179:
1470:
57:
2189:
2074:
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1614:
77:
73:
56:
To produce viral vaccines, candidate vaccine viruses are grown in
974:"Approved Products – 20 November 2012 Approval Letter- Flucelvax"
1489:
147:
143:
1300:
64:, but others are also used including monkey cell lines pMK and
686:
684:
715:
713:
233:, was approved by the Food and Drug Administration in 1987.
21:
are developed from mammalian or more rarely avian or insect
29:
chicken eggs to develop the antigens. The potential use of
25:
rather than the more common method which uses the cells in
186:
1239:"Cell culture-derived flu vaccine: Present and future"
794:"FDA approves first flu vaccine grown in insect cells"
2431:
1152:"Is Egg-based Vaccine Manufacturing on its Way Out?"
1146:
1144:
1142:
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2300:
2232:
2123:
2095:
2062:
1736:
1567:
1560:
1479:
1407:
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290:
288:
286:
284:
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130:in the United States. The vaccine was produced by
2347:Cedillo v. Secretary of Health and Human Services
1287:WHO Vaccine preventable diseases and immunization
658:Center for Infectious Disease Research and Policy
606:"Cell-based influenza vaccines: progress to date"
297:"Cell-based influenza vaccines: progress to date"
993:
991:
356:(3). American Society for Microbiology: 476–92.
1059:
1057:
972:Center for Biologics Evaluation and Research.
1312:
892:"20 November 2012 Approval Letter- Flucelvax"
572:
570:
8:
173:, produced by Novartis, was approved by the
1564:
1319:
1305:
1297:
1211:. European Medicines Agency. 15 March 2019
696:Centers for Disease Control and Prevention
507:Centers for Disease Control and Prevention
1262:
747:
737:
654:"FDA clears first cell-based flu vaccine"
621:
497:
495:
440:
369:
312:
346:"Traditional and new influenza vaccines"
295:Audsley JM, Tannock GA (1 August 2008).
2438:
1154:. The Cell Culture Dish. 4 October 2011
1117:(FDA). 20 November 2012. Archived from
957:(FDA). 20 November 2012. Archived from
503:"How Influenza (Flu) Vaccines Are Made"
278:
1175:Travel Medicine and Infectious Disease
778:(FDA). 16 January 2013. Archived from
249:based rabies vaccine approved by the
37:to the current egg-based strategies.
7:
1108:"Summary Basis of Regulatory Action"
1013:from the original on 17 October 2019
1009:. 19 September 2019. STN BL 125408.
922:"Summary Basis of Regulatory Action"
872:from the original on 14 October 2019
838:from the original on 14 October 2019
804:from the original on 14 October 2019
526:
524:
421:The New England Journal of Medicine
162:as traditional egg-based vaccines.
2374:Eradication of infectious diseases
2131:Androvax (androstenedione albumin)
14:
1964:Respiratory syncytial virus (RSV)
1072:(6). Informa UK Limited: 679–88.
902:from the original on 23 July 2017
2453:
2441:
2353:Alternative vaccination schedule
1328:Artificial induction of immunity
1237:PĂ©rez Rubio A, Eiros JM (2018).
834:. 26 February 2018. STN 125285.
623:10.2165/00003495-200868110-00002
314:10.2165/00003495-200868110-00002
1033:"Flucelvax Product Information"
604:Audsley JM, Tannock GA (2008).
417:"Designing tomorrow's vaccines"
344:Wong SS, Webby RJ (July 2013).
62:Madin-Darby Canine Kidney cells
2185:Ovandrotone albumin (Fecundin)
478:10.1016/j.jviromet.2013.04.020
466:Journal of Virological Methods
1:
1721:Group B streptococcal disease
1540:Vaccines for Children Program
1255:10.1080/21645515.2018.1460297
868:. 2 August 2019. STN 125285.
726:BioMed Research International
350:Clinical Microbiology Reviews
1115:Food and Drug Administration
1040:Food and Drug Administration
1005:Food and Drug Administration
978:Food and Drug Administration
955:Food and Drug Administration
926:Food and Drug Administration
896:Food and Drug Administration
864:Food and Drug Administration
830:Food and Drug Administration
776:Food and Drug Administration
116:Food and Drug Administration
1187:10.1016/j.tmaid.2007.07.004
720:Milián E, Kamen AA (2015).
2497:
415:Nabel GJ (February 2013).
2392:
1066:Expert Review of Vaccines
898:(FDA). 20 November 2012.
692:"Cell-Based Flu Vaccines"
533:Expert Review of Vaccines
251:World Health Organization
175:European Medicines Agency
136:Madin-Darby canine kidney
134:through culturing of the
1716:Clostridioides difficile
999:"Flucelvax Quadrivalent"
509:(CDC). 24 September 2018
1974:Tick-borne encephalitis
2384:List of vaccine topics
1384:Mathematical modelling
953:(Press release). U.S.
858:"Flublok Quadrivalent"
774:(Press release). U.S.
394:"Vaccines Protect You"
241:Verorab, developed by
146:, Influenza A subtype
2379:Vaccinate Your Family
1830:Japanese encephalitis
1243:Hum Vaccin Immunother
980:(FDA). Archived from
698:(CDC). 4 October 2018
591:10.2217/fvl-2016-0006
433:10.1056/nejmra1204186
267:Japanese encephalitis
68:and human cell lines
2262:John Franklin Enders
1042:(FDA). February 2013
362:10.1128/cmr.00097-12
1448:Virus-like particle
1372:Vaccine ingredients
984:on 3 December 2012.
800:. 14 October 2019.
739:10.1155/2015/504831
229:IPOL, developed by
190:based vaccines for
76:, Per.C6, PMK, and
19:Cell-based vaccines
2419:Never to phase III
2218:Hexavalent vaccine
2032:Epstein–Barr virus
1927:Oxford–AstraZeneca
1620:NmVac4-A/C/Y/W-135
961:on 2 January 2013.
928:(FDA). 23 May 2016
660:. 21 November 2012
2429:
2428:
2341:Vaccines and SIDS
2228:
2227:
2002:Hepatitis A and B
1978:Varicella zoster
1440:Subunit/component
1078:10.1586/erv.09.31
545:10.1586/erv.11.82
245:, is a mammalian
128:Influenza vaccine
100:Approved examples
2488:
2458:
2457:
2446:
2445:
2444:
2437:
2320:MMR autism fraud
2267:Maurice Hilleman
2252:Hilary Koprowski
1565:
1321:
1314:
1307:
1298:
1276:
1266:
1249:(8): 1874–1882.
1224:
1223:
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1205:
1199:
1198:
1170:
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1163:
1161:
1159:
1148:
1137:
1136:
1131:
1129:
1124:on 11 March 2016
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406:
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156:vaccine efficacy
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2409:Clinical trials
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2357:
2296:
2272:Stanley Plotkin
2234:
2224:
2136:Cancer vaccines
2119:
2113:Schistosomiasis
2091:
2085:Trypanosomiasis
2058:
2022:Cytomegalovirus
1932:Pfizer–BioNTech
1732:
1556:
1505:Vaccine wastage
1475:
1403:
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1231:Further reading
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782:on 18 May 2013.
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616:(11): 1483–91.
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579:Future Virology
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307:(11): 1483–91.
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198:and RotaTeq by
196:GlaxoSmithKline
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2287:Katalin KarikĂł
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2042:Herpes simplex
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1520:Vaccine injury
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1480:Administration
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1281:External links
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539:(8): 1183–94.
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396:. Vaccines.gov
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243:Sanofi Pasteur
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2349:
2348:
2344:
2342:
2339:
2337:
2334:
2332:
2329:
2327:
2324:
2321:
2319:
2314:
2311:
2309:
2306:
2305:
2303:
2299:
2293:
2292:Drew Weissman
2290:
2288:
2285:
2283:
2280:
2278:
2277:H. Fred Clark
2275:
2273:
2270:
2268:
2265:
2263:
2260:
2258:
2255:
2253:
2250:
2248:
2247:Louis Pasteur
2245:
2243:
2242:Edward Jenner
2240:
2239:
2237:
2231:
2219:
2216:
2214:
2213:DTwP-HepB-Hib
2211:
2209:
2208:DTaP-IPV-HepB
2206:
2204:
2201:
2200:
2199:combination:
2198:
2196:
2193:
2191:
2188:
2186:
2183:
2181:
2178:
2174:
2171:
2167:
2164:
2162:
2159:
2158:
2157:
2154:
2152:
2149:
2147:
2144:
2142:
2139:
2138:
2137:
2134:
2132:
2129:
2128:
2126:
2122:
2114:
2111:
2109:
2106:
2105:
2103:
2102:
2100:
2098:
2097:Helminthiasis
2094:
2086:
2083:
2082:
2080:
2076:
2073:
2072:
2071:
2068:
2067:
2065:
2061:
2053:
2050:
2048:
2045:
2043:
2040:
2038:
2035:
2033:
2030:
2028:
2025:
2023:
2020:
2019:
2017:
2013:
2010:
2008:
2005:
2003:
2000:
1999:
1998:combination:
1997:
1995:
1992:
1988:
1985:
1983:
1980:
1979:
1977:
1975:
1972:
1970:
1967:
1965:
1962:
1958:
1955:
1953:
1950:
1948:
1945:
1943:
1940:
1938:
1935:
1933:
1930:
1928:
1925:
1923:
1920:
1918:
1915:
1913:
1910:
1908:
1905:
1903:
1900:
1898:
1895:
1893:
1890:
1888:
1885:
1884:
1883:
1880:
1878:
1875:
1873:
1870:
1868:
1865:
1861:
1858:
1856:
1853:
1852:
1851:
1848:
1846:
1843:
1841:
1838:
1836:
1833:
1831:
1828:
1824:
1821:
1819:
1816:
1815:
1814:
1811:
1809:
1806:
1804:
1801:
1799:
1796:
1794:
1791:
1787:
1784:
1782:
1779:
1776:
1772:
1769:
1768:
1767:
1764:
1760:
1757:
1756:
1755:
1752:
1750:
1747:
1745:
1742:
1741:
1739:
1735:
1727:
1724:
1722:
1719:
1717:
1714:
1713:
1711:
1707:
1704:
1702:
1701:DPT/DTwP/DTaP
1699:
1698:
1697:combination:
1696:
1694:
1691:
1687:
1684:
1682:
1679:
1678:
1677:
1674:
1670:
1667:
1666:
1665:
1662:
1660:
1657:
1655:
1652:
1648:
1645:
1643:
1640:
1639:
1638:
1635:
1633:
1630:
1628:
1625:
1621:
1618:
1616:
1613:
1612:
1611:
1610:Meningococcus
1608:
1606:
1603:
1601:
1600:Leptospirosis
1598:
1596:
1593:
1591:
1588:
1586:
1583:
1581:
1578:
1576:
1573:
1572:
1570:
1566:
1563:
1559:
1551:
1548:
1546:
1543:
1541:
1538:
1536:
1535:Vaccine court
1533:
1531:
1528:
1527:
1525:
1521:
1518:
1516:
1513:
1511:
1508:
1506:
1503:
1501:
1498:
1496:
1493:
1491:
1490:GAVI Alliance
1488:
1487:
1485:
1484:
1482:
1478:
1472:
1469:
1467:
1464:
1462:
1458:
1455:
1453:
1449:
1445:
1441:
1438:
1434:
1431:
1429:
1426:
1425:
1423:
1421:
1418:
1416:
1413:
1412:
1410:
1406:
1400:
1397:
1395:
1392:
1390:
1387:
1385:
1382:
1378:
1375:
1374:
1373:
1370:
1368:
1365:
1364:
1362:
1358:
1353:
1349:
1345:
1341:
1337:
1333:
1329:
1322:
1317:
1315:
1310:
1308:
1303:
1302:
1299:
1293:
1290:
1288:
1285:
1284:
1280:
1274:
1270:
1265:
1260:
1256:
1252:
1248:
1244:
1240:
1235:
1234:
1230:
1222:
1210:
1204:
1201:
1196:
1192:
1188:
1184:
1181:(6): 327–48.
1180:
1176:
1169:
1166:
1153:
1147:
1145:
1143:
1139:
1135:
1120:
1116:
1109:
1103:
1100:
1095:
1091:
1087:
1083:
1079:
1075:
1071:
1067:
1060:
1058:
1054:
1041:
1034:
1028:
1025:
1012:
1008:
1006:
1000:
994:
992:
988:
983:
979:
975:
968:
965:
960:
956:
952:
946:
943:
939:
927:
923:
917:
914:
901:
897:
893:
887:
884:
871:
867:
865:
859:
853:
850:
837:
833:
831:
825:
819:
816:
803:
799:
795:
789:
786:
781:
777:
773:
767:
764:
759:
755:
750:
745:
740:
735:
731:
727:
723:
716:
714:
710:
697:
693:
687:
685:
681:
675:
672:
659:
655:
649:
646:
641:
637:
633:
629:
624:
619:
615:
611:
607:
600:
597:
592:
588:
585:(7): 549–62.
584:
580:
573:
571:
567:
562:
558:
554:
550:
546:
542:
538:
534:
527:
525:
521:
508:
504:
498:
496:
492:
487:
483:
479:
475:
471:
467:
460:
457:
452:
448:
443:
438:
434:
430:
427:(6): 551–60.
426:
422:
418:
411:
408:
395:
389:
386:
381:
377:
372:
367:
363:
359:
355:
351:
347:
340:
337:
332:
328:
324:
320:
315:
310:
306:
302:
298:
291:
289:
287:
285:
283:
279:
272:
270:
268:
264:
256:
254:
252:
248:
244:
236:
234:
232:
224:
222:
220:
213:
211:
205:
203:
201:
197:
194:, Rotarix by
193:
189:
181:
179:
176:
172:
165:
163:
161:
157:
153:
149:
145:
141:
137:
133:
129:
121:
119:
117:
109:
104:
99:
97:
93:
91:
83:
81:
79:
75:
71:
67:
63:
59:
51:
49:
46:
42:
38:
36:
32:
28:
24:
20:
16:
2369:Epidemiology
2345:
2317:
2203:DTaP-IPV/Hib
1994:Yellow fever
1907:EpiVacCorona
1664:Tuberculosis
1637:Pneumococcal
1605:Lyme disease
1433:Heterologous
1332:Immunization
1246:
1242:
1220:
1213:. Retrieved
1203:
1178:
1174:
1168:
1156:. Retrieved
1133:
1128:10 September
1126:. Retrieved
1119:the original
1102:
1069:
1065:
1044:. Retrieved
1027:
1015:. Retrieved
1002:
982:the original
967:
959:the original
945:
937:
930:. Retrieved
916:
904:. Retrieved
886:
874:. Retrieved
861:
852:
840:. Retrieved
827:
818:
806:. Retrieved
797:
788:
780:the original
766:
729:
725:
700:. Retrieved
674:
664:24 September
662:. Retrieved
648:
613:
609:
599:
582:
578:
536:
532:
511:. Retrieved
472:(1): 28–41.
469:
465:
459:
424:
420:
410:
398:. Retrieved
388:
353:
349:
339:
304:
300:
260:
240:
228:
217:
209:
185:
169:
125:
113:
94:
87:
55:
39:
31:cell culture
18:
17:
15:
2476:Vaccination
2405:from market
2301:Controversy
2235:researchers
2151:Hepatitis B
2037:Hepatitis C
1982:Chicken pox
1808:Hepatitis E
1803:Hepatitis B
1798:Hepatitis A
1749:Chikungunya
1726:Shigellosis
1580:Brucellosis
1466:Therapeutic
1420:Inactivated
1360:Development
1348:Inoculation
1340:Vaccination
1046:10 November
702:19 December
513:18 December
400:18 December
152:Influenza B
140:Influenza A
2470:Categories
2336:Thiomersal
2282:Paul Offit
2257:Jonas Salk
2233:Inventors/
2104:research:
2081:research:
2018:research:
1947:Skycovione
1937:Sanofi–GSK
1882:SARS-CoV-2
1793:Hantavirus
1759:rVSV-ZEBOV
1744:Adenovirus
1712:research:
1590:Diphtheria
1428:Attenuated
1017:16 October
876:14 October
842:14 October
808:14 October
732:: 504831.
273:References
263:Valneva SE
261:Ixiaro by
150:, and two
84:Advantages
52:Production
23:cell lines
2415:Phase III
2403:Withdrawn
2331:Pox party
2141:ALVAC-CEA
2063:Protozoan
1952:Sputnik V
1902:CoronaVac
1872:Rotavirus
1775:Pandemrix
1627:Pertussis
1568:Bacterial
1452:Synthetic
1415:Conjugate
1367:Adjuvants
1344:Infection
1158:9 October
1094:207223652
906:19 August
824:"Flublok"
247:vero cell
192:rotavirus
188:vero cell
182:Rotavirus
122:Flucelvax
105:Influenza
58:mammalian
27:embryonic
2481:Virology
2448:Medicine
2173:Prostvac
2166:Gardasil
2161:Cervarix
2108:Hookworm
1987:Shingles
1969:Smallpox
1887:Corbevax
1823:Gardasil
1818:Cervarix
1561:Vaccines
1515:Schedule
1486:Global:
1394:Timeline
1336:Vaccines
1273:29672213
1209:"Ixiaro"
1195:17983973
1086:19485748
1011:Archived
900:Archived
870:Archived
836:Archived
802:Archived
758:25815321
640:46960558
632:18627206
561:28477882
553:21854311
486:23684847
451:23388006
380:23824369
331:46960558
323:18627206
219:ACAM2000
214:Smallpox
142:subtype
132:Novartis
90:pandemic
41:Vaccines
35:platform
2460:Viruses
2434:Portals
2362:Related
2308:General
2070:Malaria
1957:Valneva
1922:Novavax
1917:Moderna
1912:Janssen
1897:CanSino
1877:Rubella
1835:Measles
1706:Td/Tdap
1676:Typhoid
1659:Tetanus
1654:Q fever
1585:Cholera
1575:Anthrax
1444:Peptide
1408:Classes
1389:Storage
1264:6149758
1215:27 June
976:. U.S.
932:27 June
894:. U.S.
749:4359798
442:3612922
371:3719499
206:Measles
171:Optaflu
166:Optaflu
110:Flublok
70:HEK 293
2398:WHO-EM
2318:Lancet
2195:TA-NIC
2180:NicVAX
2027:Dengue
1867:Rabies
1693:Typhus
1632:Plague
1510:Policy
1471:Toxoid
1399:Trials
1271:
1261:
1193:
1092:
1084:
798:CIDRAP
756:
746:
638:
630:
559:
551:
484:
449:
439:
378:
368:
329:
321:
257:Others
237:Rabies
45:immune
2326:NCVIA
2190:TA-CD
2124:Other
2075:RTS,S
1855:Sabin
1850:Polio
1845:Mumps
1754:Ebola
1737:Viral
1686:ViCPS
1681:Ty21a
1615:MeNZB
1545:VAERS
1495:NITAG
1424:Live
1122:(PDF)
1111:(PDF)
1090:S2CID
1036:(PDF)
1007:(FDA)
1003:U.S.
866:(FDA)
862:U.S.
832:(FDA)
828:U.S.
636:S2CID
610:Drugs
557:S2CID
327:S2CID
301:Drugs
225:Polio
200:Merck
78:WI-38
74:MRC 5
2052:Zika
2012:MMRV
1860:Salk
1840:Mpox
1786:LAIV
1781:H5N1
1771:H1N1
1647:PPSV
1530:ACIP
1526:US:
1500:SAGE
1461:mRNA
1377:list
1269:PMID
1217:2019
1191:PMID
1160:2017
1130:2015
1082:PMID
1048:2013
1019:2019
934:2019
908:2017
878:2019
844:2019
810:2019
754:PMID
730:2015
704:2018
666:2013
628:PMID
549:PMID
515:2018
482:PMID
447:PMID
402:2018
376:PMID
319:PMID
265:for
158:and
148:H3N2
144:H1N1
66:Vero
2313:MMR
2156:HPV
2146:BCG
2047:HIV
2007:MMR
1813:HPV
1766:Flu
1669:BCG
1642:PCV
1595:Hib
1550:VSD
1457:DNA
1352:J07
1259:PMC
1251:doi
1183:doi
1074:doi
744:PMC
734:doi
618:doi
587:doi
541:doi
474:doi
470:193
437:PMC
429:doi
425:368
366:PMC
358:doi
309:doi
2472::
2411::
1459:/
1450:/
1446:/
1442:/
1346:,
1342:,
1338:,
1334::
1330:/
1267:.
1257:.
1247:14
1245:.
1241:.
1219:.
1189:.
1177:.
1141:^
1132:.
1113:.
1088:.
1080:.
1068:.
1056:^
1038:.
1001:.
990:^
936:.
924:.
860:.
826:.
796:.
752:.
742:.
728:.
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712:^
694:.
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656:.
634:.
626:.
614:68
612:.
608:.
583:11
581:.
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555:.
547:.
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523:^
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494:^
480:.
468:.
445:.
435:.
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419:.
374:.
364:.
354:26
352:.
348:.
325:.
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299:.
281:^
269:.
253:.
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910:.
880:.
846:.
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760:.
736::
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620::
593:.
589::
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488:.
476::
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