Prof. Adolfo García Sastre: Influenza epidemics and pandemics
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Watch the video of the presentation on Youtube:https://www.youtube.com/watch?v=E6CmOWR8klI&feature=youtu.be Seasonal influenza continues to cause yearly epidemics resulting in severe disease and a significant number of deaths despite available vaccines and antivirals. Even more concerning is the ability of influenza virus to cause pandemics every 10-50 years. In the last years, we and other have characterized several features associated with virus virulence and tropism. In addition, new developments suggest the possibility of universal influenza virus vaccines that induce protective antibodies against conserved regions.
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Prof. Adolfo García Sastre: Influenza epidemics and pandemics
- 1. Adolfo García-Sastre Icahn School of Medicine at Mount Sinai, New York CRIP, Center for Research on Influenza Pathogenesis INFLUENZA EPIDEMICS PANDEMICS
- 4. ‘40 ‘50 ‘60 ‘70 ‘80 ‘00‘901918 H1N1 H2N2 H1N1 H3N2 A B EPIDEMIOLOGY OF HUMAN INFLUENZA VIRUSES ‘10 1957 1968 1977 pH1N1 2009
- 5. INFECTIONS IN HUMANS WITH AVIAN AND SWINE INFLUENZA A VIRUSES H5N1 H9N2 H5N1 H5N1H7N7 ‘40 ‘50 ‘60 ‘70 ‘80 ‘00‘901918 H1N1 H2N2 H1N1 H3N2 A B ‘10 1957 1968 1977 pH1N1 2009 H7N9H3N2v
- 6. Evolution and spread of flu viruses aquatic birds poultry pigs humans horses fecal/oral respiratory dogs cats
- 7. H1N1 1918
- 8. Alicia Solórzano Adolfo García-Sastre Patty Aguilar Chris Basler Peter Palese Mount Sinai Terry Tumpey Hui Zeng Nancy Cox Jacky Katz CDC David Swayne USDA Jeff Taubenberger AFIP
- 9. U.S. Life Expectancy By age 70 60 50 40 30 1900 ‘30 ‘50 ‘70 ‘90
- 11. Lung tissue samples (1918) 1918 influenza AFIP lung block Extract RNA, sequence, clone the virus
- 12. Gene sequencing Gene reconstruction Pathological specimen (circa 1918) ..... Reverse genetics Signatures of virulence of the 1918 influenza virus Phenotypic characterization in: Tissue culture Animal models
- 14. 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 %survival Days after infection Tx/91 1918 5:3 Tx/91 1918 1918 7:HA Tx/91 Intranasal inoculation of mice, 106 pfu Viral titers in lungs, day 4 103 pfu 106 pfu 108 pfu 105 pfu
- 17. 1918 VIRUS What do we know now? 1. The 1918 virus is the only known human influenza virus lethal to mice, ferrets, macaques and embryonated eggs 2. The glycoprotein (HA and NA) and non-structural (NS1 and PB1-F2 genes) of the virus contribute to enhanced virulence 3. Viruses containing 1918 genes are sensitive to existing antivirals 4. H1N1 based vaccines are protective Would a 1918-like HIN1 virus be today as lethal as in 1918?
- 18. H1N1 2009
- 19. Rafa Medina Balaji Manicassamy Estanis Nistal-Villán Adolfo García-Sastre Tshide Tsibane Chris Basler Silke Stertz Peter Palese Mount Sinai Petra Zimmermann Osvaldo Zagordi Silke Stertz University of Zurich Hanni Uusi-Kerttula Rafa Medina Universidad Católica de Chile Xiangjie Sun Terry Tumpey CDC Sharon Frey Bob Belshe SLU
- 20. ‘40 ‘50 ‘60 ‘70 ‘80 ‘00‘901918 H1N1 H2N2 H1N1 H3N2 A B EPIDEMIOLOGY OF HUMAN INFLUENZA VIRUSES ‘10 1957 1968 1977 pH1N1 2009
- 21. SWINE FLU
- 22. Human H3N2 Swine H1N1 Avian virus Human pandemic H1N1 NO 1918 PB1-F2
- 23. 1918 “Spanish” flu Pigs Humans Classical swine flu Modern human H1N1 Sa Ca2 Ca1 Cb Receptor binding site Sb Fusion peptide Antigenic sites
- 24. Pandemic H1N1 infections in humans • Infections are primarily seen in children and young adults • Serology studies show the presence of neutralizing antibodies against 2009 H1N1 virus in people older than 65 yrs Due to prior exposure to an H1 virus similar to 2009 H1N1?
- 25. Do antibodies to any specific H1N1 virus protect against SOIV 2009 H1N1? Virus Type Year (lineage) A/California/04/09 (6:2) H1N1 2009 1918-like or classical H1N1 1918 VLP H1N1 1918 A/swine/Iowa/30 H1N1 1930 (Classical) A/Weiss/43 H1N1 1943 (1918-like) A/New Jersey/8/76 H1N1 1976 (Classical?) Human H1N1(1977-2007) A/USSR/92/77 H1N1 1977 A/Houston/20593/84 H1N1 1984 A/Texas/36/91 H1N1 1991 A/Brisbane/59/07 H1N1 2007 Control (H3N2) A/NT/60/68 H3N2 1968 A/Brisbane/10/07 H3N2 2007
- 26. Vaccination and challenge experiment Vaccination 15mg -28 Boost 15mg Challenge (50 LD50) -14 Body weight & Survival 0Day - 5 week old female C57B/6 mice - Mice were vaccinated with 11 different inactivated viruses - Challenged with Neth/09 strain 14
- 27. Inactivated vaccines based in classical swine viruses (1930-2009) and in human H1N1 viruses (1918-1943) protect against lethal infection with the new H1N1
- 30. Conclusions -People carrying antibodies against H1N1 viruses that circulated 1918-1950 and A/NJ/76 (vaccination) are likely to be protected - Pigs act as reservoirs for strains that become antigenically “frozen” H3 and H1 viruses have also established lineages in pigs in 1997-1998 and 2003- 2005. Swine H3N2v jumps frequently to humans.
- 31. Sample Age Cal/09 1918 Vaccinated with Pre PrePost Post 2009 H1N1 Seasonal TIV 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 19 21 33 34 34 42 43 49 55 60 67 67 82 51 74 <10 <10 <10 <10 <10 10 <10 <10 10 <10 10 10 <10 <10 <10 80 1280 80 2560 80 320 320 40 1280 1280 640 640 2560 <10 10 10 <10 20 <10 <10 <10 20 <10 <10 10 <10 80 <10 <10 10 20 1280 40 2560 80 320 640 20 1280 1280 1280 640 640 <10 40 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes New H1N1 vaccines induce 1918 HI antibodies in humans In collaboration with Bob Belshe
- 32. Passive administration of sera from new H1N1 vaccinated humans In collaboration with Bob Belshe
- 33. Passive administration of sera from new H1N1 vaccinated humans In collaboration with Bob Belshe Vaccination (or exposure) to new H1N1 virus generates protective immunity against 1918 virus
- 34. AVIAN FLU
- 36. LOW PATHOGENIC H5N1 VIRUSES H5N1 ORIGIN
- 37. LOW PATHOGENIC H5N1 VIRUSES HIGLY PATHOGENIC H5N1 VIRUSES Mutation
- 38. H7N9
- 39. India Nepal Russia Mongolia Bangladesh Bhutan Burma Thailand Laos 0 0 500 Kilometers 500 Miles Vietnam Philippines South Korea North Korea Pakistan INNER MONGOLIA HENAN ANHUI ZHEJIANG SHANGHAI JIANGSU FUJIAN JIANGXI HUBEI SHANXI SHANDONG HEBEI BEIJING TIANJIN LIAONING Taiwan Location of H7N9 Influenza in China (Feb-Oct 2013) SHAANXI 137 total cases/45deaths Province/ City Number of Cases Anhui 4 Beijing 2 Fujian 5 Guangdong 1 Guangxi 0 Hebei 1 Henan 4 Hunan 2 Jiangsu 28 Jiangxi 6 Jilin 0 Shandong 2 Shanghai 33 Zhejiang 48 GUANGDONG HUNAN GUANGXI CHONGQING GUIZHOU NINGXIA GANSU SICHUAN YUNNAN JILIN HEILONGJIANG QINGHAI XIZANG XINJIANG HAINAN Source WHO Adapted from Taiwan 1
- 40. India Nepal Russia Mongolia Bangladesh Bhutan Burma Thailand Laos 0 0 500 Kilometers 500 Miles Vietnam Philippines South Korea North Korea Pakistan INNER MONGOLIA HENAN ANHUI ZHEJIANG SHANGHAI JIANGSU FUJIAN JIANGXI HUBEI SHANXI SHANDONG HEBEI BEIJING TIANJIN LIAONING Taiwan Location of H7N9 Influenza in China (8/4/14) SHAANXI 452 total cases/124deaths Province/ City Number of Cases Anhui 18 Beijing 5 Fujian 22 Guangdong 118 Guangxi 3 Hebei 1 Henan 4 Hunan 24 Jiangsu 61 Jiangxi 8 Jilin 2 Shandong 4 Shanghai 42 Zhejiang 140 GUANGDONG HUNAN GUANGXI CHONGQING GUIZHOU NINGXIA GANSU SICHUAN YUNNAN JILIN HEILONGJIANG QINGHAI XIZANG XINJIANG HAINAN Source WHO, flutrackers, news Adapted from Taiwan 1
- 41. Cases Deceased Cases Alive Source: WHO, Flutrackers, news reports There have now been 9 human cases from Guangdong Province over the past 7 days.
- 42. Confirmed human cases of H5N1 (2003-2013) Country Infections Deaths
- 45. Source: CDC ILI and Vaccine Distribution Data Pandemic H1N1 cases and vaccinations in US Sept 2009 – May 2010 0 20,000,000 40,000,000 60,000,000 80,000,000 100,000,000 120,000,000 140,000,000 0 1 2 3 4 5 6 7 8 9 9/3/2009 10/3/2009 11/3/2009 12/3/2009 1/3/2010 2/3/2010 3/3/2010 4/3/2010 5/3/2010 NumberofH1N1VaccineShipped %ofVisitsforILI ILI Shipped Vaccine
- 47. Neutralization of influenza viruses Nat Struct Mol Biol. 2009 Mar;16(3):233-4. HA1 HA2 Neutralizing antibodies
- 49. UNIVERSAL FLU VACCINES? Repeated vaccination with influenza virus chimeric HA vaccines induce protective antibodies against multiple subtypes of influenza virus. Irina Margine Randy Albrecht Florian Krammer Rong Hai Patrick Wilson Gene Tan S.A. Andrews Peter Palese Jon Runstadler
- 50. cH4/3 DNA cH5/3 protein boost H3 protein boost Shanghai (H7N9) challenge Control groups: cH4/3 DNA + BSA + BSA naïve (neg. contr.) matched vaccine (pos. contr.) 4 weeks3 weeks3 weeks Induction of protective levels of stalk-reactive antibodies using chimeric HA constructs in mice
- 51. cH4/3 DNA cH5/3 protein boost H3 protein boost Shanghai (H7N9) challenge Control groups: cH4/3 DNA + BSA + BSA naïve (neg. contr.) matched vaccine (pos. contr.) 4 weeks3 weeks3 weeks Induction of protective levels of stalk-reactive antibodies using chimeric HA constructs in mice
- 52. cH4/3 DNA cH5/3 protein boost H3 protein boost Shanghai (H7N9) challenge Control groups: cH4/3 DNA + BSA + BSA naïve (neg. contr.) matched vaccine (pos. contr.) 4 weeks3 weeks3 weeks Induction of protective levels of stalk-reactive antibodies using chimeric HA constructs in mice Y
- 53. cH4/3 DNA cH5/3 protein boost H3 protein boost Shanghai (H7N9) challenge Control groups: cH4/3 DNA + BSA + BSA naïve (neg. contr.) matched vaccine (pos. contr.) 4 weeks3 weeks3 weeks Induction of protective levels of stalk-reactive antibodies using chimeric HA constructs in mice Y
- 54. cHA vaccine protects against challenge with novel H7N9 virus
- 55. cHA vaccine protects against challenge with H10 and H3 viruses cH4/3 DNA + cH5/3 protein + H3 protein cH4/3 DNA + cH5/3 protein + cH7/3 protein Titers in mouse lungs, day 3 postinfection
- 57. H11 H13 H16 H1 H2 H5 H6 H17 H8 H12 H9 H7 H15 H10 H3 H4 H14 GROUP1GROUP2 0.04 Targeting group 1 HA viruses
- 58. cH9/1 DNA cH6/1 protein cH5/1 protein Control groups: cH9/1 DNA + BSA + BSA matched vaccine (pos. contr.) Y Induction of protective levels of stalk-reactive antibodies using chimeric HA constructs in mice PR8 H1N1 FM1 H1N1 pH1N1 H5N1 H6N1 challenge
- 59. Vaccination with cHA constructs protects from pH1N1 (A/Netherlands/602/09) challenge positive control (matched inactivated) cH9/1 DNA + cH6/1 protein + cH5/1 protein cH9/1 DNA + BSA +BSA Similar results for A/PR/8/34 H1N1 and A/FM/1/47 challenges
- 60. positive control (matched inactivated) cH9/1 DNA + H1 protein/cH6/1 protein + cH5/1 protein/H1 protein cH9/1 DNA + BSA +BSA cHA constructs protect mice from heterosubtypic challenge H5N1 challenge H6N1 challenge cH5/1 (H5 challenge) or cH6/1 (H6 challenge) protein was replaced by full length H1 protein to exclude head-based protection
- 61. ELISA reactivity to Cal09 (pH1N1) protein Protection is antibody mediated cH9/1 + cH6/1 + cH5/1 cH9/1 + BSA +BSA naïve serum Naïve Positive control vector +BSA+BSA cH9/1 + cH6/1 + cH5/1 Passive transfer of serum protects from viral challenge Days post challenge
- 62. cHA constructs protect ferrets from pH1N1 challenge *** ***ns
- 63. FLU, WHAT IS NEEDED? SURVEILLANCE, ERRADICATION NEW BROAD SPECTRUM ANTIVIRALS BROADLY NEUTRALIZING VACCINES TRAINING OF FUTURE INVESTIGATORS