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Lessons Learned from the Reconstruction of the 1918 Pandemic

Lessons Learned from the Reconstruction of the 1918 Pandemic. Adolfo García-Sastre, PhD Professor of Microbiology Mount Sinai School of Medicine. Lessons Learned from the Reconstruction of the 1918 Virus. Collaborative effort among different research groups and institutions.

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Lessons Learned from the Reconstruction of the 1918 Pandemic

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  1. Lessons Learnedfrom the Reconstructionof the 1918 Pandemic Adolfo García-Sastre, PhD Professor of Microbiology Mount Sinai School of Medicine

  2. Lessons Learned from the Reconstruction of the 1918 Virus Collaborative effort among different research groups and institutions • Armed Forces Institute of Pathology, Jeffery K. Taubenberger Washington DC • Mount Sinai School of Medicine, Adolfo García-Sastre New York Peter Palese Christopher F. Basler • CDC Terrence M. Tumpey • USDA, Athens, Georgia David E. Swayne • University of Washington, Seattle Michael G. Katze • Scripps Research Institute, La Jolla Ian A. Wilson James Stevens NIH/NIAID support: P01 AI0581113

  3. 70 60 50 1918 Flu Epidemic 40 30 1900 ‘50 ‘70 ‘90 ‘30 U.S. Life Expectancy By Age

  4. Influenza and Pneumonia Deaths by Age Specific Death Rate

  5. Why Study the 1918 Virus? • The 1918 virus contains determinants responsible for its success as a pandemic virus • The 1918 virus contains virulence determinants that are not understood • A new 1918-like virus may evolve • The knowledge of these determinants will allow us to better recognize the pandemic potential of circulating animal viruses and will provide us with novel targets for therapeutic and prophylactic intervention

  6. . . . . . Pathological specimen(circa 1918) Gene sequencing Gene reconstruction Reverse genetics Phenotypic characterization in: Tissue culture Animal models Signatures of Virulence of the 1918 Influenza Virus

  7. 1918 Influenza AFIP Lung Block

  8. Brevig Mission, AK Lung Tissue Sample (1918)

  9. Reconstruction of 1918 InfluenzaVirus Genes Clone, Sequence and Repair Final Product

  10. Plasmid-only InfluenzaA Virus Rescue Protein expression plasmids vRNA expression plasmids PB2 PB2 POL II pA POL I R PB1 PB1 POL II pA R POL I PA PA POL II pA POL I R NP HA pA POL II POL I R NP POL I R NA POL I R M POL I R NS-1918 POL I R Transfection 6:2 reassortant virus

  11. Tx/91:PB2, PB1, PA, NP, M, NS 1918:HA, NA Tx/91:PB2, PB1, PA 1918:HA, NP, NA, M, NS Texas/36/91 >6 4.75 5.5 1918 “Spanish” flu Mouse Lethal Dose 50 (log) of Viruses Bearing 1918 Genes MLD50?

  12. Plasmid-only Influenza A Virus Rescue vRNA expression plasmids Protein expression plasmids PB2 PB2-1918 POL II pA POL I R PB1 PB1-1918 POL II pA POL I R PA PA-1918 POL II pA POL I R NP HA-1918 POL II pA POL I R NP-1918 POL I R NA-1918 R POL I M-1918 POL I R NS-1918 POL I R Transfection Spanish flu

  13. Influenza A/CDC/1918 Virus

  14. 1918 7:HA Tx/91 Tx/91 1918 Intranasal Inoculation of Mice, 106 pfu Viral titers in lungs, day 4 105 pfu 100 103 pfu 80 % Survival 1918 5:3 Tx/91 60 106 pfu 108 pfu 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Days after infection

  15. 1918 Tx/91:HA >6 Virulence of the 1918 Virus:MLD50 Log pfu Tx/91:PB2, PB1, PA, NP, M, NS 1918:HA, NA Tx/91:PB2, PB1, PA 1918:HA, NP, NA, M. NS Texas/36/91 4.75 >6 5.5 1918 “Spanish” flu 3.3

  16. 1918 Tx/91:HA >7 Virulence of the 1918 Virus: ELD50 Log pfu Tx/91:PB2, PB1, PA, NP, M, NS 1918:HA, NA Tx/91:PB2, PB1, PA 1918:HA, NP, NA, M. NS Texas/36/91 >7 >7 >7 1918 “Spanish” flu 1.5

  17. The 1918 Virus Grows to High Titers inHuman Bronchial Epithelial Cells (Calu-3) 1918 Tx/91 1918 5:3 Tx/91 Log EID50/ml Time (h post-infection)

  18. The 1918 NA Allows GrowthWithout Trypsin

  19. Oseltamivir Protects Mice from a Lethal Challenge with 1918 HA/1918 NA Virus Percent Survival

  20. Rimantadine Protects Mice from a Lethal Challenge with 1918 M Virus Percent Survival

  21. 1918 HA/NA Sw/Iowa/30 PR8/34 Texas/91 New Cal/99 X-31(H3N2) PBS Protective Killed Inactivated Vaccines Against the 1918 HA/1918 NA Virus 100 80 60 % Survival 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Days post-challenge with 1918HA/NA virus

  22. 1918 VIRUSWhat do we know now? • The 1918 virus is the only known human influenza virus lethal to mice and embryonated eggs • The glycoprotein and polymerase genes of the virus contribute to enhanced virulence • Alveolar macrophages and neutrophils have a protective role • A single amino acid change in HA changes receptor specificity • Viruses containing 1918 genes are sensitive to existing antivirals • H1N1 based vaccines are protective Would a 1918-like HIN1 virus be todayas lethal as in 1918?

  23. 3000 H1N1 pre-existing immunity 2500 2000 1500 1000 500 0 1918 Influenza and Pneumonia Deaths by Age Specific Death Rate <1 1 to 4 5 to 14 15- 24 25- 34 35- 44 45- 54 55- 64 65- 74 75- 84 >85 Age Divisions

  24. Potential Ways to Fight a Highly Virulent 1918-like Pandemic Virus • The existing antivirals and conventional vaccines will have beneficial effects (with the caveat that it will be difficult to have these products generated in large quantities at this moment) • Consider HA and polymerase genes as targets for new antivirals • Consider strategies that immunoregulate function of alveolar macrophages

  25. Alicia Solorzano Luis Martinez Patricia Aguilar John Kash Laurel Glaser Dmitriy Zamarin Stacey Schultz-Cherry Hui Zeng Jacqueline Katz Nancy Cox NIAID Biodefense Grants P01 AI58113 U54 AI57158 (NBC) U19 AI62623 (CIVIA)

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