Planning for Respiratory Pandemics. Michael G. Ison, MD MS. Viruses in May

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1 Planning for Respiratory Pandemics Michael G. Ison, MD MS Divisions of Infectious Diseases & Organ Transplantation Transplant Infectious Diseases Service Northwestern University Comprehensive Transplant Center Viruses in May Carrington Hotel Katoomba, NSW May 12, 2011

2 Disclosures Research Support ADMA, Adamas*, BioCryst*, Chimerix, GlaxoSmithKline*, Roche*, ViraCor Paid Consultation Abbott*, Abbott Molecular*, Astellas*, Biogen Idec, Crucell*, ViraCor* Unpaid Consultation BioCryst*, Biota*, Cellex*, Clarassance*, GlaxoSmithKline*, MP Bioscience, NexBio*, Roche*, Toyama*, T2 Diagnostics Data & Safety Monitoring Board Participation Chimerix, NexBio* As of 5/6/11; Paid to Northwestern University; *Related to topic.

3 Planning for Respiratory Pandemics Influenza Pandemics Over the Past Century Lessons Learned from the 2009 H1N1 Influenza Pandemic Epidemiology Interventions Gaps in Our Current Knowledge Addressing Future Pandemics Surveillance Prevention: Vaccines, Antivirals, & Others Treatment

4 History of Influenza Pandemics Simonsen et al. J Infect Dis. 1998; 178:

5 Influenza: Epidemics & Pandemics Hemagglutinin Drift H1 N1 H1 Shift N1 Neuraminidase H1 N3

6 Influenza: Epidemics & Pandemics Hemagglutinin Drift H1 N1 H1 Shift N1 Neuraminidase H1 N1*

7 Swine-Origin Influenza A/H1N1 Garten et al. Science. 2009; 325:

8 Influenza Antigenic Mapping Smith et al. Science. 2004; 305:

9 Risk Factors with 2009 Pandemic Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. N Eng J Med. 2010;362:

03) School Transmission Each student infects 2.4 others (94% CI 1.8 3.

10 Influenza: Transmissibility Household Transmission Mean time: 2.6 days Relative susceptibility 18 yo: 1.96 (p = 0.005) 50 yo: 0.17 (p = 0.03) School Transmission Each student infects 2.4 others (94% CI ) R 0 Estimates: 2009 H1N1: H1N1: Cauchemez S et al. N Engl J Med. 2009;361: Yang et al. Science. 2009; 326:

11 2009 H1N1 in ICU (Winnepeg) 1. Viral Pneumonitis: Rapidly progressive diffuse bilateral infiltrates very severe requiring advanced ventilatory techniques and 100% oxygen with marked predilection for young (10-50 yrs); these represent 75-80% of adult cases 2. Severe COPD or athsma exacerbation lasts for weeks, CXR clear 3. Severe bacterial pneumonia complicating H1N1 lobar or bronchopneumonia Typically S. pneumoniae or S. aureus ± septic shock 4. Destabilization of chronic disease (CHF, CRF, cardiopulmonary disease, coronary syndromes, diabetes) CXR variable; do well clinically Kumar et al. JAMA. 2009; 302:

12 Radiologic Findings Personal Communications: A. Kumar, Winepeg

13 Influenza: Pathogenesis Great genetic stability (to date) Replication Efficient in respiratory tree Documented replication in the GI tract of ferrets with nasal infection Possible replication in other sites Viremia appears to be rare

14 Characteristics of 2009 H1N1 Kumar et al. JAMA. 2009; 302:

15 Characteristics of 2009 H1N1 Jain et al. N Eng J Med. 2009; 361:

16 Characteristics of 2009 H1N1 Kumar et al. JAMA. 2009; 302:

17 Influenza Mortality: Trends Over Time Fiore et al. MMWR. 2010; 59: 1-47.

18 Gaps in Knowledge Global capacity for detection of influenza viruses by molecular methods Burden and character of disease in low-resource settings Significant differences in resource utilization and types of patients severely affected Understanding of mechanisms of viral transmission Pathogenesis of disease Genetic and other host factors related to susceptibility Optimal use of antivirals and antibiotics Messaging with changing information Conducting meaningful research Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. N Eng J Med. 2010;362:

Sorbello et al. 50 th ICAAC, Boston, MA, Sept. 13, 2010, Abstract V-658. Hernandez et al., Clin Infect Dis. 2011; 52 : 695-706.

19 Sorbello et al. 50 th ICAAC, Boston, MA, Sept. 13, 2010, Abstract V-658. Hernandez et al., Clin Infect Dis. 2011; 52 : Use of IV Peramivir in the US during the 2009/10 Pandemic Period Number of Subjects Dose regimen Individual emergency IND requests (May Oct 2009) FDA Emergency Use Authorization (EUA) Oct Jun 2010 * 2 request withdrawn or documentation not received eind Population 42 requests 31 peramivir administered mg / day 5-14 days 1, mg / day 5-10 days 9 peramivir not administered 5 Died before peramivir could be administered 7 Died 4 Alive improved before peramivir administered 14 day survival 24 Alive

20 Vaccines Treanor. NEJM. 2004; 351:2039.

21 Available Vaccines Fiore et al. MMWR. 2010; 59: 1-47.

22 Inactivated Influenza Virus Vaccine Content updated yearly; approved 6mo Grown in chicken eggs and formalin inactivated With or without adjuvants Efficacy Vaccination of pregnant women may protect infants Varies with age and immunocompetence Depends on match between projected vs actual strains Elderly: 70-90% effective, 30-70% effective against admissions to the hospital NH Elderly: 23-40% effective, 45-60% effective against admit; 60% effective in preventing death Harper et al. MMWR. 2005;54 (RR8). Jefferson et al. Lancet. 2005;366: ;

23 Fluzone High-Dose in 65 yo Falsey et al. J Infect Dis. 2009;200:

24 Live Attenuated Influenza Vaccine Cold-adapted, temperature-sensitive Shed virus for 2 days, low titers Only 1 case of documented transmission Possible advantages Muscosal immune response Cross reactivity to other strains Approved for HEALTHY 2-49 yo Contraindications: Underlying medical conditions, history of GBS, pregnant women, patients chronically on aspirin Immunocompromised patients Fiore et al. MMWR. 2010; 59: 1-47.

25 Influenza Replication & Antiviral Targets a. b. c. HA Mediated Binding Release of RNPs from endosome Viral polymerase 5 Capping o Critical for viral cap snaching Unprimed replication -RNA > +crna > -RNA d. e. f. Translation, processing, and glycosylation of viral proteins NS1 inhibition of host mrna M1/NS2 export of vrnp Mediated by human CRM1 g. Budding of new viruses Das et al. Nat Struc Mol Biol. 2010; 17:

Hemagglutinin Antibodies Head Responsible for binding to sialic acids Most current vaccines affect the head Region of significant mutations resulting in drift variants Base Responsible for

26 Hemagglutinin Antibodies Head Responsible for binding to sialic acids Most current vaccines affect the head Region of significant mutations resulting in drift variants Base Responsible for conformational changes that brings the virus in proximity to cell Multiple antibodies have been generated that bind and prevent this conformational change Typically limited binding to type 1 or type 2 HA only (not both) Small Molecules TBHQ Tetra-butylhydroquinone Inhibits low ph confirmation change Only present in type 2 HAs Das et al. Nat Struc Mol Biol. 2010; 17:

positions: 26, 27, 30, 31, or 34 Retain pathogenicity & transmissibility Cross-resistance to all

27 M2 Ion Channel Spectrum: Influenza A ONLY Available Compounds: Amantadine (100mg BID) Rimantadine (100mg BID) Resistance Frequently (30-60%) develops during therapy Secondary to changes at positions: 26, 27, 30, 31, or 34 Retain pathogenicity & transmissibility Cross-resistance to all other M2 inhibitors Hayden. NEngJMed. 2006; 354: Das et al. Nat Struc Mol Biol. 2010; 17:

29 M2 Inhibitor Resistance: Impact Virus M2 Resistance Predominant Mutation Seasonal H1N1 Rare Pandemic H1N1 99.7% S31N Seasonal H3N2 ~100% S31N H5N1 Clade 1 ~100% S31N H5N1 Clade % S31N or V27A H5N1 Clade 2.2 Rare H5N1 Clade 2.3 Rare Ison MG. Therapy. 2009; 6: : Accessed 2/15/10.

30 Nucleoprotein Encapsidates the ss-rna Import of vrna into nucleus Export of vrna from nucleus Effects capping of viral mrna Das et al. Nat Struc Mol Biol. 2010; 17:

Viral Polymerase PA Subunit Endonuclease activity Req for viral mrnas Small molecule inhibitors developed Protease activity vrna/crna promotor binding PB1 Subunit PB2 Subunit Binds 5 cap of pre-mrna

31 Viral Polymerase PA Subunit Endonuclease activity Req for viral mrnas Small molecule inhibitors developed Protease activity vrna/crna promotor binding PB1 Subunit PB2 Subunit Binds 5 cap of pre-mrna Inhibition likely to be toxic as similar in host Cleaves phosphodiesterase bonds downstream from the 5 cap Initiates transcription from the viral mrna at the cleaved 3 end of the cap Das et al. Nat Struc Mol Biol. 2010; 17:

Nonstructural Proteins Inhibits IFN-α/β 2-5 -oligo A synthetase/ RNase L Inhibitor of this effect has been developed and inhibits replication Inhibits cellular proteins that would otherwise prevent

32 Nonstructural Proteins Inhibits IFN-α/β 2-5 -oligo A synthetase/ RNase L Inhibitor of this effect has been developed and inhibits replication Inhibits cellular proteins that would otherwise prevent viral replication Phosphatidylinositol-3-kinase Protein kinase R Cleavage and Poly-A specificity factor (CPSF30) which inhibits IFN-β production Zinc finger 3 mimic molecules inhibit this function and viral replication Das et al. Nat Struc Mol Biol. 2010; 17:

33 Neuraminidase 5 µm 5 µm 1 µm Moscona. NEngJMed. 2005;353:

34 Bantia et al. Antiviral Res. 2006; 69: Peramivir Investigator Brochure V.4 Jul 2009; oseltamivir, zanamivir & laninamivir package inserts. Available & Investigational NAIs Peramivir Zanamivir (Relenza ) Oseltamivir (Tamiflu ) Laninamivir (Inavir ) Structure: Dosing frequency 600mg QD 5-10 days 10mg BID 5 days 75mg BID 5 days 40mg Single dose Route of administration Parenteral Inhaled Oral Inhaled

35 In vitro Susceptibility Data: Oseltamivir, Peramivir, & Zanamivir Viral neuraminidase IC 50 [nm] (Chemiluminescence Assay) Influenza A/pH1N1, N = 204 P < zanamivir oseltamivir peramivir Viral neuraminidase IC 50 [nm] (Chemiluminescence Assay) A/H3N2, N = 59 Peramivir Oseltamivir Zanamivir Viral neuraminidase IC 50 [nm] (Chemiluminescence Assay) Influenza B, N = 32 Peramivir Oseltamivir Zanamivir Viral neuraminidase IC 50 [nm] (Chemiluminescence Assay) Influenza A/H5N1, N = 9 Peramivir Oseltamivir Zanamivir Boivin et al. Antiviral Res. 2002; 54 : Gubareva et al. AAC. 2002; 45 : Bantia et al. AAC. 2001; 45 : Goborkova et al. AAC. 2002; 45 : BCX

36 Antibody-Based Interventions Hung et al. Clin Infect Dis. 2011;52:

37 What About the Next Pandemic? Virus Type A novel virus strain H5N1, H7N1, H9N2... An Animal Strain of Current Viruses H1N1, H3N2 Recycling of Prior Viruses H2N2 Severity Same as seasonal? Significantly worse (1918)?

38 Avian H5N1 Influenza As of 8/31/10.

39 Avian H5N1 Animal Distribution As of 9/10/07.

40 Confronting Future Pandemics Surveillance Prevention Vaccines Antivirals Others Interventions Treatment Antivirals Antibacterials Immune Modulators

41 Questions? Michael G. Ison, MD MS I am a registered organ donor! Are you?

Flu, Avian Flu and emerging aspects (H1N1 resistance)

EU-CIS Seminar New trends in Infectious Diseases 26 28 November 2008 / Lyon, France Flu, Avian Flu and emerging aspects (H1N1 resistance) Pr. Florence MORFIN FRE 3011 Université Lyon 1 - CNRS Laboratory