Avian Influenza: Potential for a Pandemic : Avian Influenza: Potential for a Pandemic Richard Danila, Ph. D., M.P.H. Minnesota Department of Health


Influenza Pandemics in the Twentieth Century: Influenza Pandemics in the Twentieth Century 1918-1919 “Spanish Influenza” 1957 “Asian Influenza” 1968 “Hong Kong Influenza”


Influenza Pandemic of 1918-1919: Influenza Pandemic of 1918-1919 20% of the world’s population infected 20-40 million people died from influenza Highest mortality in people ages 20-40 yrs 675,000 Americans died of influenza 43,000 serviceman died of influenza


Influenza Pandemic of 1918-1919: Influenza Pandemic of 1918-1919 “I had a little bird, Its name was Enza. I opened the window And in-flu-enza” Children’s rhyme, 1918


Influenza Epidemiology: Influenza Epidemiology Respiratory infection Spread through direct contact and indirect contact with respiratory (large) droplets, some component of (small particle) airborne spread Most infectious 24 hours prior to onset of symptoms and during first 7 days of symptoms Incubation period: 1 to 5 days Seasonality: October through April in North America High attack rates among school-aged children (10-40%) during community outbreaks


Influenza Vaccine: Influenza Vaccine Up to 90% effective in preventing clinical illness in young, healthy adults 30%-40% effective in preventing illness among frail elderly 50%-60% effective in reducing hospitalization Up to 75% effective in preventing death


Antivirals: Antivirals Adamantanes: interfere with viral uncoating inside the cell, influenza A Amantadine: treatment and prophylaxis > 1y Ramantadine: treatment > 13 y, prophylaxis > 1 year Neuraminadase inhibitors: Interferes with release of progeny virus from infected host cells, influenza A and B Oseltamivir: treatment and prophylaxis > 1 y Zanamivir: treatment > 7 y


Influenza Virus Composition: Influenza Virus Composition hemagglutinin neuraminadase A/Beijing/32/92 (H3N2) Virus type Geographic origin Strain number Year of Isolation Virus subtype


Influenza Types (Core Proteins): Type A Antigenic shift and drift Epidemics and pandemics Humans and other animals 15 H and 9 N antigens Type B Antigenic drift Milder epidemics Humans Influenza Types (Core Proteins) Type C Antigenic drift No epidemics Mild disease Humans (rarely) and swine


Influenza Antigenic Changes: Influenza Antigenic Changes Continuous antigenic drift: point mutations in gene, same subtype Allows “new” virus to evade immunity Prior antibody provides partial protection May result in an epidemic Shift: major change Exchange of gene segment resulting in new subtype (reassortment), or adaptive mutation resulting in a major antigenic change No immunity; may result in a pandemic


Re-assortment: Re-assortment Pigs are susceptible to both avian and human influenza Pandemics may arise by re-assortments between avian viruses which provide novel glycoproteins, and human viruses which provide genes allowing efficient replication Avian H3 Human H2 Human H3


Re-assortment: Re-assortment People can be the “mixing bowl” in which an avian strain can re-assort with a human influenza strain resulting in a new strain which is immunologically novel and readily transmissible


Adaptive Mutation: Adaptive Mutation Avian strain can evolve to become more more efficient as a human pathogen 1918 strain H1N1 evolved from an avian virus Picture: JAMA 2005; 294:2416. Article. Tumpey, et al. Science 2005; 310: 77


Avian Influenza: Avian Influenza


Avian Influenza : Avian Influenza Birds of all species thought to be susceptible Two forms Low pathogenic: ruffled feathers, reduced egg production High pathogenic: extremely contagious, rapidly fatal


Bird-to-Human Transmission: Bird-to-Human Transmission Predominantly via contact with manure Handling chickens Disposing of dead chickens Walking through live poultry markets


Transmission in Birds: Transmission in Birds Large amounts of virus are secreted in bird droppings, contaminating dust and soil Mechanical vectors: farm equipment, shoes Migratory birds can spread the disease from country to country Wild ducks are a natural reservoir


Confirmed Cases of Avian to Human Transmission of Influenza A, 1995-2004 (excluding 2004-6 H5N1): Confirmed Cases of Avian to Human Transmission of Influenza A, 1995-2004 (excluding 2004-6 H5N1) * Documented human to human transmission


Current H5N1 Outbreak: Current H5N1 Outbreak


Current H5N1 Outbreak (cont.): December 17, 2003: deaths in poultry reported from Korea (onset Dec 12) January 5, 2004: WHO notified of pediatric respiratory deaths (first 5 cases 10/31-12/30 no samples available) January 11: H5N1 identified in Vietnam human cases Current H5N1 Outbreak (cont.)


Current H5N1 Influenza : Current H5N1 Influenza Found in birds in 48 countries in Asia, Europe, and Africa Found in pigs (China), felines (Thailand) and civets (Vietnam)


Human H5N1 Cases (December 2003 – April 21, 2006): Human H5N1 Cases (December 2003 – April 21, 2006) Thailand 22 confirmed cases; 14 deaths Vietnam 93 confirmed cases; 42 deaths Cambodia 6 confirmed cases; 6 deaths Indonesia 32 confirmed cases; 24 deaths China 17 confirmed cases; 12 deaths Turkey 12 confirmed cases; 4 deaths Iraq 2 confirmed cases; 2 deaths Azerbaijan 8 confirmed cases; 5 deaths Egypt 12 confirmed cases; 4 deaths Total: 204 confirmed cases; 113 deaths


Human H5N1 Cases (cont.): Human H5N1 Cases (cont.) Genes of avian origin by viral sequencing Sequencing indicates resistance to amantadine and rimantadine Oseltamivir and zanamavir thought to be effective Mouse model indicated higher dose and longer duration of oseltamivir may be required Several isolates from human cases resistant to oseltamivir Yen. J Inf Dis 2005; 192:665 Le. Nature 2005; 437: 1108 De Jong. N Eng J Med 2005; 353: 2667


H5N1 Influenza: First 10 Human Cases in Vietnam: 5 – 24 years (mean 13.7 years) Poultry exposure 2 – 4 days prior to symptom onset, 3 – 8 days of symptoms prior to hosp. Fever (38.5 – 40 C) in all SOB, cough in all Chest x-ray abnormalities in all (extensive bil. infiltrates, lobar collapse, focal consolidation, air bronchograms) 7 had diarrhea Lymphopenia, thrombocytopenia 8 died Hien. N Eng J Med 2004; 350: 1179-88 H5N1 Influenza: First 10 Human Cases in Vietnam


Person-to-Person Transmission: Person-to-Person Transmission 11 y/o girl died from viral pneumonia (had lymphopenia, thrombocytopenia, lobar consolidation) Played and slept in area where there were sick/dead chickens 26 y/o mother who had no exposure to poultry (lived in Bangkok), took care of sick daughter 16-18 hours, unprotected exposure to oral secretions Developed symptoms 3 days later Died from viral pneumonia 10 days after symptom onset (had lymphopenia thrombocytopenia, bilobar consolidation)


Person-to-Person Transmission: Person-to-Person Transmission 32 y/o aunt, care provider for girl Chicken exposure weeks-days prior to girl’s illness Cared for girl 12 hours in hospital prior to mother Developed symptoms 9 days later (17 days after poultry exposure) Developed respiratory distress 7 days after symptom onset (lymphopenia and lobar consolidation) Recovered and discharged after 14 days H5N1 identified by PCR on throat swab H5N1 identified by PCR on fixed lung tissue on mother Ungchusak. N Eng J Med 2005; 352-333-40


Environmental Stability H5N1: Environmental Stability H5N1 Ducks infected in 2003 shed virus for maximum of 10 days Ducks in 2004 typically shed for 11 days and some for >17 days 1997 strains survived at 37°C for 2 days 2004 survived at 37°C for 6 days WHO October 2004


CDC Recommendations: H5N1: CDC Recommendations: H5N1 Testing for influenza A (H5N1) is indicated for hospitalized patients with: a. Radiographically confirmed pneumonia, acute respiratory distress syndrome, or other severe respiratory illness for which an alternate diagnosis has not been established, AND b. History of travel within 10 days of symptom onset to a country with documented H5N1 avian influenza in poultry and/or humans


CDC Recommendations: H5N1 (cont.): CDC Recommendations: H5N1 (cont.) Testing for influenza A (H5N1) should be considered on a case-by-case basis in consultation with state and local health departments for hospitalized or ambulatory patients with: a. Documented temperature of >38°C (>100.4°F) AND b. One or more of the following: cough, sore throat, shortness of breath AND


CDC Recommendations: H5N1 (cont.): CDC Recommendations: H5N1 (cont.) c. History of contact with domestic poultry (e.g., visited a poultry farm, household raising poultry, or bird market) or a known/suspected human case of influenza A (H5N1) in an H5N1-affected country within 10 days of symptom onset


Infection Control: H5N1: Infection Control: H5N1 Airborne plus eye protection, Contact and Standard Precautions Do not attempt viral isolation (BSL3+) antigen detection: BSL2 PCR: BSL2 with class II biosafety cabinet Isolation continued for 14 days after onset of symptoms


Avian Influenza Vaccines for Humans: Avian Influenza Vaccines for Humans Highly pathogenic H5 and H7 difficult to use in chick embryos Regulatory and safety issues H5 and H9 appear to be less immunogenic in humans Approaches: inactivated vaccine, antigenically related non-pathogenic strains, baculovirus expressed recombinant hemagglutinin, plasmid based reverse genetics systems to generate a non-pathogenic seed strain Use of adjuvants to enhance immunogenic responses Use of mammalian cell lines rather than chick embryos


WHO Recombinant H5N1 Prototypes for Vaccine Development: WHO Recombinant H5N1 Prototypes for Vaccine Development A/Vietnam/1194/04 A/Vietnam/1203/04 A/Hongkong/213/03


Progress on H5N1 Vaccines: Progress on H5N1 Vaccines HHS contract with Sanofi-Pasteur (9/21/04) to produce 2 million doses Clinical trials of 8000 doses began spring 2005 HHS contract with Sanofi-Pasteur (9/15/05) -$100,000,000 to produce more vaccine HHS contract with Chiron Clinical trials spring 2005 Canada contracting with ID Biochemical, Quebec Clinical trials using adjuvents (“antigen sparing strategy”) Sinovac, China in “preclinical” phase development with seed virus


Preparing for Pandemic Influenza: Preparing for Pandemic Influenza


Criteria Needed for Pandemic Influenza: Criteria Needed for Pandemic Influenza Novel strain of virus Little to no immunity in the general public Virus causes disease The “novel” virus spreads from person-to-person throughout multiple countries and continents


Pandemic Influenza Stages: Pandemic Influenza Stages Interpandemic Period Phase 1: No new influenza virus subtypes have been detected in humans Phase 2: No new influenza virus subtypes have been detected in humans; however, a circulating animal influenza virus subtype poses a substantial risk of human disease


Pandemic Influenza Stages (cont.): Pandemic Influenza Stages (cont.) Pandemic Alert Period Phase 3: Human infection(s) with a new subtype but no human-to-human spread or at most rare instances of spread to a close contact Phase 4: Small cluster(s) with limited human-to-human transmission but spread is highly localized, suggesting that the virus is not well adapted to humans


Pandemic Influenza Stages (cont.): Pandemic Influenza Stages (cont.) Phase 5: Larger cluster(s) but human-to-human spread is still localized, suggesting that the virus is becoming increasingly better adapted to humans but may not yet be fully transmissible (substantial pandemic risk) Pandemic Period Phase 6: Pandemic phase: increased and sustained transmission in the general population Postpandemic Period Return to the Interpandemic Period (Phase 1)


What Can be Done to Slow the Spread of a Pandemic?: What Can be Done to Slow the Spread of a Pandemic? Vaccine: not expected to be available until later in a pandemic Antivirals insufficient quantities, efficacy unclear Disease containment measures may be the only measures available in the early stages of a pandemic may be helpful in slowing the spread of a pandemic, allowing more time for vaccine production


Rapid Development of Pandemic Influenza Vaccine: Rapid Development of Pandemic Influenza Vaccine Cooperation between WHO, HHS and influenza vaccine manufacturers In 2004 HHS worked with industry to assure year-round supply of eggs, also HHS support of development of cell culture technology Time from identification of a new strain to production, licensure and distribution is 6-8 months Seed virus prepared by public sector and provided to vaccine manufacturers Pandemic vaccine can be monovalent, but will likely need 2 doses


Vaccination Program: Vaccination Program Until vaccine available, antivirals, interventions to decrease transmission and exposure Target to priority groups initially: HCWs, essential public health safety services, certain high risk age groups, persons with high risk conditions However, anticipate shortage of antivirals and use may be limited to treatment Expect that later will have enough vaccine to vaccinate full at-risk population


Disease Containment Measures: Disease Containment Measures Isolation: restriction of movement/separation of ill infected persons with a contagious disease Quarantine: restriction of movement/separation of well persons presumed exposed to a contagious disease Self-shielding: self-imposed exclusion from infected persons or those who may be infected Social distancing: reducing interactions between people to reduce the risk of disease transmission Snow days: days on which offices, schools, transportation systems are closed or cancelled, as if there were a major snowstorm


Other Methods to Reduce Influenza Transmission: Other Methods to Reduce Influenza Transmission Hand hygiene Respiratory hygiene, e.g., “Cover your cough” Cleaning and disinfection of contaminated objects, surfaces Physical barriers (e.g., glass or plastic “windows” to protect front desk workers) Use of personal protective equipment (PPE) in some settings, including: Respirators Gowns Gloves Eye protection


Projected Impact of Pandemic Influenza in Minnesota: Projected Impact of Pandemic Influenza in Minnesota 1,544,000 ill 772,000 outpatient medical care 15,000 - 172,000 hospitalized 2,250 - 25,700 ICU care 1,120 - 12,900 mechanical ventilation 3,600 - 32,900 influenza deaths Outbreak period - 6-8 weeks