Pandemic Influenza: A Zoonotic Infection. Kathleen M. Neuzil, MD, MPH PATH University of Washington School of Medicine April 28, 2008

Transcription

1 Pandemic Influenza: A Zoonotic Infection Kathleen M. Neuzil, MD, MPH PATH University of Washington School of Medicine April 28, 2008

2 Questions What is the epidemiology of human influenza? What is the role of animals in influenza epidemiology? When do we worry about a pandemic?

3 Excess mortality: Hallmark of epidemic influenza 1837: Robert Graves, Dublin. 1847: William Farr, London : Selwyn Collins, USA.

4 Influenza 1918: The route of Victoria Story begins in Seattle, October Passengers and mail aboard Victoria for distribution to Alaskan camps and villages via dog team. Three passengers removed from the ship in Seattle due to influenza. Victoria was 9 days en route to Nome; arrived October 20, Crew was quarantined upon arrival; but mail dispersed to outlying communities 12 hours after the ship s arrival. Ganley. Circumpolar Health 1996; 247. The Victoria pulls away from the slip between Pier 2 and Colman Dock, Seattle, WA. (Courtesy of Seattle Times, March 18, 2007.)

5 Reconstructed routes of virus dispersal, Seward Peninsula, Alaska

6 By January 1, 1919, 35 to 40% of the native population along Seward peninsula had died

7 Teller Mission, Alaska: 1918 Influenza spread through the village in 5 days. Killed 72 people (85% of the adult population). Victims buried in mass grave in permafrost.

8 Teller Mission, Alaska: 1997 Four victims exhumed; in situ lung biopsy. Tissue: massive pulmonary hemorrhage (bleeding into lung) and edema (swelling of lung). Influenza RNA isolated and sequenced (A/Brevig Mission/1/18/H1N1). Reid et al. Proc Natal Acad Sci 1999; 96: Taubenberger JK et al. Science 1997; 275: 1793.

9 Influenza: An epidemic respiratory disease associated with excess deaths

10 Hunt up your wood-workers and cabinet-makers and set them to making coffins. Then take your street laborers and set them to digging graves. If you do this you will not have your dead accumulating faster than you can dispose of them. Amer J Public Health 1918; 8: 787.

11 20th Century Influenza Pandemics

12 Influenza pandemics: Mutations of animal viruses, or viral reassortants 1918 Spanish (H1N1) 1957 Asian flu (H2N2) 1968 Hong Kong (H3N2) 1977 Russian (H1N1) Avian mutated H1N1 Human H1N1 Avian H2N2 Human H2N2, avian H3Nx Virus identical to human strains million deaths H1N1 disappeared H2N2 disappeared Benign H1N1, H3N2 circulate

13 Surface antigens of the Influenza A virus Hemagglutinin Neuraminidase M2

14 PB2 PB1 NS PA HA NA M NS PB2 PB1 NS PA HA NA M NS Epidemic human virus A(H2N2) Avian virus A(H3N?) 1968 Pandemic New epidemic virus A(H3 H3N2) PB2 PB1 NS PA HA NA M NS Steinhoff MC. Epid and Prev of Influenza. In: Infectious Dis Epidemiology. Nelson et al.

15 Incidents with limited spread before Swine flu H1N1 NJ: Enzootic in swine herds H1N1 Netherlands: Swine virus from avian source Swine flu H1N1 Wisconsin: Swine virus H3N2 Netherlands: Swine human H3N2, avian H1N2. One death in military camp. One adult with severe pneumonia. Pregnant woman died. Two children; mild disease H7N7 UK: Duck virus. One adult conjunctivitis.

16 H5N1 Where did it start? 1996: First detected in geese in Guangdong Province, China. 1997: First recognized in humans: Hong Kong,18 human cases, 6 fatal. H5N1 viruses isolated from birds at wholesale and retail markets in Hong Kong. No further cases following widespread culling of chickens.

17 Avian Influenza A (H5N1) outbreak in humans Vietnam, Thailand, Cambodia 55 cases, 42 deaths Predominantly children and young adults. Rural Asia: Households maintain free-ranging poultry for income, food. Children play near poultry; families slaughter birds for food. Pathogenesis: high and disseminated viral replication and intense inflammatory response. N Engl J Med 2005: 353; 25 N Engl J Med 2004; 350: 1179

18 H5N1: How did it spread? 1997-May 2005: largely confined to SE Asia. Infected wild birds in Qinghai Lake, China; rapidly spread westward. Death of swans and geese marked spread into Europe, India and Africa. Ducks may be stealth carriers. Wild mallard ducks do not always show signs of disease when infected with highly pathogenic H5N1 viruses. N Engl J Med 2006; 355: 2174

19 Avian Influenza A (H5N1) human infections: Country Cases Deaths Azerbaijan 8 5 Cambodia 7 7 China Djibouti 1 0 Egypt Indonesia Iraq 3 2 Lao PDR 2 2 Nigeria 1 1 Thailand Turkey 12 4 Vietnam TOTAL Who is not on this list? As of April 16,

20 Avian Influenza A (H5N1) human infections: Country Cases Deaths Azerbaijan 8 5 Cambodia 7 7 China Djibouti 1 0 Egypt Indonesia Iraq 3 2 Lao PDR 2 2 Myanmar 1 0 Nigeria 1 1 Pakistan 1 1 Thailand Turkey 12 4 Vietnam TOTAL Who is not on this list? As of April 2, 2008 (

21 Why is H5N1 of particular concern? Mutates rapidly, acquires genes from viruses infecting other species. H5N1 clades and subclades differ in antigenic structure. Direct transmission from birds to humans. Causes severe disease in humans. Acquisition of drug resistance on therapy. Increasing numbers of human clusters. Environmental resistance.

22 Risk ractors for Avian Influenza Exposure to live poultry. Exposure to ill poultry and butchering of birds (NOT culling). Direct contact with poultry (plucking, preparing diseased birds; handling fighting cocks; playing with poultry; consumption of duck s blood; possibly undercooked poultry). WHO. NEJM 2005; 353;13.

23 H5N1: Human-to-human transmission? Infection after close contact with infected child leading to illness and death. Evidence of antibodies to H5 in health care workers who cared for patients in Hong Kong in Intensified surveillance (PCR) with contacts has led to detection of mild cases, more infections in older adults, and increased numbers of family clusters in Vietnam. Family clusters in Indonesia. NEJM 2005; 353;13. NEJM 2006; 355: 2186.

24 Environment-to-human transmission? Theoretical given survival of H5N1 in environment. Oral ingestion of contaminated water during swimming? Contamination of hands from infected fomites and subsequent self-inoculation? Poultry feces used as fertilizer? WHO. NEJM 2005; 353;13.

25 WHO: Pandemic alert Influenza A virus with a novel HA or novel HA and NA substantial proportion of the population has little or no antibody to the novel virus. Novel virus demonstrates ability to cause disease in humans. Novel virus demonstrates ability to spread easily among humans.

26 So H5N1 is a novel virus with ability to infect and cause disease in humans Limited human to human transmission at present Total number of cases small; case fatality rate high Exposure and risk of future cases increasing with increasing spread of virus among birds Is avian influenza worth the investment of resources, and if so, what can/should be done?

27 How do we determine the burden of illness during annual influenza epidemics? probably the most under-rated major pathogen in the developed world one of the major infectious causes of death from a single microorganism. John Bartlett Update in Infectious Diseases Annals of Internal Medicine August 1999

28 Impact of Influenza, U.S. More than 20,000 excess deaths per typical epidemic >90% of deaths in persons >65 years 110,000 or more excess hospitalizations ($600 million direct costs) Severe epidemic costs $12 billion

29 So what should be done, pre-pandemic (now!)? Improve surveillance worldwide. All types of influenza. All types of respiratory disease. Easier, more reliable, less expensive diagnostics. Year-round surveillance. Clinical research on human cases/ populations.

30 Reduce opportunities for human infection Education about human behaviors. Control spread in birds/animals (collaboration between animal and public health sectors). Improve approaches to environmental detection of virus.

31 General emergency preparedness Clearly-defined plans, leadership structure. Responsibility/accountability. Communications. Surge capacity Mass delivery mechanisms for drugs/vaccines/health services. Stockpiles of essential medical supplies. Table-top exercises.

32 February 8, 2007

33 Preventing/minimizing morbidity and mortality Pandemic vaccines Supplies, equitable access, developing country manufacturers, novel ways to use less antigen (make limited supply go further). Antivirals International stockpiles, supplies, equitable access, developing country manufacturers, international clinical trials networks. Community mitigation strategies Quarantines/border or school closures.

34 Flu vaccine supply: Inadequate, inequitable >95% of world flu vaccine comes from 9 countries 4 European companies produce 65% of world supply Fedson DS. Vaccine Development for an Imminent Pandemic. Human Vaccines 2006: 2(1) Dennis C. Flu-vaccine makers toil to boost supply. Nature 440:1099. Apr 2006.

35 Influenza vaccines landscape analysis: Key findings The global need for a pandemic vaccine is an estimated 7 billion courses. Planning for the availability of a pandemic vaccine should envision at most a six-month time horizon, and likely shorter. Should an outbreak of pandemic influenza occur today, the best case scenario within this timeframe is that 1.2 billion courses of pandemic vaccine could be produced from current capacity within six months. In the short term, new adjuvants could facilitate dose sparing but in the long term, new innovative technologies that could increase global supply are needed. Proposal approved to advance promising new pandemic flu vaccines into development.

36 Near term strategy: Is real-time response viable? Real time response is not a viable solution in the near-term since existing infrastructure would only serve a small portion of the world s population within 6 months of outbreak. Real-time Global Pandemic Capacity Best Case 7.0 B Global Demand = 6.8B 6.0 B Pandemic Courses Filled in 6 Month Timeframe 5.0 B 4.0 B 3.0 B 2.0 B 1.0 B 1.2 B 1.2 B 1.8 B 1.9 B 2.0 B 2.0 B 2.8 B 0.0 B Availability Timeframe for Global Need ~2yrs ~2yr ~1.4yrs ~1.3yrs ~1.3yrs ~1.3yrs ~1yr

37 Longer term strategy: Which technology? Live and recombinant technologies are the most cost-effective for pandemic production. Index of Manufacturing Costs (Per Course) Cost per course indexed to Egg Inactivated 1, , Egg Inactivated Cell Inactivated Egg Inactivated Cell Recombinant w / adj Inactivated w/ adj Egg Live Cell Live Recombinant w / adj High Cost Medium Cost Low Cost

38 Summary H5N1 is highly pathogenic and has crossed the species barrier to cause many human fatalities and pose an increasing pandemic threat. Yearly influenza epidemics are associated with substantial morbidity and mortality; impact in developing countries uncertain, but likely substantial. Investment in pandemic preparedness can yield more immediate health gains.