ShayNVACpanflu4 20 05

Influenza Pandemics of the 20th Century: 

Influenza Pandemics of the 20th Century David K. Shay Influenza Branch National Center for Infectious Diseases Centers for Disease Control and Prevention

Slide2: 

Influenza: Epidemics and Pandemics Influenza is an annual cause of significant morbidity and mortality: epidemics recognized in temperate areas for many years Unpredictably and at irregular intervals, pandemics associated with increased mortality occur Attack rates approach 40-50% in some populations Criteria for a pandemic influenza virus: novel influenza A strain little or no immunity in population person-to-person transmission with disease

Antigenic Change: 

Antigenic Change Antigenic ‘drift’ occurs in HA and NA Associated with seasonal epidemics Continual development of new strains secondary to genetic mutations A viruses >> B viruses Antigenic ‘shift’ occurs in HA and NA Associated with pandemics Appearance of novel influenza A viruses bearing new HA or HA & NA

Influenza Viruses Infect Several Animal Species: 

Influenza Viruses Infect Several Animal Species All influenza A subtypes recognized to date are found in wild birds Fecal transmission common among wild birds Usually, infections occur without illness Other animal species Domestic poultry (chickens, ducks and quail) Humans, swine, horses, seals, whales Humans usually infected by human influenza viruses

Slide5: 

Circulation of Influenza A viruses in humans in the last century 1918 1957 1968 1977 Spanish Influenza Asian Influenza Hong Kong Influenza H1N1 H2N2 H3N2 H1N1 ? Ag drift Ag shift

Pandemics and Pandemic Threats of the 20th Century: 

Pandemics and Pandemic Threats of the 20th Century 1918-19 “Spanish flu” H1N1 1957 “Asian flu” H2N2 1968 “Hong Kong flu” H3N2 1976 “Swine flu” episode H1N1 1977 “Russian flu” H1N1 1997 “Bird flu” in HK H5N1 1999 “Bird flu” in HK H9N2 2003 “Bird flu” in Netherlands H7N7 2004 “Bird flu” in SE Asia H5N1

Selected patterns among 20th century pandemics : 

Selected patterns among 20th century pandemics Geographic spread Mortality (vital statistics, surveys) by age group Attack rates and pneumonia rates by age group Morbidity & mortality by area Timelines for vaccine development

Slide8: 

Impact of Influenza Pandemics 1918-19 Spanish Flu (H1N1) 20 to 40 million deaths worldwide At least 550,000 US deaths (only 80% of pop. included in vital statistics data) 1957-58 Asian Flu (H2N2) ~70,000 US deaths 1968-69 Hong Kong Flu (H3N2) ~34,000 US deaths Current interpandemic influenza ~36,000 US deaths >200,000 hospitalizations

20th century mortality rates: 1918-1919: 

20th century mortality rates: 1918-1919

Slide11: 

Excess Pneumonia & Influenza Deaths in Persons <65 years during and after Pandemics (from vital statistics data) Simonsen JID 1998; 178:53-60

Slide12: 

Excess mortality among those <65 in the 20th century 1918: >90% of excess deaths occurred among those aged <65 1936-37: about 60% of excess deaths in <65 1943-44: only 30% in <65 1957-58: 36% of excess deaths in <65 1967-68 (end of H2N2 circulation): only 4% in <65 1968-69: ~40% of excess mortality in <65 Since 1992, <10% of excess deaths among those aged <65 years

Worldwide impact of 1918 influenza pandemic: 

Worldwide impact of 1918 influenza pandemic Patterson & Pye estimated 30 million deaths worldwide (Bull Hist Med 1991) Mortality rates by region 5 per 1000 in Europe and North America 9 per 1000 in Central & South America 15 per 1000 in Africa 20-34 per 1000 in Asia, with highest rates in India (estimated 12.5-17 M deaths in India)

1st wave: Sept to Oct 1918: 

1st wave: Sept to Oct 1918

Death rates in 3 cities: 1st & 2nd waves: 

Death rates in 3 cities: 1st & 2nd waves

US mortality during 1918 pandemic using Registration Area data : 

US mortality during 1918 pandemic using Registration Area data Overall excess pneumonia and influenza mortality was 5.3 per 1000 In states included (no TX, FL, GA etc) Low – 3.6 per 1000 in Wisconsin High – 7.5 per 1000 in Montana In 45 cities with >100,000 residents Low – Grand Rapids: 1.9 per 1000 High – Pittsburgh: 10.3 per 1000

WH Frost. The epidemiology of influenza. Public Health Reports 1919;34:1823-36: 

WH Frost. The epidemiology of influenza. Public Health Reports 1919;34:1823-36 “…there are notably wide differences in the mortality rates of individual cities…, even between cities close together, differences which are not as yet explained on the basis of climate, density of population, character of preventive measures exercised, or any other determined environmental factor”

USPHS surveys of 1918 pandemic : 

USPHS surveys of 1918 pandemic House-to-house surveys were conducted in 11 cities in 1919; N ~ 113,000 Overall attack rate 280 per 1000 Louisville: 150 per 1000 San Antonio: 530 per 1000 (3.5 x higher) Attack rates consistently highest among those aged 5-14 years Fell off gradually in younger and older Lowest rate among those aged 75+

USPHS survey: case rates: 

USPHS survey: case rates

USPHS surveys: pneumonia rates: 

USPHS surveys: pneumonia rates Pneumonia rates showed little correlation with attack rates Pneumonia rates also varied by city from 5.3 per 1000 in Spartanburg to 24.6 in rural Maryland (4.6 x higher) Death rates paralleled pneumonia rates 1.9 per 1000 in Spartanburg 6.8 per 1000 in Maryland (3.5 x higher)

USPHS surveys: fatality rate: 

USPHS surveys: fatality rate

USPHS surveys: death rates: 

USPHS surveys: death rates

1957-58 Asian Flu (H2N2): 

1957-58 Asian Flu (H2N2) Characterized by localized outbreaks prior to explosive spread in early fall Most deaths were in older age groups Most excess deaths were categorized as cardiovascular rather than pneumonia deaths 1st wave: Sept, Oct, Nov 1957 2nd wave: Jan, Feb, March 1958

Estimated P&I death rates: ’51, ’53, ‘57 : 

Estimated P&I death rates: ’51, ’53, ‘57

Excess deaths by month: 1957-58 compared to 1956-57: 

Excess deaths by month: 1957-58 compared to 1956-57

Excess mortality by age group: 

Excess mortality by age group

1968-69 Hong Kong Flu (H3N2): 

1968-69 Hong Kong Flu (H3N2) Widespread circulation by Dec 1968 Same virus returned the next 3 seasons Elderly again most vulnerable, but a greater proportion of deaths occurred in <65, compared to 1957-58 Excess deaths from Sept 1968 through March 1969: 33,800

Summary: 

Summary * Assume 35% attack rate using FluAid ADAPTED FROM M. MELTZER

Pandemic vaccines for widespread use: 

Pandemic vaccines for widespread use Trivalent inactivated influenza vaccines usually ready for distribution 8 months after updated strains chosen First waves of 20th century pandemics have typically spread to all continents in 6 months or less

Production of pandemic vaccines: J.M. Wood (Phil Trans R Soc 2001): 

Production of pandemic vaccines: J.M. Wood (Phil Trans R Soc 2001)

1957 A(H2N2) : 

1957 A(H2N2) First isolates to vaccine manufacturers in May; by mid-June small amounts of inactivated, whole-cell vaccine produced By Aug, production at maximum of 10 M doses per month When 1st wave peaked in Nov, 49 M doses had been produced

1968 A(H3N2): 

1968 A(H3N2) Vaccine production began within 2 months of availability of new strain, improvement of ~1 month 1st wave peaked only 4 months from start of vaccine production Only 20 M doses were available

1976 A(H1N1): 

1976 A(H1N1) Fort Dix outbreak prompted massive effort, and high-growth reassortants available, but lead time increased to 7-8 months US government guaranteed purchase Improved vaccine purification and potency testing required additional time As did legislation for indemnification 150 M doses produced in 3 months

Future?: 

Future? Despite advances in virology and vaccine technology, the rate-limiting steps in the production and distribution of pandemic vaccines may be logistical and legal It seems unlikely that large amounts of vaccine will be available during the 1st pandemic wave Potential impacts had vaccine been available during past pandemics?