Haemagglutinin HA
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Transcript of Haemagglutinin HA
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Beyond the Age-Period-Cohort Model: the impact of influenza onLexis mortality surfaces.
Cambridge Group for the History of PopulationMax Planck Institute for Demographic Research
Workshop on Lee-Carter Methods, Edinburgh, September 2004.
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Haemagglutinin
HA
Neuraminidase
NA
Influenza Virus
Viral RNA:
Redrawn from Collier and Oxford (1993)
N1H1
8 genes
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Antigenic Shift: gene reassortment
CellRedrawn from Collier and Oxford (1993)
H1N1
H2N2
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Antigenic Shift: gene reassortment
Antigenic Drift: minor mutatations
progressive and cumulative
e.g. A/Wuhan/359/1995 (H3N2)
to A/Sydney/5/1997 (H3N2)
e.g. H1N1 replaced by H2N2
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Age Effects and Influenza
2) “Response” side hypotheses:
a) “Frailty” rises with age, and other medical conditions.
b) Intrinsic immunity from mother? (under 6 months?).
1) No “input side” hypotheses.
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Age
1.0
Relative Mortality Risk
0
Age-Specific Response to
Antigenic Shift in Influenza
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Period Effects and Influenza
4) Immunity is Specific to an Influenza Sub-Type.
3) The new Sub-Type eliminates the old one.
1) Antigenic-Drift produces new variants
2) Antigenic-Shift produces new Sub-Types
5) Virus re-cycling.
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Table of shifts.
Identify laboratory versus sero-archaeology
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1820 1840 1860 1880 1900 1920 1940 1960 1980 20000
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
Antigenic Shifts in Influenza and Mortality by Age, Period and Cohort
H1N1 H3N2&H1N1H2N2H3N2
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Cohort Effects and Influenza
1) “Original Antigenic Sin”
2) Debility and Selection
Complications: Pregnancy
Cardiovascular
Respiratory
Neurological
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1917 1918 1919 1920
Birth Cohort
0
20
40
60
80
100
120
Bir
ths
60
80
100
120
140
160
180
200
220
240
260
280
300
Tot
al D
eath
s (x1
000)
Northern USASouthern USAInfluenza Deaths
Birth Cohorts of Deaf Children and Influenza Deaths
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1820 1840 1860 1880 1900 1920 1940 1960 1980 20000
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
Antigenic Shifts in Influenza and Mortality by Age, Period and Cohort
H1N1 H3N2&H1N1H2N2H3N2
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Period
Age
100
1841
0
2000
Mortality SurfaceAPC model: Age-Period-Cohort
Cohorts
Age = Period - Cohort
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Epidemic:
Period Effect
“Normal Years”
Age
100
1841
0
2000
2.6
Excess Mortality Ratio
2.61880Birth Cohort
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Cohort-Period Interaction Effects
?? H1H?
Excess
Mortality
Ratio
1.0
Antigenic Shift
19181848
Epidemic
1891
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1880 1900 1920 1940 1960 1980 20000
1
2
3
4
5
Exc
ess M
orta
lity
Rat
ioExcess Mortality in Influenza Epidemics: Influenza Deaths
Pandemics1968
England & Wales
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1880 1900 1920 1940 1960 1980 20000
1
2
3
4
5
Exc
ess M
orta
lity
Rat
ioExcess Mortality in Influenza Epidemics: Influenza Deaths
Pandemics19681969
England & Wales
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1880 1900 1920 1940 1960 1980 20000.96
0.98
1.00
1.02
1.04
1.06
1.08
Exc
ess M
orta
lity
Rat
ioExcess Mortality in Influenza Epidemics: All Deaths
Pandemics19681969
Pooled HMD data
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1820 1840 1860 1880 1900 1920 1940 1960 1980 20000.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4
2.6
Exc
ess M
orta
lity
Rat
ioExcess Mortality in Influenza Epidemics: All Deaths
PandemicsHMD pooled 1918
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1820 1840 1860 1880 1900 1920 1940 1960 1980 20001
10
100
1000
1
10
100
1000
Rat
e pe
r M
illio
nAntigenic Shifts and Influenza Mortality Rate: England and Wales
H3H1? H1 H2H3 H1/H3
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1820 1840 1860 1880 1900 1920 1940 1960 1980 20001
10
100
1000
1
10
100
1000
Rat
e pe
r M
illio
nAntigenic Shifts and Influenza Mortality Rate: England and Wales
H3H1? H1 H2H3 H1/H3
Berlin
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1840 1850 1860 1870 1880 1890 1900 1910
Birth Cohort
100
101
102
103
2
34568
2
34567
2
34567
Mor
talit
y R
ate
0
10
20
30
40
50
60
70
80
90
100
Perc
enta
ge w
ith A
ntib
odie
s
Influenza A Antibodies in 1968/9 and Period Influenza Mortality
Eng. & Wales MortalityA/Hong Kong/68 in US citizensA/England/72A/Dunedin/73
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1840 1860 1880 1900 1920 1940 1960 1980 20000
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
Antigenic Shifts in Influenza and Mortality by Age, Period and Cohort
H1N1 H3N2&H1N1H2N2H3N2
H3, H3
H3, H1
H1, H1
Log(mortality) = f(Age, Period, Cohort, HN(Cohort)*HN(Period))
H3?H1?
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Factor F P-value
Age x Country 2557 <.0001
Period x Country 173 <.0001
Cohort x Country 235 <.0001
APC Model: Sweden + England & Wales: Type III SS
Factor F P-value
Age x Country 1937 <.0001
Period x Country 76 <.0001
Cohort x Country 63 <.0001
HN(cohort) x HN(period) 220 <.0001
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1830 1840 1850 1860 1870 1880 1890 1900 1910 1920
Birth Cohort
0
100
200
300
400
500
600
700
800
900
1000
Rat
e pe
r 100
01918 Influenza Morbidity Rate: Cambridge University