Prof. Adolfo García Sastre: Influenza epidemics and pandemics
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Transcript of Prof. Adolfo García Sastre: Influenza epidemics and pandemics
Adolfo García-Sastre
Icahn School of Medicine at Mount Sinai, New YorkCRIP, Center for Research on Influenza Pathogenesis
INFLUENZAEPIDEMICS PANDEMICS
‘40 ‘50 ‘60 ‘70 ‘80 ‘00‘901918
H1N1
H2N2
H1N1
H3N2
A
B
EPIDEMIOLOGY OF HUMAN INFLUENZA
VIRUSES
‘10
1957
1968
1977
pH1N1
2009
INFECTIONS IN HUMANS WITH AVIAN AND
SWINE INFLUENZA A VIRUSES
H5N1 H9N2 H5N1 H5N1H7N7
‘40 ‘50 ‘60 ‘70 ‘80 ‘00‘901918
H1N1
H2N2
H1N1
H3N2
A
B
‘10
1957
1968
1977
pH1N1
2009
H7N9H3N2v
Evolution and spread of flu viruses
aquatic birds
poultry
pigs
humans
horsesfecal/oral
respiratory
dogs
cats
Alicia Solórzano
Adolfo García-Sastre
Patty Aguilar
Chris Basler
Peter Palese
Mount Sinai
Terry Tumpey
Hui Zeng
Nancy Cox
Jacky Katz
CDC
David Swayne
USDA
Jeff Taubenberger
AFIP
Gene sequencing
Gene reconstruction
Pathological specimen (circa 1918).. . ..
Reverse genetics
Signatures of virulence of the 1918 influenza virus
Phenotypic characterization in: Tissue cultureAnimal models
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
% s
urv
iva
l
Days after infection
Tx/91
1918 5:3 Tx/911918
1918 7:HA Tx/91
Intranasal inoculation of mice, 106 pfu
Viral titers in lungs, day 4
103 pfu
106 pfu108 pfu
105 pfu
1918 VIRUS
What do we know now?
1. The 1918 virus is the only known human influenza virus
lethal to mice, ferrets, macaques and embryonated eggs
2. The glycoprotein (HA and NA) and non-structural (NS1
and PB1-F2 genes) of the virus contribute to enhanced
virulence
3. Viruses containing 1918 genes are sensitive to existing
antivirals
4. H1N1 based vaccines are protective
Would a 1918-like HIN1 virus be today as lethal as in
1918?
Rafa Medina
Balaji Manicassamy
Estanis Nistal-Villán
Adolfo García-Sastre
Tshide Tsibane
Chris Basler
Silke Stertz
Peter Palese
Mount Sinai
Petra Zimmermann
Osvaldo Zagordi
Silke Stertz
University of Zurich
Hanni Uusi-Kerttula
Rafa Medina
Universidad Católica de Chile
Xiangjie Sun
Terry Tumpey
CDC
Sharon Frey
Bob Belshe
SLU
‘40 ‘50 ‘60 ‘70 ‘80 ‘00‘901918
H1N1
H2N2
H1N1
H3N2
A
B
EPIDEMIOLOGY OF HUMAN INFLUENZA
VIRUSES
‘10
1957
1968
1977
pH1N1
2009
1918 “Spanish” flu
Pigs Humans
Classical swine flu Modern human H1N1
Sa
Ca2
Ca1
Cb
Receptor
binding site
Sb
Fusion peptide
Antigenic
sites
Pandemic H1N1 infections in humans
• Infections are primarily seen in children and young adults
• Serology studies show the presence of neutralizing
antibodies against 2009 H1N1 virus in people older than
65 yrs
Due to prior exposure to an H1 virus similar to 2009 H1N1?
Do antibodies to any specific H1N1 virus protect against SOIV
2009 H1N1?
Virus Type Year (lineage)
A/California/04/09 (6:2) H1N1 2009
1918-like or classical H1N1
1918 VLP H1N1 1918
A/swine/Iowa/30 H1N1 1930 (Classical)
A/Weiss/43 H1N1 1943 (1918-like)
A/New Jersey/8/76 H1N1 1976 (Classical?)
Human H1N1(1977-2007)
A/USSR/92/77 H1N1 1977
A/Houston/20593/84 H1N1 1984
A/Texas/36/91 H1N1 1991
A/Brisbane/59/07 H1N1 2007
Control (H3N2)
A/NT/60/68 H3N2 1968
A/Brisbane/10/07 H3N2 2007
Vaccination and challenge experiment
Vaccination
15mg
-28
Boost
15mgChallenge (50 LD50)
-14
Body weight
& Survival
0Day
- 5 week old female C57B/6 mice
- Mice were vaccinated with 11 different inactivated viruses
- Challenged with Neth/09 strain
14
Inactivated vaccines based in classical swine viruses (1930-2009)
and in human H1N1 viruses (1918-1943) protect against lethal
infection with the new H1N1
Conclusions
-People carrying antibodies against H1N1 viruses
that circulated 1918-1950 and A/NJ/76 (vaccination)
are likely to be protected
- Pigs act as reservoirs for strains that become
antigenically “frozen” H3 and H1 viruses have also
established lineages in pigs in 1997-1998 and 2003-
2005. Swine H3N2v jumps frequently to humans.
Sample AgeCal/09 1918 Vaccinated with
Pre PrePost Post 2009 H1N1 Seasonal TIV
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
19
21
33
34
34
42
43
49
55
60
67
67
82
51
74
<10
<10
<10
<10
<10
10
<10
<10
10
<10
10
10
<10
<10
<10
80
1280
80
2560
80
320
320
40
1280
1280
640
640
2560
<10
10
10
<10
20
<10
<10
<10
20
<10
<10
10
<10
80
<10
<10
10
20
1280
40
2560
80
320
640
20
1280
1280
1280
640
640
<10
40
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
New H1N1 vaccines induce 1918 HI antibodies in humans
In collaboration with Bob Belshe
Passive administration of sera from new H1N1 vaccinated humans
In collaboration with Bob Belshe
Vaccination (or exposure) to new H1N1 virus generates protective
immunity against 1918 virus
India
Nepal
Russia
Mongolia
Bangladesh
Bhutan
Burma
Thailand
Laos
0
0
500 Kilometers
500 Miles
Vietnam
Philippines
South
Korea
North
Korea
Pakistan
INNER MONGOLIA
HENAN
ANHUI
ZHEJIANG
SHANGHAI
JIANGSU
FUJIAN
JIANGXI
HUBEI
SHANXI SHANDONG
HEBEI
BEIJING
TIANJIN
LIAONING
Taiwan
Location of H7N9 Influenza in China (Feb-Oct 2013)
SHAANXI
137 total cases/45deaths
Province/
City
Number
of Cases
Anhui 4
Beijing 2
Fujian 5
Guangdong 1
Guangxi 0
Hebei 1
Henan 4
Hunan 2
Jiangsu 28
Jiangxi 6
Jilin 0
Shandong 2
Shanghai 33
Zhejiang 48
GUANGDONG
HUNAN
GUANGXI
CHONGQING
GUIZHOU
NINGXIA
GANSU
SICHUAN
YUNNAN
JILIN
HEILONGJIANG
QINGHAI
XIZANG
XINJIANG
HAINAN
Source WHO
Adapted from
Taiwan 1
India
Nepal
Russia
Mongolia
Bangladesh
Bhutan
Burma
Thailand
Laos
0
0
500 Kilometers
500 Miles
Vietnam
Philippines
South
Korea
North
Korea
Pakistan
INNER MONGOLIA
HENAN
ANHUI
ZHEJIANG
SHANGHAI
JIANGSU
FUJIAN
JIANGXI
HUBEI
SHANXI SHANDONG
HEBEI
BEIJING
TIANJIN
LIAONING
Taiwan
Location of H7N9 Influenza in China (8/4/14)
SHAANXI
452 total cases/124deaths
Province/City
Number of Cases
Anhui 18
Beijing 5
Fujian 22
Guangdong 118
Guangxi 3
Hebei 1
Henan 4
Hunan 24
Jiangsu 61
Jiangxi 8
Jilin 2
Shandong 4
Shanghai 42
Zhejiang 140
GUANGDONG
HUNAN
GUANGXI
CHONGQING
GUIZHOU
NINGXIA
GANSU
SICHUAN
YUNNAN
JILIN
HEILONGJIANG
QINGHAI
XIZANG
XINJIANG
HAINAN
Source WHO, flutrackers, news
Adapted from
Taiwan 1
Cases Deceased
Cases Alive
Source: WHO, Flutrackers, news reports
There have now been 9 human cases
from Guangdong Province over the past
7 days.
Source: CDC ILI and Vaccine Distribution Data
Pandemic H1N1 cases and vaccinations in US Sept 2009 – May 2010
0
20,000,000
40,000,000
60,000,000
80,000,000
100,000,000
120,000,000
140,000,000
0
1
2
3
4
5
6
7
8
9
9/3/2009 10/3/2009 11/3/2009 12/3/2009 1/3/2010 2/3/2010 3/3/2010 4/3/2010 5/3/2010
Nu
mb
er
of
H1N
1 V
accin
e S
hip
ped
% o
f V
isit
s f
or
ILI
ILI ShippedVaccine
Neutralization of influenza viruses
Nat Struct Mol Biol. 2009 Mar;16(3):233-4.
HA1
HA2
Neutralizing antibodies
UNIVERSAL FLU VACCINES?
Repeated vaccination with influenza
virus chimeric HA vaccines induce
protective antibodies against
multiple subtypes of influenza virus.
Irina Margine Randy Albrecht
Florian Krammer
Rong Hai Patrick Wilson
Gene Tan S.A. Andrews
Peter Palese Jon Runstadler
cH4/3 DNA cH5/3 protein
boost
H3 protein
boost
Shanghai
(H7N9)
challengeControl groups:
cH4/3 DNA + BSA + BSA
naïve (neg. contr.)
matched vaccine (pos. contr.)
4 weeks3 weeks3 weeks
Induction of protective levels of stalk-reactive
antibodies using chimeric HA constructs in
mice
cH4/3 DNA cH5/3 protein
boost
H3 protein
boost
Shanghai
(H7N9)
challengeControl groups:
cH4/3 DNA + BSA + BSA
naïve (neg. contr.)
matched vaccine (pos. contr.)
4 weeks3 weeks3 weeks
Induction of protective levels of stalk-reactive
antibodies using chimeric HA constructs in mice
cH4/3 DNA cH5/3 protein
boost
H3 protein
boost
Shanghai
(H7N9)
challengeControl groups:
cH4/3 DNA + BSA + BSA
naïve (neg. contr.)
matched vaccine (pos. contr.)
4 weeks3 weeks3 weeks
Induction of protective levels of stalk-reactive
antibodies using chimeric HA constructs in mice
Y
cH4/3 DNA cH5/3 protein
boost
H3 protein
boost
Shanghai
(H7N9)
challengeControl groups:
cH4/3 DNA + BSA + BSA
naïve (neg. contr.)
matched vaccine (pos. contr.)
4 weeks3 weeks3 weeks
Induction of protective levels of stalk-reactive
antibodies using chimeric HA constructs in mice
Y
cHA vaccine protects against
challenge with H10 and H3 viruses
cH4/3 DNA + cH5/3 protein + H3 protein cH4/3 DNA + cH5/3 protein + cH7/3 protein
Titers in mouse lungs, day 3 postinfection
H11
H13
H16
H1
H2
H5
H6
H17
H8
H12
H9
H7
H15
H10
H3
H4
H14
GR
OU
P 1
GR
OU
P 2
0.04
Targeting group 1 HA viruses
cH9/1 DNA cH6/1 protein cH5/1 protein
Control groups:
cH9/1 DNA + BSA + BSA
matched vaccine (pos. contr.)
Y
Induction of protective levels of stalk-reactive
antibodies using chimeric HA constructs in
mice
PR8 H1N1
FM1 H1N1
pH1N1
H5N1
H6N1
challenge
Vaccination with cHA constructs
protects from pH1N1
(A/Netherlands/602/09) challenge
positive control (matched inactivated)
cH9/1 DNA + cH6/1 protein + cH5/1 protein
cH9/1 DNA + BSA +BSA
Similar results for A/PR/8/34 H1N1 and A/FM/1/47
challenges
positive control (matched inactivated)
cH9/1 DNA + H1 protein/cH6/1 protein + cH5/1 protein/H1
protein
cH9/1 DNA + BSA +BSA
cHA constructs protect mice from
heterosubtypic challenge
H5N1 challenge H6N1 challenge
cH5/1 (H5 challenge) or cH6/1 (H6 challenge) protein was replaced by full
length H1 protein to exclude head-based protection
ELISA reactivity to Cal09
(pH1N1) protein
Protection is antibody mediated
cH9/1 + cH6/1 + cH5/1
cH9/1 + BSA +BSA
naïve serum
Naïve
Positive control
vector +BSA+BSA
cH9/1 + cH6/1 + cH5/1
Passive transfer of serum
protects from viral challenge
Days post challenge