U N I V E R S I T Y
O F
B E R G E N
En fremtidig universell influensavaksine
Rebecca Jane Cox
uib.no
Influensa
2
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Impact of influenza
Deaths
Requiring
hospitalisation
Deaths Requiring
hospitalisation
Clinical
symptoms
Asymptomatic
Seasonal influenza
3
Proportion
of cases (source ECDC)
Clinical
symptoms
Asymptomatic
Pandemic influenza
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Impact of influenza
Deaths
Requiring
hospitalisation
Deaths Requiring
hospitalisation
Clinical
symptoms
Asymptomatic
Seasonal influenza
4
Proportion
of cases (source ECDC)
Clinical
symptoms
Asymptomatic
Pandemic influenza
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Intervention delays and flattens epidemic peak
Daily
cases
No intervention
With intervention
Days since first case
5
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Inactivated virusvaccine
Influenza vaccines
6
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Seasonal influenza
7
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Children are the main transmitters of influenza
Photo from reallifesurvivalguide.com
8
CDC.photos
uib.no
UK recommends influenza vaccination for all children
9
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Live Attenuated Influenza Vaccine- LAIV
In 2-8 year olds, LAIV provides better protection than
intramuscular vaccination. LAIV is therefore preferable in
this age group unless contraindicated
10
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High protective efficacy observed after LAIV
low serum HI response measured
Study
Belshe, year 1
Belshe, year 2
A/H1N1 responses
30
100
Did not circulate
26
32
28
62
86
100
47
79
73
60
92
100
50
38
25
90
82
90
56
69
80
73
Did not circulate
28
81
10
14
49 -102
94
0
57
44
90
81
Bracco, year 2
Did not circulate
61
60
Vesikari, year 2
91
5
41
Vesikari, year 1
11
68
96
Did not circulate
Tam, year 2
B strain responses
53
48
Tam, year 1
Bracco, year 1
A/H3N2 responses
25 50 75 100
Seroresponse, %
Efficacy, matched strains, %
0
25
50
75 100
-100 -75 -50 -25 0
25 50 75 100
Bandell et al., Exp Rev Vaccine 2011
uib.no
Recruitment
12
Hans Jørgen Aarstad, ENT
uib.no
Conflicts of interest
Photo: K Mohn
13
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Study design
•
•
•
•
20 boys & 18 girls
3-17 years old, median 4 years old
Median weight 19 kg
Median height 107cm
Days
n=
14
0
28
56
180
360
38
38
34
24
14
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The immune response to influenza
McKee, A.S., M.K.L. Macleod, et al. (2010).
15
BMC Biol 8: 37-‐46.
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Longevity serum antibody responses
H3N2
H1N1
n = 38
n = 38
38
38
37
21
14
1280
24
1280
14
P<0.0001
320
80
40
20
HI titer
HI titer
32
****
320
80
40
20
5
Day
37
5
0
28
56
180
365
0
28
56
180
360
Days post vaccination
Time postvaccination
Days post vaccination
16
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The immune response to influenza
McKee, A.S., M.K.L. Macleod, et al. (2010).
17
BMC Biol 8: 37-‐46.
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% of total IgG+ MBC
Longevity of memory B cell response
***
*
**
**
2.5
2.0
1.5
1.0
0.5
0.0
0
28
56
180
360
0
28
% of total IgM+ MBC
H1N1
50
56
180
360
H3N2
***
**
***
**
**
**
0
28
56
180
360
B
*
**
***
40
30
20
10
0
0
28
56
360
Days post vaccination
18
0
28
56
360
Days post vaccination
0
28
56
360
Days post vaccination
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The immune response to influenza
McKee, A.S., M.K.L. Macleod, et al. (2010).
19
BMC Biol 8: 37-‐46.
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Cell mediated immunity
Influenza Centre, Department of Clinical Science
“The estimated protection curve indicated that
the majority of infants and young children
with ≥100 SFU/106 PBMC
were protected against clinical influenza,
establishing a possible target level of CMI for
future influenza vaccine development”
Majority of subjects with ≥ 100 SFU/106 PBMC protected
against influenza infection after LAIV immunisation
Probability of protection
1,0
95% CI
0,8
0,6
0,4
0,2
0,0
0.1
1
10
100
1,000
10,000
Interferon-γ ELISPOT (SFU/106 PBMC)
Forrest Clin Vaccine Immunol 2008
20
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Longevity of T cell response in blood
*
***
800
H1N1
600
400
IFN-γ SFU/1*106 PBMC
200
0
*
**
800
600
400
H3N2
200
0
****
****
***
*
800
600
400
B
200
0
0
21
28
56
180
Days postvaccination
360
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Conclusions
22
Dr. Karl Brokstad, UIB uib.no
23
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Influenza pandemics
1918:
1957:
1968:
“Spanish Flu”
50 million
deaths
“Asian Flu”
“Hong Kong Flu”
A(H1N1)
24
5 million deaths
A(H2N2)
2 million deaths
A(H3N2)
2009:
“Swine flu”
>16700deaths
A(H1N1) 2009
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Avian influenza: the ever present threat
Low pathogenic H7N9
26
High pathogenic H7N1/H5N1
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H7 Influenza
• Influenza H7 in Europe & North America (H7N2, H7N3, H7N7)
– Conjunctivitis or mild influenza like illness
– 1 death
• H7N9 in China -656 cases
27
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Making safe H7 influenza vaccine
28
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Development of H7N1 vaccine virus
Highly pathogenic chicken virus
A/chicken/Italy/13474/99 (H7N1)
Human vaccine virus
A/Puerto Rico/8/8/34 (H1N1)
NA
HA
Removal of multibasic cleavage site in HA
Vaccine candidate
RD3 virus (H7N1)
29
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Generation of cell based H7 vaccine
30
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Phase I Clinical trial H7 (Italian) vaccine
Days 0
7 14 21 28 35 42
Serum
samples
31
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No protective antibodies after two H7 vaccinations
64
protec
HI Titre
32
16
8
4
2
32
12 12+ 24 24+
1st dose
12 12+ 24 24+
2nd dose
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H7N9 Influenza in China
33
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• 1st wave Spring 2013 136 cases -44 deaths
• 2nd wave 2013-14 -318 cases -54 deaths
• 3rd wave 2014-15 202 cases -40 deaths
34
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35
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36
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H7 divided into Eurasian & North American lineages
HA
37
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Cross reactivity to H7 viruses
Days 0
7 14 21 28 35 42
6M
Serum
samples
Florian Krammer
Mount Sinai
38
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Increase in antibody to Chinese H7 after Italian H7 vaccination
Vaccine strain
Italian H7
39
Chinese H7 strain
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Can antibodies from our vaccinees protect mice
against lethal H7N9 Chinese virus ?
Days 0
7 14 21 28 35 42
Serum
samples
40
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Antibodies protect mice against lethal H7N9 Chinese virus
41
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H7 haemagglutinin is highly conserved
Site A
Red amino acid changes between
Chinese
and Italian viruses
42
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43
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HA stalk is highly conserved
Globular Head
Immunodominant
HA
Stalk
44
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HA stalk is conserved among group 1 or group 2
H11
GROUP 1
H13
H16
H1
H2
H5
H6
H17
H8
H12
H9
Stalk
H15
H10
H3
H4
H14
GROUP 2
H7
0.04
45
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Are stalk antibodies induced after pandemic
vaccination?
46
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H7 vaccination increases H3 stalk antibody response
* p=0.0326
Irrelevant
H5 head domain
H3 stalk domain
47
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U NisI also
V E R conserved
S I T Y
O F among
B E R Ggroup
E N
HA stalk
1
H11
GROUP 1
H13
H16
H1
H2
H5
H6
H17
H8
H12
H9
H15
H10
H3
H4
H14
GROUP 2
H7
0.04
Shaw and Palese, 2011, Field’s Virology
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Phase I Clinical trial H5 vaccine
H5N1 virosomal vaccine
Days
0
7 14
3rd generation ISCOM™
21 28 35 42
6M
12M
Serum
49
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Is an H1 stalk response induced after H5 vaccination?
Irrelevant
head H6
Raffael Nachbagauer
Mount Sinai
Stalk H1
50
Florian Krammer
Mount SInai
uib.no
Significant Increase in H1 stalk antibodies after H5 vaccination
H6/H1
51
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Can these H1 stalk antibodies neutralise virus?
52
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Do stalk antibodies protect against infection?
Pre vaccination sera pooled (Day 0)
Post vaccination sera pooled (Day 42)
Infected cH6/1 virus
53
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Stalk specific antibodies protect against weight loss and lower
respiratory tract infection
54
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Mechanisms of neutralisation
Classical HI
antibodies
55
Stalk-reactive
antibodies
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Are chimeric vaccines a universal influenza vaccine?
56
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Stalk
Immunodominant
head
Therapeutic stalk antibodies in clinical trial
57
Ekiert et al., 2009, Science uib.no
The future?
Universal vaccines for specific groups
58
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Acknowledgements
K.G. Jebsen centre for
Influenza vaccine research
60
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