Adolfo García-SastreIcahn School of Medicine at Mount Sinai, New York
Influenza Universal Vaccines
P01AI097092
Disclosure: Some of these studies are funded by a GSK research agreement. AG-S is inventor in patents on universal flu vaccines.
‘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
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
03/09/2009 03/10/2009 03/11/2009 03/12/2009 03/01/2010 03/02/2010 03/03/2010 03/04/2010 03/05/2010
Nu
mb
er
of
H1N
1 V
accin
e S
hip
ped
% o
f V
isit
s f
or
ILI ILI Shipped
Vaccine
Neutralization of influenza viruses
Nat Struct Mol Biol. 2009 Mar;16(3):233-4.
HA1
HA2
Neutralizing antibodies
HA-STEM BASED UNIVERSAL FLU VACCINES?
1. Use of headless constructs
Strategies to overcome HA-head immunodominance
Sagawa et al. (1996). J Gen Virol 77 ( Pt 7), 1483-1487.
Steel et al (2010). MBio 1.
Bommakanti et al (2012). J Virol 86, 13434-13444.
Mallajosyula et al. (2014). Proc Natl Acad Sci USA 111, E2514-2523.
Lu et al. (2014). Proc Natl Acad Sci U S A 111, 125-130.
Wohlbold et al. (2015). Vaccine 33, 3314-3321.
Impagliazzo et al. (2015). Science
Yassine et al. (2015). Nat Med 21, 1065-1070
UNIVERSAL FLU VACCINES?
2. 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
Proof of principle
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
Proof of principle
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
Y
Induction of protective levels of stalk-reactive
antibodies using chimeric HA constructs in mice
Proof of principle
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
Y
Induction of protective levels of stalk-reactive
antibodies using chimeric HA constructs in mice
Proof of principle
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
GROU
P 1
GROU
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.)
YPR8 H1N1
FM1 H1N1
pH1N1
H5N1
H6N1
challenge
Induction of protective levels of stalk-reactive
antibodies using chimeric HA constructs in mice
Proof of principle
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
Prime–Boost cHA vaccines
based in
LAIV and IIV platforms
Florian Krammer, Raffael Nachbagauer,
Adolfo García-Sastre, Peter Palese and Randy A. Albrecht
cH8/1 - LAIV cH5/1 - IIV
cH8/1 - IIV cH5/1 - IIV
Boost Boost
“cH8/1 LAIV- cH5/1 IIV”
TIV
Prime
B-cH9/1
B-cH9/1
B-cH9/1 Mock Mock
Mock
Ferret vaccination groups (n=4)LAIV is based on the Ann Arbor backbone
“cH5/1 IIV- cH5/1 IIV”
“Prime-only”
“TIV”
“Naive”
Prime–Boost cHA vaccines based in
LAIV and IIV platforms
po
st-
TIV
po
st-
pr i
me
po
st-
pr i
me
po
st-
cH
8/1
IIV
po
st-
cH
5/1
IIV
po
st-
pr i
me
po
st-
cH
8/1
LA
IV
po
st-
cH
5/1
IIV
1 0 0 0
1 0 0 0 0
1 0 0 0 0 0
S ta lk -tite r (c H 6 /1 H A )
en
dp
oin
t ti
ter
c H 8 /1 L A IV - c H 5 /1 I IV
T IV
P r im e o n ly
c H 8 /1 I IV - c H 5 /1 I IV
Induction of HA stalk-specific antibodies (ELISA)
*No detectable HI titers following vaccination
Na
ive
TIV
Pr i
me
-on
ly
cH
8/1
IIV
- c
H5
/1 IIV
cH
8/1
LA
IV -
cH
5/1
IIV
1 0 0
1 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
T r a c h e a
pla
qu
e f
orm
ing
un
its
/gra
m
Na
ive
TIV
Pr i
me
-on
ly
cH
8/1
IIV
- c
H5
/1 IIV
cH
8/1
LA
IV -
cH
5/1
IIV
1 0 0
1 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
N a s a l tu rb in a te s
pla
qu
e f
orm
ing
un
its
/gra
m
Na
ive
TIV
Pr i
me
-on
ly
cH
8/1
IIV
- c
H5
/1 I
IV
cH
8/1
LA
IV -
cH
5/1
IIV
1 0 0
1 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
B r o n c h u s
pla
qu
e f
orm
ing
un
its
/gra
m
Viral titers in tissues following H1N1 challenge infection, day 4
CONCLUSIONS
LIVE ATTENUATED FOLLOWED BY INACTIVATED
CHIMERIC HA VACCINES INDUCE HA STEM AND NA
ANTIBODIES,
AND HIGH LEVELS OF PROTECTION AGAINST
HETEROSUBTYPIC CHALLENGE IN FERRETS
Acknowledgements
Randy AlbrechtMichael Schotsaert
Angela ChoiJuan Ayllon
Raffael Nachbagauer
Florian KrammerPeter PaleseRafi Ahmed
Patrick Willson