Development of safe and immunogenic reassortant viruses with 5:3 genotype for live attenuated influenza vaccine Irina Isakova-Sivak, PhD Institute of Experimental Medicine, Saint Petersburg, Russia The First WHO Integrated Meeting on Development and Clinical Trials of Influenza Vaccines that Induce Broadly Protective and Long-Lasting Immune Responses 24-26 January 2013, Hong Kong Baptist University, Hong Kong SAR, China 1 of 16
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Development of safe and immunogenic reassortant viruses with 5:3 genotype for live attenuated influenza vaccine
Irina Isakova-Sivak, PhD
Institute of Experimental Medicine,
Saint Petersburg, Russia
The First WHO Integrated Meeting on Development and Clinical Trials of Influenza Vaccines that Induce Broadly Protective and Long-Lasting Immune Responses 24-26
January 2013, Hong Kong Baptist University, Hong Kong SAR, China 1 of 16
Reassortant LAIV in Russia
> 30 years on the Market;
> 100 million doses produced;
Effectiveness of LAIV for adults (summary from 126 trials : 500 to 45,000
adults per trial; total > 500,000 adults):
Effectiveness was confirmed for each trial.
Mean effectiveness for 126 trials was 1.80 (= 45%).
Index of effectiveness was 1.5 (= 33%), even when epidemics were
caused by new antigenic variants not presented in LAIV.
Nevertheless, new approaches to improve LAIV immunogenicity and
effectiveness are of great interest 2 of 16
PB1
PA
HA
NP
NA
M
PB2
NS
PB1
PA
HA
NP
NA
M
PB2
NS
Wild-type virus Master Donor Virus
LAIV 6:2 reassortant
Reassortant LAIV
5:3? 3 of 16
Which wt internal gene would be advantageous over ca and can be included into LAIV?
PB1
PA
NP
M
PB2
NS
Retain attenuated and high-growth phenotype of LAIV;
Improve immunogenicity and cross-protection.
?
?
?
?
?
?
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Mutations in internal genes of MDV A/Leningrad/134/17/57 (H2N2)
PB1
PA
NP
M
PB2
NS
Master Donor Virus A/Leningrad/134/17/57 (H2N2)
Val-478-Leu
Unique mutations for MDV
Lys-265-Asn; Val-591-Ile
Leu-28-Pro; Val-341-Leu
none (egg-grown); Asn-492-Ser (MDCK-grown)
Ile-15-Val (M1); Phe-144-Leu (M1)
Met-100-Ile (NS2)
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PB2 gene
Ts phenotype correlates with LAIV attenuation
Can NOT be replaced by wt 6 of 16
PB1 gene
Can NOT be replaced by wt 7 of 16
PB2+PB1 genes
PB2 and PB1 genes are crucial for LAIV ts phenotype (i.e. attenuation) 8 of 16
May be replaced by wt if it doesn’t alter high-growth phenotype 12 of 16
NP gene
Can be replaced by wt 13 of 16
NP gene – major target for CTL response
CTLs targeted to some NP epitopes of Len/17 MDV do not
recognize NP of currently circulated influenza A viruses
Inclusion of NP from currently circulated influenza A viruses into LAIV formulation would
bring advantages in terms of CTL response
wt NP is the best candidate for inclusion into LAIV 5:3
reassortants
Len/17
Len/17
Len/17
Len/17
Len/17
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Reassortants Wild-type virus
Genes from
wt virus
Age No
Reactogenicity Immunogenicicty
(seronegaive)
Temperature (%) %≥4-fold rise of Ab titer
37.1-37.5 ≥37.6-38.5 1st dose 2nd dose
A/9/30/37/88 (H3N2)
A/Leningrad/37/88 (H3N2)
HA, NA, NP
Adults (≥18) (clinic)
20 0 0 50.0 55.0
Adults (≥18) 80 0 0 50.0 60.0
Children 116 5 (4.3) 0 60.0 ND
A/Leningrad/92/89 (H1N1), R-1 A/Leningrad/92/89
(H1N1)
HA, NA, NP
Adults (≥18) 20 0 0 55.5 61.1
A/Leningrad/92/89 (H1N1), R-5
HA, NA, NP
Adults (≥18) 20 3 (15) 0 61.1 66.6
47/25/1 A(H1N1)
A/Brazil/11/79 (H1N1)
HA, NA, PA
Children 7-14 334 20 (3.4)
1 (0.6) 48.1 60.0
Children 3-6 262 2 (1.54) 48.1 59.4
47/Ph A(H3N2) A/Philippine/2/87
(H3N2) HA, NA,
PB2
Children 7-14 51 2 (3.9) 0 ND 60.0
Children 3-6 53 12 (22.6) 0 ND 48.5
Retrospective analysis of 5:3 LAIVs
All 5:3 LAIVs were safe and immunogenic 15 of 16
Summary There is a possibility of modifying LAIV genome composition by
including one additional gene from wild-type parental virus;
Polymerase genes (PB2, PB1 and PA) and NS genes of MDV A/Leningrad/134/17/57 (H2N2) can not be replaced due to their impact on LAIV ts/ca and attenuated phenotype;
In some cases M gene of MDV can be replaced by one of wild-type virus (if it doesn’t alter high-growth properties of LAIV strain);
Wild-type NP gene is the best candidate for inclusion into LAIV 5:3 reassortants due to its advantages in terms of cross-reactive CD8+ CTL response;
A pair of related LAIV reassortants with 6:2 and 5:3 genome compositions (with wt NP gene) will be evaluated for the induction of cross-reactive CD8+ CTL response.
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Acknowledgements
• Professor L. G. Rudenko (Head of Department of Virology, IEM, St.Petersburg, Russia);
• R. O. Donis, L.-M. Chen, A.I. Klimov (CDC, Atlanta, USA);