i t p i v whole or split? - who | world health organization · reaching an hi titer ≥ 40 (or srh...
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1 March 28, 2012
Whole or Split?
Belgrade, Serbia
March 28, 2012
Renée van Boxtel
International Technology Platform forInfluenza Vaccines
March 28, 20122
Background ITPIVITPIV: collaboration of WHO and RIVM to set-up an expertise and training centre for WHO grantees
Aim:
● development of an influenza vaccine production process suitable for Technology Transfer
● pandemic vaccine; seasonal vaccine to use production capacity efficiently (sustainability)
� Aim of the study: to prove safety and immunogenicity in humans
March 28, 20123
Influenza vaccines● Current influenza vaccines:
● Because of their lower reactogenicity, split and subunit vaccines have largely replaced the archetype Whole virion Influenza Vaccines (WIV)
● Immunogenicity (HI titres) WIV superior to split or subunit
● Modern production technology might alleviate the reactogenicity problem of WIV vaccines
March 28, 20124
Vaccine concept
● Choice of vaccine:
– Whole virion inactivated
– Monovalent, 15 µg HA
– No adjuvans
– BPL inactivated
– Development strains:
› Seasonal strain: A/Uruguay 716/2007 reass.: NYMC-C175X (H3N2)
› Pandemic prototype strain: A/Turkey/turkey/1/2005 reass. by reverse
genetics (NIBRG23) (H5N1)
March 28, 20125
Phase 1 Clinical Trial - Objectives
● Primary: safety of WIV
– Adverse Events
● Secondary: immunogenicity of WIV (proof-of-principle)
– HI titres meeting licensing criteria
● Secondary: comparison of safety data with split vaccine (trivalent)
March 28, 20126
Phase 1 Clinical Trial – Design
• Double-blind, parallel, randomised, placebo-controlled trial (N=120)
0
WeeksAdult
(18-49 yrs) Arm
• Seasonal Influenza
3x15 µg HA (n=30) (commercial)
XXXX Blood collection
OOOO Vaccination
• Pandemic Influenza H5N1
15 µg HA (n=30)
XXXX XXXXOOOO
XXXX
OOOOXXXX XXXXOOOO
XXXX
1 3 5 7 92 4 6 8 10
AdministrationFollow-up
AdministrationFollow-up
• Seasonal Influenza H3N2
15 µg HA (n=60) XXXXAdministrationFollow-up XXXX
Comparator:
Split
Investigational
Vaccines:
WIV
XXXX����
����
���� Placebo dose
OOOO
0
WeeksAdult
(18-49 yrs) Arm
• Seasonal Influenza
3x15 µg HA (n=30) (commercial)
XXXX Blood collection
OOOO Vaccination
• Pandemic Influenza H5N1
15 µg HA (n=30)
XXXX XXXXOOOO
XXXX
OOOOXXXX XXXXOOOO
XXXX
1 3 5 7 92 4 6 8 10
AdministrationFollow-up
AdministrationFollow-up
• Seasonal Influenza H3N2
15 µg HA (n=60) XXXXAdministrationFollow-up XXXX
Comparator:
Split
Investigational
Vaccines:
WIV
XXXX����
����
���� Placebo dose
OOOO
March 28, 20127
Phase 1 Clinical Trial – Subject disposition
March 28, 20128
Phase 1 Clinical Trial – Study parameters
● Study parameters:
– Solicited adverse events in diary during 5 days after each vaccination (local and systemic reactogenicity)
– Unsolicited adverse events in diary during entire study period
– SAEs
– Basic safety parameters
– HI titres pre-vaccination,3 weeks post-vaccination
March 28, 20129
Phase 1 Clinical Trial – Results Adverse Events● Local reactogenicity:
– injection site pain, redness most frequent reported
Injection site pain
0%
10%
20%
30%
40%
50%
60%
70%
0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5
H3N2 Pla H5N1 (1) H5N1 (2) Split Pla
Days after vaccination
Percen
tag
e o
f su
bje
cts
Injection site redness
0%
10%
20%
30%
40%
50%
60%
70%
0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5
H3N2 Pla H5N1 v1 H5N1 v2 Split Pla
Days after vaccination
Percen
tag
e o
f su
bje
cts
severemoderatemild
March 28, 201210
Phase 1 Clinical Trial – Results Adverse Events● Systemic reactogenicity:
– headache, malaise most frequent reported
– no fever (T > 37.5°C)reported
Headache
0%
10%
20%
30%
40%
50%
60%
70%
0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5
H3N2 Pla H5N1 (1) H5N1 (2) Split Pla
Days after vaccination
Percen
tag
e o
f su
bje
cts
Malaise
0%
10%
20%
30%
40%
50%
60%
70%
0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5 0 1 2 3 4 5
H3N2 Pla H5N1 (1) H5N1 (2) Split Pla
Days after vaccination
Percen
tag
e o
f su
bje
cts
severemoderatemild
March 28, 201211
Phase 1 Clinical Trial – Results Immunogenicity
International Licensing Criteria
Number of seroconversion or significant increase in
anti-HA antibody titer > 40% GMT increase > 2.5
The proportion of subjects reaching an HI titer ≥ 40 (or SRH titer >25 mm2) should
be 70%
Virus strain
Outcome Fulfils criteria
Outcome Fulfils criteria
Outcome Fulfils criteria
H3N2 Seasonal
91.3% Yes 25.01 Yes 100.0% Yes
H5N1 Pandemic
69.0% Yes 8.87 Yes 69.0% No
March 28, 201212
Phase 1 Clinical Trial - Conclusions
● Safety:
– WIV can be safely used in human
– WIV common adverse events rate comparable to split vaccine
– WIV seems less reactogenic than described in literature earlier
● Immunogenicity:
– proof-of-principle of production process is shown
– H5N1 vaccine: seroprotection rate is 1% short of licensing criteria, but meets other 2 criteria
– H3N2 vaccine meets all licensing criteria
March 28, 201213
Whole or Split ?
● Whole virion Influenza Vaccine is a strong candidate for use in a pandemic situation because:
– immunogenicity is known to be higher than split or subunit vaccines in naïve population
– adjuvans is not required!
– reactogenicity levels seems comparable to split vaccines
● For seasonal vaccines both Whole virion or Split Influenza Vaccines are suitable.
March 28, 201214
Acknowledgements
Martin Friede
Marie-Paule Kieny
Florence Barthelemy
Erin Sparrow
Mariska Beukers-Reuvers Tjeert Mensinga
James SimonPaul Zoeteweij
Otto de Boer Willem Luytjes Patrick de Jong
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