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