Avian and Pandemic InfluenzaVaccine Development

John TreanorProfessor of Medicine

University of Rochester Medical CenterRochester, NY

Options for Pandemic Vaccines

• Inactivated vaccine resembling currently licensed inactivated vaccine

• Live vaccine resembling currently licensed live vaccine

• Inactivated vaccines with experimental adjuvants/route of administration

• Experimental approaches

Inactivated Vaccine Approach

• Proven technology

– Used successfully in 1957 and 1968

– Efficacy data exist for both pandemic and interpandemic years

– Large experience with clinical use

• Largest existing manufacturing capacity

• Licensing would be relatively straight-forward

Inactivated Vaccine Approach

• Unlikely to induce mucosal immunity

• Protection may be strain specific

• Requires multiple doses

• Manufacturing capacity limited by availability of eggs and capacity for expansion limited

Evaluation of Unadjuvanted Inactivated H5 Influenza Vaccines

• Avoid cleavage

– Duck Singapore/97 (H5N3)

– Recombinant, baculovirus-expressed HA of A/Hong Kong/156/97 (rH5)

– Subvirion rgA/Vietnam/1203/04 vaccine (H5N1)

Egg-grown Duck/Singapore

0

2

4

6

8

10

12

14

0 21 42

7.5 ug HA

15 ug HA

30 ug HA

Nicholson, et al. Lancet. 2001;357:1937.

Study day

H5N

3 N

eutr

aliz

atio

n G

MT

Recombinant rHA H5 Vaccine

Insect cell expressing

rHA

RBCs

Purified rHA H5SDS-PAGE

Neutralization Titers Against A/Hong Kong/156/97

3.5

4

4.5

5

5.5

6

6.5

S1 S2 S3 S4 S5 S6 S7

25 ug

45 ug

90 ug

90 ug / 10 ug

Placebo

Log

2 ti

ter

Treanor. Vaccine. 2001;19:1732.

Vaccine administered at visit S1 and S3

Response Rates Following One or Two Doses of rHA H5 Vaccine

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20

40

60

80

100

Placebo 25 mcg 45 mcg 90/10 mcg 90 mcg

Dose 1

Dose 2

Per

cent

res

pond

ing*

*4-fold or greater increase to a titter of 1:80 with positive WB.Treanor. Vaccine. 2001;19:1732.

Evaluation of rgA/Vietnam/1203/04 (H5N1) Subvirion Vaccine (DMID 04-063)

• Subjects: Healthy adults ages 18 to 64

• Design: Prospective, randomized, double blind

• Interventions: Two IM doses H5 vaccine separated by 28 days

– Placebo, 7.5 mcg, 15 mcg, 45 mcg, 90 mcg

– 1:2:2:2:2 randomization

• Endpoints

– Safety: solicited and unsolicited AEs

– Immunogenicity: neutralizing titer of 1:40

DMID 04-063: Preliminary Results

• Vaccine was well tolerated at all doses

• Dose related local pain and tenderness

• Some neutralizing responses seen at all doses

• Best responses seen at highest doses – only 45 mcg and 90 mcg gave “acceptable” responses

• Results are very consistent with previous evaluation of rHA H5 vaccine

Strategies to Overcome Poor Responsiveness

• Booster strategies – include vaccine in annual vaccination, prime population

• Adjuvant strategies – add adjuvants with dose sparing potential

• Alternative routes of administration strategies

Strategies to Overcome Poor Responsiveness

• Booster strategies – include vaccine in annual vaccination, prime population

• Adjuvant strategies – add adjuvants with dose sparing potential

• Alternative routes of administration strategies

Age had a Dramatic Effect on the Serum HAI Response to Whole Viron (WV) or Subunit (SU) H9N2 Vaccines

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50

100

150

200

day 0 day 21 day 42

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50

100

150

200

day 0 day 21 day 42

0

50

100

150

200

day 0 day 21 day 42

0

50

100

150

200

day 0 day 21 day 42

Age < 35 yr

Age> 35 yr

WV SU

Stephenson. Lancet. 2003;362:1959.

H1N1 H2N2 H3N2

0

50

100

150

200

39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83

Effect of H2N2 Exposure on H9N2 Neutralizing Antibody

Year of birthStephenson. Lancet. 2003;362:1959.

Pre

-vac

cine

MN

ant

ibod

y tit

er

Reimmunization with Duck/Singapore

0

5

10

15

20

25

30

Plain

BaseDay 4216 moDay 21

Mic

ron

eu

tra

liza

tion

GM

T

Stephenson et al. Vaccine. 2003;21:1687.

Booster Strategies

• DMID 05-043: Boosting of subjects who have previously received rH5 with rgA/VN/1203/04

• DMID 05-090: Boosting subjects in 04-063 with a third dose at 6 months

• Proposed: interaction studies with TIV

Strategies to Overcome Poor Responsiveness

• Booster strategies – include vaccine in annual vaccination, prime population

• Adjuvant strategies – add adjuvants with dose sparing potential

• Alternative routes of administration strategies

Evaluation of Whole Virus H2N2 Vaccine with Alum

Study Day

GM

T H

AI A

ntib

ody

Hehme. et al. Med Microbiol Immunol. 2002;191:203. Virus Res. 2004;103:163.

Evaluation of Whole Virus H9N2 Vaccine with Alum

Study Day

GM

T H

AI A

ntib

ody

Hehme et al. Med Microbiol Immunol. 2002;191:203. Virus Res. 2004;103:163.

Significant Enhancement of the Response to H5N3 Virus with MF59

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10

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30

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50

60

0 21 42

0

10

20

30

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50

60

0 21 42

Nicholson et al. Lancet. 2001;357:1937.

No adjuvant MF59 adjuvant

Study day Study day

H5

N3

Ne

utra

lizat

ion

GM

T

7.5 ug HA

15 ug HA

30 ug HA

Adjuvant Strategies

• Alum– H5 formulation – 30 mcg dose met EMEA criteria

– H1, H3 vaccines – little enhancement seen in either pandemic or non-pandemic setting

– Study – DMID 05-0127 dose ranging H5 on constant alum in healthy adults

• MF59– Modest enhancement with TIV

– Promising results with H5 vaccines, no obvious dose-response relationship, ? Stochiometry

– DMID 04-019: significant enhancement of H9 response

– Issues: availablility, intellectual property

• Others: MPL, CPG

Strategies to Overcome Poor Responsiveness

• Booster strategies – include vaccine in annual vaccination, prime population

• Adjuvant strategies – add adjuvants with dose sparing potential

• Alternative routes of administration strategies

Intradermal Vaccination: Post Vaccination GMT and Response Rate (%)

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100

200

300

400

500

600

700

800

H1 H3 B

IMID

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100

200

300

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500

600

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800

H1 H3 B

IMID

GM

T p

ost v

acci

natio

n H

I ant

ibod

y

18-60 yo > 60

43 32 33 35 43 27 26 18 39 16 26 18 % response

15 mcg IM vs 6 mcg ID

Evaluation of Live Attenuated Vaccines (CAIV)

• H9 and H5 candidates generated, in clinical trials

• Highly immunogenic in susceptible populations

– Critical need to define correlates of immunity

• Potential use of low doses

– Studies should evaluate full range

• Induction of mucosal immunity might reduce transmission

– Development of challenge models

Evaluation of Live Attenuated Vaccines (CAIV)

• Potential cross protection

– Evaluate responses to range of antigenic variants

• Not licensed in all populations

– Critical need to expand safety database

– Define correlates of immunity that could be extended to elderly

• Concerns regarding transmission and reassortment

– Clearly define conditions of deployment, expected shedding patterns, and biologic behavior of reassortants

Experimental Approaches

• Nasal inactivated vaccines

• Cross protective peptides/epitopes

• Virus-like particles

• Alternative live vaccines

• Vectored approaches

• DNA Vaccines

Considerations for Alternate Approaches

• Validation in clinical studies

• Extensive safety evaluation

• Specific markers of efficacy

• Individualized development strategy

• Need for early determination of potential advantages against conventional approaches

Critical Issues

• Is the H5 HA intrinsically less immunogenic?

– Mechanism unclear

• Can cross-protective immune responses be generated?

– M2 based immunity

– Cross protective epitopes

– CTL approaches