Transcript Avian and Pandemic Influenza Vaccine Development

Avian and Pandemic Influenza
Vaccine Development
John Treanor
Professor of Medicine
University of Rochester Medical Center
Rochester, 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
7.5 ug HA
15 ug HA
30 ug HA
H5N3 Neutralization GMT
14
12
10
8
6
4
2
0
0
21
Study day
Nicholson, et al. Lancet. 2001;357:1937.
42
Recombinant rHA H5 Vaccine
Insect cell
expressing
rHA
RBCs
Purified rHA H5
SDS-PAGE
Neutralization Titers Against A/Hong
Kong/156/97
6.5
Log2 titer
6
5.5
25 ug
45 ug
90 ug
90 ug / 10 ug
Placebo
5
4.5
4
3.5
S1
S2
S3
Treanor. Vaccine. 2001;19:1732.
S4
S5
S6
S7
Vaccine administered
at visit S1 and S3
Response Rates Following One or
Two Doses of rHA H5 Vaccine
Percent responding*
100
Dose 1
Dose 2
80
60
40
20
0
Placebo
25 mcg
45 mcg
90/10 mcg
*4-fold or greater increase to a titter of 1:80 with positive WB.
Treanor. Vaccine. 2001;19:1732.
90 mcg
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
WV
200
SU
200
150
150
100
100
50
50
0
0
Age < 35 yr
day 0
day 21
day 42
200
200
150
150
100
100
50
50
0
0
day 0
day 21
day 42
day 0
day 21
day 42
Age> 35 yr
day 0
day 21
Stephenson. Lancet. 2003;362:1959.
day 42
Effect of H2N2 Exposure on H9N2
Neutralizing Antibody
Pre-vaccine MN antibody titer
200
150
H2N2
H1N1
100
H3N2
50
0
39
41
43
45
47
49
51
53
55
57
59
61
63
65
Year of birth
Stephenson. Lancet. 2003;362:1959.
67
69
71
73
75
77
79
81
83
Reimmunization with
Duck/Singapore
Microneutralization GMT
30
Base
Day 42
16 mo
Day 21
25
20
15
10
5
0
Plain
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
140
15 ug HA (SV)
7.5 ug HA + Al
3.8 ug HA + Al
1.9 ug HA + Al
GMT HAI Antibody
120
100
80
60
40
20
0
0
10
Study Day
Hehme. et al. Med Microbiol Immunol. 2002;191:203.
Virus Res. 2004;103:163.
21
42
Evaluation of Whole Virus H9N2
Vaccine with Alum
140
15 ug HA (WV)
7.5 ug HA + Al
3.8 ug HA + Al
1.9 ug HA + Al
GMT HAI Antibody
120
100
80
60
40
20
0
0
10
Study Day
Hehme et al. Med Microbiol Immunol. 2002;191:203.
Virus Res. 2004;103:163.
21
42
Significant Enhancement of the
Response to H5N3 Virus with MF59
H5N3 Neutralization GMT
60
60
MF59 adjuvant
No adjuvant
50
50
7.5 ug HA
15 ug HA
40
40
30
30
20
20
10
10
0
0
0
21
Study day
42
Nicholson et al. Lancet. 2001;357:1937.
30 ug HA
0
21
42
Study day
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 (%)
GMT post vaccination HI antibody
15 mcg IM vs 6 mcg ID
800
800
700
700
600
600
500
500
IM
ID
400
IM
ID
400
300
300
200
200
100
100
0
0
H1
H3
B
H1
H3
B
43 32
33 35
43 27
26 18
39 16
26 18
18-60 yo
> 60
% response
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