# Presentation: 557542

- FDA/CBER VRBPAC Meeting
**February 27, 2007 Gaithersburg, MD**
- NIAID H5N1 Vaccine Clinical Research Program Overview
- and
- Protocol 04-063 Study Results
- Linda C. Lambert, Ph.D.
- Division of Microbiology and Infectious Diseases
- National Institute of Allergy and Infectious Diseases
- NIH/DHHS

**Notes:**
Notes here

## NIAID

**DHHS Pandemic Influenza Research Plan**
**NIAID - research on control, prevention, and treatment of seasonal and pandemic influenza**
**Assess basic biology, immunology, host response**
**Characterize newly emerging strains, molecular basis of virulence/transmission**
**Develop and clinically evaluate of new diagnostics, drugs, and vaccines; coordinate/collaborate with DHHS, NVPO, FDA, CDC and other Public Health Service efforts**
**Generate information to further inform ongoing global pandemic preparedness efforts **

**To serve public health by conducting and supporting research on infectious and allergic diseases**

## Slide 3

## NIAID H5N1 Vaccine Clinical Research Program: Objectives I

**Obtain H5N1 vaccine from manufactures with licensed products as quickly as possible**
**May 2004 award contracts to Aventis Pasteur (sanofi pasteur)**
**Produce a pilot-scale lot of H5N1 vaccine using scaled-down processes similar to those for their licensed vaccines**
**2 formulations: 30 mcg/ml, 90 mcg/ml**
**Gain experience overcoming technical and logistical issues - USG and sanofi pasteur**
**Demonstrate use of reverse genetics to generate H5 vaccine reference viruses and obtain USDA Select Agent exemption **
**Produce reagents to measure vaccine potency**
**Develop assay capacity to measure vaccine responses**
**Prepare for commercial-scale manufacturing**

## NIAID H5N1 Vaccine Clinical Research Program: Objectives II

**Rapidly implement well controlled Phase I/II clinical trials to obtain data on the safety and immunogenicity of the vaccine**
**Provide initial data on the comparative dose-ranging immune responses to form the basis of additional clinical trials**
**Assess multiple study populations: adults, elderly, and pediatric populations**
**Support H5N1 hemagglutinin (HI) and microneutralization (MN) immunoassays, data collection/analysis**

## NIAID H5N1 Vaccine Clinical Research Program: sanofi pasteur

**June 2004:  NIAID provided clade 1 H5N1 reference virus to sanofi pasteur**
**rgA/Vietnam/1203/2004; with neuraminidase (NA) and genetically modified hemagglutinin (HA) gene + 6 PR8 genes**
**March 2005: sanofi pasteur delivered vaccine**
**April 2005: NIAID initiated H5N1 vaccine trial in adults**
**3 VTEU sites; fully enrolled May 20****th**
**NIAID transfers preliminary and final data sets for 04-063 to sanofi pasteur for BLA submission**
**John Treanor – results adult study (NIAID Protocol 04-063; published; NEJM 3/2006) and brief overview of follow-on studies**

## NIAID evaluation of sanofi subvirion inactivated rgA/Vietnam/1203/04 x PR8 H5N1 Vaccine

- Presentation to the FDA VRBPAC Meeting 27 February 2007

- J. Treanor, J. Campbell, and K. Zangwill
-  for the DMID 04-063 study team

## NIAID approach to evaluation of sanofi subvirion H5N1 vaccine

- Protocol 04-063

- Protocol 04-076

- Protocol 04-077

## 04-063:  sanofi subvirion inactivated H5N1 vaccine in healthy adults

- Published data up to and including day 56 (NEJM 354 (13): 1343-51, March 30, 2006)
- Healthy adults ages 18 to 64
- Prospective, multicenter, randomized, double blind clinical trial
- Interventions:  dose ranging, two IM doses of H5 vaccine or placebo separated by 28 days
- 7.5 mcg, 15 mcg, 45 mcg, 90 mcg, (n~100/group)
- Endpoints
- Safety:  solicited and unsolicited AEs
- Co-primary Immunogenicity: neutralizing and HAI antibody
- Determined proportion achieving titer of _>_ 1:40 28 days after 2nd dose
- Correlation of either assay with protection against H5N1 infection or disease is unknown

## Demographics of enrolled subjects:  Protocol 04-063

| Demographics of enrolled subjects |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Number of subjects (%) in the following dose groups |  |  |  |  |
| Characteristic | Placebo
(n=48) | 7.5 mcg
(n=101) | 15 mcg
(n=101) | 45 mcg
(n=98) | 90 mcg
(n=103) |
| White | 39 (81.3) | 81 (80.2) | 78 (77.2) | 75 (76.5) | 84 (81.6) |
| Black | 3 (6.3) | 5 (5.0) | 6 (5.9) | 12 (12.2) | 11 (10.7) |
| Asian | 4 (8.3) | 13 (12.9) | 13 (12.9) | 10 (10.2) | 8 (7.8) |
| Pacific Islander | 0 (0.0) | 0 (0.0) | 1 (1.0) | 0 (0.0) | 0 (0.0) |
| Multiracial | 2 (4.2) | 2 (2.0) | 2 (2.0) | 1 (1.0) | 0 (0.0) |
| Hispanic | 4 (8.3) | 13 (12.9) | 11 (10.9) | 6 (6.1) | 13 (12.6) |
| Female | 22 (45.8) | 51 (50.5) | 65 (64.4) | 42 (42.9) | 55 (53.4) |
| Previous vaccine | 20 (41.7) | 39 (38.6) | 42 (41.6) | 42 (42.9) | 44 (42.7) |
| Age (median, range) | 38 (21-62) | 39 (18-64) | 40 (22-64) | 38 (19-63) | 38 (18-64) |

## Summary of safety, Protocol 04-063

- Dose-related pain and tenderness at injection site (0% severe, 7% moderate, 53% mild at 90 mcg, dose 1)
- Rates are similar after dose 1 and dose 2
- No difference in rates of systemic side effects between any dose and placebo
- 1 SAE not related to vaccine occurred within 56 days of dose 1

## Reverse cumulative distribution of MN antibody at day 56 (28 days after dose 2)

**Percent at or above indicated titer**

- 54% (43%,64%)

- NEJM 354:1343-51, 2006

**Reciprocal titer**

## Reverse cumulative distribution of HAI antibody at day 56 (28 days after dose 2)

**Percent at or above indicated titer**

- 58% (47%, 67%)

- NEJM 354:1343-51, 2006

**Reciprocal titer**

## Protocol 04-063 reanalysis

- Changes in analysis were suggested after study completion and publication (March 06) based on FDA guidance document (March 06) and discussions with FDA (April 21, 2006).
- HAI became primary focus of immunogenicity evaluation.
- FDA recommended redefining the value assigned for the first dilution from 1:20 (as published) to 1:10
- HAI seroresponse redefined with FDA consultation as requiring [1] four-fold increase over baseline and [2] titer of 1:40 or greater.
- Reanalysis involves recalculations using 1:10 definition of the starting dilution, and reduces all reported titers by one dilution.
- No retesting of sera was performed.  Only recalculations of results based on new definitions were done.

## Reverse cumulative distribution of HAI antibody at day 56 (28 days after dose 2)

**Percent at above indicated titer**

- 58% (47%, 67%)

**FIRST WELL dilution defined as ****1:20**

**Reciprocal HAI titer**

- NEJM 354:1343-51, 2006

## Reverse cumulative distribution of HAI antibody at day 56 (28 days after dose 2)

## Current cumulative experience with sanofi vaccine at 90 mcg

- Studies
- Randomized trials
-   04-063/05-090
-   04-076
- Open label studies
-   05-0043
-   05-0129
-   05-0130
- Total 90 mcg recipients

- Populations
- Healthy adults
- Elderly adults
- Previous rH5
- Manufacturers
- Lab workers

- One
- 103
- 105
-   37
-   83
-   35
- 363

- Two
-   99
-   94
-   -
-   76
-   35
- 304

- Three
-   86
-   80
-   -
-   -
-   -
- 166

- Number of subjects receiving one, two, or three 90 mcg doses of sanofi vaccine

## NIAID evaluation of 90 mcg dose in open label populations:  safety

- Protocols 05-043, 05-129, 05-0130
- No SAE related to vaccine to date
- Rates of local and systemic solicited adverse events are similar to rates at 90 mcg in Protocol 04-063

## NIAID controlled evaluation of sanofi H5N1 vaccine in additional populations

- Elderly adults (N=259)
- Children 2-9 years old (45 mcg, N=125)
- Database is not locked and only aggregate analysis available
- No vaccine related serious adverse events
- Local and systemic reactogenicity mostly reported as mild or moderate, rarely (1% or less) reported as severe