# Presentation: 572100

- HHS Influenza
- Vaccine Projects
- for NVAC Meeting
- June 7, 2006

**By: Dr. Robin Robinson **
**Acting Assoc. Director **
**ORDC/OPHEP/DHHS              **
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## Overview

- Key Winter/Spring Events
- H5N1 Vaccine: Pre-Pandemic Vaccine Stockpile
- H5N1 + Alum Adjuvant Vaccine Candidates
- Egg-based Influenza Vaccine Contract: H7 & H5 Vaccines
- Cell-based Influenza Vaccine Contracts
- RFP 05-08 Optimization of Influenza Vaccine Antigen

## Key Winter/Spring Influenza Events

- National & HHS Pandemic Influenza Plans released (11/05)
- Clinical results of alum adjuvant on H5N1 vaccine immunogenicity
- Molecular pathogenesis of H5N1 virus in lower respiratory tree
- Continued spread and genetic “drift” of H5N1 viruses in birds from Asia to Europe & Africa
- HHS awards multiple contracts to advance development of cell-based influenza vaccines for U.S. licensure & capacity building in U.S.
- Further emergence of H5N1 virus clade 2 isolates in Eurasia
- More H5N1 vaccine + adjuvant clinical trials
- Plans to manufacture H5N1 clade 2 vaccine candidates for clinical trials
- Continued U.S. stockpiling of flu antiviral drugs & H5N1 clade 1 vaccine

## HHS Pandemic Vaccine Goals 

**Goal #1: To establish and maintain a dynamic pre-pandemic influenza vaccine stockpile available for 20 million persons: H5N1 stockpiles **
**Goal #2: To provide pandemic vaccine to all U.S. citizens within six (6) months of a pandemic declaration**
**Basis: two doses/person x  90 ug HA/dose (antigen alone) x 300 million persons = 600 million doses = 54 kilograms H5 antigen = 160 kg inactivated virus vaccine**
**Method: To expand and diversify influenza vaccine types, increase number of domestic manufacturers, and enlarge pandemic influenza vaccine manufacturing surge capacity **
**Possible Substrate Sources: eggs, mammalian cells, recombinant vaccines**

## H5N1 Vaccine: Pre-Pandemic Vaccine Stockpiles 

- HHS Pandemic Plan goal: establish & maintain pre-pandemic vaccine stockpile for 20 M persons in critical workforce & high priority groups
- Contracts awarded for commercial scale production of egg-based inactivated monovalent split H5N1 bulk vaccine during seasonal vaccine manufacturing off-season to establish stockpile
- SP: 0.33 M doses @ 90 ug HA/dose Sept. 04; _**completed Nov. 04**_
- SP: 5.8 M doses @ 90 ug HA/dose Sept. 05; _**completed Dec. 05**_
- Chiron: 1.3 M doses @ 90 ug HA/dose Oct. 05; _**completed Feb. 06**_
- Manufacturing virus reference strain: reverse genetics reassortant avian influenza A/H5N1/Vietnam/2004/1203 x PR8 (St. Jude)
- Indemnification & licensure issues await resolution in summer 2006
- Formulation and fill finish of H5N1 vaccine for DOD set for summer 2006
- Remaining H5N1 vaccine await results of NIAID/NIH clinical studies using adjuvants in 2006

## H5N1 + Alum Adjuvant Vaccine Candidates 

- Six formulations of H5N1 +/- alum vaccine (SP) completed in Nov. 05
- NIAID/NIH commenced clinical studies with H5N1 +/- alum vaccine in Mar. 2006 for safety and immunogenicity
- Other NIAID/NIH clinical studies with H5N1 vaccine  administered as antigen alone or with alum or MF-59 adjuvant at bedside

## Egg-based Influenza Vaccine Contract: H7N7 & H5N1 clade 2 Vaccine Candidates 

- Contract awarded Sept. 2004 to Sanofi Pasteur for establishment of secure, year-round embryonated hen’s eggs and other essential supplies for five years
- Final testing of pilot investigational lots of H7N7 + alum adjuvant vaccine in progress for safety & immunogenicity evaluation in clinical trials by NIAID/NIH VTEUs later in 2006
- Several H5N1 clade 2 virus reference strains will be studied  for production & antigenicity to produce clinical lots for safety & immunogenicity evaluation in clinical trials by NIAID/NIH

## Egg vs. Cell-based Influenza Vaccines

**Egg-based production**
**FDA-licensed with good safety and decent efficacy profile**
**Incumbent business market model (50+ yrs.)**
**Historically cheap method**
**Domestic capacity – 60 M trivalent doses (100 M licensed doses)**
**Global capacity – 325 M trivalent doses **
**Requires adaptation of human flu vaccine virus strains  to eggs**
**Egg product allergies**
**Dependent on egg availability & specialized egg-handling equipment **
**Cell-based production**
**Only licensed (registered) in The Netherlands**
**Oncogenicity/Tumorigenicity issue of cell lines**
**Adventitious agent issue for cell banks**
**Cell bank consistency **
**Flexible surge capacity**
**Equipment amenable to multi-product operations**

##  Influenza Vaccine Cell Substrates

- Vero cells (Baxter)
- monkey kidney cell line
- Non-tumorigenic cell line at limited passage
- Adherent, flu virus titers -107pfu/ml, febrile SAE in humans
- MDCK cells [MedImmune, GSK (IDB), Solvay, Novartis (Chiron)]
- Darby Canine kidney cell line
- Tumorigenic cell line
- Adherent/Suspension, flu virus titers -108 pfu/ml
- PER.C6 cells (SP)
- Ad5 E1 gene transformed human fetal retinal cells
- Weakly oncogenic cell line
- Suspension, flu virus titers -108 pfu/ml

## Cell-based Influenza Vaccine Contract: PER.C6 Cell Line

- Contract awarded Apr. 2005 to sanofi pasteur over five years to facilitate advanced development of a PER.C6 human cell-based influenza vaccine U.S. towards U.S. licensure in U.S. mfg facilities with surge capacity of 300 M monovalent doses of pandemic vaccine (15 ug/dose)
- Manufacturing of pilot investigational lots completed in France for safety & immunogenicity clinical evaluation in U.S.
- Phase I studies scheduled for 2006

## RFP 05-04 Cell- & Recombinant-based Influenza Vaccines

- Goal: Expansion and acceleration of influenza vaccine surge capacity & diversification of influenza vaccine
- Solicitation for contract proposals to facilitate development of cell- or recombinant-based seasonal and pandemic influenza vaccines towards U.S. licensure and manufacturing
- Surge capacity of 150 M doses of pandemic vaccine
- RFP issued April 29, 2005
- Proposals evaluated for technical merit
- Contract awards awarded (May 1, 2006)

## RFP ORDC V&B 05-04: Contract Solicitation Facts

- RFP intent is to facilitate advanced development of cell- or recombinant-based seasonal and pandemic influenza vaccines towards FDA licensure and commitment to U.S.-manufacturing site at a pandemic surge capacity of 150 M doses/6 mos.

- Contracting office – ORDC/OPHEP/HHS
- Project Management – ORDC/OPHEP/HHS
- Funding – OPHEP FY06 $1 B

- Support Activities
- Clinical manufacturing
- Product assay develop.
- Clinical evaluation
- Clinical assay develop
- Process/Scale-up mfg develop
- Product-related equipment
- Process validation
- Mfg facility concept design
- Deliverables
- Product Develop Plan
- Clinical & Regulatory Plan
- Facility Plan
- Feasibility Plan
- Pan Vaccine Dev Milestones
- Seasonal Vaccine Dev Milestones

## New Cell-based Contracts: Budgets  

| Company  | Funding Term | Funding Amt. |
| --- | --- | --- |
| GSK (ID Biomed) | Full (5 yrs.) | $274,752,168  |
| MedImmune | Full (5 yrs.) | $169,462,231  |
| Novartis (Chiron) | Full (5 yrs.) | $220,507,491  |
| DynPort (Baxter) | thru  Jul 07 | $40,971,895  |
| Solvay  | Full (5 yrs.) | $298,594,057  |
|   | Total | $1,004,287,842  |

## HHS Cell-based Contracts: Seasonal Influenza Vaccine Product Development

| Company  | Source | Pre-Clinical | Phase I | Phase II | Phase III | Licensed |
| --- | --- | --- | --- | --- | --- | --- |
| GSK (ID Biomed) | Egg |   |   |   |   | U.S./E.U. |
|  | Cell | E.U | U.S. |  |  |  |
| MedImmune | Egg |   |   |   |   | U.S. |
|   | Cell | U.S. |  |  |  |  |
| Novartis (Chiron) | Egg |   |   |   |   | E.U. U.S |
|  | Cell | U.S. |   |   | E.U. |  |
| DynPort (Baxter) | Egg |   |   |   |   | E.U. |
|   | Cell |   |   |   | E.U. |  |
| Solvay | Egg |   |   |   |   | E.U. |
|  | Cell |   | U.S. | E.U. |  |  |
| sanofi pasteur | Egg |   |   |   |   | E.U. U.S |
|   | Cell |   | U.S. |  |  |  |

## Pan Flu Vaccine Forecast: Egg- and Cell-based Vaccines 

## RFP 05-08 Optimization of Influenza Vaccine Antigen 

- Solicitation for contract proposals to facilitate development of adjuvant and biological products, medical devices, and/or methods that optimize influenza HA antigen in vaccines to stretch the influenza vaccine supply
- Scope includes:
- Adjuvants
- Immune cytokines
- Alternative delivery devices
- Other delivery methods
- RFP issued Mar. 17, 2005
- Contract awards expected in 3Q06