FOOD AND DRUG ADMINISTRATION

 

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CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

 

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VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE

 

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MEETING

 

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TUESDAY,

FEBRUARY 27, 2007

 

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            The meeting convened at 8:00 a.m. in Salons A, B, and C of the Hilton Washington D.C. North/Gaithersburg, 620 Perry Parkway, Gaithersburg, Maryland, Ruth A. Karron., Chair, presiding.

 

ADVISORY COMMITTEE MEMBERS PRESENT:

 

RUTH A. KARRON, M.D., Chair

ROBERT COUCH, M.D., Temporary Voting Member

NANCY COX, Ph.D., Non-Voting Member

THEODORE EICKHOFF, M.D., Temporary Voting

      Member

MONICA M. FARLEY, M.D., Member

BRUCE GELLIN, M.D., M.P.H., Temporary Voting

      Member

WAYNE HACHEY, D.O., M.P.H., Temporary Voting

      Member

SETH HETHERINGTON, M.D., Industry

      Representative

LISA JACKSON, M.D., M.P.H., Member

SUSAN KRIVACIC, Patient Representative

PAMELA McINNES, D.D.S., Temporary Voting

      Member

JOHN MODLIN, M.D., Member

CINDY PROVINCE, R.N., M.S.N., M.A.,

      Temporary Voting Member

STEVEN SELF, Ph.D., Member

JACK STAPLETON, M.D., Member

JOHN TREANOR, M.D., Temporary Voting Member

ROBERT WEBSTER, Ph.D., Temporary Voting

      Member

MELINDA WHARTON, M.D., M.P.H., Temporary

      Voting Member

BONNIE WORD, M.D., Member

 

This transcript has not been edited or corrected, but appears as received from the commercial transcribing service.  Accordingly, the Food and Drug Administration makes no representation as to its accuracy.

 

 

FDA PARTICIPANTS:

 

CHRISTINE WALSH, R.N., Executive Secretary

NORMAN BAYLOR, Ph.D., Director, Office of

      Vaccines Research and Review

ROBERT BALL, M.D., M.P.H., Sc.M., Vaccine

      Safety Branch, Division of

      Epidemiology, CBER

JESSE L. GOODMAN, M.D., M.P.H., Center for

      Biologics Evaluation and Research

ANDREA N. JAMES, M.D., Division of Vaccines

      and Related Product Applications

JOSEPH G. TOERNER, M.D., M.P.H., Vaccine and

      Clinical Trials Branch, DVRPA

 

SPEAKERS:

 

PATRICK CAUBEL, M.D., Ph.D., Sanofi Pasteur

KENNETH P. GUITO, MBA, Sanofi Pasteur

PHILIP HOSBACH, Sanofi Pasteur

LINDA C. LAMBERT, Ph.D., Division of

      Microbiology and Infectious Diseases,

      NIAID, NIH

ROBIN ROBINSON, Ph.D., Acting Associate

      Director, HHS/ASPR/OPHEMC

DAVID K. SHAY, M.D., M.P.H., Centers for

      Disease Control and Prevention

JOHN TREANOR, M.D., University of Rochester

      Medical Center

 

 

PUBLIC SPEAKERS:

 

MANON COX, Protein Sciences

BRUCE INNIS, GlaxoSmithKline

I-N-D-E-X

 

Open Session

      Call to Order and Opening Remarks/

      Ruth A. Karron, M.D., Chair                    5

 

Administrative Matters/

      Christine Walsh, R.N., FDA                 5

 

Topic 1:  Safety and effectiveness of H5N1 Inactivated

Influenza Vaccine Manufactured by Sanofi Pasteur

FDA Introduction/Norman Baylor, Ph.D, FDA       15

 

Sanofi Pasteur Introduction/

      Kenneth P. Guito, MBA, STANDPOINT         20

 

Overview of HHS Procurement of Sanofi Pasteur's

      H5N1 Inactivated Influenza Vaccine/

      Robin Robinson, Ph.D, HHS                 25

 

Introduction to NIH's Clinical Study/

      Linda Lambert, Ph.D, NIH                  33

 

NIH Presentation of H5N1 Study Results

      John Treanor, M.D., URMC                  38

 

FDA Presentation of Immunogenicity and Safety Data/

      Andrea James, M.D., FDA                   52

 

      Questions/Clarifications                  69

 

      CDC - Post Marketing Collection

      of Effectiveness Data

      David K. Shay,M.D., M.P.H., CDC           69

 

Sanofi Pasteur Presentation of Pharmacovigilance

      Plan

      Patrick Caubel, M.D., Ph.D., STANDPOINT  120

 

FDA Comments on Sanofi Pasteur Pharmacovigilance

      Plan/

 

I-N-D-E-X (Continued)

 

Post Marketing Safety Monitoring During an

      Influenza Pandemic

Robert Ball, M.D., M.P.H., Se.M., DA           133

 

      Questions/Clarifications                 145

 

      Open Public Hearing                      154

FDA Presentation of Questions

      Andrea James, M.D., FDA                  154

 

Committee Discussion/Recommendations           216

 

Open Session

Topic 2:  Clinical Development of Influenza Vaccines

for Pre-Pandemic Uses

 

Introduction/Jesse Goodman, M.D., M.P.H., FDA  236

 

Scientific Data Needed to Support Pre-Pandemic Uses

      Joseph Toerner, M.D., M.P.H., FDA        257

 

Boosting Study Results

      John Treanor, M.D., URMC                 266

 

      Questions/Clarifications                 281

 

      Open Public Hearing                      284

 

      Committee Discussion                     301

 

      Adjourn for the Day                      354

             P-R-O-C-E-E-D-I-N-G-S

            DR. KARRON:  I'd like to call this meeting to order if everyone would please take their seats.  And I'd like to ask Ms. Christine Walsh to make some announcement.

            MS. WALSH:  Good morning.  I'm Christine Walsh, the Executive Secretary for today's meeting of the Vaccines and Related Biological Products Advisory Committee.  I would like to welcome all of you to this meeting of the advisory committee.  Today and tomorrow's sessions will consist of presentations that are open to the public.

            I would like to request that everyone please check your cell phones and pagers to make sure they are off or in the silent mode.

            I would also like to request that any media inquiries be directed to either Heidi Rubello (phonetic) or Karen Reilly (phonetic) from FDA Office of Public Affairs, Karen and Heidi.

            I would like to read into public record the conflict of interest statement for today's meeting.  The Food and Drug Administration, FDA, is convening today's meeting of the Vaccines and Related Biological Products Advisory Committee under the authority of the Federal Advisory Committee Act, FACA, of 1972.  With the exception of the industry representative, all participants of the committee are special government employees, SGEs, or regular federal employees from other agencies and are subject to the federal conflict of interest laws and regulations.

            The following information on the status of this advisory committee's compliance with federal ethics and conflict of interest laws, including but not limited to, 18 U.S.C. 208 and 21 U.S.C. 355(n)(4) is being provided to participants in today's meeting and to the public.  FDA has determined that all members of this advisory committee are in compliance with federal ethics and conflict of interest laws including but not limited to 18 U.S.C. 208 and 21 U.S.C. 355(n)(4).  Under 18 U.S.C. 208, applicable to all government agencies, and 21 U.S.C. 355(n)(4), applicable to certain FDA committees, congress has authorized FDA to grant waivers to special government employees who have financial conflicts when it is determined that the agency's need for a particular individuals services outweighs his or her potential financial conflict of interest, Section 208, and where participation is necessary to afford essential expertise, Section 355.

            Members and participants of the committee who are special government employees at today's meeting including special government employees appointed as temporary voting members have been screened for potential financial conflicts of interest of their own as well as those imputed to them including those of their employer, spouse or minor child related to Topic 1, Discussion and Recommendation on the Safety and Immunogenicity of an H5N1 Inactivated Influenza Vaccine sponsored by Sanofi Pasteur; Topic 2, Discussion of Pandemic Influenza Vaccine Strategies and Clinical Development of Pandemic Influenza Vaccines; for Topic 3, Discussion and Recommendations on the Selection of Strains to be Included in the Influenza Virus Vaccine for the 2007-2008 Season; for Topic 4, Discussion of Influenza B Strain Including the History of B Strain Circulating Lineages.

            Financial interests may include investments, consulting, expert witness testimony, contracts, grants, CRADAs, teaching, speaking, writing, patents and royalties and primary employment.  Today's agenda involves a discussion and recommendation of the safety and immunogenicity of an H5N1 inactivated influenza vaccine.

            In accordance with 18 U.S.C. Section 208(b)(3), waivers were granted to Dr. Robert Couch, Dr. Lisa Jackson, Dr. Ruth Karron, Dr. John Modlin, and Dr. Robert Webster.  Dr. Bruce Gellin and Dr. Wayne Hachey have been fully screened for conflicts of interest under usual procedures and have been advised that there are no financial conflicts of interest that would preclude participation or voting in this meeting or that might require a waiver under relevant statutes and regulations.

            I note, however, that Dr. Gellin is involved in the process of pandemic vaccine procurement for the Office of Secretary of the Department of Health and Human Services in his capacity of Director of the National Vaccine Program Office.  To avoid any perceptions of inappropriate influence in the actions of this committee, Dr. Gellin will not be voting on Topic 1.  Dr. Hachey, who is director of Deployment, Medicine and Surveillance for the Department of Defense and whose office has responsibilities for procurement, likewise, will not be voting on Topic 1.

            For the discussion of Topic 2 on Pandemic Influenza Vaccine Strategies and Clinical Development of Pandemic Influence Vaccines, Dr. John Treanor received a waiver under 18 U.S.C. Section 208(b)(3).  Dr. Treanor will not participate in the discussion of Topic 1.  For Topic 1, Dr. Treanor will serve as a guest speaker making a presentation.  Dr. Treanor is Professor of Medicine, Infectious Diseases Unit, at the University of Rochester Medical Center.  He will present data related to Topic 1 on behalf of NIH.

            With regard to FDA's other guest speaker for Topic 3, the agency has determined that the information provided is essential.  The following information is being made public to allow the audience to objectively evaluate any presentation and/or comments.  Mr. Albert Thomas is employed as Director, Viral Manufacturing, Sanofi Pasteur in Swiftwater, Pennsylvania.

            Dr. Seth Hetherington is serving as the industry representative acting on behalf of all related industry and is employed by Icagen, Inc.  Industry representatives are not special government employees and do not vote.  In addition, there may be regulated industry and other outside organization speakers making presentations.  These speakers may have financial interests associated with their employer and with other regulated firms.  The FDA asks, in the interest of fairness, that they address any current or previous financial involvement with any firm whose product they may wish to comment upon.  These individuals were not screened by the FDA for conflict of interest.  This conflict of interest statement will be available for review at the registration table.

            We would like to remind members and participants that if the discussions involve any other products or firms not already not on the agenda for which an FDA participant has a personal or imputed financial interest, the participants need to exclude themselves from such involvement and their exclusion will be noted for the record.  FDA encourages all other participants to advise the committee of any financial relationships that you may have with a sponsor, it's product and, if known, its direct competitors.

            Thank you.  Dr. Karron, that ends the conflict of interest statement, and I turn the meeting over to you.

            DR. KARRON:  Thank you, Christine.  I'd like to welcome everybody to this VRBPAC meeting for what promises to be a very interesting two-day discussion on seasonal and pandemic influenza vaccines.  I'd like to begin by going around the room and having all of the participants introduce themselves.  I'll start with Dr. Modlin.

            DR. MODLIN:  This is John Modlin from Dartmouth Medical School.

            DR. COUCH:  Robert Couch, Baylor College of Medicine.

            DR. FARLEY:  Monica Farley, Emory University School of Medicine.

            DR. SELF:  Steve Self, Hutchinson Cancer Center.

            DR. EICKHOFF:  Ted Eickhoff, University of Colorado.

            DR. WHARTON:  Melinda Wharton, Centers for Disease Control and Prevention.

            MS. KRIVACIC:  Susan Krivacic, Patient Representative, Austin, Texas.

            DR. HETHERINGTON:  Seth Hetherington, Icagen, Inc., Research Triangle Park, North Carolina.

            DR. WORD:  Bonnie Word, Baylor College of Medicine.

            DR. JACKSON:  Lisa Jackson, Group Health Center for Health Studies.

            DR. GELLIN:  Bruce Gellin, Department of Health and Human Services.

            MS. PROVINCE:  Cindy Province, Acting Consumer Representative, Center for Bioethics and Culture.

            DR. STAPLETON:  Jack Stapleton, University of Iowa.

            DR. HACHEY:  Wayne Hachey, Department of Defense.

            DR. WEBSTER: Robert Webster, St. Jude Children=s Research Hospital.

            DR. McINNES:  Pamela McInnes, National Institute of Dental and Craniofacial Research, National Institutes of Health.

            DR. JAMES:  Andrea James, FDA.

            DR. BAYLOR:  Norman Baylor, FDA.

            DR. GOODMAN:  Jesse Goodwin, FDA.

            DR. KARRON:  And I'm Ruth Karron from Johns Hopkins University.  Our first speaker will be Dr. Norman Baylor from the FDA.

            DR. BAYLOR:  Good morning.  I'm Norman Baylor.  I'm the Director of the Office of Vaccines Research and Review at the FDA's Center for Biologics Evaluation and Research.  Today I'm going to provide a brief overview, set the stage for today's meeting, in particular this session on our discussion of the BLA for Sanofi Pasteur's H5N1 vaccine.

            Today we'll be presenting data in support of the first Biologics Licensed Application for a vaccine against H5N1 influenza viruses.  This vaccine was manufactured by Sanofi Pasteur using the same manufacturing process as used for their licensed seasonal vaccine.  The safety and immunogenicity data for the H5N1 strain were derived from a clinical trial completed by three National Institutes of Health Vaccine Treatment and Evaluation Centers.

            As most of you know, there are currently no human vaccine licensed in the United States for avian influenza viruses such as H5N1.  We at the FDA are working with our partners in the Government such as the National Institutes of Health, the Centers for Disease Control and the Department of Health and Human Services as well as the vaccine industry to facilitate the licensure of safe and effective vaccines for the use against potential pandemic influenza strains.

            We're also trying to facilitate the evaluation of vaccines for potential use in the period prior to a pandemic including the potential uses for priming and cross-protection against evolving strains.  And you will hear more about this in the discussion following this session.

            We know that the risk of a pandemic is serious.  H5N1 is present in large parts of Asia as well as now in the continent of Africa, Nigeria, Egypt.  There is increased risk that more human cases will occur.  The continuing presence and spread of the virus to new areas in poultry and wild birds increases the opportunities for human cases to occur.  And we know that each additional human case provides this virus with an opportunity to improve its transmissability in humans and thus develop into a pandemic strain.

            The timing and severity of the next pandemic we cannot predict.  However, the probability that a pandemic will occur has increased and vaccines will be an important intervention against pandemic influenza and there are modeling studies that suggest that even a single dose of a vaccine of limited effectiveness may have significant effects early in a pandemic and reducing illness and spread of the virus.

            I show this slide -- this is a cumulative number and I don't know if you can see this from the back, but the important thing is these two numbers.  It's a cumulative number of confirmed human cases of avian influenza from H5N1 reported by the WHO last week.  And as I said, the important thing here is as of February 19th, there were 274 cases.  I believe there's 278 now.  And of this 274, there have been 167 deaths which you can't see, but there are a variety of countries, as I mentioned before, Asia and the continent of Africa.

            So as a background to the product we're looking at today, as I said before, this product uses the same manufacturing process as the licensed seasonal influenza manufactured by Sanofi.  For U.S. licensed seasonal vaccines, no clinical data are required to substitute new strains into the vaccine such as we call a strain change.

            The clinical data for Sanofi's H5N1 vaccine is designed primarily as a dose ranging study.  And as a result, you'll note today that these data are limited.  The immunogenicity was evaluated in the clinical studies.  The proposed indication from the firm is for individuals 18 to 64 years of age for use during a pandemic or for those at high risk of exposure to H5N1.  This vaccine will not be marketed commercially but is intended for the U.S. stockpile.

            So in summary, we are bringing this vaccine to you today because we know the threat of an influenza pandemic is real and likely to continue.  This vaccine that we're discussing today is intended to be an initial step to support preparedness and to facilitate a rapid early vaccine response.  If licensed, this vaccine will become the first licensed vaccine available in the United States against an H5N1 strength.

            The vaccine industry, in partnership with the Departments of Health and Human Services, is pursuing other approaches intended to elicit enhanced immune responses and require less antigen.  And these are vaccines, for example, formulated with novel adjuvants which will not be the topic of our discussion today.  We'll save that for another day.

            If and when vaccines such as those formulated with novel antigens are found to be safe and effective, they're likely to supplant the use of the vaccine in discussion today.  But we have to keep in mind that the benefit of having a licensed vaccine available now against a potential pandemic influenza strain must be weighed against the potential risk of having no vaccine at the time of a pandemic.

            So that's my brief introduction and I'll be followed by Mr. Ken Guito from Sanofi Pasteur unless there are quick questions for clarification for me.

            DR. KARRON:  Thank you.  Mr. Guito?

            MR. GUITO:  Thank you, Dr. Baylor.  Dr. Karron, distinguished members of the advisory committee, ladies and gentlemen, good morning.  I am Ken Guito and I represent the Strategic Project Office at Sanofi Pasteur.  Sanofi Pasteur is pleased to the opportunity, along with our U.S. Government to present the first pandemic influenza vaccine for licensure, the H5N1 Influenza Vaccine, A/Vietnam 2004 (clade 1) 90 microgram formulation.  Sanofi Pasteur views this formulation as an important first step which is based on time tested manufacturing technology, and we believe this represents unprecedented successful public-private partnership to prepare our nation for the threat of influenza pandemic.

            As a recognized leader in influenza vaccine development and manufacturing, the U.S. Government collaborated with us to manufacture first generation H5N1 pandemic vaccines for clinical studies and stockpiling.  Sanofi Pasteur has the only licensed U.S. manufacturing facility for inactivated influenza virus vaccines.  We're also the largest manufacturer globally producing roughly half of the world's of influenza vaccine.

            Our H5N1 vaccine development efforts have relied upon time-proven technology that have been licensed for inter-pandemic vaccine production for many years in the U.S.  Sanofi Pasteur has extensive candidate vaccine efforts under development utilizing both traditional technology as well as novel cell-based production and adjuvant technologies.  We are collaborating extensively with government agencies domestically and abroad.

            Sanofi Pasteur's presence here today with the first pandemic vaccine applicant demonstrates our sense of urgency and our commitment to prepare for a possible pandemic event.  We and other manufacturers continue on our efforts to develop additional strains of vaccine each and improvement on the last.

            The H5N1 unit dose material used in a DMID clinical trial 04-063 was produced in 2004 under Health and human Services RFP award with Sanofi Pasteur functioning as a contract manufacturer.  You'll hear more this morning on the DMID 04-063 trial from Dr. Treanor from the University of Rochester and from Dr. James from the FDA and more on the influenza pandemic RFP process from Dr. Robin Robinson from Health and Human Services in subsequent presentations.

            As noted by Dr. Baylor, Sanofi Pasteur submitted a biologics license application for the H5N1 influenza virus vaccine in October 2006.  In 2004 through 2005, Sanofi Pasteur produced U.S. Government stockpile doses of the same H5N1 clade 1 vaccine under subsequent HHS RFP awards.  To date, in total, route 6 million 90 microgram-equivalent doses have been produced in the stockpile.  It's important to note the majority of this vaccine is being held as a bulk formulation to allow longer shelf life and flexibility in subsequent formulation and in final packaging.

            As Dr. Baylor and I have noted, the influenza virus vaccine, A/Vietnam 2001 (clade 1) 90 microgram formulation represents an important first in the response to influenza pandemic preparedness efforts.  Sanofi Pasteur has a special responsibility and commitment to assist public health authorities in preparing for the possibility of a pandemic and to protect human health.  We and other manufacturers, along with our Government collaborators, continue development efforts aimed at bringing forward subsequent more advanced candidate vaccines that will allow us to respond in the event of a pandemic emergency.

            It is now my pleasure to introduce Dr. Robin Robinson, Acting Associate Director, Public Influenza, Health and Human Services, unless there are any clarifying questions.  Okay.  Thank you.

            DR. ROBINSON:  Good morning, distinguished panelists and guests.  We are here today to discuss the H5N1 vaccines that the HHS has brought together for stockpiling. What I'd like to discuss briefly with you this morning is the department's and the nation's strategic plans and goals, our program portfolio matrix to carry out those and achieve those goals, the stockpile requirements for the H5N1 vaccines, the H5N1 vaccine production where we are today, and finally have a few summary remarks on the H5N1 vaccine being discussed this morning.

            Why are we here today?  Dr. Baylor has already alluded to that.  In 1997, in Hong Kong, the city was hit with a poultry epidemic with high pathogenic avian influenza that wiped out many of the birds in the bird market and also crossed over into humans that were in contact with these infected birds.  After cleansing and closure of these live bird markets, the epidemic was halted.  However, in the winter of 2003 and 2004, H5N1 highly pathogenic avian influenza viruses re-emerged in water fowl and domestic poultry to cause an epidemic in Eastern Asia and also causing human deaths in Thailand and Vietnam.

            In response to these events, the National Strategy for Pandemic Influenza was prepared and issued November 1, 2005.  The President requested appropriations of $7.1 billion dollars of which $5.3 billion dollars has been appropriated thus far.  In this strategy, the department and the nation communicated the needs for vaccine, antiviral and diagnostic research and development, stockpiling of antiviral and vaccines and the communication of other infrastructure building for the vaccine industry to address pandemic preparedness and response needs.

            From that strategy, an implementation plan was prepared and issued in May of 2006.  In this implementation plan, there are over 300 action items that the departments within the U.S. Government and the individual agencies within each department are responsible for implementing this pandemic preparedness and response actions.  It provides guidance for each of these items and it defines the specific roles, responsibilities, metrics and timelines for accomplishing these action items.  Further, it communicates to other non-federal entities including state and local governments, industry and even personal actions that can be taken for pandemic preparedness and response.

            Also, within the pandemic strategy and implementation plan is, where possible, the use of licensed antiviral drugs and vaccines.  From the strategy and implementation plan, there are a number of goals that have been enumerated.  I draw your attention to two of these goals for vaccines.  One is to establish and maintain a dynamic pre-pandemic influenza vaccine stockpile available for 20 billion persons in the critical workforce including first responders.  Secondly, and built onto that, is to provide pandemic vaccines for all U.S. citizens within six months of the onset of a pandemic and, therefore, if a pandemic vaccine is two doses per person, that would mean that we need 600 million doses.

            How did HHS try to accomplish and account for these goals?  Well, we've developed an approach that was considered a program portfolio matrix, and I draw your attention to this approach for vaccines, antivirals and diagnostics and the areas of advanced development, stockpiling acquisitions and infrastructure building.  Specifically, for this particular discussion, H5N1 vaccine stockpiles were established and developed in association with our sister agencies, the NIH, CDC, FDA and our industry partners that are U.S. licensed influenza vaccine manufacturers.

            In 2004, we set out to establish these stockpiles giving industry the experience necessary to produce these vaccines at commercial scale, and we had a number of requirements to establish and maintain this stockpile.  First, that it should be fore 20 million persons in the critical workforce including the first responders.  Second, it would be for the usage at the onset of an H5N1 virus pandemic prior to the release of a well-matched pandemic vaccine.  Thirdly, that this vaccine stockpiling manufacturing should be done without disrupting seasonal influenza vaccine manufacturing campaigns.  Fourth, usage of apathogenic reassortants of high-risk virus strains as virus reference seeds were mandated for this manufacturing and that the manufacturing should be done at influenza vaccine sites, because these sites are the professionals at making influenza vaccine, and they use the commercial scale manufacturing process for the licensed inactivated split monovalent influenza vaccines.  Therefore, as Dr. Baylor said, it would be a strain change for an antigen alone vaccine.

            This vaccine, as already pointed out, is stored both as bulk and final container vaccine, and stability testing has been ongoing since September of 2004 when the first contracts were let.  Further, by most of the vaccine being involved form, we're able to formulate the final container vaccine as antigen alone or with adjuvant as safety and immunogenistic cross protective data become available and warrant its usage.

            The industry was given liability relief in the form of the PREP Act earlier this month.  And finally, the goal of securing U.S. licensed vaccine product prior to usage was a mandate where possible.

            So where are we today with this H5N1 vaccine stockpiling production?  We see that we have two clades, clade 1 and clade 2, the clade 1 being the Vietnam strain 1203; the clade 2 being the Indonesian 0505 strain.  I draw your attention that a dose for these calculations was based on 90 micrograms per dose and that a vaccine course is two doses per person.  In a 2004 campaign, .47 million vaccine courses were produced by Sanofi Pasteur.  In subsequent years, in 2005, multiple manufacturers were producing stockpiles.  So in 2005, we had 8 million vaccine courses produced of clade 1 vaccine.  In 2006, last year, we had 1 million clade 1 vaccine courses produced and an estimated amount of 4.8 million vaccine courses of clade 2 vaccine.

            At this present, we have contracts for at least 1.6 million vaccine courses for this year.  And there may be more produced later on in this fall.

            So currently, for clade 1 vaccines, we have enough vaccine for 9.5 million persons.  And clade 2, we have enough for probably 6.5 million depending on what the actual potency assay data has come out to be.  That's an antigen preparation.

            Finally, again, why are we here today?  Well, one of the things is that today represents the cooperative leveraging of resources throughout HHS, the NIH, CDC, FDA and ASPR with industry to develop, manufacture and test an H5N1 vaccine candidate most similar to the U.S. licensed seasonal influenza vaccines.  Also, today is a discussion of the first H5N1 vaccine candidate that could be licensed for immediate usage if an H5N1 pandemic emerges this year.

      Thank you.  Any questions?  Otherwise, Dr. Linda Lambert from the NIH will share with you the important work that they've done on development of this vaccine.

            DR. LAMBERT:  Thank you so very much.  I've been asked to give you a brief introduction to NIAID's pandemic vaccine research development efforts and then really to set the stage for Dr. John Treanor who will present results from the New England Journal of Medicine article and comment on safety data from some of our follow on studies.

            The overall goal of the National Institutes of Health and the National Institute of Allergy and Infectious Diseases in particular is to serve the public health by conducting and supporting research on infectious and allergic diseases.  And as you've heard Dr. Robinson previously indicate, we are all part of a broader Department of Health and Human Services pandemic influenza research plan.

            For NIAID, that means research on controlling, preventing and treating seasonal and pandemic influenza.  And at NIAID, we do that through a variety of different levels of research from assessing the basic biology of the virus to understanding the immunology and host response to characterize newly emerging influenza strains and understanding the molecular basis of virulence and transmission and to develop and clinically evaluate new diagnostics, drugs and vaccines and to coordinate and collaborate these efforts with other parts of the U.S. Government, most notably DHHS, NVPO, FDA, CDC and other public health service efforts, and finally, to generate information that will further inform ongoing global pandemic preparedness efforts.

            So let me take you back in time.  This map looks a little different from some of those that you are familiar seeing with.  This is actually the map that is from late January 2004, and you heard Dr. Robinson allude to the outbreaks that were going on in Hong Kong in 1997.  But in this map in January of 2004, we were dealing with yet another level of unprecedented outbreak.  And so as of just a little over three years ago, there were outbreaks in humans in two countries and poultry outbreaks in a number of countries.  And you know subsequently to this slide and over the last several years, that has expanded greatly.  But in early 2004, this is what the map looked like.

            So NIAID's response to that, that unprecedented level of outbreaks, both in human and poultry, was to obtain H5N1 vaccines for manufacturers with licensed products as quickly as possible.  And in May of 2004, NIAID awarded a contract on behalf of DHHS to Aventis Pasteur, so Sanofi Pasteur, to produce a pilot scale lot of H5N1 using a scaled down manufacturing process that was as similar as possible to their licensed vaccines.  And we asked for two formulations, 30 micrograms and 90 micrograms per mil.

            So the goal of this -- there were many goals associated with obtaining this vaccine, certainly to gain experience overcoming both technical and logistical issues, and that was for the U.S. Government as well as the manufacturer, so to demonstrate the use of reverse genetics to generate an H5 vaccine reference virus and obtain select agent exemption from the U.S. Department of Agriculture; to produce reagents -- and this was done largely between Sanofi Pasteur and the FDA to generate the types of reagents that were needed to assess the potency of the vaccine; to develop assay capacity to be able to measure antibody responses to individuals who received the vaccine.  And then, really, of all this set the stage for developing a framework and groundwork by which the companies could move to, if needed, commercial-scale manufacturing.

            Other objectives -- clearly, to rapidly implement well-controlled Phase I and Phase II clinical trials; to obtain data on the safety and immunogenicity of the vaccine.  And the goal for this was to provide initial data comparing dose ranging immune responses to form the basis of additional clinical trials and to assess multiple populations, so just not in health adults but also in the elderly and pediatric populations, and then support the development and use of an H5N1 hemagglutination HI assay and microneutralization assay and be able to have an infrastructure that supported rapid data analysis data collection.

            So specifically now focused on Sanofi Pasteur, in June of 2004, NIAID provided a clade 1 H5N1 reference virus to Sanofi Pasteur, and that virus was an A/Vietnam 1203 2004 strain with a neuraminidase and genetically modified hemagglutinin gene and the remaining six genes from the PR8 virus.  In March of 2005, Sanofi Pasteur delivered that vaccine to the NAIAD.  In April of 2005, NIAID initiated the first H5N1 vaccine in healthy adults.  And as you've heard Dr. Baylor say, that was done at three of our VTEU sites, and the study started in early April but was fully enrolled as of May 20th.  And then NAIAD transferred preliminary and safety data sets for that study, 04-063, to Sanofi Pasteur for their BLA submission.

            So at that point, I'd like to turn it over to Dr. John Treanor who will give you an update or a summary of the results of the adult study.  That's NAIAD 04-063 that was published in the New England Journal and a brief overview of our follow on studies.

            DR. TREANOR:  Thanks, Linda.  What I'm going to talk about then is the evaluation of the Sanofi subvirion vaccine made from the reverse genetically engineered virus, created it at St. Jude and put on the PR8 background that was done in health adults at three of NAIAD's VTEUs, our site at the University of Rochester, the University of Maryland led by a co-investigator, Jim Campbell, and the UCLA led by Ken Zangwill in collaboration with SRI which performed the immunologic assays and EMMES Corporation which did data management and statistical analysis.

            Now this slide is an overview of the study design.  You can see here where the vaccine was administered, the red triangles; where safety assessments were done; and where antibody sera were obtained.  The study was done in a two stage design.  Because this was the first human experience with the vaccine, approximately one-quarter of the subjects were enrolled in Stage 1 and were randomized to receive either placebo or vaccine at 90, 45, 15 or 7.5 micrograms.  And in addition to assessing safety by memory aids and medical histories and follow-up visits, these subjects also had laboratory safety done before vaccination an