AU G U S T 2 0 10

Executive Office of the President

President’s Council of Advisors on

Science and Technology

R EPORT TO THE PR ESIDENT ON 

R EENGINEER ING THE INFLUENZA 

VACCINE PRODUCTION ENTER PR ISE 

TO MEET THE CH ALLENGES 

OF PANDEMIC INFLUENZA

AU G U S T 2 0 10

Executive Office of the President

President’s Council of Advisors on

Science and Technology

R EPORT TO THE PR ESIDENT ON 

R EENGINEER ING THE INFLUENZA 

VACCINE PRODUCTION ENTER PR ISE 

TO MEET THE CH ALLENGES 

OF PANDEMIC INFLUENZA
About the President’s Council of 

Advisors on Science and Technology 

The President’s Council of Advisors on Science and Technology (PCAST) is an advisory group of the 

Nation’s leading scientists and engineers, appointed by the President to augment the science and 

technology advice available to him from inside the White House and from cabinet departments and 

other Federal agencies. PCAST is consulted about and often makes policy recommendations concerning 

the full range of issues where understandings from the domains of science, technology, and innovation 

bear potentially on the policy choices before the President. PCAST is administered by the White House 

Office of Science and Technology Policy (OSTP). 

For more information about PCAST, see www.whitehouse.gov/ostp/pcast
★ i ★

The President’s Council of Advisors 

on Science and Technology

John P. Holdren

Assistant to the President for 

Science and Technology

Director, Office of Science and 

Technology Policy

Eric Lander

President

Broad Institute of Harvard and 

Massachusetts Institute of 

Technology

Harold Varmus

President

Memorial Sloan-Kettering 

Cancer Center

Co-Chairs

Members

Rosina Bierbaum

Dean, School of Natural Resources and 

Environment

University of Michigan

Chrisine Cassel

President and CEO

American Board of Internal Medicine

Christopher Chyba

Professor, Astrophysical Sciences and 

International Affairs

Director, Program on Science and Global Security

Princeton University

S. James Gates, Jr.

John S. Toll Professor of Physics

Director, Center for String and Particle Theory

University of Maryland, College Park

Shirley Ann Jackson

President

Rensselaer Polytechnic Institute

Richard C. Levin

President

Yale University

Chad Mirkin

Rathmann Professor, Chemistry, Materials 

Science and Engineering, Chemical and 

Biological Engineering and Medicine

Director, International Institute of 

Nanotechnology

Northwestern University

Mario Molina

Professor, Chemistry and Biochemistry

University of California, San Diego

Professor, Center for Atmospheric Sciences at the 

Scripps Institution of Oceanography

Director, Mario Molina Center for Energy and 

Environment in Mexico City

Ernest J. Moniz

Cecil and Ida Green Professor of Physics and 

Engineering Systems

Director, MIT’s Energy Initiative

Massachusetts Institute of Technology

Craig Mundie

Chief Research and Strategy Officer

Microsoft Corporation
★ ii ★

R EP O RT TO T H E P R E S I D EN T O N R EEN G I N EER I N G T H E I N F LU EN Z A VACC I N E 

P RO D U C T I O N EN T ER P R I S E TO M EE T T H E C H A LLEN G E S O F PA N D EM I C I N F LU EN Z A

Ed Penhoet

Director, Alta Partners

William Press

Raymer Professor in Computer Science and 

Integrative Biology

University of Texas at Austin

Maxine Savitz

Vice President

National Academy of Engineering

Barbara Schaal

Chilton Professor of Biology

Washington University, St. Louis

Vice President, National Academy of Sciences

Eric Schmidt

Chairman and CEO

Google, Inc.

Daniel Schrag

Sturgis Hooper Professor of Geology

Professor, Environmental Science and 

Engineering

Director, Harvard University-wide Center for 

Environment

Harvard Univeristy

David E. Shaw

Chief Scientist, D.E. Shaw Research

Senior Research Fellow, Center for 

Computational Biology and Bioinformatics,

Columbia University

Ahmed Zewail

Linus Pauling Professor of Chemistry and Physics

Director, Physical Biology Center

California Institute of Technology

Staff

Deborah Stine

Executive Director, PCAST

Mary Maxon

Deputy Executive Director, PCAST
★ iii ★

EXECUTIVE OFFICE OF THE PRESIDENT

PRESIDENT’S COUNCIL OF ADVISORS ON SCIENCE AND TECHNOLOGY

WASHINGTON, D.C. 20502

President Barack Obama

The White House

Washington, DC 20502

Dear Mr. President,

We are pleased to send you this report, Reengineering the Influenza Vaccine Production Enterprise to Meet the 

Challenges of Pandemic Influenza, prepared by your President’s Council of Advisors on Science and Technology 

(PCAST). This report examines how the Nation can more rapidly and reliably produce effective vaccines, at a 

sufficient scale to protect all of the Nation’s residents, in response to the emergence of pandemic influenza. 

To provide a solid scientific and economic basis for our recommendations, the Council assembled a PCAST 

Working Group of non-governmental experts, and met with government officials, industry representatives, 

and public health experts to discuss how to enhance the influenza vaccine manufacturing process. Based 

on these discussions, PCAST identified several shortcomings in the complex system that must move quickly 

from the appearance of a new pandemic virus to the manufacture of effective influenza vaccines. 

The report recommends a number of steps that can be taken over the next one to two years to cut several 

weeks from the time currently needed to produce the first doses of a new vaccine. In addition, PCAST identified actions that could greatly improve the reliability of the vaccine manufacturing enterprise over a two to 

ten year timeframe, further shortening the time required to provide vaccine to the entire U.S. population. 

Several of the recommendations can also improve the Nation’s ability to mount medical counter-measures 

against a variety of infectious agents. Finally, the successful production of an effective pandemic influenza 

vaccine requires coordinated actions on the part of government and the private sector; as part of its review, 

PCAST identified ways to better utilize public-private partnerships to optimize the Nation’s vaccine production enterprise. 

PCAST hopes that its Executive Report and the full Working Group report help lay a foundation for the decisions that you and others in the Federal Government must make. We are grateful for the opportunity to serve 

you and the country in this way.

Sincerely,

John P. Holdren Eric Lander Harold Varmus

Co-Chair Co-Chair Co-Chair

★ v ★

The President’s Council of Advisors 

on Science and Technology

Executive Report

Reengineering the Influenza Vaccine Production Enterprise to Meet the 

Challenges of Pandemic Influenza

Between April 2009 and February 2010, the United States experienced its most recent outbreak of 

pandemic influenza, this one resulting from the appearance of a novel strain of Type A, H1N1 virus. From 

the earliest recognition of the pandemic, public health officials in the United States moved rapidly to 

respond, but their efforts were impeded by unanticipated delays that arose in manufacturing what was 

supposed to be the most powerful tool for preventing widespread morbidity and mortality: a vaccine 

designed to protect against the 2009 H1N1 virus. Fortunately, the pathogenic potential of the 2009 

H1N1 virus remained relatively mild, limiting morbidity and mortality, although a disproportionate 

number of deaths occurred among children and young adults. This less-than-optimal experience—one 

that developed despite the appropriate and energetic response of vaccine manufacturers and public 

health officials—raised new awareness of the limitations of the system by which influenza vaccines are 

produced today.

At the request of the Executive Office of the President, the President’s Council of Advisors on Science and 

Technology (PCAST) undertook a review of the processes currently employed for producing influenza 

vaccines. To execute this review, PCAST formed the Influenza Vaccinology Working Group, chaired by two 

of the PCAST co-chairs and further composed of six non-governmental experts in virology, immunology, 

vaccine manufacturing, and public health. PCAST considered ways the Federal Government might help 

to improve the technologies used for making vaccines for pandemic influenza, with a special focus on 

efforts that would address the following question:

How can the Federal Government help to reduce the time required for the Nation to supply 

effective vaccine to its population when the next influenza pandemic occurs? 

It is useful to put this in a quantitative context by considering the time frame for action in 2009 and the 

future. In the case of 2009 H1N1, the time between the declaration of a need for a vaccine against the 

pandemic virus and the start of the second wave of the pandemic in the United States was 18 weeks, 

and the time to the peak of the second wave was about 26 weeks. Each pandemic will surely differ, but 

this provides a reasonable indication of the time in which a large supply of effective vaccine might be 

required in subsequent pandemics. 

The case of 2009 H1N1 also shows the challenges in meeting these time lines. Due to difficulties in 

producing vaccine, initial doses became available only after about 26 weeks, sufficient doses to cover 

half the population became available at 38 weeks and supply adequate to protect the entire Nation 
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would have taken approximately 48 weeks to produce. This timeline was far too slow, by approximately 

3 to 5 months. 

Protecting the nation from an influenza pandemic thus requires tightening the schedule for making 

vaccine substantially: in a serious pandemic, saving weeks could translate into saving tens of thousands 

of lives.

With the goal of identifying ways to reduce the time to protect the public from the next pandemic, PCAST 

examined each step in the manufacturing process now used to make influenza vaccines, addressed the 

impact of improvements in each component on the time required to deliver the first doses of a new 

pandemic vaccine and to deliver all of the vaccine that would be required to protect the United States 

population. In addition, PCAST assessed a number of economic and regulatory issues that, regardless 

of technological developments, are potential barriers to improving the Nation’s ability to protect its 

residents against pandemic influenza. In its review, PCAST also considered how changes in the production of pandemic influenza vaccines would affect the manufacture of seasonal influenza vaccines, and 

its work was also recognized as related to simultaneous studies of the larger United States medical 

countermeasure effort, which also includes vaccine development as part of its charge. PCAST’s deliberations were informed by discussions with government officials and others in industry and academia with 

expertise in vaccine development and manufacturing. 

In considering a path forward for reengineering the Nation’s influenza vaccine enterprise, PCAST has 

developed a series of specific recommendations for action by the Federal Government. PCAST’s analysis 

identified several components of the current influenza vaccine manufacturing process that could be 

improved substantially within the next two years without substantial alterations to the overall influenza 

vaccine enterprise, as well as transformations that will require action and support for the next two to 

six or more years. The effects of PCAST’s recommendations on the delivery of pandemic influenza vaccines are summarized in Table ER-1 below. Comparisons of the approximate timelines for delivery of the 

first dose of vaccine are shown in Figure ER-1 for the current production method, using virus grown in 

embryonated chicken eggs, and for two of the most promising techniques for shortening those time 

lines, vaccines that uses viruses grown in cultured cells and those made with proteins produced with 

recombinant DNA technology.

PCAST has not determined anticipated costs for the projects required to make these improvements 

and has not attempted to allocate the share of financial responsibility to be borne by the governmental 

agencies or the companies. It is fair to assume, however, that an initial $1 billion in Federal funds—and 

at least similar sums over the subsequent few years—would be required to make the changes that will 

allow the Nation to mount a vigorous effort that can protect its population as well as possible in the 

event of another pandemic, an event that could have catastrophic consequences. Even in the relatively 

mild 2009 pandemic, over 2000 lives—mostly relatively young people, with an average age of less 

than forty—could have been saved if vaccination had begun even one month earlier. Furthermore, as 

this report makes clear, most of the Federal funds used to increase capacity to respond more quickly 

to influenza pandemics would also help to develop the technical platforms and production facilities 

that would support medical countermeasures more broadly against a variety of pathogens. For these 

reasons, an investment of $1 billion or more for several years can be justified on a cost:benefit basis.
The President ’s Council of Advisors on Science and Technology

★ vii ★

Table ER-1. Effects of Recommended Actions on Delivery of Pandemic 

Influenza Vaccines

Recommended 

Change

Estimated Time 

Required to Make 

the Change

Effects on 

Time to 

First Dose

Effects on Bulk 

Production Until 

Demand Satisfied

Alternative 

Uses in Medical 

Countermeasure

Increased 

Surveillance 1-3 years

Moves the starting 

line forward by 

weeks or more

None Yes

Faster Production 

of Optimal Vaccine 

Seed

1-2 years Up to several 

weeks

Up to several weeks 

(if more efficient 

virus growth)

No

Modernized 

Sterility Tests 1-2 years Approximately 1 week None Yes

Improved 

Generation of 

Potency Reagents

1-2 years

Avoids possible 

delay of up to 

several weeks

None Possibly

Expanded and 

Streamlined 

Fill and Finish 

Procedures

1-3 years Slight Up to weeks Yes

Shift to Cell 

Culture to make 

Killed Vaccine

1-3 years A few weeks Up to several weeks Possibly

Shift to Cell 

Culture for Live 

Attenuated 

Vaccine

2-6 years A few weeks Up to several weeks Possibly

Recombinant–

based Vaccine 2-10 years Several weeks Up to several weeks Yes
★ viii ★

R EP O RT TO T H E P R E S I D EN T O N R EEN G I N EER I N G T H E I N F LU EN Z A VACC I N E 

P RO D U C T I O N EN T ER P R I S E TO M EE T T H E C H A LLEN G E S O F PA N D EM I C I N F LU EN Z A

Recommendations for Actions with Short-term Impact

Several recommended actions could improve the reliability and speed of delivering influenza vaccines 

over the next one to three years, without fundamental changes in the modes of manufacturing. Each 

of these actions could significantly shorten the time to delivery of the first doses of vaccine by one to 

several weeks. In the aggregate, these improvements could reduce the time predicted for first deliveries of vaccine after deciding to make a pandemic vaccine by approximately half of the current twenty 

weeks. Furthermore, improved surveillance could advance the start of the entire process of vaccine 

development by up to several weeks. 

• Accelerate the identification of new pandemic threats by directing the Centers for Disease 

Control and Prevention (CDC) to fund the development and adoption of molecular platforms 

and supplement traditional clinical and microbiological methods that would enhance surveillance of human beings and certain animals for influenza viruses and other agents of respiratory 

illness. 

Early detection of a viral pathogen, especially a pandemic strain of influenza virus, using the tools 

of modern molecular biology and diagnostic technologies can provide a powerful advantage by 

Approximate time lines to production of first dose of vaccine when producing inactivated influenza vaccine in 

chicken eggs and cell culture and recombinant vaccine produced in cell culture; time to final doses needed 

depends on manufacturing capacity. 

Week

2 4 6 8 10 12 14 16 18 20 22 24 26

Egg-based (inactivated)

Cell Culture

HA Recombinant

Potency Reagents for HA Vaccines (FDA) **

Prepare, verify,

distribute vaccine strain

to manufacturers (CDC)

Optimize seed virus

growth for working 

seed (Mf)

Manufacture bulk

vaccine, QC test, &

pool (Mf)

Release of

Vaccine

(FDA)

Fill & ­nish

vaccine:

First lots (Mf)

Note: Mf = Manufacturers

Figure ER-1. A Comparison of Vaccine Production Timelines
The President ’s Council of Advisors on Science and Technology

★ ix ★

identifying a potential pathogen at an earlier time than is often possible with systems that are based 

largely on the recognition of overt disease in places thought to be at especially high risk. Earlier identification and reporting of the 2009 H1N1 virus could have helped to provide earlier delivery of first doses 

and greater amounts of vaccine before the peak of the second wave of the pandemic by advancing the 

start of the vaccine production process. 

• Facilitate preparation of the virus strains to be used for vaccine production (so-called “seed 

viruses”) by directing the National Institute of Allergy and Infectious Diseases (NIAID) and the 

Biomedical Advanced Research and Development Authority (BARDA) to use focused contracts 

to ensure the development and dissemination of new influenza virus “backbones” that can 

exchange genes with new pandemic strains and are optimized for rapid growth.

The difficulty of creating strains of influenza virus suitable for use as seed strains optimized to grow 

rapidly under the conditions used to manufacture influenza vaccine proved to be a major bottleneck 

in responding to the 2009 H1N1 pandemic. Several technologically feasible options are available for 

hastening and regularizing the process of generating an initial seed strain. These include the development of a pre-existing set of viral backbones, increasing the likelihood that a highly proliferative seed 

virus can be quickly generated and that the initial seed virus will require little or no further optimization.

• Shorten the time required for sterility testing of vaccines (for influenza and other vaccines) 

before vaccine release, by directing BARDA and the Food and Drug Administration (FDA) to fund 

applied research that will adapt rapid nucleic acid amplification and sequencing methods to 

test for sterility, rather than depending on classical microbial assays.

Each batch of vaccine material must pass a sterility test to ensure that it is not contaminated with 

bacteria or fungi. While current methods of doing this are reliable, they take approximately two weeks. 

More rapid sterility test methods, based on array-based sequencing methods and other technologies, 

are available and could cut the time for vaccine release by at least a week. 

• Shorten the time and increase reliability for preparation of reagents for potency testing,

by directing BARDA and the FDA to fund applied research that will develop rapid methods for 

assessing the concentration of antigenic materials, circumventing the need for production of 

new antibodies and/or traditional immunological tests.

A critical step in manufacture of many vaccines, including inactivated influenza vaccines is testing vaccine material to determine the concentration of correctly folded antigen. This process is called “potency” 

testing, although it actually measures the amount of physical material that reacts with antibodies, 

rather than its true ability to induce an effective immune response. The method used today for testing 

potency of inactivated or killed vaccine is straightforward and by itself is not time consuming. However, 

the reagents used in the test are sheep antibodies raised against the viral protein hemagglutinin, and 

the steps required to produce those antibodies can take 8 to 12 weeks or longer if problems result. It 

should be possible, however, to develop new approaches to potency testing, using technologies available today that would eliminate the unpredictable nature of the current methods.

• Assemble a manufacturing network with sufficient capacity to rapidly fill the vials, syringes, 

and sprayers required for delivery of vaccines for influenza and other viruses, by working with 
★ x ★

R EP O RT TO T H E P R E S I D EN T O N R EEN G I N EER I N G T H E I N F LU EN Z A VACC I N E 

P RO D U C T I O N EN T ER P R I S E TO M EE T T H E C H A LLEN G E S O F PA N D EM I C I N F LU EN Z A

industry to adopt advanced manufacturing practices, modify existing facilities, or construct new 

facilities. As part of this effort, the Federal Government, working closely with manufacturers, 

should undertake a comprehensive study within six months to quantitatively assess current 

fill-finish capacity and to develop a plan to ensure adequate capacity to produce sufficient 

quantities of pre-filled syringes, vials and/or nasal sprayers to meet the national need.

All vaccines must eventually be packaged. The “fill-finish” step for inactivated influenza vaccines involves 

transferring bulk vaccine into individual single-dose syringes as well as the single or multi-dose vials used 

for inactivated influenza vaccines or to nasal sprayers required for the live attenuated virus vaccines. This 

step is a major hurdle on the path to vaccine distribution to providers, and represents a costly and laborious phase of manufacturing that can be expanded only in a linear fashion, and it generally proves to be 

a major rate-limiting step in the process of delivering vaccine, especially under pandemic conditions. 

Recommendations for Actions with Longer-Term Impact

In addition to examining the vaccine manufacturing enterprise with an eye on short-term fixes, PCAST 

also considered the prospects for making substantial changes in the composition of influenza vaccines or 

in the methods by which influenza vaccines are produced. These actions are likely to require significant 

additional investments on the part of both the Federal Government and the private sector, and they 

will require close collaboration between the private and public sectors. PCAST’s recommendations for 

action that would substantially reengineer the vaccine manufacturing enterprise over a longer time 

period include:

• Understand current capacity for cell culture production and develop incentives to expand 

capacity. 

PCAST recognized that without replacing the inherently time-consuming egg-based method of production with either a cell culture-based method or a recombinant DNA-based method of production, 

delivery of all of the needed vaccine, up to the last dose, will remain a long and unpredictable process. 

However, it is likely that existing facilities available for cell culture production do not have adequate 

capacity to meet vaccine demand. DHHS, DHS, and BARDA should lead a systematic, rapid study, 

involving governmental and non-governmental experts, of the requirements for and cost-benefit ratio 

of additional investments in cell culture manufacturing facilities. This study should also balance the 

magnitude of investment and time frame for expansion of cell culture facilities against the likelihood 

of developing approved recombinant influenza vaccines in the foreseeable future, the probability of 

another pandemic, and the advantages of greater use of live attenuated influenza vaccines. 

• Accelerate clinical research studies and regulatory approval for wider use of live attenuated influenza virus (LAIV) vaccines.

Influenza vaccines made with live attenuated influenza virus may be able to trigger a more effective 

immune response than can inactivate virus vaccines. As a result, production capacity demands in the 

event of a pandemic would be lower if the majority of vaccine production was devoted to LAIV vaccines. However, the immunological basis of the clinical protection afforded by LAIV vaccines is not fully 

understood. Therefore, the FDA requires that LAIV vaccines—whether produced in chicken eggs or 
The President ’s Council of Advisors on Science and Technology

★ xi ★

cell culture, be shown through an extensive efficacy trial to be as effective as inactivated virus vaccines 

currently produced in embryonated chicken eggs; the cost of such studies typically range from $50 

million to as much as $100 million. This cost is a major barrier to the more widespread development of 

LAIV vaccines, whether for seasonal or pandemic influenza.

• Launch an aggressive initiative that supports the development, clinical testing, and 

approval of influenza vaccines made using recombinant DNA technology, with the goal 

of achieving proofs-of-principle for at least three strategies for recombinant vaccines within 

three years. 

Recombinant DNA technology is already used to make vaccines against hepatitis B and human papilloma viruses, and early evidence suggests that recombinant DNA technology can also be used to create 

influenza vaccines. Using recombinant DNA technology and other advanced methodologies to produce 

influenza vaccines would shorten the time to both first and last dose of vaccine, and could offer other 

advantages for vaccine manufacturers. 

• Develop an investment strategy that allows flexibility in financing of promising vaccine 

production platforms, and create downstream incentives for products that meet the 

target product profile and production criteria.

Given the commodity nature of the influenza vaccine market, it may be necessary for the Federal 

Government to establish downstream incentives, such as guaranteed purchases or a high-value prize, 

and to work in concert with venture capital firms and other investors to make direct investments in 

companies with promising next-generation vaccine platforms. 

• Support clinical tests of existing and new vaccines in the presence of adjuvants, the 

development of a regulatory guidance document for adjuvants, and further research and 

development on adjuvants.

By stretching the limited vaccine supply, addition of adjuvants to a vaccine formulation can shorten the 

time between provision of the first and last doses by several weeks. Adjuvants may also be required to 

elicit maximum immunity from vaccines produced using recombinant DNA technology.

• Support basic immunology research aimed at understanding how the immune system 

responds to influenza virus with the goal of developing a “universal” influenza vaccine that 

would provide broad protection for multiple years against both existing and new strains of 

influenza virus.

Unlike most vaccines that afford long-term protection against pathogenic viruses, new influenza vaccines must be developed each time a novel influenza virus appears in the human population. However, 

recent research suggests that it may be possible to create a “universal” influenza vaccine that could provide broader protection against both seasonal and pandemic influenza, but additional work is needed 

to further explore the promise of developing such a vaccine. 

• Implement a new management structure for overseeing the mission-driven enterprise to 

reengineer the Nation’s influenza vaccine development and production enterprise. 
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PCAST also recommends that the Administration develop a new management structure that vests 

authority with the Assistant Secretary for Preparedness Response (ASPR) at the Department of Health 

and Human Services (HHS) to coordinate and task component agencies at HHS with activities necessary 

to support the reengineering process recommended above. To assist with these activities, HHS should 

also establish a small advisory committee, comprised of representatives from the biotechnology, pharmaceutical and investment communities, to guide its engagement with industry. This committee’s advice 

should be considered seriously in all decisions and actions by the Department, given the paramount 

importance of the relationship between the Federal Government and industry partners. Finally, all of 

the Administration’s efforts to improve the Nation’s capacity to respond quickly and effectively to the 

next influenza pandemic should be closely monitored by the White House, especially by the staff of the 

National Security Council.
★ xiii ★

The President’s Council of Advisors 

on Science and Technology

Reengineering the Influenza Vaccine Production 

Enterprise to Meet the Challenges of Pandemic Influenza

Working Group Report

★ xv ★

PCAST Influenza Vaccinology 

Working Group

Peter Emanuel

Assistant Director for Chemical & Biological 

Countermeasures

Office of Science and Technology Policy 

Deborah D. Stine 

Executive Director, PCAST

* PCAST member

Co-Chairs

Eric Lander*

President

Broad Institute of Harvard and Massachusetts 

Institute of Technology 

Harold Varmus*

President

Memorial Sloan-Kettering Cancer Center

Members

Staff

Ann Arvin

Vice Provost and Dean of Research

Lucile Salter Packard Professor of Pediatrics 

Professor of Microbiology & Immunology

Stanford University 

David Baltimore

President Emeritus

Robert Andrews Millikan Professor of Biology

California Institute of Technology

Emilio A. Emini

Executive Vice President

Vaccines Research and Development

Wyeth Pharmaceuticas

Harvey V. Fineberg

President

Institute of Medicine

Steve Reed

President and CEO 

Immune Design Corporation

Founder and Head of Research and Development

Infectious Diseases Institute

Rajeev Venkayya

Director of Global Health Delivery

Bill & Melinda Gates Foundation

★ xvii ★

Table of Contents

I. Introduction, Charge, and Summary of Findings . . . . . . . . . . . . . . . . . . 1

The Pandemic of 2009 and the Vaccine Problem . . . . . . . . . . . . . . . . . . . 1

PCAST on Influenza Vaccinology and its Charge 2

The Analysis of the Problem and Major Findings . . . . . . . . . . . . . . . . . . . 4

II. The Influenza Vaccine Problem . . . . . . . . . . . . . . . . . . . . . . . . 11

Framework for Analysis: Timelines for Vaccine Production 12

Weighing Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Economics of Vaccine Manufacture . . . . . . . . . . . . . . . . . . . . . . . 17

Components of a National Response: An Overview . . . . . . . . . . . . . . . . . 18

III. Potential Benefits of Short-Term Changes in Methods for Making Influenza Vaccines . . 21

Surveillance 21

Development of Influenza Vaccine Seed Strains . . . . . . . . . . . . . . . . . . 24

Potency Testing of Influenza Vaccine During Production and Release . . . . . . . . . . 25

Sterility Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Manufacturing Fill-Finish Capacity . . . . . . . . . . . . . . . . . . . . . . . . 28

IV. Production of Influenza Vaccines in Cultured Cells 29

Cell Culture-Based Production . . . . . . . . . . . . . . . . . . . . . . . . . 29

Advantages of Producing Influenza Vaccine Using Mammalian Cell Culture 32

Barriers Impeding Influenza Vaccine Production Using Mammalian Cell Culture . . . . . . 33

Live Attenuated Influenza Vaccine . . . . . . . . . . . . . . . . . . . . . . . . 35

V. Recombinant Influenza Vaccines . . . . . . . . . . . . . . . . . . . . . . . . 37

Production of Recombinant DNA-Based Vaccines . . . . . . . . . . . . . . . . . . 37

Experience with Recombinant Vaccines . . . . . . . . . . . . . . . . . . . . . . 40

Taking the Initiative 42
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P RO D U C T I O N EN T ER P R I S E TO M EE T T H E C H A LLEN G E S O F PA N D EM I C I N F LU EN Z A

VI. Adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

What Is an Adjuvant and Why Are Adjuvants Added to Vaccines? . . . . . . . . . . . . 45

Adjuvant Candidates for Influenza Vaccines . . . . . . . . . . . . . . . . . . . . 47

VII. “Universal” Influenza Vaccines . . . . . . . . . . . . . . . . . . . . . . . . 51

Is a Universal Vaccine Conceivable? . . . . . . . . . . . . . . . . . . . . . . . 52

VIII. A New Way of Doing Business 57

Assigning Responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Alignment with Broader Federal Medical Countermeasure Efforts . . . . . . . . . . . 60

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Appendix A: List of Acronyms 65
★ 1 ★

I: Introduction, Charge, and 

Summary of Findings

The Pandemic of 2009 and the Vaccine Problem

The 2009 influenza pandemic, caused by a novel strain of Type A, H1N1 virus (2009 H1N1), was initially 

detected as an unexpected outbreak of influenza-like illnesses in Mexico in mid-March, 2009. The virus 

spread rapidly in Mexico, the United States, and elsewhere; by June 11, the World Health Organization 

(WHO) declared a Phase 6 epidemic. (A more detailed summary of the 2009 pandemic is provided in 

Box 1-1 at the end of this chapter.) 

From the earliest recognition of the pandemic, public health officials in the United States moved rapidly 

to respond. It was assumed that vaccines would be an essential countermeasure, likely the most critical, 

on a list that also included antiviral drugs, social measures to diminish transmission, and intensive care 

for the critically ill.1 Ideally, vaccine would have been available before the second wave of the pandemic, 

which was expected to begin as early as late August. Yet when the second wave arrived, on schedule, 

the first doses of vaccine against the new strain of influenza virus were not available; in fact, they did 

not become available for use in the United States until October 5, about six weeks later. Moreover, only 

124 million doses, enough to immunize about forty percent of United States residents, were distributed 

by the end of January, three months after the incidence of infection peaked in late October. As of April, 

2010, an estimated 81-91 million doses of vaccine had been administered, covering about one-quarter 

of the US population. Much of it has still not been used, and little has been delivered to countries in 

the developing world. (A chronological account of vaccine production and delivery is also included in 

Box 1-2.)

Fortunately, the pathogenic potential of the 2009 H1N1 virus has remained relatively mild. The Centers 

for Disease Control and Prevention (CDC) estimates that 15 to 25% of the United States population was 

1. President’s Council of Advisors on Science and Technology. August 2009. Report to the President on U.S. 

Preparations for 2009-H1N1 Influenza. Available at www.whitehouse.gov/assets/documents/PCAST_H1N1_Report.pdf.

CHAPTER SUMMARY

This introductory chapter describes the pandemic caused by a novel H1N1 strain of influenza virus in 

2009; the difficulties in delivering vaccine to protect the US population against the second wave of the 

pandemic; and the convening of a Working Group, under PCAST, to study current methods for making 

vaccines against pandemic influenza, to recommend improvements in those methods, and to identify 

roles for the Federal Government in making those improvements. The chapter also outlines the nature of 

the relatively short-term and longer-term improvements that the Working Group has recommended in 

later chapters, and it describes both the components of the analysis (science, technology, public health, 

economics, regulation) and the relationship of the study to broader efforts by the United States to improve 

medical counter-measures against biological threats. 
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infected; between April 2009 and February 2010, 8500 to 17600 deaths were related to the pandemic. If 

this virus had been as lethal as those encountered in the more severe epidemics of the 20th century, the 

number of deaths in an unprotected United States population could have been 10- to 100-fold higher. 

Still, in contrast to the usual behavior of seasonal influenza, the burden of disease fell largely on young 

age groups: about 90% of hospitalizations and deaths occurred among people under the age of 65, and 

a disproportionate number of deaths (estimated by the CDC to be about 1280) occurred among those 

in the 0 to 17 year old age group.

While vaccine production fell short of the desired timetable, vaccine manufacturers and public health 

agencies operated appropriately and energetically, despite difficult circumstances. Vaccine makers 

typically produce seasonal influenza vaccine over a 9-10 month time frame that begins with the identification of viral strains by health officials in February and vaccine delivery in November or December of 

the same year. In contrast, the vaccine for the 2009 H1N1 virus was prepared and the initial doses were 

distributed less than six months after identification of the virus. Even so, that was too late to provide 

protection for most of the United States population, since the second wave of the pandemic began in 

the United States in late August and distribution of the bulk of the vaccine did not occur for another 

three or four months. (A brief description of the properties of influenza viruses responsible for seasonal 

and pandemic influenza and of the corresponding vaccines can be found in Box 1-3.) 

As will be described in detail in Chapter 2, the time to delivery of vaccine against the 2009 H1N1 virus 

could have been considerably shorter if the virus had been detected and isolated earlier (allowing more 

time between isolation of the virus and the return of the pandemic), if the working seed virus for making 

vaccine had been more quickly optimized, and if the seed strains had grown more abundantly in eggs 

(allowing more efficient production of vaccine). In short, despite valiant efforts by Federal agencies 

and several commercial manufacturers, vaccine was not available to protect a large segment of the 

public against a potentially devastating infection. The fault lay not in the execution, but in the inherent 

shortcomings of current technologies for the development and production of influenza vaccines.

PCAST on Influenza Vaccinology and its Charge

This sobering experience with 2009 H1N1 vaccines has refocused attention on national preparedness 

against infectious agents in general and against influenza viruses in particular. In August of 2009, before 

the second wave of the pandemic occurred in the United States, the President’s Council of Advisors on 

Science and Technology (PCAST) published a report on the various measures that were being taken to 

combat the on-going pandemic.2 While praising those efforts, the report also cautioned that vaccine 

was unlikely to arrive in time to protect the most vulnerable people—those who would normally receive 

the first doses of vaccine—and that production might also be inadequate to protect the majority of all 

people before the second wave of the pandemic peaked. 

When the pandemic subsided at the start of 2010, the Executive Office of the President (EOP) asked 

PCAST to revisit the processes currently employed for production of influenza vaccines, especially 

against pandemic influenza, and to consider whether and how the government might encourage the 

2. President’s Council of Advisors on Science and Technology. August 2009. Report to the President on U.S. 

Preparations for 2009-H1N1 Influenza. Available at www.whitehouse.gov/assets/documents/PCAST_H1N1_Report.pdf. 
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application of improved technologies to the problem of making influenza vaccines. In January 2010, 

PCAST formed a Working Group on Influenza Vaccinology, composed of experts in virology, immunology, vaccine manufacturing, and public health, to answer the following question:

How can the Federal Government help to reduce the time required for the nation to supply 

effective vaccine to its population when the next influenza pandemic occurs? 

It is useful to put this in a quantitative context:

• The interval between the recognition in late April 2009 of the need for a vaccine and the start 

of the second wave of infection in late-August 2009 was about 18 weeks; in future pandemics, 

the interval could be shorter. The time to the peak of the second wave was about 26 weeks.

• The WHO’s standard schedule for producing vaccine against pandemic influenza anticipates an 

approximately 20-week time schedule for initial availability of a new vaccine, with the subsequent time to produce enough doses to cover the entire nation depending on manufacturing 

capacity. 

• In the case of 2009 H1N1, difficulties in producing a vaccine stretched this timeline: it was about 

26 weeks until initial doses became available, it took a total of 38 weeks until sufficient supply 

was on hand to cover half the population, and it would have taken 48 weeks to have supply 

adequate to protect the entire Nation. This timeline was far too slow, by approximately 3 to 5 

months. 

• The timelines above focus only on vaccine production. Some additional time is required for 

vaccine distribution and administration, as well as 1-2 weeks for vaccinated individuals to gain 

immunity.

Protecting the nation from an influenza pandemic thus requires tightening the time schedule for vaccine production substantially. In a serious pandemic, saving weeks could translate into saving tens of 

thousands of lives.

To identify ways in which the time line could be shortened, PCAST considered: (i) each step in the 

WHO’s schedule for producing vaccine against pandemic influenza; (ii) the events that determined the 

dates of delivery of vaccine during the 2009 H1N1 influenza pandemic; (iii) a wide range of options for 

shortening the time to delivery of vaccines (by altering the type of vaccine, the mode of production, 

and the steps required to develop a new vaccine in response to a pandemic); and (iv) the economic and 

regulatory issues that pose potential barriers to altered methodologies. PCAST then developed a set of 

recommendations to guide the Federal Government’s efforts to improve the situation.

In addressing its question, PCAST took into account two aspects of the problem: the time to deliver 

initial supplies of vaccine (“time to first dose”), an important measure of protection of the most vulnerable, high-risk populations; and the time to deliver sufficient vaccine to meet the entire national need 

(“time to last dose”). The results of this analysis and PCAST’s recommendations are described in detail 

in subsequent chapters.
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The Analysis of the Problem and Major Findings

PCAST first reviewed all of the steps in the existing process that precede the packaging of finished 

vaccine products at manufacturing sites, with the intention of identifying procedures that could be 

improved or accelerated, assuming the country continues to depend on egg-based production of vaccines. These steps include: the surveillance that detects and isolates viral pathogens; the generation of 

derivative viruses that can be used for vaccine production (“seed” viruses); the growth of virus in chicken 

eggs; the production of reagents for testing vaccine preparations for potency; sterility tests of the vaccine; and filling syringes, vials, or sprayers for delivery of the vaccine to the public. Events that follow the 

completion of manufacture—such as distribution of vaccine, prioritization of users, and administration 

by health care workers—are, of course, also important in management of a pandemic response, but 

were considered to lie beyond the group’s charge and were not examined in detail.

PCAST then considered the prospects for making substantial changes in the composition of influenza 

vaccines or in the methods by which influenza vaccines are produced. In particular, it evaluated the 

relative merits of: 

• continuing egg-based production of the two currently approved forms of influenza vaccines, 

chemically inactivated virus (“killed virus” vaccine) and live attenuated influenza virus (LAIV) 

vaccine; 

• shifting to cell culture-based methods of virus production for these two vaccines; 

• increasing the proportion of LAIV vaccine relative to killed virus vaccines;

• replacing vaccines composed of LAIV or killed virus preparations with the protein products of 

recombinant DNA technologies (“recombinant vaccines”); 

• adding immunological stimulants (adjuvants) to the killed vaccine preparation; and

• pursuing research to develop a ‘“universal” influenza vaccine that might provide protection 

against a wide range of influenza strains.

PCAST’s analysis identified several components of current methodology that could be improved 

substantially even without altering fundamental vaccine production strategies. These findings and the 

recommended actions to be taken by the United States Government are described in detail in Chapter 

3, along with the anticipated effects of the proposed improvements on the time required to provide 

the first doses of vaccine and to fulfill the goal of supplying enough vaccine to protect the United States 

population by vaccinating most or all of its residents. (Eighty percent of the population—requiring about 

250 million doses of vaccine—is a realistic estimate of the vaccine recipients necessary to provide the 

optimal achievable protection.)

These relatively short-term improvements, potentially achievable in the next one to three years, 

include:

1. Increasing the time available for making vaccine after identification of a new pandemic strain 

by improving methods for surveillance for new respiratory viruses, including influenza viruses.
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2. Shortening the time to provide the first dose of vaccine by streamlining the methodology for 

producing the seed virus (a virus strain that grows efficiently and carries the relevant immune 

components); for making reagents necessary for potency tests; for testing the sterility of vaccine preparations; and for placing vaccine materials in appropriate delivery devices (“fill and 

finish”).

3. Insuring that vaccine is made available to people rapidly in an appropriately prioritized fashion.

Successful development and deployment of the recommended changes in production of egg-based 

vaccines could reduce the time to delivery of first doses of vaccine after identification of a new strain 

by as much as six to ten weeks of the 20 weeks currently envisioned by the WHO in the standard time 

line. In addition, better surveillance could advance the starting point for vaccine development, and 

streamlined delivery would get the first doses of vaccine to the appropriate target populations in a 

more timely manner. 

PCAST recognized that, without replacement of the inherently time-consuming egg-based method of 

production, delivery of all of the needed vaccine, up to the last dose, will remain a long and unpredictable 

process. For that reason, PCAST also outlined paths towards more efficient vaccine production, based 

on several alternative methods, including production of virus in cell culture (Chapter 4), development 

of vaccines made with recombinant DNA technology (Chapter 5), and (in the more distant future) 

improved design of antigens to create a so-called universal vaccine that would elicit more durable and 

more cross-reactive immunological responses (Chapter 7). 

Since it is difficult to predict how many years would be required for an effective recombinant vaccine 

to be approved and ready for wide-spread use, PCAST also considered increasing the proportion of 

LAIV vaccine, as opposed to killed virus vaccine, used to immunize against either pandemic or seasonal 

influenza. By combining the higher yield of LAIV vaccine with the more efficient cell culture-based production methods, significant savings could be made in time to delivery of last doses. But the shift to cell 

culture-based production of vaccine would also require new facilities, with economic consequences that 

need to be weighed with respect to the likelihood of another influenza pandemic and the alternative 

uses of cell culture facilities. This dilemma is discussed at greater length in Chapter 4.

PCAST also reviewed the potential utility of adjuvants in most of the contemplated vaccine strategies: 

egg-based, inactivated virus vaccines (in which adjuvants are known to increase effectiveness and are 

approved for use in Europe), cell-based inactivated virus vaccines (predicted to behave like egg-based 

vaccines of the same type), recombinant vaccines (which may require adjuvants, especially if they are 

composed of only a single viral protein), and universal vaccines. These issues are considered in depth 

in Chapter 6.

PCAST notes that while the urgent national need is to ensure protection against a severe pandemic, 

improvements will likely be implemented first in the context of annual production of vaccine against 

seasonal influenza. The reasons for this are obvious: seasonal influenza is a predictably recurrent, 

large-scale phenomenon, whereas pandemics are infrequent and difficult to anticipate; furthermore, 

seasonal and pandemic influenza vaccines are currently produced in an identical manner, with the 

vaccines differing only with respect to viral strains. (Indeed, the seasonal influenza vaccine for 2010 will 

incorporate the 2009-H1N1 strain.) 
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PCAST therefore considered in Chapter 2 the economics of seasonal influenza vaccine from the perspective of manufacturers. Influenza vaccine is a commodity product characterized by relatively low profit 

margins that fail to attract large investments to improve manufacturing processes. Notably, the WHO 

timeline for pandemic vaccine production is generally more than adequate for producing seasonal 

influenza vaccines in advance of annual winter outbreaks. Fundamental changes in the production 

methods used in such an industry will typically occur only slowly, especially since most of the newer 

methods still require further development, laboratory and clinical tests, and regulatory approval. PCAST 

thus discussed ways to create economic incentives to speed innovation.

Finally, PCAST has viewed this study as part of a wider effort to re-evaluate the nation’s capacity to 

respond to various kinds of threats, including biological agents that emerge and re-emerge naturally 

or that serve as agents of bioterrorism. Influenza differs in many ways from certain biological threats, 

such as smallpox, anthrax, or other rare and often highly lethal agents, because of its regular (seasonal) 

recurrence on a large scale, the requirement for frequent vaccination, the need for large-scale dedicated 

production facilities for seasonal vaccines, and the virtual certainty of repeated pandemics, even though 

they cannot be accurately predicted. (See Box 1-3 on influenza viruses for an explanation of some of 

these phenomena.)

In his 2010 State of the Union Address, the President underscored the Administration’s commitment to 

developing better medical counter measures against biological agents: 

We are launching a new initiative that will give us the capacity to respond faster and more 

effectively to bioterrorism or an infectious disease—a plan that will counter threats at home 

and strengthen public health abroad.3

In response to the President’s declaration, the Administration has undertaken a broader survey of countermeasures and the opportunities for improving them. While recognizing that influenza represents 

only one type of threat and that all threats have particular properties that must be appropriately considered, PCAST also believes that the scientific, technical, and economic challenges posed by influenza 

vaccinology are relevant to efforts to address other threats through, for example, the enhancement of 

surveillance, construction of shared technology platforms, improvements in regulatory science, and 

identification of economic incentives for industry.

3. Obama BH. “Remarks by the President in the State of the Union Address.” January 2010. Available at 

www.whitehouse.gov/the-press-office/remarks-president-state-union-address.
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BOX 1-2. EVENTS AFFECTING PRODUCTION OF 2009 H1N1 VACCINES4

1. Prepare, verify, distribute vaccine seed strain to manufacturers. On April 27, the WHO recommended the use of the influenza A/California/05/2009(H1N1) virus for vaccine production. This strain 

was isolated, prepared, and validated by the CDC, then a seed strain was prepared by reassortment with 

standard vaccine stocks. The CDC shipped this starting seed strain to manufacturers on May 26, 2009. 

2. Optimize seed virus growth. In June, manufacturers tested the seed strain provided by the CDC and 

found that virus growth in eggs was not optimal for large-scale vaccine production. Manufacturers then 

used genetic methods to improve the working seed and were ready to begin bulk production between 

June 20-30, 2009.

3. Manufacture bulk vaccine, QC test, & pool. On July 16, the FDA notified manufacturers that the 2009 

H1N1 virus would be subjected to the release criteria normally used for seasonal vaccine, so the testing 

was confined to measurement of “potency” (to assure that doses of inactivated virus vaccine contained 

15 micrograms of hemagglutinin (HA) antigen) or to assay of infectious virus for LAIV vaccine. Clinical 

tests for induction of antibodies (with a hemagglutination inhibition [HAI] assay) were not required, 

4. The topical headings correspond to activities depicted on the time lines shown in Figure 2-1.

BOX 1-1. IMPORTANT MILESTONES IN THE 2009 PANDEMIC 

• The first cases of what became the 2009 influenza pandemic were initially detected as influenzalike-illnesses in Mexico in late February and March. The first laboratory confirmed case, documented 

retrospectively, occurred on February 24, 2009. 

• The novel type A influenza virus, referred to here as 2009-H1N1, was first identified by the CDC on April 

15 in a respiratory specimen obtained from a child in California on April 1. The genome of this isolate 

was sequenced and designated A/California/05/2009(H1N1). Specimens from two other cases, obtained 

on March 28 and March 30, were later confirmed to be H1N1; these were the earliest documented H1N1 

cases in the United States. 

• Spread of H1N1 virus was quickly documented in many states in the United States and in other countries when the sequence of the virus was reported and specific testing could be done. Testing showed 

that the occurrence of influenza-like illnesses beyond the usual seasonal influenza epidemic period was 

usually caused by H1N1. 

• The WHO determined that the spread of the new virus had been sufficient to declare a Phase 6 pandemic on June 11. 

• While the number of cases declined in the Northern Hemisphere during the summer months, many 

cases were observed in the Southern Hemisphere, as was well-documented, for example, in Australia 

and New Zealand. The pandemic then resurged in late August in North America and Europe. The peak 

number of reported cases in the United States occurred in the last week of October, 2009. 

• The pandemic is estimated by the CDC to have caused infection in 15 to 25% of the United States population, with between 8,520 and 17,620 2009 H1N1-related deaths between April 2009 and February 13, 

2010. 
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although the inactivated vaccine was reported in early September to have the expected immunogenic 

potential as a single 15 microgram dose. The first bulk 2009 H1N1 vaccine was available for testing by 

the Food and Drug Administration (FDA), to determine if it was suitable for public release, during the 

first week of September.

4. Release. Tests for concentrations of viral hemagglutinin in inactivated vaccine, using reagents 

described below (point 6), were completed by the FDA between September 15 and 18.

5. Fill & finish vaccine. Initial lots of H1N1 vaccine were placed in syringes and vials or nasal sprayers and 

packaged by September 30. Given the urgency associated with the developing pandemic, manufacturers shipped 2009 H1N1 vaccines before sterility testing was completed, recognizing that some lots 

might need to be recalled; no microbial contamination was detected, and the first doses of vaccine 

were available for clinical use on October 5.

The supply of H1N1 inactivated vaccine was limited early in the manufacturing phase of the immunization campaign. Approximately 26.7 million doses of this vaccine were available for distribution at the 

end of October 2009. Because of relatively poor virus production per egg, fewer doses of inactivated 

vaccine than expected were produced per egg (0.3-0.5 doses/egg as compared to the usual 2.0 to 3.0 

doses/egg) which contributed to the less than expected supply. Significantly higher numbers of doses 

of LAIV vaccine were produced per egg (75-100 doses/egg), but only 20% of the total vaccine produced 

was LAIV because only one fill-finish production line was available up until late October 2009 when a 

second line became available.5

By mid-November, about 30 million doses of vaccine were ready for use, and about 60 million doses by 

the end of month. During December, vaccine surpluses replaced shortages, as the supply reached 90 

million doses. Afterwards, supplies continued to increase. By the end of February, an estimated 81 to 91 

million doses had been administered, covering about a quarter of the US population. 

6. Prepare potency reagents. The reference virus was provided to the FDA by the CDC on May 26, at the 

time it was also shipped to manufacturers. The sheep antisera required for potency testing of inactivated vaccines (measurement of HA antigen in immunodiffusion gels) were available August 12.

5. Robin Robinson, Director, Biomedical Advance Research and Development Authority, Personal 

Communication, June 9, 2010.
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BOX 1-3. BRIEF PRIMER ON INFLUENZA

Influenza viruses cause frequent widespread infections—annual (“seasonal”) epidemics and occasional, 

potentially severe, world-wide epidemics (“pandemics”). These epidemiological patterns are associated 

with the genetic plasticity of influenza viruses, producing both gradual and sudden changes in genes 

encoding viral proteins, including the proteins that enable viral entry into and release from cells and the 

proteins responsible for eliciting the host’s immune response. At least two kinds of genetic changes can 

occur. First, influenza genes are not copied accurately during virus growth; hence many errors (mutations) 

occur. These small changes (along with the genetic selection that occurs to fix these mutations in the 

virus) are called “antigenic drift,” and they can affect any of the viral proteins, including major viral surface 

proteins such as the HA protein that mediates entry into host cells and serves as the major target for the 

immune response. While antigenic drift may be subtle biochemically, it can have large consequences for 

the human host, since the immunity acquired from infection during a previous epidemic will not fully protect the host against infection by the new virus. Second, the genes of influenza viruses are present on eight 

separate segments that together make up the viral RNA genome (in effect, the virus has 8 chromosomes). 

When two virus particles infect a single cell, the genes of the two viruses can mingle and be efficiently 

reassorted into the progeny virus. The natural reservoirs for influenza viruses are mostly aquatic birds but 

they can transmit their viruses to farm animals, such as pigs and ducks. Novel strains infectious for humans 

can emerge when reassortment occurs among the genetic segments of two or more viruses that have 

co-infected the various hosts. These major changes, called “antigenic shifts,” escape all previous immune 

protection, contributing to the development of a pandemic when they occur in a virus that is also transmitted efficiently from person to person. 

Annual influenza epidemics, known as seasonal influenza, usually occur in late fall and winter in the 

United States, and take their greatest toll among the elderly and the very young. Seasonal influenza is 

caused by virus strains that have undergone antigenic drift and differ minimally from strains that have 

circulated in previous years. In contrast, pandemics, larger-scale epidemics that often affect people in the 

prime of life, occur whenever a new influenza strain, generally one exhibiting antigenic shift, appears in a 

largely naive human population and is then transmitted efficiently from one person to another. An influenza pandemic is defined by the number and global distribution of cases, not by the severity of the illness 

or the percentage of deaths caused by the novel strain.

Influenza vaccines are used to reduce influenza morbidity and mortality by inducing an immune 

response against viruses predicted to cause seasonal outbreaks or against new viruses isolated early in a 

wider outbreak that shows signs of developing into a pandemic. Immunization against seasonal influenza 

viruses compensates for gaps in pre-existing immunity when viruses undergo antigenic drift and for the 

absence of strain-specific immunity if antigenic shift has occurred to produce a pandemic strain. Vaccines 

can also provide primary protection for infants and children who have not yet been infected with any 

influenza viruses. 

Both inactivated and live attenuated influenza vaccines are approved in the United States. These vaccines are manufactured annually by growth of appropriate strains of virus in embryonated chicken eggs. 

(In this country, no cell culture-based vaccines or vaccines supplemented with adjuvant are approved for 

use.) The vaccine strains are developed after surveillance for viruses causing respiratory illness, conducted 

by the CDC and the WHO network of 120 National Influenza Centers located in more than 90 countries. 

Early each year, or late in the previous year, the CDC selects component strains for the coming autumn’s 
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influenza vaccines to protect against seasonal influenza. Late selection of strains is sometimes necessary 

and can delay vaccine production, but the period available for manufacturing each annual season’s influenza vaccine is usually at least six months. 

In contrast, a pandemic strain of influenza virus can emerge at any time, as illustrated by the novel 2009 

variant of H1N1. Such strains can cause illnesses outside the usual period of seasonal influenza, provide 

limited time for vaccine production between the first and second wave of infections, and effectively 

replace the predicted seasonal strains of virus. All of these phenomena were observed in the 2009 

pandemic.

 

This is a picture of a cluster of six H1N1 influenza 

virus particles taken with an electron microscope, 

showing the cores and the spikes of virus surface 

proteins. 

Source: Centers for Disease Control and 

Prevention.

Above is a cartoon depicting a single influenza virus particle, 

with its eight RNA segments inside as ribonucleoprotein (RNP) 

surrounded by the major structural proteins of the virus, including 

the surface proteins neuraminidase (NA) and hemagglutinin (HA) 

that are used to classify virus strains (e.g. H1N1). 

Source: College of St. Benedict/St. John’s University.
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II. The Influenza Vaccine Problem

Improving the prospects for making vaccines against pandemic strains of influenza viruses in a timely 

fashion requires more than making adjustments to manufacturing procedures. Several steps are involved 

in the development of a pandemic vaccine, and these depend on public health practices, virology, and 

the host immune response, as well as manufacturing and packaging of the vaccines. Current influenza 

vaccines are prepared from materials grown in chicken eggs, a cumbersome method that appears outmoded in a world dominated by production of many viral vaccines in cell culture or by new vaccines 

designed with recombinant DNA methods. However, proposals to make major changes in large-scale 

influenza vaccine production technologies in order to protect the nation against an unpredictable risk 

of pandemic raise economic and regulatory issues that need to be discussed in the context of what is 

essentially a commodity business dependent on the annual production of smaller amounts of vaccine 

against seasonal influenza. And because financial incentives for making such changes may seem weak, 

the government needs to contemplate unusual actions to stimulate, coordinate, and even lead any 

recommended actions.

CHAPTER SUMMARY

Current influenza vaccines are prepared from materials grown in chicken eggs, a cumbersome method 

that appears out-moded in a world dominated by growth of vaccine viruses in cell culture or by new vaccines designed with recombinant DNA methods. However, proposals to radically change manufacturing 

processes proven historically to be capable of producing vast quantities of influenza vaccine raise scientific, 

economic, and regulatory issues that the Federal Government needs to address. 

This chapter includes the Working Group’s survey of this complex landscape. The chapter first reviews 

the strategy for dissecting the steps in vaccine preparation in order to determine the sources of difficulty 

in 2009 and the prospects for improvement in future pandemics. As the reference point for its analysis, 

the Working Group used the timeline developed by the World Health Organization (WHO) for egg-based 

production of inactivated influenza vaccine in a pandemic. The chapter then discusses the kinds of choices 

to be considered and the economic and regulatory barriers to change, and presents the plan for discussing 

the recommended options. 

In particular, the Working Group concluded that because of the commodity nature of influenza vaccine, 

with its low profit margin, there is little economic incentive for vaccine manufacturers to make major 

investments in order to change the type of vaccine they manufacture or alter the egg-based process they 

use to make it. However, there are a number of improvements that the Federal Government and manufacturers can make within the next few years, with little research and development, at relatively low cost, and 

with no economic impact on manufacturers. These steps include instituting better surveillance to detect 

new influenza strains earlier, creating stocks of “seed viruses” needed to manufacture vaccines, developing methods to better measure vaccine potency and monitor sterility, and building additional capacity to 

place vaccine in delivery units.
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This chapter includes PCAST’s survey of this complex landscape. The chapter first reviews the strategy 

for dissecting the steps in vaccine preparation in order to determine the sources of difficulty in 2009 and 

the prospects for improvement in future pandemics. The chapter then discusses the kinds of choices to 

be considered and the economic and regulatory barriers to change, and presents a plan for reviewing 

the recommended options.

Framework for Analysis: Timelines for Vaccine Production

To develop a rigorous analysis of the central question posed by PCAST (see Chapter 1), it has been necessary to identify the components of the vaccine production process and to align possible improvements 

in those components with the timeline for production. In this way, PCAST has made predictions about 

the effects of each recommended change on the time to delivery of first doses of vaccine and on the 

time to delivery of sufficient vaccine to protect 80% of the United States population in a pandemic. 

The timeline developed by the WHO for egg-based production of inactivated influenza vaccine in a 

pandemic serves as a starting point for this analysis (Figure 2-1). This is the major form of influenza 

vaccine used to protect the United States population against either seasonal or pandemic influenza. 

The timeline shows the estimated durations of six sets of actions that need to be taken after the isolation and identification of a new strain of influenza virus. Five of these steps are sequential and hence 

directly determine the time to first dose (about 20 weeks): verification and distribution of the vaccine 

strain by the CDC; development by manufacturers of an optimized seed strain that encodes the newly 

identified HA protein and grows well in embryonated eggs; production, inactivation, and quality control 

of vaccine materials, followed by pooling; permission from the FDA to package and release vaccine for 

distribution; and filling single-dose syringes or multi-dose vials by the manufacturers. The sixth task, 

FDA’s preparation of reagents for potency testing, usually occurs concordantly with other actions, but 

if excessively prolonged can also affect the time to delivery of vaccine. 

In addition to the inactivated vaccine, an LAIV vaccine is also approved in the United States, although 

its use has been more limited. While the initial steps involved in production of this vaccine are similar to 

those of the inactivated vaccine, production is substantially more efficient for several reasons: potency 

tests can be eliminated in favor of a simple, rapid determination of the amount of infectious virus in 

a traditional plaque assay in cultured cells; existing backbones of cold-adapted viruses shorten the 

preparation of seed strains for attenuated vaccine; and less virus is required per dose of vaccine, reducing 

production time. Hence, the time to first doses can be shortened slightly, as indicated in the legend to 

Figure 2-2, whereas time to last dose can be reduced substantially. The time for subsequent production 

of the doses required to provide full population coverage can vary substantially depending on several 

key factors, each of which is considered in this report: the growth efficiency of the seed strain of virus 

for vaccine production; the availability of means of production (e.g. embryonated chicken eggs); and 

the capacity to place the vaccine into the delivery package (e.g. syringes, vials, nasal sprayers).

PCAST used the WHO timeline to help explain the slower-than-desired delivery of vaccine in the 2009 

pandemic (Figure 2-2). The major delay in the delivery of first doses was caused by the relatively long 

time required for the manufacturers to optimize the seed strain supplied by the CDC for growth in eggs. 

Because production of virus for killed vaccine in eggs inoculated with the working strain was poor, fewer 

doses of vaccine than usual were produced per egg, markedly increasing the time to produce vaccine 

in large amounts. 
I I . The Influenza Vaccine Problem

★ 13 ★

Figure 2-1. Timeline for Production of Inactivated Pandemic Influenza Vaccine

The timeline for an effective vaccine response to a pandemic begins when a new strain of influenza virus causes human 

disease and serial transmission in the community has been documented. Upon declaration of an epidemic and a decision to produce vaccine to combat it, a series of steps illustrated in the central portion of the figure must be executed; the 

expected times for performance of each step, as estimated by the WHO for production of egg-based inactivated vaccine, 

are illustrated by the lengths of each horizontal bar, with the two-color format connoting variation in predicted time. At the 

tail end of the vaccine production process, manufacturing capacity will determine how much time is required to provide 

and distribute enough doses to vaccinate 80% of the population. All of the steps shown here, from surveillance to delivery of 

final doses, are critical for interrupting the spread of the pandemic virus.

New Virus 

Introduced 

into 

Human 

Population

Pandemic

Evolves

Pandemic

Declared

First Doses

of 

Vaccine

Scale Up

&

Delivery

Last Doses

of

Vaccine TIMELINE FOR VACCINE PRODUCTION

2 4 6 8 10 12 14 16 18 20

Prepare, verify,

distribute vaccine 

strain to (CDC)

Optimize seed virus

growth for working 

seed (Mf)

Manufacture bulk

vaccine, QC test, &

pool (Mf)

Release (FDA)

Fill and nish

vaccine (Mf)

Prepare potency

reagents (FDA)

WHO Predicted

WHO Predicted

WHO Predicted

WHOP

WHOP = World Health Organization Predicted

Week

WHO Predicted

WHOP
★ 14 ★

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Figure 2-2. 2009 H1N1 Vaccine Production Timeline

This figure compares the actual times and WHO predicted times to complete key steps in the production of 2009 H1N1 

egg-based inactivated vaccine. As shown in the top segment, the vaccine seed strain was prepared and distributed to the 

manufacturers in less time than predicted, but the time needed to optimize this seed strain and prepare a working seed 

suitable for manufacturing was significantly longer, as seen in the second segment from the top. The preparation of 

potency reagents necessary for inactivated vaccines was accomplished in a shorter interval than predicted and did not 

delay release. Initial lots of LAIV were prepared in a shorter time than inactivated influenza vaccine. 

Week 2 4 6 8 10 12 14 16 18 20 22 24 26

Prepare, verify,

distribute vaccine 

strain to (CDC)

Optimize seed virus

growth for working 

seed (Mf)

Manufacture bulk

vaccine, QC test, &

pool (Mf)

Release (FDA)

Fill and  nish

vaccine (Mf)

Prepare potency

reagents (FDA)

WHOP = World Health Organization Predicted

WHO Predicted

WHO Predicted

WHOP

WHO Predicted

H1N1 Actual

H1N1 Actual

H1N1 Actual

H1N1 Actual

H1N1 Actual

H1N1 Actual

First Doses in Clinic

6 Weeks Behind Schedule

NOTE: This production time line shows time to first doses of inactivated influenza vaccine; time to release of first 

doses of LAIV was 21 weeks.

WHO Predicted

WHOP
I I . The Influenza Vaccine Problem

★ 15 ★

PCAST then examined the possible effects on the timeline of various proposed changes in methodologies. Some changes—in preparation of seed stocks, for example—could improve steps in the timeline 

by reducing the average length of the step or its variability, even without altering the strategy for vaccine 

production. Other changes, such as in the means of vaccine production through the use of recombinant 

DNA technology, could eliminate steps in the timeline. Through this type of analysis, PCAST developed 

estimates for how much the times for the initial delivery of vaccine and for provision of the full complement of doses might be shortened by the use of improved technologies. These proposed changes and 

their effects on the delivery of first and last doses of vaccine are described in detail in Chapters 3, 4, and 5. 

Weighing Options 

Decisions about whether to pursue those improvements and whether to complete them over a certain 

period of time cannot be made in a vacuum. These decisions need to take into consideration the likelihood of a new pandemic; the potential impacts of pandemics of variable severity in the number of lives, 

and years of life, that might be saved; the costs to industry and to the Federal Government of making 

the improvements; and the feasibility of success in achieving recommended goals.

In particular, the investment required by the Federal Government to ensure each potential action 

described in this report must be estimated, and making such an estimate requires understanding the 

economics of the vaccine market. Manufacturers may lack sufficient economic motivation to invest 

in actions that may be useful only in the case of a pandemic, and even then they may not realize a 

substantial economic return on that investment. For this reason, the Federal Government may need 

to provide substantial economic incentives to enhance preparedness for an influenza pandemic. To 

recommend such incentives, the potential benefits of each action must be balanced against the likely 

cost to the Federal Government and evaluated with respect to the likelihood and probable pace of 

progress in developing the next generation of vaccine production technologies. In addition, a plan for 

coordination and oversight of such efforts would be needed to ensure that the program is executed in 

a timely and responsible manner.

The benefits that may result from reducing the number of weeks to initial vaccination cannot be predicted accurately. However, as an illustration, one study indicates that in the relatively mild 2009 H1N1 

pandemic, an additional 2,200 lives could have been saved in the United States if vaccinations had 

started one month earlier.6 It is important, in making such calculations, to remember that in comparison 

with seasonal flu the 2009-H1N1 pandemic had a much greater impact on younger individuals—more 

than 85% of the deaths during the 2009 H1N1 pandemic were in people younger than 60, with an 

overall mean age of 37.4 years, as compared to an overall mean age of 75.7 years for victims of seasonal 

influenza. The benefits of delivering vaccine early, of course, also include reducing the overall burden 

of morbidity and disruption caused by a pandemic and potentially reducing the likelihood of recurrent

6. Matrajt L, Longini IM. Optimizing Vaccine Allocation at Different Points in Time during an Epidemic. 

UW Biostatistics Working Paper Series 2010, No. 363. Available at 

http://www.bepress.com/cgi/viewcontent.cgi?article=1202&context=uwbiostat.
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 waves of infection.7 Finally, Federal funds used to support the development of new influenza vaccine 

manufacturing platforms and facilities (and thus enhance our capacity to respond to pandemics) could 

potentially enhance our ability to develop medical countermeasures against other novel pathogens. 

It is difficult, if not impossible, to undertake this analysis in a fully rigorous and quantitative manner. 

Nonetheless, a framework for decision-making can help clarify the issues. For example, egg-based influenza vaccines are not an adequate long-term solution for responding to a pandemic, mainly because, 

as occurred in 2009, the complete process may fail to provide adequate vaccine in time to block the 

second wave of disease. Nonetheless, egg-based production of a combination of killed vaccine and 

LAIV vaccine is currently the only FDA-approved technology with sufficient capacity to supply enough 

doses for the entire United States population; this will probably remain the case for at least three years 

and possibly more. For this reason, it is easy to justify modest investments, such as developing a set 

of viral backbones for making seed stocks rapidly or increasing the use of LAIVs vaccines, that could 

significantly shorten the time to respond to a pandemic with egg-based vaccines. 

Shifts to new technologies for vaccine production, including cell culture-based vaccines or vaccines 

derived from recombinant DNA methods, present greater complexities in decision-making. While a 

switch to cell culture for virus growth will not materially accelerate the time to first dose, it can significantly accelerate the time to last dose because cell-based production of virus is more readily scaled up 

than egg-based production. The vaccines produced in cell culture are essentially identical to currently 

approved egg-grown vaccines, both inactivated or LAIV. However, cell culture-based influenza vaccines 

have not been approved by the FDA, and turning to cell culture systems will likely require construction 

of additional facilities to permit adequate levels of production even with a major production shift from 

inactivated vaccines to the more efficiently produced LAIV vaccines, as discussed in Chapter 4.

Recombinant DNA technology would significantly shorten both the time to first dose and the time 

to last dose because it eliminates the need for seed strains of virus and speeds up production of viral 

antigen. However, no recombinant influenza vaccine has been FDA approved, technological risks remain 

unresolved, and safety and efficacy of recombinant vaccines must be demonstrated. These uncertainties 

create a dilemma for decision-makers that is discussed more fully in Chapter 5. 

Addition of immune stimulants (adjuvants) to certain vaccines can make vaccines more effective, 

allowing smaller amounts of viral material to be used per dose of vaccine (thereby, in effect, accelerating production). However, these gains need to be balanced against uncertainties about safety and 

acceptance of adjuvanted vaccines and the possibility of developing better adjuvants in the near future, 

as described in Chapter 6. A universal influenza vaccine that could provide lifelong protection against 

a wide range of influenza strains would clearly be the optimal solution, but current knowledge does 

not allow a prediction of whether such a vaccine will ever be possible. With the goal of developing a 

universal vaccine in mind, substantial investments in basic research as part of a portfolio seem sensible, 

as discussed in Chapter 7, but large investments in a universal vaccine strategy as part of a preparedness 

plan is difficult to justify.

7. Matrajt L, Longini IM. Optimizing Vaccine Allocation at Different Points in Time during an Epidemic. 

UW Biostatistics Working Paper Series 2010, No. 363. Available at 

http://www.bepress.com/cgi/viewcontent.cgi?article=1202&context=uwbiostat.
I I . The Influenza Vaccine Problem

★ 17 ★

A key consideration in this analysis is the over-arching uncertainty as to when the next serious influenza pandemic may occur. During the past 100 years, there were four influenza pandemics (in 1918, 

1957, 1968, and 2009), and the death tolls in the US were estimated to have been, respectively, 5000, 

1000, 170, and 50 deaths per million inhabitants. Given this frequency, it is possible that no serious 

pandemic will occur during the next decade or two, providing appreciable time to develop new vaccine strategies for pandemics while depending on current egg-based vaccines for protection against 

seasonal influenza. However, this may be a highly misleading estimate of pandemic frequencies and 

severities. Increased travel and migration and the growing intensity of farming birds and swine (critical 

reservoirs for influenza), particularly in the developing world, may enhance the rate of viral spread and 

evolution, thereby promoting pandemics, and a pandemic of avian influenza might be more virulent or 

transmissible between humans than it has been in most previous outbreaks. Although it is impossible 

to predict with any certainty, the Federal Government might assume, solely for planning purposes, at 

least a 3 percent per annum probability of an influenza pandemic; a pandemic that caused 1000 deaths 

per million would translate to 300,000 deaths in the United States. Given these assumed probabilities 

and potential consequences, it would seem reasonable for the Federal Government to invest at least 

$1 billion per year to prevent such an outcome. 

Economics of Vaccine Manufacture 

Influenza vaccine manufacturing is a commodity business, with little differentiation among products 

and consequently relatively low profit margins. The United States population is served by five major 

influenza vaccine manufacturers: Sanofi-Pasteur, Novartis, GlaxoSmithKline, MedImmune, and CSL. Of 

these, only MedImmune makes LAIV vaccine; the others produce killed vaccines. In a typical year, only 

about one-third of the United States population receives seasonal influenza vaccine, corresponding to 

a total annual US market size of between 80-100 million doses. The difficulties of predicting how many 

people will take the vaccine each year and of timing the supply to match peak demand can result in the 

production of millions of excess doses of vaccines each year. Manufacturers absorb the cost of those 

unused vaccines through rebates to purchasers.

Manufacturers typically receive a wholesale price of about $5-10 per dose for seasonal influenza vaccine; 

doses that reach the market earlier in the season command a slightly higher price, which declines over 

the season. The precise profit margin is proprietary information, but knowledgeable observers estimate 

that it is about 20 percent (reflecting the costs of the considerable manual labor involved in egg-based 

production, the cost of filling syringes, and the annual rebates). A manufacturer with 50 percent market 

share might thus net about $30 million in annual profit. 

By contrast, pharmaceutical companies typically have profit margins of 50-95 percent, with the highest 

margins for novel, proprietary drugs. Such large profit margins for novel drugs are the norm because of 

lower competition, and companies justify them as a means to recover the costs involved in developing 

and testing drugs and securing regulatory approval. The high return-on-investment for these products 

affects manufacturers’ willingness to invest capital in a commodity business such as influenza vaccine; 

such investments are often evaluated against the “opportunity costs” of alternative investments with 

higher returns.
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Nevertheless, it is in the national interest to improve preparedness for an influenza pandemic, even 

though substantial investment in innovations and substantial economic risks may be required to create a new vaccine that can reduce the timeline for production. Manufacturers have a limited economic 

incentive to invest in such innovations for seasonal influenza vaccines, because there is much less time 

pressure in the preparation for seasonal influenza than for a pandemic. 

To induce existing manufacturers to shift to vaccine production methods that would allow a rapid 

response in the event of future sporadic pandemics, the Federal Government may need to cover a significant fraction of the cost of such innovations and take an active role in convening and coordinating 

work with the multiple pharmaceutical and biotechnology companies engaged in the development and 

production of influenza vaccines. For example, building a new cell culture-based vaccine manufacturing facility may cost more than $1 billion. With annual profits of only $30 million, it would take over 30 

years to recover the investment in nominal dollars (leaving aside the need for a return on investment). 

Novartis recently constructed such a facility in Holly Springs, North Carolina. To partially offset the cost, 

the Department of Health and Human Services provided $497 million in Federal funding. 

While manufacturers have limited incentives to invest solely to reduce timelines, there may be synergies that could provide some incentives for investment. For example, some innovations that reduce 

timelines may also result in improved, more desirable, and hence more widely used products (such as 

those that provide better protection of the elderly, who are at particular risk during epidemics of seasonal 

influenza). Some innovations may also decrease manufacturing costs (leading to a higher profit margin 

for the manufacturers that adopt them). 

Finally, serious regulatory issues can impede innovation. Uncertain pathways to secure FDA approval for 

cell culture-based vaccines, recombinant vaccines, and vaccines containing adjuvants inhibit investment, 

because manufacturers may not know whether or when they could expect to bring such vaccines to 

market. Provision of clear regulatory guidance by the FDA would be one of the most important—and 

least expensive—steps to lower barriers to innovation in influenza vaccine production.

Components of a National Response: An Overview

Several types of improvements can be envisioned in the methods that contribute to the production of 

pandemic (and seasonal) influenza vaccines. Some of these, such as better ways to detect new strains, 

make seed stocks, control vaccine potency, monitor sterility, and place vaccine in delivery devices, could 

be instituted in the near future. When taken in concert, these improvements could advance the starting 

point for vaccine production by several weeks and reduce the WHO time course to delivery of first doses 

(see Chapter 3). Moreover, such improved methods may be applied to the manufacturing of influenza 

vaccines by different means (in eggs, in cell culture, or by recombinant technologies) and sometimes 

to other vaccines and medical problems. In this sense, they may constitute “platform technologies” and 

are so noted when presented in Chapter 3.

Other changes represent more fundamental alterations in the mode of production of influenza vaccines. 

Transformation of production of a vaccine strain of virus from an egg-based to a cell culture-based 

industry would not, by itself, have a major effect on the time to delivery of first doses, but could dramatically reduce the time to delivery of last doses by half or more, because of the rapid scale-up of growth. A 
I I . The Influenza Vaccine Problem

★ 19 ★

change from killed-virus vaccine to LAIV vaccine would also shorten the time to last doses by reducing 

the amount of virus required for each dose of vaccine by up to one hundred fold. However, only one 

manufacturer is licensed to make LAIV vaccine, and the methodology is proprietary to that company. A 

more radical change in design of influenza vaccines to a method based on recombinant DNA technology 

could have even greater effects, since at least one time-consuming step, the preparation of seed stocks 

of virus, would be eliminated and the scale-up in production of vaccine materials (in this case, proteins 

encoded by viral nucleic acids) could together shorten the time to delivery of first doses to 13 weeks. 

The attractions and difficulties of making these major changes are discussed in Chapter 5.

Two other scientific and technological issues could have important effects on the production and use 

of influenza vaccines. Adjuvants could significantly reduce the amount of antigenic material required 

in any type of influenza vaccine and thereby shorten the time required to provide all of the necessary 

doses. As considered in Chapter 6, there are substantial obstacles—scientific, regulatory, and commercial—to adoption of adjuvanted vaccines, but approval of such vaccines in other countries, improved 

adjuvants, and better understanding of the mechanisms by which they augment the immune response 

all argue for greater use of adjuvants in influenza vaccines in the future. In addition, it remains plausible 

to envision influenza vaccines that induce a more durable and more broadly cross-reactive immune 

response, thereby eliminating the need for yearly vaccinations against seasonal influenza and offering 

better protection against new pandemic strains of virus. Strategies for developing such vaccines and 

the kinds of fundamental research required to encourage development are outlined in Chapter 7.

Finally, wide-ranging efforts to hasten and improve the production of influenza vaccines will require 

unaccustomed levels of coordination among government agencies, academic scientists, and the industrial sector, as well as investments of public funds as part of a package of incentives. Such planning and 

spending can only be achieved by assigning implementation and oversight to responsible components 

of the Federal Government or to a government-chartered entity. Recommendations for doing this are 

presented in Chapter 8.

The effects of PCAST’s recommendations on the delivery of pandemic influenza vaccines are summarized 

in Table 2-1 on the following page. 
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Table 2-1. Effects of Recomended Actions on Delivery of Pandemic 

Influenza Vaccines

Recommended 

Change

Estimated Time 

Required to Make 

the Change

Effects on Time to 

First Dose

Effects on Bulk 

Production Until 

Demand Satisfied

Alternative 

Uses in Medical 

Countermeasures

Increased 

Surveillance 1-3 years

Moves the starting 

line forward by 

weeks or more

None Yes

Faster Production 

of Optimal Vaccine 

Seed

1-2 years Up to several 

weeks

Up to several weeks 

(if more efficient 

virus growth)

No

Modernized 

Sterility Tests 1-2 years Approximately 1 week None Yes

Improved 

Generation of 

Potency Reagents

1-2 years

Avoids possible 

delay of up to 

several weeks

None Possibly

Expanded and 

Streamlined 

Fill and Finish 

Procedures

1-3 years Slight Up to weeks Yes

Shift to Cell 

Culture to make 

Killed Vaccine

1-3 years A few weeks Up to several weeks Possibly

Shift to Cell 

Culture for Live 

Attenuated 

Vaccine

2-6 years A few weeks Up to several weeks Possibly

Recombinant–

based Vaccine 2-10 years Several weeks Up to several weeks Yes
★ 21 ★

III. Potential Benefits of Short-Term Changes 

in Methods for Making Influenza Vaccines

As described in Chapter 2, the several steps involved in the development and production of pandemic 

influenza vaccines are predicted to require an average of about 20 weeks after isolation of the pandemic 

strain until the first doses of vaccine are available from manufacturers. Chapter 2 also noted that the 

supply of vaccine sufficient to protect the entire population is susceptible to delays in virus growth, in 

the final fill-finish packaging of the vaccine, and other vulnerabilities. PCAST has considered ways to 

improve each of these steps and has found that most can be improved in the relatively near future, possibly within the next three years if funds are available and regulatory issues are addressed. This chapter 

outlines steps that can be taken in the short term, describes how some of the improvements can help 

establish platform technologies applicable to a variety of situations involving biological threats, and 

envisions the impacts of the proposed improvements on the time to delivery of first and last doses of 

pandemic vaccine. In the following chapters, proposals for transfer of vaccine production to cell culture 

and the longer term potential of recombinant technology for making influenza vaccines are discussed.

Surveillance

The initial trigger for assessing whether a pandemic vaccine will be needed is the identification of a novel 

influenza virus exhibiting antigenic shift and circulating in the human population. The transmissibility 

CHAPTER SUMMARY

A major lesson of the 2009 H1N1 influenza pandemic is that the supply of vaccine sufficient to protect the 

United States population is vulnerable to delays at the beginning of the process, when the vaccine virus 

must be optimized for manufacturing, and at the end of the process, during the final fill-finish packaging of the vaccine. The decision to begin influenza vaccine production depends on surveillance for early 

detection of a new influenza strain. Global surveillance for emerging influenza viruses requires no new 

technology, but does need better coordination among the WHO, CDC, and local hospitals and diagnostic 

laboratories and wider dissemination of modern viral detection technologies. An investment in developing new viral backbones optimized for growth in chicken eggs or mammalian cell culture would lessen 

the chances that seed viruses will grow poorly when put into production and likely increase vaccine yields, 

reducing the time needed to produce enough vaccine to immunize all of the Nation’s residents. Potency 

testing of inactivated influenza vaccine relies on an outmoded technology prone to delays, but with a 

focused research effort it should be possible to adapt contemporary methods for use during the vaccine 

manufacturing process. Sterility testing can also be done more rapidly with recently developed technologies. No new technologies are needed to substantially reduce the fill-finish bottleneck, but industry and 

the Federal government must develop a plan and identify the necessary financial resources to ensure 

adequate capacity to produce sufficient quantities of pre-filled syringes, vials, and/or nasal sprayers to 

meet the national need. 
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of the novel virus is a key criterion for declaration of a global pandemic, which is the responsibility of 

WHO. This declaration happens, as in the 2009 influenza pandemic, when an unusual cluster of cases 

of influenza-like illnesses is noted by public health workers and patient samples are then sent to a 

diagnostic laboratory capable of identifying subtypes of influenza virus. Even if a novel virus proves not 

to be readily transmissible, the first steps towards developing seed strains for possible use as a vaccine 

are not costly and can be undertaken well before the decision about declaring a pandemic is made.

Surveillance precedes the starting point for the timelines shown in Figure 2-1, and therefore does not 

directly affect assessments of the time required for vaccine production that begins with the declaration 

of a pandemic and ends with delivery of vaccine. However, earlier detection of an influenza virus with 

pandemic potential has obvious benefits. The likelihood that surveillance will detect new pathogens 

more effectively can be increased by widening the use of surveillance methods geographically, by lowering the criteria for collecting and submitting samples to a reference laboratory, and, when appropriate, 

by testing animal as well as human hosts. In this way surveillance can lengthen the time available for 

making enough vaccine to protect the population. In 2009, identification of the new H1N1 and tracking 

its transmissibility in the human population even two months earlier would have allowed the first doses 

of vaccine to be delivered before the next wave of the pandemic began in late August and might have 

interrupted this second wave, which peaked in the fall before vaccine was widely available. 

Since better surveillance accelerates the decision to make a pandemic vaccine, it is a fundamental 

component of pandemic preparedness. A cluster of unexplained illnesses or deaths is usually the 

first marker of an incipient pandemic. Although the expectation has been that influenza strains with 

pandemic potential will emerge in Asia, clusters of influenza-like illness subsequently attributed to the 

novel 2009-H1N1 virus were first identified in Mexico and the United States, supporting the importance 

of comprehensive global surveillance. Much can be done to recognize and spread the news about such 

clusters, given contemporary global communications tools. One approach would be to further develop 

an integrated Web-based system for electronic reporting of unexpected numbers of patients with 

respiratory illnesses outside the usual influenza season or with unusual disease profiles, e.g., greater 

severity, unexpected complications, or higher attack rates among young adults rather than the elderly 

during the usual influenza season.

Recognition of illness clusters is not useful without efficient collection and shipping of patient materials to reference laboratories for diagnostic testing. The WHO influenza surveillance network has made 

influenza diagnostic reagents and polymerase chain reaction (PCR) equipment to detect influenza 

viruses more widely available in recent years. This infrastructure helped to demonstrate quickly the 

global reach of the 2009 H1N1 pandemic. Enhancing the capacity of these centers to rapidly identify 

non-subtypable influenza viruses in patients and report those finding to WHO reference laboratories or 

to the CDC could reduce substantially the timeline for recognizing an emerging pandemic. The United 

States Agency for International Development (USAID), the Department of Defense (DoD), and national 

public health programs in any country at risk could also contribute in useful ways to the development 

of more effective surveillance networks.

Reinforcing current disease detection and laboratory diagnostic networks is feasible in the short term, 

but novel technologies that are simple, sensitive, precise, rapid, and designed for use in resource-poor 
III. Potential Benefits of Short-Term Changes in Methods for Making Influenza Vaccines

★ 23 ★

settings are needed for global distribution. The goal of such innovation should be a sustainable, multiuse respiratory disease surveillance platform, deployable worldwide, for rapid detection by reverse 

transcription PCR (RT-PCR) sequencing or proteomics methods to detect major changes in existing 

human influenza strains as well as influenza H2, H4, H6, H7, H9, and H10 Type A influenza viruses that 

constitute pandemic threats. Such technologies have broad applications for identifying other emerging infections as well and hence qualify as multi-use platforms for emergency preparedness. Where 

appropriate, these platforms should leverage standardized diagnostic platforms for infectious agents 

now being developed, such as the Next Generation Diagnostic System that is being funded in the FY 

2011 budget of the DOD.

New influenza viruses that threaten the human population emerge from animal reservoirs, either directly 

or more often by transfer of parts of the viral genome into co-existing viruses already adapted to infect 

people. Surveillance of wild birds, domestic poultry, and pigs with multi-use platform technology for 

respiratory viruses by the United States Department of Agriculture (USDA), other US agencies, and 

agriculture and wild life programs of other nations could lead to early recognition of influenza strains 

with pandemic potential. Meanwhile, progress could be made using existing detection methods if 

disincentives for agricultural surveillance and global collaboration were addressed. These disincentives 

include concerns about the real threat of commercial impact, including disruption of businesses and 

tourism, and about national jurisdiction and control over the information and materials resulting from 

surveillance.

RECOMMENDATION 3-1: SURVEILLANCE FOR AND IDENTIFICATION OF NOVEL VIRUSES

The CDC should develop improved strategies for global influenza surveillance, taking advantage of the 

existing CDC/WHO collaboration and considering additional partnerships with USAID, DoD, USDA, other 

United States agencies, and foreign public health systems. These strategies should be implemented within 

two years and should include:

• Pursuing improvements that enhance global networks for electronic reporting of clusters of cases of 

respiratory illness that are atypical of seasonal influenza; this type of surveillance is symptom-based and 

does not require immediate access to a diagnostic laboratory. 

• Developing and assessing innovative approaches that exploit contemporary communications tools, 

including cell phones and the Internet, or that expedite reporting of novel cases and clusters of respiratory illness. 

• Improving rapid collection and transfer of patient specimens to WHO influenza reference laboratories.

• Supporting better global access to PCR-based detection of novel respiratory pathogens. 

• Increasing surveillance of certain animals known to be natural hosts for influenza viruses, especially pigs 

and some domestic fowl.
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In addition, the National Institute of Allergy and Infectious Diseases (NIAID), Biomedical Advanced 

Research and Development Authority (BARDA), and CDC should support innovation grants and contracts 

to academic and private sector teams for new multi-use technologies to detect novel respiratory viruses 

with pandemic potential and consider coordination with similar programs supported by the DOD. The 

focus should be on platform technologies with the capacity to detect other infectious agents as well 

as influenza viruses.

Development of Influenza Vaccine Seed Strains 

At present, influenza vaccines approved in the United States must be manufactured in eggs, yet influenza 

viruses that infect humans often grow poorly in eggs. Therefore, developing a vaccine seed virus entails 

creating a hybrid virus containing viral genes coding for the new HA and neuraminidase (N) proteins 

in a backbone of other influenza genes that help the virus to infect eggs. Creating these vaccine seed 

strains (also known as reassortants) is achieved by mixing the new influenza strain with a virus adapted 

to infect eggs and monitoring virus progeny for gene swapping after infection of eggs with both viruses. 

The seed strain for LAIV differs from that required to make the killed virus vaccine; LAIV must be made 

by swapping the new HA and N genes into an existing genetically defined influenza backbone that 

is adapted to grow at the lower temperature of the nasal passages where the vaccine is delivered. It 

is also impaired, or attenuated, for growth at the higher body temperature of the lung. In either case, 

the basic problem for preparing vaccine seed strains for manufacturing is that effects on growth are 

unpredictable when HA and N genes from one influenza virus are recombined with the other six genes 

of another strain because functions of these genes are influenced by the context provided by other viral 

genes. The difficulties of creating a high titer seed strain, especially one that will grow efficiently when 

scaled up for manufacturing, can cause significant delays in the time line for first delivery of pandemic 

influenza vaccines, as was the case with the 2009 H1N1 vaccine. 

Reassortent techniques are readily applicable to deriving influenza seed strains because of the ease 

with which influenza viruses exchange genes (see Box 1-3). However, contemporary molecular genetic 

methods can be used to optimize this process and can be applied to create viral recombinants that 

grow more efficiently in embryonated eggs or in cultured cells used to produce influenza vaccines in 

Europe (see Chapter 4). Even though the viral backbone remains the same for each LAIV product, reverse 

genetic methods are also applicable in this context because the novel HA gene can be manipulated to 

minimize interference with vaccine virus growth. 

Given the many years of experience with developing vaccine seed strains that grow well and the 

availability of these seed viruses, along with contemporary rapid sequencing tools, research can be 

undertaken to better understand the interactions of influenza genes and should make the behavior of 

influenza reassortants more predictable with respect to likely growth in eggs. It should be feasible, for 

example, to develop libraries of backbone viruses that can be used to make reassortants with new HA 

and N genes for the manufacture of inactivated vaccines, and the reassortants can then be screened 

rapidly to identify those with the best growth characteristics. If the transition to cell culture production 

moves forward in the United States, similar molecular approaches can be used to derive a panel of 

influenza backbones with good growth potential in cultured cells. 
III. Potential Benefits of Short-Term Changes in Methods for Making Influenza Vaccines

★ 25 ★

Genetic methods can also be used to test HA and N genes for minor mutations (outside the major 

antigenic regions of HA) that are associated with better yields, despite their transfer into a non-native 

influenza genome. Making LAIV requires that the backbone remain unmodified so that the vaccine 

virus retains the cold-adapted, temperature-sensitive-characteristics needed for optimum safety and 

effectiveness. Therefore, there is substantial experience with the consequences on viral growth of introducing novel HA and N genes into this backbone. Such reassortants are a resource for understanding 

how to optimize growth by making minor modifications of the HA gene when it is necessary to swap 

in new HA and N genes to make a pandemic vaccine. 

The opportunity also exists to make libraries of influenza seed strains with good growth characteristics 

that have HA and N genes from influenza viruses considered to have pandemic potential and store these 

reassortants for immediate use in manufacturing if the need arises. 

Potency Testing of Influenza Vaccines During Production and Release

A critical step in manufacture of many vaccines, including inactivated influenza vaccines, is testing vaccine material to determine the concentration of correctly folded antigen (immuno-reactive protein). 

This is referred to as “potency” testing, although it actually measures the amount of physical material 

that reacts with antibodies, rather than its true ability to induce an effective immune response when the 

standard 15 microgram dose of HA antigen in the inactivated vaccine is administered. These measurements are necessary for manufacturers to monitor production of the vaccine strain during virus growth 

in eggs (or cell culture) and for the FDA to authorize the release of pooled lots of vaccines. Although 

not a direct test of immunogenicity, vaccines that fail the criteria for release based on potency testing 

are expected to be poorly immunogenic in many vaccine recipients. The potency of LAIV is determined 

by a rapid, standard plaque assay in cultured cells; this test measures the concentration of infectious 

virus—also not a direct test of immunogenicity—but it does not require the generation of immunological reagents that sometimes impedes the production and release of inactivated vaccines.

The method currently used to detect HA in inactivated vaccines requires sheep antisera containing 

antibodies that bind to the novel HA antigen in its native state. To make this key reagent, sheep are 

immunized with the new HA antigen to produce large quantities of antisera against HA. Under current 

practice, the CDC provides the reference (pre-seed) influenza virus to the FDA, which is then responsible 

for making purified HA to immunize sheep and for overseeing production of the HA antiserum. The 

amount of HA in a sample of inactivated vaccine is then determined using a radial immunodiffusion 

RECOMMENDATION 3-2: DEVELOP OPTIMIZED SEED VIRUSES 

NIAID and BARDA should ensure the development and dissemination of a panel of viral backbones to 

create seed viruses optimized for rapid growth. Such backbones can accelerate production of inactivated 

vaccines either in eggs or in mammalian cell culture. Studies of HA and N genes in the context of these 

backbones and in the LAIV backbone should also be pursued to maximize growth. This should be accomplished through focused contracts, with the aim of producing such viral backbones within 2-3 years.
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assay, a method first described in 1957. The sheep antiserum is suspended in agar and a test specimen 

from the bulk vaccine is placed in a well cut in the agar; the antigen diffuses from the well and binds to 

HA antibodies in the agar, forming a visible circle around the well. The amount of HA in the vaccine is 

calculated from the diameter of the circle. 

 Though this process may sound straightforward, problems with making potency reagents are a wellknown source of delays in manufacturing seasonal influenza vaccines, since serious bottlenecks in 

production and delivery can occur if effective reagents are not available when vaccine materials are ready 

for testing and packaging. The time needed to make sheep antisera varies from 8-12 weeks (see Figure 

2-1), depending on the time that it takes for the animals to mount an immune response to the specific 

HA. Moreover, the quality of the HA antiserum that an immunized animal will produce is unpredictable. 

If the HA antibodies are of low affinity, it may be necessary to repeat the process in other animals. 

Approaches to develop faster and more predictable methods to generate reagents and measure HA 

content could reduce the risk of delaying vaccine release; some of these would be applicable not only 

to inactivated vaccines against multiple types of influenza viruses, but also to certain vaccines for other 

infectious agents. Such strategies might eliminate the need to immunize sheep and thereby hasten the 

availability of antisera for potency testing. In addition, antigen for immunization might be produced 

more quickly—for example, by cloning a newly identified HA gene into an expression vector to generate large quantities of recombinant HA in mammalian cells for immunizing animals. The use of antisera 

raised with recombinant HA would, of course, need to be validated in the radial immunodiffusion assay 

using previously tested vaccine material. These reagents can also be coupled to more contemporary 

biochemical or physico-chemical platforms for measurement of HA concentration, such as enzyme 

immunoassays or immunoprecipitation/mass spectroscopy assays. Work done by the Centers for Disease 

Control suggests that isotope dilution mass spectrometry methods could be used to reduce substantially the time to measure the antigen content of influenza vaccines and thus make influenza vaccines 

available 4-8 weeks earlier. Additional work incorporating antibody capture of antigen prior to mass 

spectrometry analysis will be published soon. Compared to the current potency assay, the antibodycapture mass spectrometry method provides better selectivity for different influenza antigens, better 

accuracy and precision, shorter analysis time and better sensitivity that enables direct analysis of the 

small amounts of antigen in vaccines, including adjuvant-based vaccines for the first time.8 The time 

to availability might be reduced even more decisively by preparing panels of HA antibody reagents in 

advance, using phage libraries or pre-synthesized panels of monoclonal antibodies against HA molecules 

from influenza viruses identified as potential pandemic strains. These reagents would be ready to screen 

for reactivity against HA made by the newly identified virus in infected cells or the cloned HA gene and 

used in antibody-based assays to measure the HA content of vaccine preparations. Validation of these 

approaches to meet regulatory requirements would be necessary. 

Another rationale for developing these methods and reagents is their potential application to the 

problem of understanding the reasons for HA instability in some influenza vaccines; loss of potency was 

encountered with some lots of 2009-H1N1 vaccine. Potency testing will also be necessary for use with the 

second generation influenza vaccines based on recombinant DNA technologies, discussed in Chapter 5. 

8. Williams TL, Luna L, et al. Quantification of Influenza Virus Hemagglutinins in Complex Mixtures using Isotope 

Dilution Tandem Mass Spectrometry. Vaccine 2008; 26:2510-20.
III. Potential Benefits of Short-Term Changes in Methods for Making Influenza Vaccines

★ 27 ★

Sterility Testing

Each batch of vaccine material must be tested to ensure that it is not contaminated with bacteria or fungi, 

a recurrent problem in egg-based manufacture and one that can also occur when vaccine is prepared 

in cell culture. Sterility testing is currently accomplished by incubating vaccine material in conventional 

growth media and waiting to observe bacterial or fungal growth, a process that typically takes about 

two weeks. It is possible to ship the vaccine while awaiting the results of sterility testing, although the 

vaccine cannot be administered until the testing is completed. 

New, more rapid sterility testing methods are feasible. These methods include PCR and sequencing or 

array-based technologies using reagents that will identify a wide range of organisms, and rapid, massively parallel sequencing to detect microbes without prior assumptions about what contaminants 

may be present. Use of such molecular techniques to test directly for microbial contamination could 

reduce the time to release a batch of vaccine by at least one week, could be more sensitive, and could be 

applicable to many kinds of vaccines and biologicals, not just influenza vaccines, and hence constitute 

a multi-use platform technology.

RECOMMENDATION 3-3: POTENCY TESTING

FDA and BARDA should fund applied research to develop rapid methods for making potency assays for 

testing inactivated influenza vaccines. This should be a high-priority effort carried out through a combination of in-house programs at FDA and contracts to companies, aimed at creating and implementing such 

methods within a 2-3 year time frame. Possible methods include mass spectroscopy coupled with molecular biological techniques for making affinity reagents. Such methods will need to be carefully validated by 

comparison with the standard radial immunodiffusion assay. 

In addition, FDA should develop a well-defined regulatory process for introducing alternative assays for HA 

potency for seasonal influenza vaccines, initially alongside existing assays. 

RECOMMENDATION 3-4: DEVELOP PLATFORM TECHNOLOGY FOR STERILITY TESTING

The FDA and BARDA should support the development of rapid methods to test the sterility of influenza 

vaccines, through such molecular biological techniques as PCR and shotgun DNA sequencing. This should 

be carried out through private sector contracts and in collaboration with manufacturers. 

The methods should be performed in parallel with existing sterility testing of seasonal influenza vaccines, 

to demonstrate the sensitivity and validity of the methods.

The FDA should define a regulatory process to guide development and implementation.
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Manufacturing Fill-Finish Capacity

All vaccines must be packaged for clinical use. The fill-finish step for inactivated influenza vaccines 

involves transferring bulk vaccine into individual single-dose syringes as well as the single or multi-dose 

vials used for inactivated influenza vaccines or to nasal sprayers required for the live attenuated vaccines. This step is a major hurdle on the path to vaccine distribution to providers. It represents a costly 

and laborious phase of manufacturing that can be expanded only in a linear fashion, and it generally 

proves to be a major rate-limiting step in the process of delivering vaccine, especially under pandemic 

conditions. The effects of delays in the fill-finish step are felt mainly as production is scaled-up, with little 

effect on the time to delivery of first doses. Packaging a greater proportion of vaccine in multi-dose 

vials could eliminate several weeks from the time needed to deliver all of the needed doses of vaccine, 

but the savings in time must be balanced against the increased risk of contamination of the vial or 

inadvertent failure to change needles between doses; moreover, multi-dose vials generally require the 

inclusion of preservatives. 

Greater capacity can also be achieved by the construction and validation of additional facilities with 

more machines for sterile filling and finishing, but the additional costs for such added facilities will not 

be readily absorbed by the manufacturers. Use of facilities and filling machines that can process different 

vaccines at different times of the year would expand fill-finish capacity at a less onerous expense, but 

guidance from regulators would be required to avoid safety violations and delays in manufacturing. 

Having agreements to allow rapid transfer of production facilities to pandemic vaccine production 

could be done in advance, possibly including providing a retainer to companies in order to maintain 

this capability. Developing pre-approved options for nasal administration in addition to sprayers could 

reduce the barrier to rapid distribution of live attenuated vaccines. Improving the machinery that performs all of these tasks may also be possible, and government incentives to promote such advances in 

manufacturing should be considered, especially if they can be designed as multi-use platforms.

Today, fill-finish to meet the Nation’s demand for seasonal influenza vaccines is done at four facilities 

in the United States, as well as three facilities outside of the Nation’s borders. Options for sustaining or 

rapidly mobilizing facility and personnel capacity needed for this critical task need to be studied further. 

RECOMMENDATION 3-5: FILL-FINISH CAPACITY

The Federal Government, working closely with manufacturers, should undertake a comprehensive study 

within six months to quantitatively assess current fill-finish capacity and to develop a plan to ensure 

adequate capacity to produce sufficient quantities of pre-filled syringes, vials and/or nasal sprayers to meet 

the national need. The study should evaluate the use of existing facilities or the creation of new facilities 

that could be used in the event of a pandemic, including necessary agreements, preparations and licensure. It should also address maintaining a sufficient stockpile of vaccine containers and delivery devices.
★ 29 ★

IV. Production of Influenza 

Vaccines in Cultured Cells

Today, the only approved method for making either inactivated influenza or LAIV vaccines for use in 

the United States involves the production of the selected viral strains in embryonated chicken eggs. In 

principle, however, influenza vaccines can be prepared using viruses grown in cultured cells or using 

proteins made with recombinant DNA methods. A number of these technologies are currently in various 

stages of development. Shifting the method of production and/or in the composition of the vaccines 

can markedly affect the time course for delivery of vaccines and the reliability of delivery. These possible 

changes are considered in detail in this and the following chapters.

Cell Culture-Based Production

The change in approach to vaccine production most likely to have an impact in the short term involves 

producing vaccine viruses in cell culture-based propagation systems rather than in embryonated 

chicken eggs. Cell culture-based systems would be used to produce the same kind of vaccines that are 

currently made, i.e., whole disrupted (inactive) virus as well as genetically attenuated virus (LAIV), and 

hence will pose less biological uncertainty and fewer regulatory difficulties than recombinant influenza 

vaccines (see Chapter 5). A transition to cell culture-based production has been under consideration for 

many years, and several companies are proceeding to develop and commercialize vaccine produced 

by this method. Cell culture production alone provides some improvements in time to first dose in the 

event of a pandemic, but does not alleviate the earlier potential bottlenecks such as optimization of an 

appropriate vaccine production strain. However, the use of cell culture can significantly accelerate the 

time to last dose. The markedly shorter time to production of last dose can be attributed to speed with 

which the cells required to produce virus can be scaled up geometrically from abundant frozen stocks 

(to the limit of the manufacturing capacity). In contrast, embryonated eggs are often in limited supply, 

CHAPTER SUMMARY

Today, all influenza vaccine used in the United States is made by growing the selected viral vaccine strains 

in embryonated chicken eggs. Alternative methods for producing influenza vaccines, using mammalian 

cell culture (or, as discussed in Chapter 5, recombinant DNA technology), are in development, and each has 

the potential to make vaccine production more reliable and faster. 

Expansion of the capacity to produce influenza vaccine in mammalian cell culture would permit more 

rapid scale-up in the face of a pandemic, thereby shortening the time for production of sufficient quantities of vaccine needed to protect the United States population. However, such expansion faces fiscal and 

regulatory uncertainties that need to be fully understood and alleviated. An important aspect of such an 

assessment includes evaluating the barriers to the use of LAIV produced in cell culture, possibly permitting 

a more efficient use of existing production facilities. 
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especially under pandemic conditions, and can only be increased by acquiring more freshly laid eggs. 

For mid-level developing countries in particular, cell culture production might also be more efficient, 

considering the difficulty in producing sterile embryonated chicken eggs. 

Figure 4-1. Production Timelines for Egg and Cell Culture Inactivated 

Vaccines

Producing influenza vaccines in cell culture is expected to shorten the timeline for the availability of the first doses of 

inactivated vaccine (second line) when compared to the WHO’s prediction for the production of inactivated vaccine in eggs 

(top line); the time to release of the final doses will depend on the manufacturing capacity. Improving the initial steps to 

prepare, verify, and distribute vaccine strain to manufacturers and to optimize the seed virus can also be accelerated when 

vaccines are made in cell culture; the effects of those additional changes are shown in the third line. However, because of 

the accelerated manufacturing schedule, the availability of potency reagents for release testing of inactivated vaccines will 

become rate-limiting (orange arrow). Based on WHO predictions, potency reagents might not be available until six weeks 

after they were needed for final manufacturing and release. 
I V. Production of Influenza Vaccines in Cultured Cells

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Mammalian cell culture techniques are used already to make a variety of human and veterinary vaccines 

and biologic therapeutic agents, and they have the capability to offer a predictable, rapid, and responsive 

method for production of well-tolerated and effective vaccines. And as was discussed in Chapter 3, other 

steps in the production process—development of an optimized seed strain, preparation of potency 

reagents, sterility testing, and fill-finish—will still have to be addressed to alleviate potential bottlenecks. 

The methods for using mammalian cell culture to produce vaccines in general—and influenza vaccines in 

particular—are well developed, and at least two companies have used cell culture to produce influenza 

vaccines that have received regulatory clearance in Europe. The majority of companies that have used 

or are developing cell culture methods for influenza vaccine production rely on continuous mammalian 

kidney cell lines, as the vehicle for producing vaccines. The main components of a mammalian cell-based 

influenza vaccine production system are:

• Selection of a mammalian cell line that is well-defined from a safety perspective and that is 

particularly suited to high-yield production of the vaccine antigen. Once the cell line is defined 

and characterized, it can be used for production of influenza vaccine year after year.

• Selection of an influenza seed virus that can grow to high levels in the production cell line. The 

seed virus would have to be antigenically matched to a given year’s circulating influenza virus 

strain, as derived by forming reassortants between the pandemic strain and viruses known to 

replicate efficiently in cell culture.

• Scale-up of the cell culture (and production) in a large-scale bioreactor, using defined growth 

medium.

• Harvesting of the virus, and subsequent processing, treatment and purification to yield bulk 

vaccine ready for finishing into final containers (syringes, vials, etc.) These latter steps will differ 

depending on whether the vaccine is to be composed of inactivated or live attenuated virus.

The basic production process is straightforward. Mammalian cells are treated with the enzyme trypsin to 

create a cell suspension, which is then introduced into a bioreactor (as large as 6000 liters) that allows a 

dramatic expansion of cell numbers. When the desired number of cells is reached, the seed strain of virus 

is introduced into the bioreactor, and the virus infects and replicates in the cells, The virus particles are 

then harvested, inactivated (except in the case of live attenuated vaccines) and purified using specially 

designed methods. Once this bulk vaccine is tested for concentration of antigen (potency testing for 

killed virus vaccine or plaque assays for LAIV) and for the absence of biological contaminants in sterility 

tests, it is shipped to a fill-finish facility for final preparation in individual or multipack dosage forms.

Several current vaccine manufacturers and biotechnology companies are developing technology 

to produce influenza vaccines using mammalian cell culture. For example, Baxter International used 

mammalian kidney cells to produce its 2009-H1N1 pandemic influenza vaccine that was approved in 

Europe on October 6, 2009, while Novartis used a different line of mammalian kidney cells to produce 

its 2009-H1N1 pandemic influenza vaccine approved in Europe on November 5, 2009. However, current 

capacity in the United States is inadequate to supply the quantities of cell culture-produced vaccine, 

especially inactivated vaccine, needed to immunize the entire population in the case of a pandemic. 
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Advantages of Producing Influenza Vaccine Using Mammalian Cell Culture

Using mammalian cell culture systems for producing influenza vaccine has several advantages over 

egg-based production. The list of advantages includes:

• Pre-production preparedness. The appropriate mammalian cell lines can be stored in freezers 

and readied in a matter of days or weeks for large-scale production demands. In contrast, eggbased production requires secure supplies of pathogen-free, embryonated eggs, and it usually 

takes four to six months to generate the necessary supply of eggs from biosecure chicken flocks 

to meet the demands associated with either seasonal or pandemic influenza. 

• Yield and scale. Mammalian cell lines are selected for rapid growth and production of high titers 

of virus, and scaling is a matter of growing more cells in bioreactors. One of the advantages of 

using cells to produce vaccine is that cells grow exponentially, allowing for the rapid expansion 

of the production substrate into large bioreactor volumes. In addition, these bioreactors can 

be used multiple times. Together, this allows for a relatively rapid and consistent scale-up of 

production, compared to what is achievable using chicken eggs. 

BOX 4-1. ESTIMATING THE PRODUCTION CAPACITY NEEDS TO COVER THE US POPULATION

Vaccination of about 80% of the total US population as soon as possible after an influenza pandemic is 

declared—certainly before a second wave of infection begins—is the conventional goal for vaccine makers 

during a pandemic. That means providing about 240 million doses (Md) within one to two months after 

the first doses of vaccine are delivered—translating into 30 to 60 Md/week. In comparison, in 2009-2010, 

less than half of the desired number of doses, mostly killed, egg-based vaccine, were provided to the US 

population in the first three months after the first doses were delivered in early October, an average rate of 

about 10 Md/week.

Many variables affect the estimates of whether desired rates can be achieved: the virus yields (from eggs 

or cell culture), the number of manufacturers and their facilities (including the supplies of sterile embryonated eggs and the numbers and sizes of available bioreactors for cell culture), and the composition of the 

vaccine. For example, the yield of doses of LAIV vaccine is generally 10 to 100 times greater than for killed 

virus vaccine for the same amount of virus material. In addition, the number of doses of killed virus vaccine 

can be increased two- to ten-fold when an adjuvanted vaccine is used.

The Working Group learned that Medimmune projects that it could generate about 30 Md/week of LAIV 

from cell culture in four large bioreactors (G. Kemble) and that Novartis is able to produce about 10 Md/

week of cell culture-derived killed vaccine (containing 3.75 ug rather than the usual 15 ug per dose, 

because an adjuvant was included) at its Holly Springs plant (R.Rappuoli). 

Cell culture-derived vaccines and adjuvants do not yet have regulatory approval in the US and thus were 

not used in the US during the 2009 pandemic. However, these numbers indicate how a well-planned effort 

to use cell culture, LAIV, and adjuvants—together with some expansion in manufacturing capacity—could 

dramatically reduce the time required to provide 240 Md to the US population to one to two months.
I V. Production of Influenza Vaccines in Cultured Cells

★ 33 ★

• Faster time to last dose. Although it is possible to eliminate some time from the start of production to first dose using cell culture, the ability to more rapidly scale up production of virus 

in cell culture translates into a real benefit in terms of time required for the production of the 

so-called last dose, the amount needed to potentially immunize the entire population. 

• Simplified preparation and higher initial purity. Harvesting vaccine virus particles from 

mammalian cell bioreactors is simpler than the methods used for sterile harvest of chicken 

egg allantoic fluid. In addition, the subsequent purification of the virus yields a product of 

higher purity, free of contamination with egg-based allergens that can trigger hypersensitivity 

responses in susceptible individuals.

Barriers Impeding Influenza Vaccine Production Using Mammalian Cell 

Culture

The use of mammalian cell culture to produce influenza vaccines is not free of its own set of problems 

impeding adoption. These include:

• Capacity. Although vaccine production in cell culture is more readily scaled up than an eggbased process, there is still insufficient capacity at present to meet future demands in a pandemic with cell culture-based inactivated vaccine. A careful assessment of the difference 

between current capacity for cell culture-based production and the needed capacity to meet 

national demand for a pandemic inactivated influenza vaccine is required. The increase in capacity would involve the construction of facilities for additional bulk production and subsequent 

steps in manufacturing, as well as more efficient and flexible use of these facilities. Capacity 

issues would be greatly reduced if cell culture systems were also used to make LAIV vaccines, 

which are many-fold more potent than inactivated virus vaccine. 

• Construction costs. The enormous expense for plant construction and validation for use as a 

biologics production facility poses a major problem. Novartis spent over $1 billion to construct 

its new large-scale cell culture-based influenza vaccine manufacturing facility in Holly Springs, 

NC, with the Department of Health and Human Services (HHS) contributing $487 million, or 

40%, of the construction and validation costs. New plant construction, including validation and 

regulatory approval, takes three to four years to complete. It may be possible, however, to use 

existing facilities to produce virus for vaccine preparation under the appropriate biocontainment 

requirements in the event of an influenza pandemic.

• Additional costs. In any given year, a vaccine production facility may remain unused for six 

months in the absence of demand for a pandemic influenza vaccine, since it would be used 

only for seasonal vaccine. However, preparedness for production of pandemic influenza vaccines would require maintaining trained crews to operate the cell culture production system, a 

significant operational cost that no company would be willing to bear. In addition, there is the 

“opportunity cost” of investing in plant construction and necessary research and development 

activities that few companies are willing to bear given the low margin nature of the influenza 
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vaccine business. Some of these difficulties would be obviated if the facilities could be used for 

purposes other than production of cell-based influenza vaccines.

• New seed viruses and potency assay reagents. Currently, seed viruses are optimized for 

production of virus in chicken eggs, so it is likely that new virus backbones will be required for 

inactivated virus vaccines adapted to growth in mammalian cell culture. The LAIV backbone 

remains the same because of its attenuating characteristics but some minor modifications 

may enhance cell culture growth. These improvements will demand additional research and 

development. Some work may also be needed to optimize the production of potency reagents 

specifically for vaccine antigens produced in mammalian cell culture. 

• Regulatory uncertainty and expense. Though two pandemic influenza vaccines (against H1N1 

and a potential pandemic strain) produced in cell culture have been approved by European 

regulatory agencies, the Food and Drug Administration (FDA) has yet to approve an influenza 

vaccine produced in cell culture for use in the United States. However, on March 2, 2010, the 

FDA issued a final guidance document whose intent is to reduce the uncertainty surrounding 

the regulatory pathway for influenza vaccines produced using cell culture.9 FDA scientists 

spent more than a decade conducting the research required for the document, as well as 

9. Department of Health and Human Services, Food and Drug Administration Center for Biologics 

Evaluation and Research. February 2010. Guidance for Industry: Characterization and Qualification of Cell 

Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease 

Indications. Available at http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRe%20

gulatoryInformation/Guidances/Vaccines/UCM202439.pdf. 

RECOMMENDATION 4-1: UNDERSTAND AVAILABLE CAPACITY FOR CELL CULTURE PRODUCTION 

AND DEVELOP INCENTIVES TO EXPAND CAPACITY

HHS, the Department of Homeland Security (DHS), and BARDA should commission a 6-month study in 

close collaboration with industry to determine the Nation’s needs and capacity for cell culture-based 

production of pandemic influenza vaccine, and to develop a set of economic incentives that would 

catalyze the development of new influenza vaccines made in cell culture systems. Such incentives might 

include rapid depreciation of physical plant costs; research contracts; guaranteed purchases; cost-sharing 

during idle times in production plants; and construction subsidies. This study should also focus both on 

new capacity and the potential to utilize existing production facilities now dedicated to producing other 

biologicals in cell culture systems. Finally, the study should carefully consider the balance between the 

investment needed to increase cell culture production capacity and the possibility that novel recombinant 

technologies might become available soon enough to substantially diminish the need for the increased 

capacity required to cope with another influenza pandemic.

RECOMMENDATION 4-2: DEVELOP OPTIMIZED SEED VIRUSES AND POTENCY ASSAYS

NIAID and BARDA should issue a 2-year contract to develop new vaccine backbones to create seed viruses 

optimized for rapid growth in mammalian cell culture.
I V. Production of Influenza Vaccines in Cultured Cells

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consulting with other scientists, the vaccine industry, and the public about it. In addition to 

providing advice to manufacturers about the scientific principles of cell substrate development, 

the guidance describes tests that may be used to evaluate cell substrates intended for use in 

viral vaccine production.

Live Attenuated Influenza Vaccine

LAIV vaccines appear to induce a potentially more effective immune response than do the comparable 

inactivated vaccines, especially when the vaccine recipient is “naïve” or has limited prior infections with 

influenza. For example, data from recent studies comparing the efficacy of inactivated influenza vaccine 

and LAIV vaccine in protecting children six to 59 months of age found that there were 54.9% fewer cases 

of confirmed influenza in the group receiving LAIV vaccine than in the group receiving inactivated virus 

vaccine. Superior protection against viruses that had drifted antigenically during influenza season was 

also seen with LAIV vaccine than with inactivated virus vaccine.10

Because LAIV vaccines may be able to trigger a more effective immune response than inactivated virus 

vaccines, production capacity demands in the event of a pandemic would be lower if the majority of 

vaccine production was devoted to LAIV vaccines. There will, however, continue to be a need to produce 

inactive virus vaccine because LAIV is not recommended for certain individuals such as infants and those 

with compromised immunity. In addition, the immunological basis of the clinical protection afforded 

by LAIV vaccines is not fully understood. 

The FDA requires that LAIV vaccines produced in mammalian cells be shown, through an extensive 

efficacy trial, to be as effective as LAIV vaccines currently produced in embryonated chicken eggs; the 

cost of such studies typically range from $50 million to as much as $100 million. This cost is a major 

barrier to the more widespread development of LAIVs produced in mammalian cell culture, whether 

for seasonal or pandemic influenza.

10. Belshe RB, Edwards KM, et al. Live Attenuated versus Inactivated Influenza Vaccine in Infants and Young Children. 

New England Journal of Medicine 2007; 356(7):685-696.

RECOMMENDATION 4-3: INVESTIGATE THE IMMUNE RESPONSE TO LAIV

NIAID should increase funding for basic academic research to develop an understanding of the human 

immune response to LAIV vaccines and to conduct a thorough, in-depth analysis of the mechanisms that 

produce influenza immunity in humans. The goal of this research should be both to improve the fundamental understanding of how the human immune system responds to influenza virus and to develop new 

potency reagents and in vitro assays that correlate with protective immunogenicity, particularly for LAIV 

vaccines. Collaboration with MedImmune, the sole commercial producer of the LAIV vaccine, would be 

required for some of this work.
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Use of cell culture to grow cold-adapted, heat-sensitive strains of influenza virus for preparation of LAIV 

vaccines would have special value for shortening the time line, because viral backbones needed to 

generate seed stocks with appropriate properties are already available (to hasten the time to first doses) 

and because 50- to 100-fold less virus is generally required for an effective dose of vaccine (accelerating the time of last doses). In addition, the amount of material in LAIV vaccines is monitored by tests 

for infectious virus, not by potency tests, eliminating the possibility that the time course of production 

could be prolonged by the difficulty of preparing reagents for potency testing. However, increased 

production of LAIV vaccine in cell culture will not occur until clinical studies have been performed with 

vaccine made using this method and the vaccine has been tested in age groups for which LAIV is not 

currently approved. 

RECOMMENDATION 4-4: SUPPORT LAIV CLINICAL TRIALS

HHS and BARDA should facilitate and share the costs of conducting the necessary clinical trials to license 

LAIV vaccines produced in cell culture and to generate the correlative data that will enable future LAIV 

vaccines to be approved for use in the same simplified manner that seasonal influenza vaccines produced 

in chicken eggs are today. 
★ 37 ★

V. Recombinant Influenza Vaccines

Production of Recombinant DNA-Based Vaccines

Today’s influenza vaccines are made from whole viruses, which are strong stimulants of the immune 

system but are complex mixtures of materials. Egg-based products also contain potentially allergenic 

proteins from chicken eggs. Fortunately, growing influenza viruses in chicken eggs or in mammalian 

cells in culture are not the only two methods available for making influenza vaccines. Using modern 

molecular technologies, a number of companies are developing what are known as recombinant vaccines—vaccines containing viral proteins synthesized under the direction of molecularly cloned viral 

genes and expressed in and purified from bacterial, yeast, insect, plant, or mammalian cells. 

Some of the new vaccines on the market for viruses such as human papilloma and hepatitis B viruses 

are recombinant vaccines. Such vaccines are considered by many to be the wave of the future, but there 

are obstacles that must be overcome before the vaccine industry will shift from existing technologies to 

recombinant DNA-based technologies to replace existing vaccines. For example, as with any entirely new 

vaccine, recombinant vaccines require long programs of testing to establish their efficacy and safety. In 

addition, pure proteins often do not stimulate effective immunity and may have to be aggregated into 

virus-like particles and/or formulated with adjuvants to elicit protective immunity. Finally, the cost of 

developing such a product is an economic challenge, even for large companies.

To make recombinant influenza virus vaccines, viral genes encoding the new variant proteins must be 

cloned into expression vectors, most commonly viruses that infect cells of higher organisms (mammalian, insect, or plant cells) or plasmids that can replicate in bacteria or yeast. The primary goal is 

generally to produce large amounts of HA and other virus proteins, either as part of a virus-like particle 

(VLP) or as a soluble protein. In either case, proper folding of the protein will likely be needed for vaccine recipients to produce an immune response that is protective against subsequent infection by the 

virus. Also in development are VLPs linked to DNA sequences, which act as a built-in adjuvant, or soluble 

hemagglutinin protein linked to bacterial flagellin protein, which also acts as an adjuvant. Table 5-1 lists 

recombinant influenza vaccines being developed. 

CHAPTER SUMMARY

The greatest potential for substantially shortening the time and increasing the reliability of influenza vaccine production lies in the use of recombinant DNA technologies. However, as for the proposal to transition 

from egg-based to cell-based methods of vaccine production, there are economic barriers and regulatory 

uncertainties, as well as inherent biological uncertainties that are impeding the full development of these 

technologies. All of these uncertainties require careful definition. The economic and regulatory hurdles 

may require the Federal Government to provide novel incentives and pathways for development.
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Table 5-1. Examples of Recombinant Influenza Vaccines in Clinical 

Development

Vaccine/Manufacturer Type Mode of 

Preparation Adjuvant Developmental/ Regulatory Status

FluBlok®(seasonal 

influenza)/Protein 

Sciences

Soluble protein 

(HA), Trivalent (3 

strains)

Insect cell culture/

baculovirus None

Biological License 

Application 

Pending

PanBlock®(seasonal 

influenza)/Protein 

Sciences

Soluble protein (HA) Insect cell culture/

baculovirus

None (Inulin, GLA 

being evaluated) Clinical Trials

Influenza/Novavax VLP (HA, N, and M) Insect cell culture/

baculovirus None Clinical Trials

Pandemic & Seasonal 

Influenza/Medicago VLP (HA and N) Plant cell culture None Preclinical

Seasonal and 

Pandemic Influenza/

VaxInnate

Soluble human and 

avian protein (HA) E. coli Flagellin Preclinical

Universal Influenza/ 

Dynavax

Soluble protein (NP, 

M2e) E. coli CpG Preclinical

Pandemic & Seasonal 

Influenza/Lentigen VLP (HA and N) Human cell culture/

lentivirus None Preclinical

VLP=virus-like particle; HA=hemagglutinin; N=neuraminidase; NP=influenza nuclear protein; M=influenza matrix protein; 

M2e=influenza integral membrane protein; GLA=glycopyranosyl lipid adjuvant; CpG=synthetic oligonucleotide adjuvant.
V. Recombinant Influenza Vaccines

★ 39 ★

These recombinant influenza vaccines hold the promise of:

• shortening the time to first dose of vaccine following the identification of a novel strain of 

influenza virus. As illustrated in Figure 5-1, recombinant vaccines would eliminate the time now 

required to prepare and optimize vaccine seed stocks of virus, since production would depend 

instead upon molecular cloning of the viral HA gene (and perhaps other genes) from the isolated 

pandemic virus. If preparation of potency reagents can be accelerated, the first doses of vaccine 

could be available in less than ten weeks. 

• producing larger volumes of vaccine in any given timeframe resulting from the ability to use 

high-capacity platforms such as bioreactors or plants. Scaled-up production of recombinant 

vaccines should permit delivery of all needed doses—estimated to be in the range of 250 million—in another 4 to 6 weeks after the first doses, provided that the fill-finish process does not 

prove to be a bottleneck.

• establishing extensive surge capacity as a result of the nature of the production process, 

which can be readily scaled-up to meet extraordinary demands.

• using the platform to produce other products when it is not being used for influenza vaccine. 

For example, other recombinant products for use as vaccines or biological therapies might be 

made in the same facilities, given regulatory clearance.

• reducing lot-to-lot variability and the level of effort necessary for quality assurance. 

Recombinant procedures, in general, are more readily regularized and monitored than production of virus in eggs or mammalian cells.

• lowering the cost of goods relative to current production technologies. Recombinant methods 

are in general less expensive means of production and less subject to unexpected variations 

in efficiency.

• transferring the technology to other countries, thereby enhancing self-sufficiency of the 

global community and reducing political pressure on the United States to assure influenza vaccine supply for the rest of the world. Such methods have already been used to make hepatitis 

B vaccines in developing countries and that success should be replicable with recombinant 

influenza vaccines.

• platform flexibility, since recombinant methods can be used to design more potent HA and 

other antigens that might be effective for more than a single influenza season or against future 

pandemics, as discussed further in Chapter 7.
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Figure 5-1 Production Timelines for Egg-based Inactivated and HA 

Recombinant Vaccines

Using recombinant technology to make influenza vaccines is predicted to have a significant effect on the timeline for 

vaccine production (second and third lines) compared to the WHO’s prediction for the production of inactivated vaccine 

in eggs (top line). Because there is no need with recombinant technology to create a vaccine seed virus, the process can 

begin as soon as the CDC has sequenced the new HA gene designated for production of pandemic influenza vaccine. 

Since manufacturing is readily scaled up, the time to availability of initial doses is reduced from the 20 weeks estimated for 

egg-based killed virus vaccine to about 12 weeks or less. To take advantage of this accelerated time line, an alternative to 

radial immunodiffusion with newly generated antiserum for measuring HA content as an assay of potency will be essential. 

The figure illustrates the time to availability of the first vaccine doses; the time to release of final doses will depend on the 

manufacturing capacity.

Experience with Recombinant Vaccines

The majority of vaccines currently available for immunization of human beings against viral pathogens 

are composed of killed or live attenuated viruses, but effective recombinant vaccines against hepatitis B 

and human papilloma viruses (HBV and HPV) have been developed, approved, and widely used. These 

vaccines are manufactured by gene expression in budding yeast (Gardisil and Recombivax), mammalian cells (Energix-B), or insect cells (Cervarix). In the case of Cervarix, insect cell lines are infected with 

*Assumes an additional reduction time if the HA gene is cloned for possible vaccine production immediately

after a novel virus is identified as causing human infection but before the virus is confirmed as a pandemic threat. 

Week

2 4 6 8 10 12 14 16 18 20 22 24 26

Egg-based (inactivated)

Recombinant

Recombinant*

Potency Reagents for HA Vaccines

Prepare, verify,

distribute vaccine strain

to manufacturers (CDC)

Optimize seed virus

growth for working 

seed (Mf)

Manufacture bulk

vaccine, QC test, &

pool (Mf)

Release of

Vaccine

(FDA)

Fill & ­nish

vaccine:

First lots (Mf)
V. Recombinant Influenza Vaccines

★ 41 ★

baculovirus containing a gene encoding an HPV protein, with the protein secreted into the culture 

medium; the vaccine protein assembles spontaneously into a VLP (virus-like particle), which increases 

its immunogenicity. The virus surface protein used in the HBV vaccine produced in yeast also assembles 

into a VLP. 

Influenza vaccine antigens can also be expressed in recombinant systems, either as soluble proteins or 

as VLPs. Both Protein Sciences Corp. and Novavax are testing recombinant influenza vaccines. Protein 

Science’s FluBlok, a seasonal influenza vaccine composed of purified recombinant HA antigens produced 

in a baculovirus cell culture system, is currently under review for licensing at the FDA. Phase III clinical 

trials suggest that FluBlok may be more effective than standard influenza vaccine in triggering an HA 

antibody response equal to that produced by standard vaccine in people over 65, a population that 

accounts for over 90% of influenza-related deaths in most years. The company’s PanBlok, a pandemic 

influenza vaccine candidate comprising purified recombinant HA from the H5N1 avian influenza virus, is 

in Phase II clinical trials. Novavax’s recombinant pandemic influenza vaccine, this one designed to protect 

against the 2009 H1N1 influenza virus, consists of VLPs composed of HA and N produced in a baculovirus 

cell culture system. This vaccine is currently in Phase II trials. The company’s seasonal influenza vaccine, 

also consisting of recombinant antigens produced in baculovirus cell culture, is in Phase IIa clinical trials.

One of the major advantages of using eukaryotic cells—those of higher organisms, including mammals—to produce viral proteins for vaccines is that they generate proteins that are more likely to be 

properly folded and modified with the proper sugar molecules than are proteins produced in bacterial 

expression systems. Although the pattern of glycosylation (the arrangement of sugars on a protein) 

obtained using insect cells may differ from that in mammalian or avian cells, influenza proteins produced 

with baculovirus vectors in insect cells have proven to be immunogenic and to provide protection 

against influenza in the widely used ferret challenge model11, 12. These proteins have also been able to 

trigger antibody production against the recombinant proteins in human clinical trial subjects.13

It is possible that recombinant vaccines will not trigger an immune response strong enough to protect 

against infection. In such cases, it is likely that adjuvant will be needed to overcome that limitation. (See 

Chapter 6 for a discussion of adjuvants.)

Once a recombinant influenza vaccine is established as safe and effective through clinical trials, the 

FDA will likely approve future recombinant vaccines made using the same expression system by a 

mechanism similar to the regulatory process now used to approve new seasonal influenza vaccines 

containing different strains of virus.

11. Ross TM, Mahmood K, et al. A Trivalent Virus-Like Particle Vaccine Elicits Protective Immune 

Responses against Seasonal Influenza Strains in Mice and Ferrets. PLoS ONE 2009; 4(6): e6032. Available at: 

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0006032. 

12. Perrone LA, Ahmad A, et al. Intranasal vaccination with 1918 influenza virus-like particles protects mice and 

ferrets from lethal 1918 and H5N1 influenza virus challenge. Journal of Virology 2009; 83(11):5726-34.

13. StreetInsider. March 2010. Novavax (NVAX) Announces Results for Influenza VLP Phase II. Available at: 

http://www.streetinsider.com/Corporate+News/Novavax+(NVAX)+Announces+Results+for+Influenza+VLP+Phase+II/

5476269.html.
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Taking the Initiative

Despite their potential advantages, recombinant influenza vaccines—with the possible exception of 

Protein Sciences’ Flu Blok which is currently under review by the FDA—will likely take several years, and 

possibly more than a decade, to reach the market. This is especially true without the direct involvement 

of and active management by the Federal Government. While there are ongoing efforts to develop 

recombinant influenza vaccines (predominantly by biotechnology companies), the seasonal vaccine 

market is currently fully saturated with effective and modestly priced vaccines; hence the economic 

incentives that would normally drive the application of novel technologies are not present. PCAST 

believes the Federal Government should take a number of steps to provide clear signals that endorse 

financial and regulatory support to the industry, and to the investment, public health, and medical 

communities, so that they are more likely to undertake the efforts necessary to bring these products 

to market for seasonal influenza, and to ensure that these technologies will be available to produce 

influenza vaccines during a pandemic. 

RECOMMENDATION 5-1: LAUNCH A 3-BY-3 RECOMBINANT INFLUENZA VACCINE INITIATIVE

The working group recommends that the Federal Government establish a recombinant influenza vaccine initiative (see box below for details), constituted under the authority of the Assistant Secretary for 

Preparedness and Response (ASPR) at HHS, with a goal of advancing at least three recombinant influenza 

vaccines that are suitable for use against seasonal or pandemic influenza to proof-of-concept trials within 

three years. This initiative should be overseen by a group comprised of representatives from BARDA, FDA, 

NIAID, and CDC, reporting to the ASPR, with input from the relevant components of DOD and DHS. 

BOX 5-1. ELEMENTS OF A RECOMBINANT INFLUENZA VACCINE INITIATIVE

A recombinant influenza vaccine initiative will consist of several components, each of which will require 

action on the part of HHS to achieve the initiative’s goal of advancing candidate vaccines to proof-ofconcept trials within the next three years. In order to achieve this goal, HHS should: 

1. Engage representatives from industry and the investment community in the design and management 

of the initiative. HHS has limited experience managing complex external research and development 

projects. Moreover, the biotechnology and pharmaceutical industries operate in a complex marketplace. It is therefore important that the Federal Government engage these communities in the design 

and execution of the initiative. As a starting point, the Federal Government should publish a roadmap 

of the steps it is taking to accelerate the development of recombinant influenza vaccines in order to 

ensure broad awareness and input to the design and execution of this enterprise. An advisory committee, including representatives from industry and the investment community, should be established 

to ensure that HHS’s decisions and actions are informed by perspectives from these two stakeholders, 

given the importance that their actions will have on the success and sustainability of the initiative. 

2. Provide clean guidance on the minimal essential attributes of a novel recombinant influenza vaccine, 

and capture these attributes in a target product profile. In consultation with stakeholders in the Federal 

Government, industry, and the medical and public health communities, the Federal Government
V. Recombinant Influenza Vaccines

★ 43 ★

should define the minimal attributes of the desired vaccine, for both seasonal and pandemic uses, 

including criteria for: formulation, presentation, storage and administration, safety, immunogenicity 

and efficacy. This guidance should be updated as new tools for validation (e.g., potency assays, immune 

correlates) are identified.

3. Provide clean guidance on the minimal essential attributes of a novel recombinant influenza vaccine, 

and capture these attributes in a target product profile. In consultation with stakeholders in the Federal 

Government, industry, and the medical and public health communities, the Federal Government 

should define the minimal attributes of the desired vaccine, for both seasonal and pandemic uses, 

including criteria for: formulation, presentation, storage and administration, safety, immunogenicity 

and efficacy. This guidance should be updated as new tools for validation (e.g., potency assays, immune 

correlates) are identified.

4. Provide clear guidance on the required timeline for production of the first doses of pandemic vaccine 

and the number of doses that must be produced within a window of time. The principal benefit of a 

recombinant influenza vaccine in the context of pandemic planning is the speed of production of the 

first doses of vaccine and scale-up of manufacturing. The minimum requirements for the time to first 

dose and the time to production of sufficient doses for the United States population should be defined 

at the outset of this effort, and should be driven by what is necessary to ensure an effective pandemic 

response, rather than what is thought to be possible with today’s technologies.

5. Establish a regulatory pathway for the review and approval of this platform for seasonal influenza, 

and the regulatory requirements for a pandemic vaccine produced on this platform. There is currently 

great uncertainty about the regulatory pathway for recombinant influenza vaccines. To focus current 

product development efforts and provide a level of certainty to the biotechnology and investment 

communities, it is essential that the Federal Government define the regulatory pathway for these new 

technologies for seasonal influenza, and the criteria that will be applied in the context of a pandemic, 

for platforms that have been approved for the production of a seasonal vaccine. 

6. Develop an investment strategy that allows co-financing of promising vaccine production platforms, 

and create downstream incentives for products that meet the target product profile and production 

criteria. To advance promising technologies, and to incentivize additional external investment, the 

Federal Government may need to make direct investments in companies with promising platforms to 

push them through clinical development and eventual licensure for seasonal influenza. Making this 

investment may necessitate co-financing with venture capital firms and other investors; it may also 

require flexibility in the terms of such investments. Investing in recombinant vaccines may also require 

the establishment of additional downstream incentives such as advance market commitments or 

prizes, and allowance for companies to use the technologies and platforms to produce products for 

other conditions, including those that provide greater profit incentive and more certainty of demand.

7. Establish Federal policy for the use of recombinant influenza vaccines in seasonal influenza campaigns 

and during a pandemic, once they have been proven to be safe and efficacious. Given the barriers to 

entry of a novel vaccine into the mature influenza vaccine market, the Federal Government should 

make it clear that recombinant vaccines will eventually comprise a portion of the Federal tender for 

seasonal influenza vaccines, and that appropriate technical platforms are part of a long-term strategy 

for pandemic preparedness. This will serve as an incentive for manufacturers, and should also serve to 

make their technologies more attractive to the investment community.

★ 45 ★

VI. Adjuvants 

Regardless of how influenza vaccine is produced, whether in eggs, cell culture, or by recombinant 

methods, adjuvants are a key component to improving how pandemics can be dealt with in the future. 

Adjuvants are components that boost vaccine potency, so that the vaccines can induce an effective 

immune response with lower doses of vaccine protein. Adopting adjuvants, several of which are already 

components in approved vaccines, including certain influenza vaccines used in Europe, can be both a 

mid- and long-term solution to boosting influenza vaccine supply. Adjuvants can be stockpiled in large 

amounts, and there is no need to vary adjuvant composition from one pandemic strain to the next. In 

addition, adjuvants can increase the breadth of the immune response to afford protection against both 

the targeted vaccine strain as well as related strains. 

Adjuvants have a long history of safe and effective use in human vaccines, but their use in influenza 

vaccines has been limited. This chapter will discuss how adjuvants might fit into a national pandemic 

influenza strategy and examine steps that the Federal Government can take to facilitate the use of 

adjuvanted influenza vaccines. 

What Is an Adjuvant and Why Are Adjuvants Added to Vaccines?

An adjuvant is a substance or mixture of substances added to a vaccine to enhance the immune response 

to the vaccine. Examples of adjuvants used today in human viral vaccines, or under development for 

future use, include alum (aluminum hydroxide), oil-and-water emulsions, particulates, microbial and 

plant derivatives, and so-called Toll-like receptor (TLR)-related molecules designed to stimulate the 

Toll-like receptors, which are involved in triggering an immune response.

There are four potential benefits to using adjuvants to improve vaccines:

• to boost the immune response in certain age groups (particularly the elderly) or in people with 

underlying health conditions who cannot mount an adequate immune response to a vaccine 

made without adjuvant; 

CHAPTER SUMMARY

Adjuvants are substances or mixtures of substances added to a vaccine to enhance the immunological 

response to the vaccine. Although their use in influenza vaccines has been limited to date, adjuvants 

have a long history of safe and effective use in human vaccines. Their primary use in vaccines has been 

to boost the immune response to vaccination among the elderly and other individuals with health 

conditions that suppress the normal immune response; broaden the immune response to a vaccine to 

provide better protection against a virus if it mutates; prolong the duration of immunity; and stretch the 

supply of vaccine when supplies are tight. Because of these benefits, adjuvants should have an important role to play in meeting the Nation’s demand for influenza vaccine during a pandemic, but scientific 

and regulatory barriers present significant obstacles that can be addressed through additional research 

and guidance from the FDA.
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• to broaden the immune response to a vaccine to provide better protection that can accommodate the genetic diversity of influenza viruses;

• to prolong the duration of immunity and improve immunological memory that can protect 

against infection for years; and 

• to increase or stretch the vaccine supply if it is limited. 

Antigens vary in their physical, biological and immunogenic properties and may have different needs for 

help from an adjuvant. Successful vaccine development requires knowing which adjuvants to use based 

on the antigen and the desired immune response, as well as knowing how to formulate adjuvants and 

antigens to achieve stable, safe, and immunogenic vaccines. For some vaccines, such as those produced 

by recombinant methods (see Chapter 5), adjuvants may prove to be critical for triggering a sufficient 

immune response following vaccination. By stretching a limited vaccine supply, addition of adjuvants 

can shorten the time between provision of the first and last doses by several weeks. In addition, because 

some adjuvants cost less than the viral materials in killed vaccines, regardless of whether the virus is 

produced in an egg-based or cell culture system, adjuvant use can reduce the cost of the final vaccine 

by increasing the number of doses that can be prepared from viral materials. This could have especially 

important implications for provision of a pandemic vaccines to poor countries.

Selection of appropriate adjuvants, from the limited number available, is based on the nature of the 

antigen and immune response desired. For a long lasting immune response, adjuvants that stimulate T 

cell responses are desired. However, T cell responses are not optimally induced by emulsions or alum, particularly when used with purified recombinant proteins that do not trigger activity via TLRs on immune 

cells. Vaccines produced from virus grown in chicken eggs or cell culture contain variable amounts of 

viral RNA, which can be a natural adjuvant and is not present in vaccines composed of recombinant 

proteins. The mechanisms by which adjuvants boost the immune response are understood in some 

cases, but less so for most adjuvants.

No human influenza vaccines licensed in the United States use an adjuvant, though adjuvanted influenza 

vaccines are approved for human use in Europe. Until recently, alum was the only adjuvant approved 

for use in human vaccines, and in fact, the FDA does not approve adjuvants per se, but does approve 

specific adjuvant-vaccine combinations. Gardasil, the first HPV vaccine licensed in the United States, 

uses alum as its adjuvant. In late 2009, the FDA approved the use of AS04, a new adjuvant composed of 

RECOMMENDATION 6-1: IMPROVE BASIC KNOWLEDGE ABOUT ADJUVANT IMMUNOLOGY

The National Institute of Allergy and Infectious Diseases (NIAID) should increase funding for basic research 

on immunology with the goal of understanding how adjuvants improve the body’s response to vaccination, particularly in the context of recombinant vaccine candidates. Not only will such research clarify the 

basic mechanisms by which adjuvants work, but it should also lead to more potent vaccines that are safe 

and well-tolerated. This avenue of research could also alleviate perceived safety concerns among some 

segments of the public. It will be important to include early stage clinical studies as an essential part of the 

research.
V I . Adjuvants

★ 47 ★

alum and a bacterial product known as monophosphoryl lipid A (MPL), as components of Cervarix, the 

second vaccine licensed to prevent HPV infection. In the event of a declared emergency, the FDA can 

approve the use of adjuvanted vaccine under an Emergency Use Authorization, and during the 2009 

H1N1 pandemic, HHS purchased supplies of adjuvant as a contingency, although adjuvanted vaccine 

was not used.

Adjuvant Candidates for Influenza Vaccines

The most commonly used adjuvant formulations include alum, which helps promote antibody responses 

for many vaccines. Alum is used in vaccines because of its long-term safety record and the ease with 

which it can be formulated with vaccine antigen. However, alum has not proven to be effective for 

influenza vaccines. For influenza vaccines, developers are focusing on two types of adjuvants: emulsions 

(oil in water) and TLR-related molecules. For next generation vaccines, there will be several adjuvant 

options available that should be explored. 

Emulsions. These are the most widely use adjuvants for influenza vaccines. Indeed, there is an extensive 

history of using vaccines containing oil. Ninety years ago, the United States military developed typhoid 

vaccines that were mixed with oil with the intent of doing what vaccine manufacturers are still striving for 

today—decreasing the amount of vaccine antigen needed for protection, and decreasing the number 

of immunizations required for protection. The next generation of oil-based adjuvants were water-in-oil 

emulsions, used in a licensed influenza vaccine in the United Kingdom in the 1960s. Although the overall 

safety profile for this vaccine was excellent, the occurrence of local inflammatory responses in some 

patients led to withdrawal of the vaccine.

Today, three major emulsion-type adjuvants are under development. 

• AS03, created by GlaxoSmithKline and contained in an influenza vaccine licensed in Europe, 

is a squalene-based emulsion that also contains vitamin E. Squalene is a naturally occurring 

chemical involved in the body’s production of cholesterol and vitamin D. For commercial use, 

squalene is harvested primarily from shark liver oil, but also from plant vegetable oils. Vaccines 

containing ASO3 have been evaluated in thousands of individuals, and an ASO3-H5N1 influenza 

vaccine has been reported to be safe in both adults and children. AS03 is being developed for 

both seasonal and pandemic influenza vaccines, including pre-pandemic vaccines to prime 

RECOMMENDATION 6-2: DEVELOP ADJUVANT GUIDANCE DOCUMENT

Adjuvants can be an important mid-term solution to vaccine supply and will be an essential component to 

a long term solution of developing recombinant protein based influenza vaccines. The FDA should develop 

and issue a guidance document that defines a clear regulatory pathway for the approval of adjuvants for 

use in human vaccines, including those for seasonal and pandemic influenza. This guidance document 

should define the goals for adjuvant use (i.e., dose sparing, boosting efficacy in the elderly), specify rational 

endpoints for clinical trials, and stipulate safety criteria. Because the safety and efficacy of adjuvants can 

only be evaluated in the context of the final vaccine product, the current practice of approving final products, as opposed to adjuvants alone, is a rational one. 
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individuals against H5 viruses to induce at least partial immunity against related influenza 

variants. The vaccine has been reported to be immunogenic, dose-sparing, and able to induce 

immune responses against influenza viruses in the H5 family other than the one incorporated 

in the vaccine. Approximately 70 million doses of AS03-containing H1N1 vaccine were distributed during the 2009 pandemic, with several million doses used in Canada and throughout 

the European Union (EU).

• Novartis’s squalene-containing adjuvant, MF59, is licensed in Europe for use in influenza vaccines, and MF59-antigen formulations have been tested in herpes simplex virus (HSV), hepatitis 

B virus (HBV), and human immunodeficiency virus (HIV) vaccine candidates. Increased immunogenicity has been achieved with MF59-adjuvanted seasonal influenza vaccines in the elderly, 

and with MF59-adjuvanted vaccines against cytomegalovirus and HIV in young children. An 

estimated 45 million doses or more of Novartis’s MF59-containing seasonal influenza vaccine 

have been administered in Europe, providing a good safety data base for MF59. During the 2009 

H1N1 pandemic, approximately 70 million doses of an MF59-adjuvanted H1N1 vaccine were 

distributed, with an estimated 15 million doses administered in Canada and the EU.

• AF3 is a third squalene-based emulsion adjuvant, developed by Sanofi Pasteur. This adjuvant 

has been evaluated in a H5N1 vaccine candidate in 251 healthy adults; the vaccine was found 

to be adequately safe and immunogenic, and the adjuvant demonstrated both a dose sparing 

and immune broadening effect. 

TLR-related molecules. This class of adjuvants includes the bacterial component MPL, the only TLRrelated molecule licensed for use as an adjuvant in human vaccines. MPL is a component of both HPV 

and HBV vaccines, although the latter is licensed only in Europe. MPL is also a component of a vaccine 

used to desensitize against pollen allergies, and has been demonstrated to be safe, well-tolerated, and 

effective. Another bacterial protein, known as flagellin, is being tested as an adjuvant in an influenza 

vaccine being developed by Vaxinnate. Clinical studies have demonstrated that flagellin does boost 

vaccine potency, but with a narrow dose range of tolerability. None of these TLR-related adjuvants have 

yet been used to demonstrate dose-sparing capabilities. 

In addition to emphasizing development, investment in manufacturing of new adjuvants will be critical for ensuring adequate supply. Such an investment will represent eventual cost savings as needs for 

vaccine manufacturing capacity will be reduced as a result of including adjuvants in the final product. It 

is likely, too, that emulsions currently used in killed influenza vaccines can lead to a dose-sparing effect 

RECOMMENDATION 6-3: NEW ADJUVANTS

Because adjuvants are a critical component of both mid- and long-terms solutions for improving quality 

and quantity of influenza vaccines, NIAID and BARDA should increase funding for the development of new 

adjuvants for use with influenza vaccines based on advances in understanding mechanisms of how adjuvants work. It is likely that such adjuvants will also be effective at boosting the potency of other vaccines 

that are important for medical countermeasures. 
V I . Adjuvants

★ 49 ★

of at least 2-4 fold, which could significantly increase current supply. The role of adjuvants in enhancing 

potency of LAIVs is less clear, and studies should be undertaken to investigate this possibility. Because 

the nature of the vaccine (i.e. recombinant, killed, or attenuated virus) will directly influence the choice 

of adjuvants, it is increasingly important to develop a broader adjuvant pipeline. It is recommended 

that the FDA work closely with vaccine manufacturers to meet the goal of approving a minimum of two 

adjuvanted influenza vaccines in the next two years. 

Adjuvants can be an important component of addressing influenza vaccine supply, particularly at the 

global level. In the short term, emulsions can be used to begin to address this need, as they can be 

produced on a large scale, have good stability, and can be combined with several of the current vaccines. However, emulsion technology itself will eventually need to be improved, as all contain shark 

liver oil, a non-sustainable resource. In the mid-term, improved emulsions, as well as emulsions or other 

formulations containing immune activators such as TLR-related molecules, are likely to be included as 

key components of vaccine development, but only if a clear regulatory pathway for their approval can 

be defined.

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VII. “Universal” Influenza Vaccines 

Life-long vaccine protection against most viral pathogens is conceptually easy to imagine. Starting with 

a natural strain of the virus, one makes a preparation of live, killed, or subunit viral material which, when 

injected into a person, provides the protection. This has worked for each of the 3 strains of poliovirus, 

for smallpox, mumps, measles, hepatitis B, and several other viruses. The injected preparation induces 

the person’s immune system to make antibody proteins, which provide the first line of protection, and 

perhaps immune killer cells that contribute to host defenses. Life-long protection is provided because 

the viruses never significantly change their structure sufficiently to elude the primed immune system 

of the vaccinated person. 

Almost all viruses for which we have long-lasting vaccine protection are viruses that have evolved for 

millions of years as human pathogens. Most of them infect only humans. They have developed a nonlethal relationship with humans; the viruses don’t kill most infected people, although infection can be 

very unpleasant. We make vaccines to protect against the rare lethal consequences of infection and to 

minimize illnesses, but the natural relationship of the viruses to their hosts is a truce. If these viruses 

infected animals, they would have the chance to mutate into a different form, possibly eluding the truce 

with humans and becoming more lethal. However, it is hard for a virus to infect two different species 

efficiently because in adapting to one, it loses adaptation to the other. 

For most viruses for which vaccines have been successfully created, the vaccine is either a chemically 

treated, non-infectious form of the virus or a live but genetically altered virus strain that grows in a vaccinated person but does not cause symptoms. Examples include polio, measles, mumps, and varicella 

(chicken pox) vaccines. More recently, for some viruses that have not been amenable to development 

of the classic forms of vaccine, vaccines containing only viral proteins have been created using recombinant DNA techniques. These recombinant vaccines are safe, because they do not start with live virus 

but rather consist of purified proteins made in animal or plant cells, yeast, or bacteria. 

CHAPTER SUMMARY

Influenza virus is an unusual pathogen, one that evolves regularly into new strains that avoid the protection conferred by vaccines that induced protection against strains of influenza virus circulating in prior 

years. As a result, each influenza season brings with it the need to prepare a new influenza vaccine against 

that year’s crop of seasonal influenza viruses. More importantly, the same need to create a new vaccine 

arises when a new strain of pandemic influenza virus appears on the world stage. However, recent research 

raises the tantalizing possibility that there may be parts of the influenza virus that do not mutate and that 

could serve as the immunological basis for creating a “universal” influenza vaccine, one that would protect 

against both present and future strains of influenza virus. Though it is uncertain that a universal influenza 

vaccine is possible, the game-changing potential of such a vaccine warrants a concerted research effort 

supported by the Federal Government.
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There are three viruses for which even modern protein technology has so far been unable to generate 

long-lasting immunity: hepatitis C virus, human immunodeficiency virus (HIV), and influenza virus. For 

each of these, the challenge is different, and each must be approached separately. As described in the 

earlier sections of this report, effective influenza vaccines do exist, but they are not universal; they do not 

protect against the virus generically but rather protect against only a very limited set of closely related 

influenza strains. The challenge of producing a universal influenza virus vaccine is to find a region of 

the virus that does not vary year to year but is both a target of antibodies and is able to induce such 

antibodies. 

Up to now, the vaccine industry has focused on making vaccines to order for each year’s expected 

outbreak of seasonal influenza. This works well as long the drift of virus structure is small and the forewarning is early enough to allow the slow process of vaccine production to make sufficient vaccine for 

the expected yearly appearance of the new strains in the late fall or winter of the year. However, there 

would be serious trouble if the warning is late, if a strain appears at an odd time, if a shift of viral structure 

has occurred, if a virulent bird strain were to adapt to humans directly, or if other imaginable events 

occurred to limit vaccine effectiveness. The other parts of this report deal with stop-gap measures that 

would speed up the response if any of these problems arose. However, there is another way to prepare 

for such eventualities: to produce a single vaccine that provided wide coverage against many if not all 

flu strains for a long time, maybe a lifetime, just like we do for so many other viruses. We propose to call 

such a vaccine a “universal vaccine”. 

Is a Universal Vaccine Conceivable?

When killed preparations of influenza virus are used as a vaccine, a vaccinated person produces antibodies. These antibodies bind to active virus particles of the same type and make them non-infectious, a 

process called virus neutralization. This reaction of antibody with virus protects a vaccinated individual 

against getting the symptoms of influenza disease after exposure to virus. The body’s immune system, 

which makes antibodies, also produces a different form of immunity, one managed by so-called T cells. 

Vaccination may also produce a T cell response, but it is not clear whether it contributes to protection, 

although it is likely to help antibody production and could kill infected cells. 

With influenza virus, the anti-viral antibodies react with viral HA protein. Figure 7-1 shows the structure 

of the portion of the HA protein that is normally found on the surface of the virus. HA is responsible for 

binding to the surface of an infected cell and initiating the infection of that cell. It does so by binding to a 

sugar called sialic acid, which is a material attached to many of the proteins found on the surface of cells. 

The cell is then stimulated to take the bound virus particle into its interior. (From here on, infection of the 

cell involves the virus taking over the RNA and protein synthetic ability of the cell and diverting these 

capabilities to the manufacture of new virus.) Anti-HA antibodies react with the top of the HA protein, 

occluding the hole at the top of HA into which the sialic acid must fit if infection is to be initiated. Like 

all proteins, HA is made of amino acids; the antibodies actually bind to the amino acids lining the hole. 

Influenza virus can elude immune attack by mutating, which can change the amino acids around the 

hole. Presumably, this happens occasionally when the virus is multiplying in a human host, but these 

altered strains generally take a year or longer to become a dominant part of the influenza virus mixture 
V I I . “ Universal” Influenza Vaccines

★ 53 ★

spreading among humans. Thus, the vaccine works for about a year but by then the spreading influenza 

virus has a predominant structure that is resistant to the antibodies elicited by the strain of the past year. 

One might imagine that there could be amino acids at the top of HA that are so important to the function 

of the protein that they cannot be changed without compromising virus infectivity. Such amino acids 

could then be the target of a universal vaccine. However, no such amino acids are known; therefore, if 

we are to make a universal vaccine, it would seem to require a new approach. 

Recent research has identified antibodies that react with another part of the HA and neutralize the virus.14

These antibodies react with the long stem of HA, not the top part; how they neutralize the protein and 

its function is unclear. HA undergoes an obligate structural alteration to get influenza virus into host 

cells, and the antibody is likely to interfere with the protein’s molecular movement. These antibodies 

react with a wide range of influenza strains but not all; they are a clear starting point for development 

of a universal vaccine. 

Figure 7-1. Influenza Hemagglutinin Protein

Molecular model of the part of the hemagglutinin (HA) protein that forms a “spike” on the surface of the influenza 

virus particle, showing the site of the highly conserved region that offers vulnerability to a “universal” vaccine. The 

HA spike is composed of an upper (head) and lower (stem) region; it mediates attachment and entry of influenza 

virus into cells of the respiratory tract; and it serves as the target for neutralizing antibodies against influenza viruses. 

The sites of amino acid variability among different influenza strains (red, purple, blue) and the location of the highly 

conserved site (yellow), the target for cross-reactive antibody against the stem portion, are highlighted. 

14. Kwong P, Wilson I. HIV-1 and influenza antibodies: seeing antigens in new ways. Nature Immunology 2009; 10:573-

578.

Source: Gary Nabel, Director, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Personal 

Communication, May 28, 2010.
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Having antibodies that neutralize a wide range of influenza virus strains is only a start toward a universal 

vaccine. The next step is to design an immunogen, a material that can induce people’s immune system 

to make such antibodies. This is not an easy task, since it means making a mimic of the region of HA 

to which the neutralizing antibody binds. This is a very difficult design challenge; no vaccine available 

today involves a protein mimic of this sort. 

It is possible to imagine other targets for a universal vaccine. The neuraminidase (N) protein could be a 

target, since it is also a target for neutralizing antibodies although the mechanism of neutralization is 

not certain. There is a small amount of a third protein in the virus’s surface, called M2, that is needed for 

infection. It, too, is being developed as a target for vaccination.15 There are others regions of proteins in 

the virus structure that could be targets of T cell immunity, but they are unlikely to be universal targets 

because T cells recognize small fragments of viral proteins together with the highly variable host cell 

proteins to which they are bound. The consequence is that a vaccine stimulating T cell immunity may 

be effective in some people but not others. 

Antibodies that neutralize many influenza strains are not only valuable for guiding immunogen design. 

They could, in principle, be made in large quantities using recombinant DNA technology and be delivered to protect against influenza viruses. To be protective, the antibodies themselves would have to be 

administered to people on a periodic basis, with that interval depending on the stability of the antibodies 

in the body. Antibodies are quite stable proteins in the blood, so the interval between administrations 

could be as long as 6 months; but this is not as convenient as the life-long protection offered by vaccines 

containing immunogen. Antibodies are being considered as protective materials for preventing AIDS 

in high risk populations, but for something as widespread as influenza virus infection, it is unclear that 

treatment with antibody would be cost-effective or even feasible. 

However, discovery of an antibody that protects against infection should generate concentrated activity to produce an immunogen that elicits the antibody. In particular, the discovery of an antibody that 

protects against many influenza strains should stimulate research to mimic the surface of the influenza 

HA to which the antibody binds, in an effort to immunize with a mimic of the binding site. This is already 

under way for the antibodies that bind to the so-called “stem” region of HA. 

An important question about a universal vaccine is how “universal” it is. There are multiple Type A influenza strains and also a B strain incorporated into current seasonal vaccines. Type A and B viruses might 

prove to be sensitive to some of the same antibodies but, more likely, each will require its own vaccine. 

Also, we can imagine that some improved immunogens might induce reactivity with some HA subtypes 

of A strains but not others. Thus, there may be a need for multiple components to make influenza vaccines that approach universality. Furthermore, if the antibodies elicited by a vaccine are highly focused 

on one part of the HA molecule, the virus may be able to mutate to resistance, evading the protective 

effects of the antibodies. Such a virus could then spread widely, making the vaccine impotent. 

In truth, we have much to learn about human immunity and about how protective antibodies are elicited 

from the huge repertoire of antibodies that the body could make. Study of antibody production by the 

15. Flanders Institute for Biotechnology. Universal Influenza Vaccine Tested Successfully In Humans. ScienceDaily 25 

January 2008. Available at www.sciencedaily.com/releases/2008/01/080124185522.htm.
V I I . “ Universal” Influenza Vaccines

★ 55 ★

human immune system has been neglected by immunologists in recent times in favor of work on T cell 

immunity, which is thought to be the more exciting field of research today. But since antibodies seem 

to be the major form of protection against most viruses, with some assistance from T cells, a renewed 

research focus on antibody elicitation is in order. 

The value of having a universal influenza vaccine would be enormous because it would be made by 

chemistry or by simple protein production methods, and therefore the vaccine would be scalable and 

storable. If it were truly universal—that is covered all of the known HA subtypes—then the likelihood 

of a resistant strain emerging would be slight (one might come from a strain not encountered to date in 

nature or from a rare recombinant between existing strains). A universal vaccine would be a “disruptive 

technology,” but it would reward its inventors handsomely because it would be so much preferable to 

the present annual race to make vaccine or the periodic race to blunt a pandemic. 

RECOMMENDATION 7-1: UNIVERSAL VACCINE INITIATIVE

Because a universal vaccine would completely change the outlook on protecting the population against 

influenza virus infections, the Federal Government should support and encourage efforts to design a 

universal vaccine through various mechanisms. One is the standard mechanism of peer-reviewed grants 

that supports all basic health science. Imaginative ideas should be encouraged and money should be set 

aside for this effort. Because some ideas are further advanced, they should be supported by more targeted 

efforts to bring them to clinical testing. When proof of principle has been attained, the relevant agencies 

should encourage and, when necessary, support, commercial development. An X Prize-like competition 

should be considered for stimulating research on forms of a universal vaccine.

RECOMMENDATION 7-2: BASIC IMMUNOLOGY

Although there is much to be learned yet from model organisms such as the mouse, there is insufficient 

research effort focused on understanding the human immune system. In particular, there should be a targeted focus on a better understanding of antibody production in human beings. The NIAID should expand 

and emphasize programs of support for the basic science underlying vaccine development. 

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VIII. A New Way of Doing Business 

While the recent H1N1 pandemic stretched the United States Government’s capabilities, it is clear that 

the situation could have been much worse. Taken in conjunction with the lessons learned about pandemic preparedness and the broader medical countermeasure enterprise over the past several years, 

the Federal Government should view this as a wake-up call and an opportunity to rethink the manner 

in which it prepares for pandemic influenza and other biological threats. 

CHAPTER SUMMARY

In this report, the PCAST Influenza Vaccinology Working Group lays out a number of near-, mid-, and shortterm strategies to shorten the time required to produce influenza vaccine against new pandemic influenza 

viruses and to reduce the risk that the Nation will be unable to respond effectively in the event of an influenza pandemic. For this effort to succeed, the Federal Government must take a mission-driven approach 

to reengineering the vaccine enterprise, with clear milestones and deliverables, and develop new policies, 

regulations, systems, and processes to support this effort. 

HHS is the agency charged with protecting the Nation’s health, and is best positioned to oversee this effort. 

Given the ambition and complexity of this undertaking, the Working Group believes that HHS should 

ensure that the capabilities and capacities necessary to execute this mission-driven research and development enterprise are in place. Indeed, the Working Group believes that a new way of doing business is in 

order, one that centralizes authority and accountability for the influenza vaccine enterprise and that can 

manage the complex set of short, medium, and long-term actions necessary to achieve its vaccine development and production objectives. 

HHS should vest ASPR with the authority to coordinate and task its component agencies with activities 

necessary to support the goals of the influenza vaccine enterprise. In addition, HHS should establish a 

small advisory committee, comprised of representatives from the biotechnology, pharmaceutical and 

investment communities, to guide its engagement with industry. This committee’s input should be considered seriously in all decisions and actions by the Department, given the importance of the relationship 

between the Federal Government and industry partners.

HHS should also establish a dedicated entity, either within the Department (for example, under BARDA) 

or through an external organization, such as an FFRDC or PDP, to oversee the entire portfolio of Federal 

investments in the influenza vaccine enterprise. 

Whatever the details of this new management structure, it is essential that any planning activities for this 

reengineering take place with the full cooperation and participation of the private sector, that HHS work 

collaboratively with other federal agencies, and that the White House, most appropriately the National 

Security Council, assume responsibility for defining and monitoring progress towards the goals of the vaccine program. It is also important that the Federal Government’s influenza vaccine efforts be aligned with 

changes being made to the Nation’s broader medical countermeasures enterprise.
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This report outlines a series of near-, mid-, and long-term strategies to shorten the timeframe to availability of sufficient influenza vaccine to protect the domestic population. For this effort to be successful, 

the Federal Government must take a mission-driven approach to reengineering the influenza vaccine 

enterprise, with clear milestones and deliverables, and develop new policies, regulations, systems, and 

processes to support this effort.

Assigning Responsibilities

While HHS and its component agencies (NIH, FDA, CDC, and BARDA) are responsible for the health of 

the Nation and medical elements of pandemic preparedness, aligning the efforts of these agencies 

toward a common objective can be challenging. Each agency has its own mandate and budget, as well 

as ongoing responsibilities and capacity limitations. Moreover, HHS has limited experience in missiondriven research and development.

In order for HHS to execute the recommendations in this report, it will be necessary for the Department 

to establish a new way of doing business. This will necessitate the centralization of authority and 

accountability for the influenza vaccine enterprise within the Department, and the establishment of 

an entity to manage the complex set of short, medium, and long-term actions necessary to achieve its 

vaccine development and production objectives. While HHS could establish this capacity and expertise 

“in house,” another option is for these responsibilities to be handled through an external agent such as 

a Federally Funded Research and Development Center (FFRDC) or a Product Development Partnership 

(PDP), similar to those that have been established to coordinate and drive the development of specific 

countermeasures against global health threats, such as the Malaria Vaccine Initiative and the TB Alliance. 

This entity should oversee the breadth of activities necessary for the success of the enterprise and the 

portfolio companies, including horizon (technology) scanning, portfolio management, pre-clinical 

and clinical development, regulatory affairs, commercialization, financial management, and business 

development.

It is also important that HHS leverage the expertise and capacity of relevant departments and agencies 

across the Federal Government, including DOD, DHS, the Department of Agriculture (USDA) and the 

State Department, as it executes this mission. A number of attempts have been made to do this in the 

past, including through coordination by HHS or the White House. The lessons from these efforts should 

be incorporated into a management structure that places HHS in charge of this mission to protect the 

civilian public, but ensures that the Department is sufficiently coordinated with the other relevant 

components of the Federal Government. This can be accomplished by a clearly-delineated set of goals 

and deliverables that are developed and monitored by the White House, most appropriately by the staff 

of the National Security Council, in coordination with the Departmental agencies.
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RECOMMENDATION 8-1: MANAGING A MISSION-DRIVEN ENTERPRISE

The Administration should clearly delineate its short-, medium-, and long-term influenza vaccine development and production goals, with associated milestones and deliverables. HHS should be given responsibility for progress toward these goals and for coordinating its activities with the relevant departments and 

agencies that have expertise and programs relevant to influenza vaccine development and deployment. 

Given that the Secretary of HHS has limited authority to direct the actions of other departments such as 

DoD, the responsibilities of these other agencies should be made explicit by the White House.

While HHS will manage the day-to-day activities of the influenza vaccine enterprise, it is important that 

the Administration track progress toward its pandemic preparedness goals and the contributions of the 

relevant departments and agencies by establishing accountability mechanisms. The White House has 

traditionally played this role in policy development and execution, and the National Security Council (NSC) 

would be the most appropriate lead for this function. 

RECOMMENDATION 8-2: COORDINATION OF ACTIONS WITHIN HHS

HHS should vest ASPR with the authority to coordinate and task its component agencies with activities 

necessary to support the goals of the influenza vaccine enterprise. Each agency should have clearly-delineated responsibilities and deliverables that should be reflected in their respective budgets and programs, 

and each should be held accountable for progress toward these goals. To support this coordination function, HHS should establish a program management capability to direct and track the activities of internal 

and external stakeholders, and provide regular reports to ASPR, the Secretary of HHS, and the White House.

RECOMMENDATION 8-3: PUBLIC-PRIVATE ADVISORY COMMITTEE

HHS should establish a small advisory committee, comprised of representatives from the biotechnology, 

pharmaceutical and investment communities, to guide its engagement with industry. This committee’s 

input should be considered seriously in all decisions and actions by the Department, given the importance 

of the relationship between the Federal Government and industry partners. 

RECOMMENDATION 8-4: OVERSIGHT OF FEDERAL INVESTMENT IN INFLUENZA VACCINE EFFORT

HHS should also establish a dedicated entity, either within the Department (for example, under BARDA) 

or through an external organization, such as an FFRDC or PDP, to oversee the entire portfolio of Federal 

investments in the influenza vaccine enterprise. This entity should ensure that: (1) product development 

efforts proceed as expeditiously as possible, in full coordination with other activities supported by the 
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Alignment with Broader Federal Medical Countermeasure Efforts 

While these recommendations are driven by the recent H1N1 pandemic, any reengineering of Federal 

Government’s influenza vaccine efforts must be done in coordination with changes to the broader medical countermeasure (MCM) enterprise. This should not be difficult—the attributes desired in the MCM 

enterprise are consistent with the approach proposed in this report. Moreover, influenza vaccines can 

serve as a timely and relevant pathfinder for changes to the United States Government’s MCM strategy.

Specifically, the recommendations in this chapter are aligned with the Administration’s prioritization of 

the following attributes in its MCM enterprise.

• The development of multi-use platforms and countermeasures is consistent with the recommendations to deploy platform technologies to speed up production of current influenza 

vaccines and to engineer next-generation influenza vaccines (Chapters 3, 4, and 5). These 

approaches will be relevant to both influenza and other public health threats, and the use of 

these technologies will help address both seasonal and pandemic influenza.

• Partnerships and collaborations are an essential element of the short, medium and long-term 

strategies proposed in this report. The development of partnerships and collaborations is most 

critical for industrial relations with the Federal government, given the pivotal role that the private 

sector will play in the achievement of these objectives.

• Regulatory innovation and advancement of regulatory science, particularly with regard to 

the mid and long-term approaches recommended here, are critically important to provide a 

roadmap for product development and certainty in the market for industry partners and the 

investment community.

• Multidisciplinary project management capacity must be established within the United States 

Government, possibly in concert with an external entity, to ensure that the complex interactions 

and partnerships are managed in a way that ensures the success of the enterprise. 

US Government; (2) relevant government agencies (eg, FDA) have constant situational awareness of, and 

input to, these product development activities so issues can be identified and addressed as they arise; (3) 

companies have a channel for ongoing engagement with the US Government as data is gathered and 

product development proceeds; and (4) HHS has early awareness of external factors that could adversely 

impact companies’ ability to advance product development efforts (eg, financial solvency, competing 

priorities, lack of critical expertise) and can raise these issues with company leadership before they jeopardize product development. Given the critical importance of these product development efforts for US 

preparedness, this kind of “hands on” engagement is necessary to ensure that these efforts proceed as 

expeditiously and predictably as possible.

This entity should track all elements of the product development effort, provide guidance to industry partners on regulatory and clinical development issues, identify problems and bottlenecks as they develop, 

bring them to the attention of the respective agency, and identify new technologies and potential partners 

for the Federal Government’s influenza vaccine enterprise. It is essential that the entity have sufficient 

resources and staff with the necessary expertise in product development, commercialization, regulatory 

policy, portfolio management, financial planning and industrial relations.
★ 61 ★

Acknowledgments

PCAST wishes to express gratitude to the following individuals who contributed in various ways to the 

preparation of this report:

Joe Alper

Writer

Beth Bell

Associate Director for Science

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Robert Coffman

Vice President and Chief Scientific Officer

Dynavax

Manon M. J. Cox

Chief Operating Officer

Protein Sciences 

Nancy Cox

Influenza Division

Centers for Disease Control and Prevention

Bill Enright

President and Chief Executive Officer

Vaxin Inc.

Anthony Fauci

Director, National Institute of Allergy and Infectious Diseases

National Institutes of Health 

Michael Finney

Acting Chief Executive Officer

Vaxart

Bruce Gellin

Deputy Assistant Secretary for Health and Director

National Vaccine Program Office

Department of Health and Human Services
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Douglas Given

Chief Executive Officer and Chairman

Vivaldi BIosciences

Jesse Goodman

Chief Scientist and Acting Deputy Commissioner

Food and Drug Administration

Richard Hatchett

Director for Medical Preparedness Policy

National Security Staff

Executive Office of the President

Doug Holtzman

Senior Program Officer

Bill and Melinda Gates Foundation

Bruce Innis

Vice President and Director

Global Clinical R&D, Vaccines for Influenza, MMR, Varicella and Dengue, GlaxoSmithKline

Paul E. Jarris

Executive Director

Association of State and Territorial Health Officials

Til Jolly

Associate Chief Medical Officer for Medical Readiness

Office of Health Affairs

Department of Homeland Security

George Kemble

Vice President, Vaccine Research and Development

Medimmune 

Marie-Paule Kieny

Director, Initiative for Vaccine Research

World Health Organization

Richard Klausner

Managing Partner

The Column Group
Acknowledgments

★ 63 ★

James Lawler

Director for Medical Preparedness Policy

National Security Staff

Executive Office of the President

Nicole Lurie

Assistant Secretary for Preparedness and Response

Department of Health and Human Services

Frank Malinoski

Chief Medical Officer

Liquidia Technologies

Thomas Monath

Partner, Pandemic and Biodefense Fund

Kleiner Perkins Caufield & Byers 

Thomas Muster

Chief Executive Officer and Chief Scientific Officer

AVIR Green Hills Biotechnology AG

Gary Nabel

Vaccine Research Center

National Institute of Allergy and Infectious Diseases

National Institutes of Health

Vasant Narasimhan

President, Vaccines & Diagnostics USA

Head, Vaccines North America

Novartis Vaccines and Diagnostics, Inc

Rino Rappuoli

Global Head of Vaccine Research

Novartis

Robin Robinson

Director

Biomedical Advanced Research & Development Authority (BARDA) 

Alan Shaw 

President & Chief Executive Officer

VaxInnate 
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Rahul Singhvi

President and Chief Executive Officer

Novavax

Tadataka Yamada

President

Global Health Program

Bill & Melinda Gates Foundation
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Appendix A: List of Acronyms

ASPR Assistant Secretary for Preparedness and Response

BARDA Biomedical Advanced Research and Development Authority

CDC Centers for Disease Control and Prevention

DHS Department of Homeland Security

DOD Department of Defense

EOP Executive Office of the President

FDA Food and Drug Administration

FFRDC Federally Funded Research and Development Center

HA Hemagglutinin protein

HAI Hemagglutinin inhibition

HBV Hepatitis B

HHS Department of Health and Human Services

HPV Human papilloma virus 

LAIV Live attenuated influenza virus 

M Influenza virus matrix protein

MCM Medical countermeasure

N Neuraminidase protein

NIAID National Institute of Allergy and Infectious Diseases

NIH National Institutes of Health

NGIV Next-generation influenza vaccine

PCAST President’s Council of Advisors on Science and Technology

PCR Polymerase chain reaction

PDP Product Development Partnership

TLR Toll-like receptor

USDA Department of Agriculture

VLP Virus-like particle

WHO World Health Organization