RTI Project Number

0208665.001

Influenza Vaccine Overview: Summary And Assessment

Issue Brief

October 2005

Prepared for

Amy Nevel, MPH

Senior Public Health Policy Analyst

Office of Science and Data Policy

Assistant Secretary for Planning and Evaluation

Department of Health and Human Services

Mail Stop 445F

200 Independence Ave., SW

Washington DC 20201

Prepared by

Lucia Rojas Smith, DrPH, MPH

Christine Layton, PhD, MPH

Tara Robinson, BA

RTI International\*

Health, Social, and Economics Research

Research Triangle Park, NC 27709

\*RTI International is a trade name of Research Triangle Institute.

Contents

Page

1\. Introduction [2](#introduction)

2\. Stakeholders in the Influenza Vaccination System
[2](#stakeholders-in-the-influenza-vaccination-system)

3\. Overview of Influenza Vaccine Manufacturing and Supply Issues
[2](#overview-of-influenza-vaccine-manufacturing-and-supply-issues)

4\. Overview of Influenza Purchase and Distribution Issues
[2](#overview-of-influenza-purchase-and-distribution-issues)

5\. Case Study of the Influenza Seasons from 1999 through 2005
[2](#case-study-of-the-influenza-seasons-from-1999-through-2005)

5.1 Prevailing Strains and Vaccine Composition
[2](#prevailing-strains-and-vaccine-composition)

5.2 Manufacturing and Distribution [2](#manufacturing-and-distribution)

5.3 Changing Advisory Committee on Immunization Practices (ACIP)
Recommendations
[2](#changing-advisory-committee-on-immunization-practices-acip-recommendations)

5.4 Impact of Bioterrorism Preparedness on Influenza Awareness and
Planning
[2](#impact-of-bioterrorism-preparedness-on-influenza-awareness-and-planning)

6\. Summary and Conclusions [2](#summary-and-conclusions)

References [2](#references)

List of Figures

Number Page

[1. Vaccine Manufacturing Timeline 2](#__RefHeading___Toc118274779)

[2. Influenza Vaccine Distribution Pathways
2](#__RefHeading___Toc118274780)

[3. Influenza Vaccine Doses Produced and Distributed for the U.S. Market
1999--2004 2](#__RefHeading___Toc118274781)

[4. Public Health Poster from 1911 2](#__RefHeading___Toc118274782)

List of Tables

Number Page

[1. Stakeholder Involvement in Influenza Vaccines
2](#__RefHeading___Toc118526935)

[2. Influenza Vaccines, Manufacturers, and Seasons during which each
Vaccine Was Sold 2](#__RefHeading___Toc118526936)

[3. Major Buyers of Influenza Vaccine 2](#__RefHeading___Toc118526937)

[4. VRBPAC Recommended Vaccine Compositions 1999--2005
2](#__RefHeading___Toc118526938)

[5. Summary of 1999--2005 Influenza Seasons
2](#__RefHeading___Toc118526939)

[6. Tiered Approach to Allot Inactivated Influenza Vaccine During a
Shortage 2](#__RefHeading___Toc118526940)

This issue brief is one of five produced for the Assistant Secretary for
Planning and Evaluation (ASPE) by RTI International. The contents of
these briefs is based on research involving a review of literature
including peer-reviewed journals, media reports, and other nonreferenced
sources (including those identified using the World Wide Web search
engine Google) as well as confidential interviews with 30 key informants
representing influenza vaccine manufacturers, wholesalers, community
immunizers, state and local public health officials, and other experts.
The other briefs in the series are

-   *Influenza Vaccine Economics*

-   *Influenza Vaccine: Who Buys It and Who Sells It*

-   *Influenza Vaccine Manufacturing*

-   *Influenza Vaccine Demand: The Chicken and the Egg*

This issue brief was written by Lucia Rojas Smith, DrPH, MPH, Christine
Layton, PhD, MPH, and Tara Robinson, BA.

# Influenza Vaccine Overview: Summary and Assessment

## 1. Introduction

Immunization tops the list of the 10 great public health achievements
during the last century (Centers for Disease Control and Prevention
\[CDC\], 1999a). Despite this achievement, each year less than half of
those who are at highest risk for influenza-related complications are
vaccinated. Meanwhile, influenza is the leading cause of mortality due
to infectious disease (CDC, 2005a), causing an average of 36,000 deaths
(Thompson et al., 2003) and 226,000 hospitalizations annually (Thompson
et al., 2004).

The capacity of the health care delivery system to accommodate the
demand for influenza vaccine depends largely on a combination of factors
that shift from year to year, including the virulence of the circulating
influenza strains, the ability of manufacturers to match a vaccine to
these strains, and the timeliness of vaccine distribution. Moreover,
influenza immunization is unique when compared to other types of
immunizations for several reasons:

-   The influenza vaccine is reformulated each year in an attempt to
    match the strain(s) of the virus anticipated to circulate in the
    coming season.

-   Because it is reformulated annually, the influenza vaccine has a
    limited shelf life.

-   The influenza vaccine is typically administered prior to the start
    of the influenza season (approximately October to early December).

-   Various factors related to the marketplace and supply chain affect
    the timely and efficient distribution of influenza vaccines.

The unique characteristics of the influenza vaccine and the complexity
of the market forces that determine its supply and demand present
policymakers and public health officials a dynamic set of challenges
each influenza season. Thus, there is no "normal" influenza season,
although the epidemic usually peaks in the United States between January
and March (Harper, Fukuda, Uyeki, Cox & Bridges, 2005). To respond
rapidly and effectively to an unpredictable and dynamic set of
circumstances requires public health systems to be nimble, flexible, and
creative in their approach to managing annual influenza outbreaks.

In 2004, the Office of the Assistant Secretary for Planning and
Evaluation (ASPE) contracted RTI International to produce a series of
five briefs on subjects related to the dynamics of influenza vaccine
supply and demand between 1999 and 2005. These issue briefs are based on
information gathered from confidential interviews conducted with 30 key
informants from federal, state, and local health agencies; vaccine
manufacturers and wholesalers; community immunizers; and other experts
and on information available in peer-reviewed journals, reports, media,
and other relevant sources.

An in-depth examination of the factors explored in these key informant
discussions can be found in the other four issue briefs. *Influenza
Vaccine Economics* describes the characteristics of the influenza
vaccine market, industry regulatory requirements for vaccine production,
and factors affecting the profitability of vaccine production compared
to producing other biologic products or pharmaceuticals. It also
considers factors affecting the decisions of individual suppliers about
how much vaccine to produce in a given year and possible policy
approaches to prevent future shortages of influenza vaccine. *Influenza
Vaccine: Who Buys It and Who Sells It* describes the vaccine supply
chain as well as potential means for facilitating vaccine purchase and
distribution. *Influenza Vaccine Manufacturing* describes the unique
characteristics of the influenza vaccine and discusses the structure of
the vaccine manufacturing industry, the nature of the market, decisions
about the amount of vaccine produced each year, investments in new
technologies to produce vaccine, the implications of relying on global
manufacturers for the U.S. domestic vaccine supply, and the factors that
influence manufacturers' decisions to enter or exit the market.
*Influenza Vaccine Demand: The Chicken and the Egg* examines the factors
that impact the demand for influenza vaccine and how they can affect
supply.

This brief, *Influenza Vaccine Overview: Summary and Assessment*,
summarizes the key points of the other issue briefs and is organized
into six sections, including this Introduction. Section 2 describes the
roles and responsibilities of the various influenza vaccine
stakeholders. Section 3 discusses key issues relevant to influenza
vaccine manufacturing and supply. Section 4 discusses factors impacting
purchasing and distribution of influenza vaccine. Section 5 presents a
case study of the influenza seasons from 1999 through 2005 and
highlights the important challenges that arose during each season. We
also discuss the impact of bioterrorism preparedness planning on
influenza planning during that period. In Section 6, we conclude with a
brief review of key issues to consider in developing influenza vaccine
policy.

## 2. Stakeholders in the Influenza Vaccination System 

Given its complexity, the influenza vaccination system has a number of
stakeholders, with corresponding roles and responsibilities. To outline
these stakeholders and the areas in which they are involved, we adapted
a list of stakeholders in the U.S. influenza vaccine system created by
the former director of CDC's National Immunization Program, Walter
Orenstein, and colleagues (see Table 1):

[]{#__RefHeading___Toc118526935 .anchor}**Table** 1. Stakeholder
Involvement in Influenza Vaccines

<table>
<colgroup>
<col style="width: 29%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="10"><strong>Stakeholders</strong></td>
</tr>
<tr class="even">
<td><strong>Areas</strong></td>
<td><blockquote>
<p><strong>Federal Government</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>State/ Local Government</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>Academia</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>Health Care Providers</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>Community Immunizers</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>Health Insurance Companies</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>Vaccine Industry</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>Wholesalers</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>Professional Societies</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>Consumers</strong></p>
</blockquote></td>
</tr>
<tr class="odd">
<td>Health burden determination</td>
<td>●</td>
<td>●</td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Vaccine discovery</td>
<td>●</td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Vaccine development</td>
<td>●</td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Vaccine production<sup>1</sup></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Vaccine distribution</td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>●</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Regulation</td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Vaccine policy</td>
<td>●</td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td>●</td>
<td></td>
</tr>
<tr class="even">
<td>Vaccine recommendations</td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Vaccine financing</td>
<td>●</td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td>●</td>
</tr>
<tr class="even">
<td>Vaccine administration</td>
<td></td>
<td>●</td>
<td></td>
<td>●</td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Monitoring vaccine use</td>
<td>●</td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Monitoring vaccine effectiveness</td>
<td>●</td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Monitoring vaccine safety</td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Vaccine injury compensation and liability</td>
<td>●</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>●</td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

^1^Although the primary responsibility for influenza vaccine production
falls to the vaccine industry, CDC prepares reference strains of
influenza virus for the FDA to distribute to influenza vaccine
manufacturers.

Adapted from Orenstein, Douglas, Rodewald, & Hinman (2005).

The complexity of the influenza vaccine system cannot be grasped fully
without appreciating the variety of stakeholders that develop, produce,
distribute, administer, and finance influenza vaccine and vaccination
programs and the fact that the roles and responsibilities of these
stakeholders often overlap and at times, some would argue, conflict with
one another. The federal government (through the National Institutes of
Health, CDC, and U.S. Food and Drug Administration \[FDA\]), academic
researchers, and vaccine manufacturers are all involved in some aspect
of vaccine discovery and development, although production is the primary
responsibility of the manufacturers.[^1] The stakeholders mainly
responsible for the administration of vaccine to individuals include
state and local governments, health care providers, and community
immunizers. However, vaccine regulation and policy development remain
the primary responsibility of policymakers and the federal government,
although they often seek the input of other stakeholders, such as
academic researchers and vaccine industry officials. Moreover, financers
such as health insurers can institute policies that are capable of
creating de facto regulations among their health care providers. For
example, insurers can link provider reimbursement to immunization rates
of their patients.

## 3. Overview of Influenza Vaccine Manufacturing and Supply Issues

Unlike other commodities, the annual supply of influenza vaccine is
largely immune to demand pressures. Because of the time required for
production, manufacturers must estimate at least 6 months in advance how
much vaccine to produce for the upcoming season. The complexities of
producing influenza vaccine, coupled with the small number of influenza
vaccine manufacturers, make it nearly impossible to produce more vaccine
than originally planned in advance. Therefore, one manufacturer cannot
make up another's shortfall when vaccine is lost or delayed. Figure 1
summarizes the vaccine production process and its timeline.

Typically, firms operating in an industry with only a few producers base
their output decisions in part on their beliefs about their competitors'
output decisions. However, for producers of influenza vaccines,
competitors' output levels are likely to be difficult to predict,
because changes in the virus strains from year to year necessitate
changes in the production process. As a result, influenza manufacturers
calculate the amount to be produced each year based on a process known
as prebooking, in which buyers reserve what they intend to purchase.

Moreover, influenza vaccine manufacturers rarely worry about the threat
of competition from new firms because the industry tends to be
characterized by significant barriers to entry including significant
government regulation, large capital expenses, and the long time period
required to produce each year's supply of influenza vaccine. Moreover,
the influenza manufacturing industry assumes significant financial risk
due to the fragility of the production process and the volatility of the
demand for the product. As a result, a number of manufacturers have
dropped out of the influenza vaccine market in recent years, including
Parkedale in 2000 and Wyeth in 2002. Financial and other issues reduced
the number of influenza vaccine

[]{#__RefHeading___Toc118274779 .anchor}Figure 1. Vaccine Manufacturing
Timeline

![](media/image1.wmf){width="6.493055555555555in"
height="5.191666666666666in"}

manufacturers licensed in the United States from four during the
1998--1999 influenza season to two in the 2004--2005 influenza season.
Table 2 illustrates how the number of manufacturers has changed from
1993 to 2005.

[]{#__RefHeading___Toc118526936 .anchor}Table 2. Influenza Vaccines,
Manufacturers, and Seasons during which each Vaccine Was Sold

<table>
<colgroup>
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 21%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="2"></td>
<td colspan="13"><strong>Influenza Season<sup>a,b</sup></strong></td>
</tr>
<tr class="even">
<td colspan="2"><strong>Vaccine Trade Name</strong></td>
<td><strong>Manufacturer</strong></td>
<td><blockquote>
<p><strong>1993–94</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>1994–95</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>1995–96</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>1996–97</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>1997–98</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>1998–99</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>1999–00</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>2000–01</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>2001–02</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>2002–03</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>2003–04</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>2004–05</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>2005–06</strong></p>
</blockquote></td>
</tr>
<tr class="odd">
<td colspan="2">Fluarix</td>
<td>GlaxoSmithKline (GSK)</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td><strong>•</strong></td>
</tr>
<tr class="even">
<td colspan="2">FluMist<sup>c</sup></td>
<td>MedImmune Vaccines, Inc.</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
</tr>
<tr class="odd">
<td colspan="2">Fluogen</td>
<td>Parkedale Pharmaceuticals Inc.<sup>d</sup></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td><strong>•</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td>Parke-Davis</td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">FluShield<sup>e</sup></td>
<td>Wyeth Laboratories, Inc.</td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Fluvirin<sup>f</sup></td>
<td>Chiron Corporation</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td><sup>g</sup></td>
<td><strong>•</strong></td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td>Evans Vaccines Ltd.</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td><strong>•</strong></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td>PowderJect Pharmaceuticals plc</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td>Medeva Pharma Ltd.</td>
<td></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Fluzone</td>
<td>Sanofi-Pasteur Inc.<sup>h</sup></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td><p>Connaught</p>
<p>Laboratories</p></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td><strong>•</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Flu-Imune</td>
<td>Lederle Laboratories</td>
<td><strong>•</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

^a^ Vaccine Adverse Event Reporting System (VAERS) data used in this
table includes manufacturer and trade name information taken only from
specific incidence reports of vaccine adverse reactions. Data that did
not specify specific influenza seasons were not used.

^b^ Influenza seasons 1993--1994 through 2000--2001 (CDC, 1993, 1994,
1995, 1996, 1997, 1998, 1999, 2000). Influenza seasons 2001--2002
through 2004--2005 (FDA, 2005).

^c^ Wyeth and MedImmune had a collaboration for the commercialization of
FluMist for the 2003-2004 influenza season. The companies announced the
dissolution of their collaboration in April 2004.

^d^ Parkedale Phamaceuticals, Inc., was ordered to discontinue
production of influenza vaccine following a 2000 FDA inspection.

^e^ 1993--1994 trade name not available. Wyeth left the market after
losing \$50 million over the prior three influenza seasons; 2001--2002
was the worst season, during which the company lost \$30 million and had
7 million doses of the vaccine that never sold (Ferguson, 2004).

^f^ In 2003, Chiron acquired PowderJect as a wholly owned subsidiary. In
2001, PowderJect acquired Medeva---which had previously acquired Evans
Medical Ltd.---and restored the Evans name to Evans Vaccines Ltd, a
wholly owned subsidiary of PowderJect. Prior to this, Evans Medical Ltd.
had acquired the vaccine business of Wellcome. For more information on
company acquisitions and mergers, see *Vaccine Identification Standards
Initiative: Manufacturer Abbreviations* (CDC, 2003d).

^g^ On October 5, 2004, Chiron's influenza vaccine plant was forced to
cease production by government regulators due to contamination issues.

^h^ In 1999, Aventis Pasteur, Inc., obtained FluZone vaccine ownership
from Connaught Laboratories, Inc. In 2004, Sanofi merged with Aventis
Pasteur to create the Sanofi Aventis Group. The vaccine division of the
Sanofi Aventis Group changed its name to Sanofi Pasteur.

## 4. Overview of Influenza Purchase and Distribution Issues

The process by which influenza vaccine is bought and sold is unlike that
of other vaccines, which lack seasonality. The process involves numerous
entities and different channels, many of which are little understood
outside the vaccine industry. The major buyers of vaccine are presented
in Table 3.

[]{#__RefHeading___Toc118526937 .anchor}Table 3. Major Buyers of
Influenza Vaccine

+---------------------+-------------------------+----------------------+
| **Wholesale         | **Providers**           | **State/Federal      |
| Distributors**      |                         | Government**         |
+---------------------+-------------------------+----------------------+
| -   Medical supply  | -   Private physicians  | -   State health     |
|     distributors    |                         |     departments      |
|                     | -   Managed care        |                      |
| -   Pharmaceutical  |     organizations       | -   U.S. Department  |
|     distributors    |                         |     of Health and    |
|                     | -   Hospitals           |     Human Services   |
| -   Pharmaceutical  |                         |                      |
|     redistributors  | -   Long-term           | -   U.S. Department  |
|                     |     care/nursing home   |     of Defense       |
|                     |     facilities          |                      |
|                     |                         | -   U.S. Department  |
|                     | -   Work and            |     of Veterans      |
|                     |     retail-based        |     Affairs          |
|                     |     community           |                      |
|                     |     immunizers          |                      |
|                     |                         |                      |
|                     | -   Local public health |                      |
|                     |     departments         |                      |
+---------------------+-------------------------+----------------------+

The distribution of influenza vaccine reflects the complex network of
private and public components that constitute the U.S. health system
(Figure 2). In the simplest case scenario, a private physician may buy
vaccine directly from a manufacturer to administer to his/her patients.
More typically, vaccine will have passed through multiple intermediaries
before reaching the individual consumer. Health care providers of
various sorts (physicians, community immunizers, state health
departments, local public health departments) may buy vaccine from a
distributor who bought it directly from a manufacturer. Alternatively,
health care providers may obtain their vaccine through a state or
federal vaccine program that bought it through a distributor or directly
from a manufacturer. For example, CDC contracts with manufacturers for
influenza vaccines. States buy vaccine through these contracts using
their own funds or other government funds. The vaccine is then
distributed to health care providers (including state and local health
departments) through a variety of mechanisms.

As with the manufacturing sector, the buying and selling of influenza
vaccine is rife with financial risk. The primary challenge to the entire
system of purchase and distribution is balancing the potential financial
liability of unused (and thus unpaid for) vaccine with the desire to
provide influenza vaccine to those who need it. Like manufacturers, many
distributors are so

[]{#__RefHeading___Toc118274780 .anchor}Figure 2. Influenza Vaccine
Distribution Pathways

![](media/image2.wmf){width="6.3in" height="3.1958333333333333in"}

DoD = U.S. Department of Defense; ERs = emergency rooms; LHDs = local
health departments;\
MMCAP = Minnesota Multi-State Contracting Alliance for Pharmacy; VA =
U.S. Department of Veterans Affairs; VNAs = Visiting Nurse Associations

concerned about the problems created by a fluctuating and unreliable
influenza vaccine supply that they question their continued role in
influenza vaccine distribution.

## 5. Case Study of the Influenza Seasons from 1999 through 2005

In examining the features of the influenza seasons from 1999 through
2005, one key finding is clear: there are no predictable factors that
characterize a "normal" influenza season. Year to year, the strain and
virulence of the virus varies, and it is difficult with any degree of
certainty to forecast which strain will predominate 6 months in advance
of the influenza season, when manufacturing decisions are made. Problems
with manufacturing and distribution are difficult to predict, and rarely
does the same problem arise more than once. Recommendations for who
should receive vaccine also change according to scientific discoveries
and the available supply of vaccine.

### 5.1 Prevailing Strains and Vaccine Composition

Each year, the influenza vaccines produced include two influenza A
strains and one influenza B strain. In four of the last six influenza
seasons from 1999 to 2005, A(H3N2) was the prevailing influenza A
strain, but A(H1N1) and A(H1) were the prevailing strains in 2000--2001
and 2002--2003, respectively. During this period, the FDA Vaccines and
Related Biologic Products Advisory Committee (VRBPAC) recommended, and
manufacturers subsequently produced, 11 different vaccine compositions
for the U.S. market. Only two of the 11 compositions,
A/Caledonia/20/99(H1N1) and A/Moscow/10/99 (H3N2), were produced for
three or more influenza seasons. In five of the last six influenza
seasons, the recommended vaccine compositions matched the prevailing
strains. However, in 2003--2004 the prevailing strain (H3N2) was more
closely matched to a drift variant of A/Fujiian/411/2002/(H3N2), not the
recommended vaccine composition for that year, A/Moscow/10/99 like
(H3N2) (Table 4). Such alternative strains are used in situations in
which the prevailing strain has a history of poor growth and/or poor
yield during vaccine production.

[]{#__RefHeading___Toc118526938 .anchor}Table 4. VRBPAC Recommended
Vaccine Compositions 1999--2005

  ---------------------- ---------------- ---------------- ---------------- ---------------- ---------------- ----------------
  **VRBPAC Recommended   **Influenza                                                                          
  Vaccine Composition**  Season**                                                                             

                         **1999--2000**   **2000--2001**   **2001--2002**   **2002--2003**   **2003--2004**   **2004--2005**

  A/Beijing/262/95       ▲                                                                                    
  (H1N1)                                                                                                      

  A/Fujian/411/2002 like                                                                                      ▲
  (H3N2)                                                                                                      

  A/New Caledonia/20/99                   ▲                ▲                ▲                ▲                ▲
  like (H1N1)                                                                                                 

  A/Moscow/10/99 like                                      ▲                ▲                ▲                
  (H3N2)^a^                                                                                                   

  A/Panama/2007/99 like                   ▲                                                                   
  (H3N2)                                                                                                      

  A/Sydney/5/97/(H3N2)   ▲                                                                                    

  B/Hong Kong/330/2001                                                      ▲                ▲                

  B/Beijing/184/93       ▲                                                                                    

  B/Sichuan/379/99                                         ▲                                                  

  B/Shanghai/361/200                                                                                          ▲
  like                                                                                                        

  B/Yamanashi                             ▲                                                                   
  ---------------------- ---------------- ---------------- ---------------- ---------------- ---------------- ----------------

^a^A/Moscow could be used in lieu of A/Panama.

Sources: CDC, 1999b; CDC, 2000a; CDC, 2001a; CDC, 2001c; CDC, 2002a;
CDC, 2002b; CDC, 2003a; CDC, 2003c; CDC, 2004a; CDC, 2004c; CDC, 2004d;
CDC, 2005b.

### 5.2 Manufacturing and Distribution

From 1999 to 2004, annual influenza vaccine production rose steadily
from 77.2 million to 99.5 million doses. A similar trend was seen for
the number of doses distributed (Figure 3). Despite the progress made
toward increasing production of influenza vaccine for U.S. distribution,
it remains well below the 183.3 million doses recommended by the
Advisory Committee on Immunization Practices (ACIP) to immunize all
people in all target groups.[^2]

[]{#__RefHeading___Toc118274781 .anchor}Figure 3. Influenza Vaccine
Doses Produced and Distributed for the U.S. Market 1999--2004

![](media/image3.wmf){width="6.333333333333333in" height="4.28125in"}

^a^ Targeted population includes persons 65 years of age or older, those
with defined chronic diseases, pregnant women, children 6 to 23 months
of age, household contacts of those previously mentioned, health care
personnel, and healthy persons 50 to 64 years of age.

Sources: CDC, 2005c; Santoli, 2005.

Manufacturing problems arose in two of the last six influenza seasons.
In 2000--2001, manufacturing problems at two companies resulted in lower
than expected yields, causing delays in delivery of vaccine that created
de facto shortages (Layton, Honeycutt, Levy, Kessler, & Liao, 2001). In
2001--2002, spot shortages were reported in some areas early in the
season (CDC, 2001c) and were more widespread in 2003--2004 (Mitka,
2005). In 2004--2005, U.K. regulators suspended production at Chiron
after the company failed to resolve ongoing production problems,
resulting in the widely publicized loss of nearly half the U.S. vaccine
supply for that season. This was the only season in which rationing
occurred (CDC, 2004b). Table 5 summarizes some of the key issues
occurring during these six influenza seasons.

[]{#__RefHeading___Toc118526939 .anchor}Table 5. Summary of 1999--2005
Influenza Seasons

  ----------------- ---------------- ---------------- ---------------- ---------------- ---------------- ----------------
  **Event**         **Influenza                                                                          
                    Season**                                                                             

                    **1999--2000**   **2000--2001**   **2001--2002**   **2002--2003**   **2003--2004**   **2004--2005**

  Prevailing        A(H3N2)          A(H1N1)          A(H3N2)          A(H1)            A(H3N2)          A(H3N2)
  influenza strain                                                                                       

  Production        No               Yes              No               No               No               Yes
  problems                                                                                               

  Delays in         No               Yes              Yes              No               No               Yes
  delivery                                                                                               

  Spot shortages    No               Yes              Yes              No               Yes              Yes

  Vaccine rationing No               No               No               No               No               Yes

  ACIP broadens     No               Yes              No               No               No               Yes
  identified target                                                                                      
  groups                                                                                                 

  ACIP updated      No               No               Yes              Yes              Yes              Yes
  recommendations                                                                                        
  ----------------- ---------------- ---------------- ---------------- ---------------- ---------------- ----------------

Sources: CDC, 1999b; CDC, 2000b; CDC, 2001a; CDC, 2001c; CDC, 2002a;
CDC, 2002b; CDC, 2002c;\
CDC, 2003a; CDC, 2003b; CDC, 2004a; CDC, 2004c; CDC, 2004d; CDC, 2004f;
CDC, 2005b; FDA, 2001.

### 5.3 Changing Advisory Committee on Immunization Practices (ACIP) Recommendations

ACIP is a 15-member panel of experts on immunization from the fields of
medicine, immunology, and public health. ACIP advises CDC and the U.S.
Department of Health and Human Services and develops written
recommendations for routine vaccine administration. In three of the last
six influenza seasons, ACIP has revised its recommendations for
influenza administration. Recommendations to broaden target groups have
reflected evolving science, which has shown benefits associated with
immunizing increasing proportions of the public. In 2000, ACIP broadened
its initial target group---persons 65 years of age or older and persons
with health conditions that would place them at particular risk for
influenza-related complications---to include all persons 50 years of age
or older regardless of health status (CDC, 2001b). In 2004, the
recommendations broadened again to include young children 6 to 23 months
of age (CDC, 2004a).

Although ACIP recommends that *all* individuals who wish to avoid
influenza be immunized, ACIP's identified target groups are those who
are especially vulnerable to influenza-associated complications. These
groups are generally the very young, elderly, chronically ill, and
immunocompromised. Recommendations to prioritize target groups or
otherwise "ration" influenza vaccine in times of shortage have been the
subject of considerable debate. Due to problems in previous influenza
seasons, in 2003, ACIP began to recommend that those at highest risk for
influenza complications receive immunizations in September and October,
but others should wait until November (CDC, 2001b). Although ACIP
recognizes the need for coherent and consistent recommendations, it also
wants to assure the means to target specific priority groups in times of
vaccine shortage. Thus, in 2005, ACIP recommended a tiered use of
inactivated influenza in the case of vaccine shortage (CDC, 2005d). Such
a tiered approach is outlined in Table 6. However, it should be noted
that, among the key informants, there was no agreement regarding how a
shortage should be defined.

[]{#__RefHeading___Toc118526940 .anchor}Table 6. Tiered Approach to
Allot Inactivated Influenza Vaccine During a Shortage

+-----+--------------+--------------------------------+---------------+
|     | **Priority   |                                |               |
|     | Groups**     |                                |               |
+-----+--------------+--------------------------------+---------------+
| T   | A            | B                              | C             |
| ier |              |                                |               |
| 1   | Persons 65+  | Persons 2 to 64 years of age   | Health care   |
|     | years of age | with comorbid conditions       | personnel     |
|     | with         |                                |               |
|     | comorbid     | Persons 65+ years of age       | Household     |
|     | conditions   | without comorbid conditions    | contacts and  |
|     |              |                                | out-of-home   |
|     | Residents of | Children 6 to 23 months of age | care givers   |
|     | long-term    |                                | of children   |
|     | care         | Pregnant women                 | \< 6 months   |
|     | facilities   |                                | of age        |
+-----+--------------+--------------------------------+---------------+
| T   | Household    |                                |               |
| ier | contacts of  |                                |               |
| 2   | children and |                                |               |
|     | adults at    |                                |               |
|     | increased    |                                |               |
|     | risk for     |                                |               |
|     | influ        |                                |               |
|     | enza-related |                                |               |
|     | c            |                                |               |
|     | omplications |                                |               |
|     |              |                                |               |
|     | Healthy      |                                |               |
|     | persons 50   |                                |               |
|     | to 64 years  |                                |               |
|     | of age       |                                |               |
+-----+--------------+--------------------------------+---------------+
| T   | Persons 2 to |                                |               |
| ier | 49 years of  |                                |               |
| 3   | age without  |                                |               |
|     | comorbid     |                                |               |
|     | conditions   |                                |               |
+-----+--------------+--------------------------------+---------------+

### 5.4 Impact of Bioterrorism Preparedness on Influenza Awareness and Planning

The terrorist attacks in the U.S. during the fall of 2001 increased
awareness of the potential for infectious agents to be used for
bioterrorism. As one key informant noted, "The big targets are going to
be what you eat, breathe, and drink ... and that's public health
infrastructure, which is already strapped. I'd think you'd want to
eliminate an additional threat if you could." Since fiscal year (FY)
2002, states have expended an estimated \$2 billion in bioterrorism
funds to develop preparedness for a range of natural and terrorist
disasters and other public health emergencies, including pandemic
influenza (U.S. Government Accounting Office, 2005).

In general, those with whom we spoke viewed bioterrorism preparedness
within a broader context of public health preparedness. Most key
informants were positive about the impact of preparedness planning on
influenza planning and vice versa. At the state level, funding for
bioterrorism preparedness has established mechanisms for coordination
and communication to deal with man-made and naturally occurring public
health crises.

States used the challenges arising during the influenza seasons of
2002--2003 and 2003--2004, in particular, to initiate and "test" their
emergency preparedness plans---activating their command incident centers
and using their Health Alert Network to determine which providers had
influenza vaccine and how much. Also, states have had to increase their
capacity to distribute many more doses of vaccine than in previous
years. During the 2003--2004 season, one state conducted a 1‑day mass
immunization event to assess whether they had the capacity to conduct
such an effort (they did, in fact, successfully administer an estimated
53,000 doses in 1 day).

During periods of vaccine shortages, states have also, by necessity,
taken on new roles as brokers---finding new vaccine storage facilities,
reaching out to a range of new providers---to ensure that scarce vaccine
is distributed to those most in need. For community immunizers, the
experience of the 2003--2004 influenza season prompted the establishment
of explicit procedures for crowd control and planning of mass
immunization events.

A positive effect of bioterrorism preparedness, mentioned by nearly all
of our key informants, is enhanced communication. State health officials
reported better communication with their stakeholders both within and
outside the health department. Federal health officials cited better
communication between state entities and CDC, and manufacturers and
distributors noted better communication with CDC and greater
private/public partnering. One community immunizer explained,

> *What I've been seeing from the past year or so, there've been some
> great public-private partnerships that I think have shown a lot of
> people what we need to do for pandemic planning and bioterrorism
> planning. I know that's a big thing going on. But at the same time,
> there are still locations \[that\] really don't have a realistic plan
> on what to do if something happened ... there really needs to be
> multiple levels of involvement and plans put far enough in advance.*

Despite enhanced communication among stakeholders at all levels and a
greater understanding of state capability for mass immunization, a few
informants noted that the merits of bioterrorism preparedness have yet
to be fully realized. As one informant noted, states need "a dose of
reality;" some of the preparedness plans in place simply are not
realistic because they ignore the inability of the manufacturing and
distribution sectors to produce more vaccine in a short period of time.
Moreover, while the willingness to "band together and get things done"
is commendable, some stakeholders are still very unclear as to how they
should respond in an emergency. Following the 2004--2005 season, one
community immunizer said,

> *In case of emergency---a vaccine shortage---there has to be a plan in
> place already and something that can be easily adjusted within a
> matter of a day or two because we lost 2 or 3 weeks of getting vaccine
> out to the right people. I think that's one of the big reasons why
> there was vaccine wasted.*

There is also uncertainty among federal officials about how their own
agencies would respond in a crisis. For example, during the 2003--2004
season, CDC repositioned and reassigned staff to new duties in ways that
were unclear to personnel. While CDC management clearly felt the need to
keep staffing flexible and fluid during a crisis, some of our informants
argued that the process isolated and disregarded the expertise of key
staff; in their view, this resulted in poor decision making. Thus, it
would seem that in the absence of any concrete "crisis plan" that is
understood and agreed to by all key personnel a priori, the potential
exists for miscommunication, inefficiency, and the loss of important
knowledge and expertise when it is needed most.

Thinking about influenza immunization in the broader sphere of public
health, some key informants addressed the roles of various stakeholders
and emphasized the importance of defining the roles and responsibilities
of all involved. This is particularly important as various components of
the influenza immunization infrastructure are privatized. One community
immunizer from a for-profit firm explained,

> *... The scenario now is that private companies really don't want to
> spend a lot of time doing \[preparedness planning\] because it's all
> pie-in-the-sky stuff. There's no funding. Unfortunately, private
> companies have to make a living in order to help anybody. As long as
> we're in America.*

Another community immunizer asserted,

> *The government needs to take a more serious stand in taking the risk
> away and incentivizing manufacturers to make influenza vaccine to
> stabilize demand and supply issues so that providers---very much
> including community immunizers---stay in the business because in the
> case of an emergency scenario---whether it's influenza or other needs
> which require vaccine or mass distribution of medication---you want
> those community immunizers to already have an infrastructure to work
> closely ... with public health because I just don't see how public
> health agencies can take that on their own.*

On the other hand, another key informant, an expert in the field of
immunization, felt not only that all immunization was fundamentally a
job for the public sector, but that it ought to be a primary concern:

> *I tend to view vaccination as a matter of national health security.
> If you use as a paradigm national security, which is a responsibility
> of the department of defense ... We don't leave national defense to
> the private sector. ... It is idiotic, idiotic for us to regard
> vaccine-preventable diseases as anything other than health
> security---particularly when we're concerned about influenza and a
> threat of a pandemic. To think that this is something that can be led
> in a market-oriented way by profit-seeking companies and essentially
> holding national health hostage to what corporations do and do not
> want to do is ludicrous.*

## 6. Summary and Conclusions

The issues and challenges raised here are intended to inform policies
affecting the production, distribution, and administration of influenza
vaccine. While these issues are difficult and evolving quickly over
time, four features remain fundamental to an understanding of the
influenza vaccine market in the U.S.:

-   **The complexity of influenza vaccine demand, supply, and
    distribution.** The production and distribution of influenza vaccine
    is unique and cannot be compared to any other vaccines or
    pharmaceuticals. The complexity of the system is borne out of the
    time-consuming technologies used to produce influenza vaccine, the
    immense unpredictability of the demand for the vaccine, and the
    public reaction to supply shortages or surpluses.

-   **The high level of financial risk incumbent on vaccine
    manufacturers and wholesalers.** Manufacturers carry a financial
    risk producing influenza vaccines with complicated technology for an
    unpredictable market that can leave them with tens of thousands or
    even millions of unused or, as in the case of Chiron, unusable
    doses. This risk is transferred to the wholesalers once vaccine
    supplies are booked and sold to other distributors or immunization
    providers. Additional protections from the public sector (e.g.,
    commitments to purchase surplus vaccine) may be needed to reduce the
    risk that manufacturers and distributors face in a marketplace with
    relatively low profit margins compared to other pharmaceuticals.

-   **The fundamental need to better educate the public.** A more
    informed public can increase demand for vaccine, which in turn could
    solve many of the vaccine supply, demand, and distribution issues in
    and of itself. Greater demand and therefore a greater supply would
    in turn alleviate the prebooking requirements that can generate
    shortages.

-   **The complexity of the problem, which requires multifaceted
    strategies.** Solutions that will improve vaccination supply and
    distribution cannot be achieved solely by any single participant, be
    they manufacturers, health care providers, or distributors. The
    production system needs greater creativity and innovation that will
    foster new technologies to manufacture the vaccine more quickly and
    efficiently.

Former CDC National Immunization Program Director, Walter Orenstein, has
called influenza "the most significant vaccine-preventable disease."
Despite this, many people still think of influenza as a mild
illness---even though it kills more people annually than prostate or
cervical cancer.[^3] Nevertheless, the approach to influenza's
prevention has not been proportionate to the threat it poses. It is
clear that in order to effectively provide annual influenza immunization
to targeted groups that the various components of the vaccine
immunization infrastructure must work toward this goal in a coordinated
and collaborative fashion. Examples of the efforts required by various
groups are described in the recent report written by members of the
National Vaccine Advisory Committee (NVAC), *Strengthening the Nation's
Influenza Vaccination System* (Helms et al., 2005). Such collaboration
is depicted in a 1911 public health poster (Figure 4). The public's
health is protected by infrastructure composed of many components. All
of these components are not sufficient on their own, but together they
create a means to assure the public's health---the essential form of
national security.

[]{#__RefHeading___Toc118274782 .anchor}Figure 4. Public Health Poster
from 1911

![](media/image4.jpeg){width="6.504166666666666in"
height="4.032638888888889in"}

Source: Ehrenreich and English (1973).

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[^1]: Although the primary responsibility for influenza vaccine
    production falls to the vaccine industry, CDC prepares reference
    strains of influenza virus for the FDA to distribute to influenza
    vaccine manufacturers.

[^2]: Priority groups include persons 65 years of age or older, persons
    of any age with chronic diseases, pregnant women, children 6 to 23
    months of age, health care personnel, and household contacts of
    previously listed groups. Target (or targeted) groups include
    priority groups plus healthy adults 50 to 64 years of age.

[^3]: While influenza causes approximately 36,000 deaths annually, in
    2001 prostate cancer caused 30,719 deaths and cervical cancer 4,100.
    In that same year, breast cancer killed 39,800 people. (CDC, 2004e.)