**APPROVED BY NVAC -- December 2, 2004**

**Strengthening the Nation's Influenza Vaccination System: An NVAC
Assessment**

**Executive Summary**

Influenza is the nation's largest vaccination effort. Each year more
Americans are vaccinated for influenza than for any other disease.
Although vaccine shortages and delays have garnered much attention
during the past several years, it is important also to highlight the
success of the program. Millions of persons are vaccinated in a short
time period each year; good collaboration exists between public and
private sectors, which have documented an ability to respond
appropriately to vaccine supply problems and other events; health care
providers and the public have acted responsibly in targeting vaccine to
those who need it most at times of shortage. Nevertheless, one cannot
underestimate the importance and impacts of vaccine supply shortages,
particularly that occurring for the 2004-05 season. A sufficient and
predictable vaccine supply is critical for a successful prevention
program and uncertainties jeopardize the ability to plan and make
program improvements. Several interventions have been implemented to
reduce the risk of future supply disruptions and strengthen influenza
vaccine security for annual disease and as a component of preparedness
for an influenza pandemic.

Even during seasons of adequate influenza vaccine supply, disease
prevention is far from optimal. With an estimated average of 36,000
influenza-related deaths.^1^ and over 200,000 hospitalizations annually
in the United States,^2^ influenza causes more mortality and morbidity
than all other vaccine preventable diseases combined. While coverage
rates for pediatric vaccines generally exceed 90%, of the more than 185
million persons recommended for annual influenza vaccine, fewer than
half are vaccinated.

In 2004, the Acting Assistant Secretary for Health, Department of Health
and Human Services (DHHS) requested that the National Vaccine Advisory
Committee (NVAC) evaluate strategies and capabilities to improve
influenza prevention in the U.S. An NVAC Influenza Vaccine Working Group
evaluated both published and unpublished data and held discussions with
stakeholders, including industry, public health officials, providers,
purchasers, and consumers to develop recommendations. 

Working Group recommendations are based on three overarching findings:

-   The current influenza vaccine is not optimally effective among some
    groups recommended for vaccination or during every influenza season

-   Current influenza vaccination recommendations are likely not optimal
    to prevent disease and death.

-   In any given year, the majority of people for whom influenza vaccine
    is recommended do not get vaccinated.

    Based on these findings, the Working Group developed several
    recommendations by which to improve influenza prevention in the
    United States:

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-   Improve vaccination coverage among recommended groups by
    facilitating the delivery of influenza vaccines in a range of
    settings, especially in "medical homes,", other medical sites,
    workplaces, and community sites where people have not previously had
    access to vaccination

-   Make influenza vaccine purchase less of a burden and financial risk
    for providers.

-   Explore options for a comprehensive vaccination program for adults.

-   Increase the rate of influenza vaccination among health care
    workers.

-   Consider expanding influenza vaccination recommendations.

-   Implement systems to better understand the burden of influenza
    illness in the U.S. and to better assess the impact of vaccination
    programs and vaccine effectiveness

-   Conduct a comprehensive review of the influenza research program to
    identify gaps and areas for additional support.

**Background**

The CDC and its Advisory Committee on Immunization Practices (ACIP)
recommends annual influenza vaccinations for persons at increased risk
of severe influenza infection, their close contacts, and all health care
workers.^3^ Influenza vaccination uptake increased dramatically through
the 1990's. However, since the late 1990s, only about 80 million of the
185 million people for whom the vaccination is recommended are
vaccinated in a typical influenza season.^3^  Vaccination coverage falls
far short of the goals established by the DHHS in the *Healthy People
2010* (*HP 2010*) objectives,^4^ which include influenza vaccine
coverage of 90% among of adults aged 65 and older, children between 6
and 23 months of age, and persons in long-term institutional care or
nursing homes; and 60% coverage in non-institutionalized adults who are
less than 65 years old and have medical conditions that place them at
increased risk of mortality and serious morbidity.^3^ Although influenza
vaccine supply disruptions have affected the amount or timeliness of
vaccine availability in recent years, even when vaccine supply is
adequate there is no evidence of a trend toward higher vaccine
coverage.^5^ This suggests that, in the absence of substantial
systematic changes, *HP* 2010 coverage goals will not be met.

One question that must be asked is: will meeting influenza vaccine
coverage goals lead to the substantial reduction in influenza disease
and death, as has been seen with the pediatric vaccination program? For
every routinely recommended childhood vaccine, when coverage rates have
exceeded 90%, reductions in disease have been for similar or greater
magnitude.^6^ By contrast, the impact of increased influenza vaccination
coverage under current recommendations is likely to be of a lesser
magnitude. The effectiveness of inactivated influenza vaccine depends
primarily on the age and immunocompetence of the vaccine recipient and
the degree of similarity between the viruses in the vaccine and those in
circulation. Influenza vaccines must be changed annually to match the
strains that are predicted to circulate in the population during the
influenza season. In most years the match is good, but occasionally
vaccine does not match the circulating strain and vaccine effectiveness
is diminished, as occurred during the 2003-04 season,^7,8^.

When the match is good, influenza vaccine prevents influenza illness
among approximately 70%\--90% of healthy adults aged less than 65
years.^9-14^and vaccination of healthy adults has resulted in decreased
work absenteeism and decreased use of health-care resources, including
the use of antibiotics.^12,13^ Older persons and persons with certain
chronic diseases might develop lower post-vaccination antibody titers
than healthy young adults and thus can remain susceptible to
influenza.^15-17^ Among elderly persons 65 years and older not living in
nursing homes or chronic-care facilities, influenza vaccine is 30%\--70%
effective in preventing hospitalization for pneumonia and influenza
diagnoses.^18,19^ Among older nursing home residents aged 65 years and
older, influenza vaccine can be 50%\--60% effective in preventing
hospitalization or pneumonia and 80% effective in preventing death,
although the effectiveness in preventing influenza illness often ranges
from 30% to 40%.^20,21^

In spite of numerous studies demonstrating effectiveness in small
settings, national trend data raise questions regarding the overall
impact of the current influenza vaccination program under current
recommendations in reducing mortality. During the past several decades,
as annual influenza vaccine use increased from about 20 million doses in
the 1980s to the current total of about 80 million doses per year, there
has not been a commensurate decrease in influenza mortality.^22^ Even
when controlling for the aging of the U.S. population, expected program
impacts have not been observed. In addition, the risk of mismatch
between vaccine and circulating strains and the suboptimal vaccine
effectiveness, particularly in high risk populations, suggest that
research is needed to develop better influenza vaccines that can provide
improved prevention.

The fragility of the U.S. influenza vaccine supply threatens the ability
to implement an effective vaccination program, to increase coverage, and
to prevent disease. Rates and severity of influenza disease vary
annually, affecting demand. Against this backdrop, production issues in
recent years have led to delays, spot shortages, and the substantial
shortfall expected for the 2004-05 influenza season. Yet, in other
years, there has been significant excess vaccine, and millions of
vaccine doses have not been administered. ^23^ Even in 2003-04, when the
combination of early widespread influenza outbreaks, coupled with the
reports of influenza-related deaths in children led to increased demand
for inactivated influenza vaccine, several million doses of a newly
licensed and more expensive live, attenuated influenza vaccine
(*FluMist®*) went unused. Because vaccine supply and investments into
the development of new technologies are related to the size and
predictability of the market and vaccine price, there is an intrinsic
relationship between vaccine recommendations and program implementation
and vaccine supply and research. Thus, although the NVAC Working Group
recommendations do not directly focus on vaccine supply, their
implementation would have a major and positive impact on vaccine supply,
uptake and on investments in new vaccines and technologies.

**Process**:

At the request of the Acting Assistant Secretary for Health, Dr.
Cristina Beato, NVAC established a Working Group to evaluate strategies
to reduce the impact of influenza disease in the U.S. and make
recommendations on how to substantially improve influenza prevention and
reduce disease burden. The Working Group was encouraged to ask
challenging questions and consider new strategies, paradigms,
infrastructures, and technologies as well as incremental changes that
could be made to the current system. In February 2004, the NVAC
Influenza Working Group was appointed, chaired by Dr. Charles Helms,
current NVAC Chair. The Working Group was divided into three subgroups
to focus on separate key issues:

-   The Influenza Vaccine Delivery, Financing, and Demand Subgroup was
    chaired by Dr. Fernando Guerra. This subgroup examined private and
    public delivery systems, communications issues, and vaccine demand.

-   The Influenza Vaccine Recommendations and Strategies Subgroup was
    chaired by Dr. Jerome Klein. This subgroup studied issues related to
    the measurement of the burden of disease, the impact of the
    vaccination program, and vaccine efficacy; and the considering
    consideration of alternative vaccine recommendations.

-   The Influenza Vaccine Research, Development, and Production Subgroup
    was chaired by Dr. Ann Arvin. This subgroup assessed the influenza
    vaccine research and development enterprise in the public and
    private sectors.

During the spring of 2004, the subgroups reviewed published and
unpublished data, consulted with DHHS agencies and their advisory
committees, influenza vaccine manufacturers, clinicians, professional
and advocacy associations, researchers, vaccine distributors, and health
care providers to thoroughly review the program. Based on these
investigations the subgroups developed key findings and recommendations
which were presented and discussed at the NVAC meetings in June and
October 2004. This report was developed following those discussions and
was approved by the Committee for presentation to the Acting Assistant
Secretary for Health in December 2004.

**Recommendations and Rationales**

***Vaccine Financing and Demand***

[1) Improve vaccination coverage among recommended groups by
facilitating the delivery of influenza vaccines in a range of settings,
especially in "medical homes," other medical sites, workplaces, and
community sites where people have not previously had access to
vaccination.]{.underline}

*Rationale*: Several barriers exist to achieving high rates of influenza
vaccine coverage among recommended groups through vaccination at primary
-care provider physicians offices.^24,25^ While children commonly make
routine age-based well child care visits, most adults seek health care
only in the context of an acute or chronic illness. In this setting,
there is unlikely to be time or focus on delivery of preventive services
such as vaccination. Many women receive their primary care from
gynecologists and some persons with chronic illness receive primary care
from sub-specialists, both of whom may be less likely to deliver
vaccinations.^26,27^ Financial barriers also may decrease the likelihood
that vaccination will be provided by primary-care physicians.^24^

To increase influenza vaccine coverage, effective strategies must be
implemented to increase vaccination at other sites where adults receive
health care or where preventive services could be delivered.^28,29^
Every contact with the health care system should be used as an
opportunity to vaccinate.^30^, Emergency departments, which are
increasingly being used as sources of care by the poor and underinsured,
may be cost-effective sites for delivering preventive services such as
vaccination and preventing future hospitalization among the most
medically and socially vulnerable.^31,32^ A strategy of routinely
offering influenza vaccination in emergency rooms to patients between
September and December (and later if vaccine supply allows) could
markedly decrease missed opportunities for vaccination.(CDC unpublished
data)

Provision of vaccination at places not used for health care, such as
work sites, grocery stores, pharmacies, shopping malls, detention
centers, and other places where people can conveniently be reached
during the months before influenza season has been shown to increase
vaccination coverage among groups who do not usually receive influenza
vaccination.^33^ Increasing vaccination at these sites requires
overcoming barriers that may include limits on who can administer
vaccinations and the need for a physician's order before vaccination.
The use of "standing orders" avoids the need for individual physician's
orders and has been effective in increasing vaccination at sites outside
of provider offices.^34,35^ Development of toolkits that include model
standing orders and other materials to facilitate vaccination at
alternate sites, active distribution of these materials and promotion of
program goals, and active follow-up are needed for effective
implementation. Resources to coordinate these programs should be made
available to State and local immunization programs.

[2) Make influenza vaccine purchase less of a burden and financial risk
for providers.]{.underline} *Rationale*: Studies have shown that
providers have concerns regarding the costs of purchasing and
administering influenza vaccine and their level of reimbursement. Health
plan payment rates may not adequately compensate for these costs, and,
for many providers, influenza vaccination is a financial loss. When all
costs for influenza vaccine, its administration, office staff time, and
practice overhead are compared with average Medicare immunization
reimbursement payments of \$17.76 in 2003, one study indicates that
providers' per-shot losses range from \$3.36 to \$32.76.^36^ A recent
CMS proposal to increase reimbursement for influenza vaccine
administration from \$8 to \$18 will significantly improve the financial
balance for office based vaccination; however, in some settings, the
balance will still remain negative. In addition, providers must order
and purchase vaccine months before it is administered resulting in a
substantial capital outlay. Finally, manufacturers have adopted a "no
return" policy for influenza vaccine; thus providers are wary about
potentially ordering excess vaccine and receiving no reimbursement for
unused product. Given these factors, there has been little incentive for
health care providers to increase coverage rates for influenza
vaccination within a practice. Because private insurers generally have
followed the lead of Medicare in reimbursement policy, the recent policy
change by CMS to increase influenza vaccination coverage may increase
the use of influenza vaccination by providers nationwide. Further
consideration with CMS of financial issues for providers may be an
efficient and effective approach to identify additional solutions.

[3) Explore options for supporting a comprehensive vaccination program
for adults.]{.underline}

*Rationale*: Financial barriers limit health care providers' willingness
and ability to increase influenza vaccination among adults. Costs also
may limit the willingness of persons in recommended groups to be
vaccinated in the absence of health insurance or when reimbursement does
not cover all costs. Studies have shown a 10-30% increment in coverage
when vaccine is provided without charge to patients.^37-40^ In Ontario,
Canada the combination of free vaccine and a universal recommendation
has resulted in 77% coverage among the elderly (about 10% better than in
the U.S.) and 42% coverage in the entire population of the province.

Cost may be a substantial barrier particularly among persons who are
poor, uninsured, or disabled. In 2000, only two state Medicaid programs
met standards for a comprehensive adult immunization policy, which
includes: covering ACIP recommended vaccines; permitting only a nominal
co-pay; providing vaccine replacement; and allowing separate billing for
vaccine administration. One option to improve on this would be to
establish a comprehensive program nationwide, focusing on the poor and
uninsured, and analogous to the Vaccines for Children program, but other
approaches also may be envisioned. A systematic evaluation of options
that includes discussion with stakeholder groups could provide
information to DHHS that can lead to policy decisions.

[4) Increase the rate of annual influenza vaccination among health care
workers]{.underline}.

*Rationale*: Despite longstanding recommendations for vaccination of
health care workers, many still do not get vaccinated. Vaccination of
health care workers (HCWs) has been shown to prevent mortality in their
patients^41^ as well as reduce influenza infection and absenteeism in
the HCWs^9^ themselves and may sometimes result in financial savings to
the sponsoring health institutions.^9^ Despite this, only 38% of HCWs
received influenza vaccine the previous year according to the 2002
National Health Interview Survey ^3^. Federal advisory committees
including the Advisory Committee on Immunization Practices (ACIP) and
NVAC have highlighted the need to improve vaccine uptake in this
recommended group. As is the case for the general public, making receipt
of influenza vaccine convenient and eliminating costs to HCWs are
effective interventions, particularly when combined with comprehensive
programs to increase influenza vaccination coverage. Reducing barriers
to vaccination may be particularly important in settings such as nursing
homes where many HCW salaries are low and where residents are at highest
risk for severe and fatal influenza. As professional organizations and
advisory committees emphasize the importance of recommendations for HCW
vaccination, and health care organizations implement programs to improve
influenza vaccination coverage, identifying successful strategies,
promoting large scale organizational change, and monitoring coverage all
are important.

***Influenza Burden and Program Impacts***

[5) Develop a Working Group to consider critical issues and barriers to
expanded influenza vaccination recommendations and to propose
solutions.]{.underline}

*Rationale:* The current burden of influenza related deaths and
hospitalizations, despite increased vaccine coverage over the past
decades, raises questions about program effectiveness and impact. This
has led to an evaluation of influenza prevention strategies including
the possible need to expand vaccination recommendations. Expanded
vaccination recommendations that include school-aged children, for
example, could enhance protection of older adults and those at high risk
of serious illness by decreasing transmission of disease within families
and communities. In addition, vaccine recommendations based on age
groups may be more effectively implemented than current recommendations
to vaccinate only persons with high-risk medical conditions among those
between two and 49 years of age.

U.S. vaccination recommendations are made by the Centers for Disease
Control and Prevention, based on advice from the Advisory Committee on
Immunization Practices (ACIP). In February 2004, the ACIP Influenza
Working Group began an evaluation of a possible expansion of influenza
vaccination recommendations. Expanding vaccination recommendations
raises important issues including the capability of our immunization
system to implement a broader program and achieve high vaccination
coverage, the capability of our vaccine supply system to reliably
produce the doses necessary, and the Nation's ability to finance
vaccination and achieve equitable implementation among the economically
disadvantaged. The NVAC will continue to work closely with the ACIP as
expanded influenza vaccination recommendations are considered.

Vaccine supply can be a critical barrier to expanding influenza
vaccination recommendations. Current production capacity is insufficient
to support a substantial increase in vaccine use. Continued efforts are
needed to promote expanded production capacity and diversification of
supply across more manufacturers and technologies to support increased
annual vaccination under current or expanded recommendations.

The ability to effectively deliver vaccine under expanded vaccination
recommendations also is important. One likely target for vaccination
will be school-aged children, yet this population is not targeted by
current vaccine recommendations and the ability to achieve high coverage
in this group has not been documented. Strategies for vaccination of
school aged children and adolescents need to be defined and evaluated,
both because of their importance for implementation of expanded
influenza vaccination recommendations and because many of the vaccines
currently being developed also will focus on this population. Given that
traditional vaccination delivery using needle and syringe may be
unwieldy and unpopular in school aged populations, new delivery systems
such as nasal spray or a transcutaneous patch should be assessed. The
experience gained during the introduction of the live, attenuated
influenza vaccine (*FluMist®*) into the U.S. market in 2003-2004 and the
lessons from the launch of this product should be examined.

[6) Implement systems to better understand the burden of influenza
illness in the U.S. and to better assess program impacts and vaccine
effectiveness]{.underline}.

*Rationale*: Annual influenza vaccine use in the U.S. has increased from
about 10 million doses in 1976, at the time of the swine influenza
scare, to about 80 million doses in recent years. Despite this increase,
influenza is estimated to cause an average of 36,000 deaths and over
200,000 hospitalizations each year.^1,2^ Ecological or trend studies
have suggested that increased vaccination coverage has not been
accompanied by similar increases in preventing death, even when
controlling for the aging of the U.S. population. By contrast,
epidemiological studies using other methods to evaluate the impact of
vaccine have shown significant effectiveness for disease and death
outcomes.^42^ Reconciling the differences in study results is important
in considering possible new influenza vaccine recommendations and
whether alternative vaccination strategies are needed.

The conflicting results of epidemiological studies and the need to
estimate influenza related hospitalization and death by modeling also
highlight the current inability to directly assess influenza disease
burden and measure vaccination program impacts. Efforts to characterize
the impacts of the vaccination program on influenza are hampered by
several factors: annual variations in influenza outbreaks, which make
tracking disease trends difficult; the absence of a unique clinical
influenza syndrome and lack of an etiological diagnosis in most persons
with febrile or respiratory illness; and the contribution of influenza
in exacerbating non-respiratory illnesses such as acute myocardial
infarction or congestive heart failure. While influenza surveillance
systems in the U.S. have been developed to monitor annual spread,
causative strains, and location and timing of an outbreak, directly
assessing disease burden, program impacts, and annual vaccine
effectiveness have not been primary objectives.

New sentinel surveillance systems should be implemented to help fill
this gap. One approach is to directly measure hospitalizations from
influenza disease in facilities where etiological diagnosis is enhanced,
and to link these data with vaccination rates among patients and in the
surrounding community. A pilot program using this approach in children
has been implemented in three metropolitan areas. Surveillance of
pediatric populations is particularly important as new recommendations
for universal vaccination of children between six and 23 months old were
adopted in 2004 and further expansions of the vaccination program are
being considered. Strategies to directly assess influenza disease and
program impacts also should be implemented among adults. CDC recently
has begun a project to assess vaccine effectiveness during the influenza
season based on rapid analysis of an administrative managed care
database.

***Research***

[7) Conduct a comprehensive review of the influenza research program to
identify gaps and areas for additional support.]{.underline}

*Rationale:* Scientific research leads to the development of tools that
make effective disease prevention possible. New diagnostic tests using
molecular approaches can improve surveillance and assessment of program
impacts. Genomic analysis of influenza strains identified globally and
studies of how disease spreads from animals to humans and between human
populations can provide critical information that will improve the
ability to predict what strains will emerge and should be included in
vaccines. This expanding database of genomic information should be made
available to the research community.

An improved understanding of immune mechanisms of protection against
influenza, immune response in young infants, and changes in immunity
that occur with aging can lead to development of better prevention
strategies in vulnerable populations. Improved methods to develop
vaccine reference strains and process development improvements can
increase the speed and volume of vaccine production. Development of new
vaccine delivery systems can increase the safe mass delivery of
influenza vaccine. Research on new influenza vaccines may lead to
vaccines that accelerate the immune response to the first dose, which is
important during a rapidly moving epidemic. Research to improve vaccine
immunogenicity may yield ways to provide better protection in elderly
and high risk populations or provide more long-lasting protection so
that annual vaccine no longer would be needed.

**Concluding Remarks**

A wide range of influenza disease and prevention related research is
being supported and conducted by multiple agencies in the public and
private sectors. An influenza research program review that describes
ongoing activities, defines key objectives, and identifies gaps in the
research portfolio is an important first step in strengthening the
program and providing the techniques and tools that will improve the
ability to prevent the most common and most deadly of all vaccine
preventable diseases in the United States.

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