Cost Effectiveness of Influenza Vaccination

December 1981

NTIS order #PB82-178492
Library of Congress Catalog Card Number 81-600183

For sale by the Superintendent of Documents,

U.S. Government Printing Office, Washington, D.C. 20402
Foreword

The report noted that influenza vaccine was likely to be cost effective as well.

Early in 1980, the House Interstate and Foreign Commerce Committee (now Energy

and Commerce) asked OTA to conduct a cost-effectiveness analysis of influenza vaccine and influenza immunization programs similar to that developed for pneumococcal vaccine.

The study was conducted by OTA staff using a computer model similar to that of

the pneumococcal vaccine study. A number of expert consultants assisted with the

study. Drafts of the final report were reviewed by the Health Program Advisory Committee, chaired by Dr. Sidney Lee, and by approximately 25 other individuals with expertise in economics, vaccines, or health policy (see Acknowledgments in app. F). We

are grateful for their assistance.

Director

111
OTA Health Program Advisory Committee

Sidney S. Lee, Chairma

Vice President, Michael Reese Hospital and Medical Center

Stuart H. Altman

Dean

Florence Heller School

Brandeis University

Robert M. Ball

Senior Scholar

Institute of Medicine

National Academy of Sciences

Lewis H. Butler

Health Policy Program

School of Medicine

University of California,

San Francisco

Kurt Deuschle

Professor of Community Medicine

Mount Sinai School of Medicine

Rashi Fein

Professor of the Economics

of Medicine

Center for Community Health and

Medical Care

Harvard Medical School

Melvin A. Glasser

Committee on National Health Insurance

Patricia King

Professor

Georgetown Law Center
OTA Health Program Staff

Joyce C. Lashof, Assistant Director, 0TA

Health and Life Sciences Division

H. David Banta, Health Program Manager

Michael A. Riddiough, Project Director

Jane Sisk Willems, Health Economics and Policy *

John Bell, System Analysis and Computer Modeling

Kerry Britten Kemp, Editor**

Virginia Cwalina, Administrative Assistant

Lorraine Ferris, Secretary

Nancy L. Kenney, Secretary

OTA Publishing Staff

John C. Holmes, Publishing Officer

John Bergling Kathie S. Boss Debra M. Datcher Joe Henson

● Veterans Administration Scholar.

**OTA contract personnel.
Contents

Chapter Page

I. FINDINGS, ISSUES, AND OPTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
LIST OF TABLES

Table No. Page

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

E-1.

E-2.

E-3.

E-4.

E-5.

E-6.

E-7.

E-8.

E-9.

E-10.

E-11.

E-12.

E-13.

Size of General and High-Risk Populations Vaccinated With Influenza Vaccine, 1970-71 “

Through 1977-78. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Percentage of General and High-Risk Populations Vaccinated With Influenza Vaccine, 1970-71

Through 1977-78. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .; . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Assumptions Employed in Both the Base Case and Sensitivity Analysis. . . . . . . . . . . . . . . . . . . . . . 19

Values Assigned to Uncertain Variables in the Base Case and Sensitivity Analysis. . . . . . . . . . . . . . 20

Base Case Analysis: Per Vaccination Cost Effectiveness of Annual Influenza Vaccination,

1971-72 Through 1977-78. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Base Case Analysis: Cumulative Population Costs and Health Effects of Annual Influenza

Vaccination, 1971-72 Through 1977-78. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Sensitivity Analysis: Per Vaccination Cost Effectiveness of Annual Influenza Vaccination,

1971-72 Through 1977-78. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Self-Reported Excess Work Loss Related to Medically Attended Influenza, 1971-72

Through 1977-78. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Productivity Loss Related to Self-Reported Excess Work Loss From Medically Attended

Influenza, 1971-72 Through 1977-78. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Base Case Analysis: Effects of Vaccination on Reduction in Work Loss and Productivity Loss

From Influenza, 1971-72 Through 1977-78. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Base Case Analysis: Effects of Vaccination on Reduction in Housekeeping Loss and Imputed

Productivity Loss Related to Influenza, 1971-72 Through 1977-78. . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Size and Percent of High-Risk Population 20 Years and Older Vaccinated During

Fiscal Years 1973-78. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Per Vaccination Cost-Effectiveness Ratios for Annual Influenza Vaccination Among High-Risk

Persons Compared to Ratios Among the General Population, 1971-72 Through 1977-78.. . . . . . . 29

Effect on Medicare Costs of Annual Influenza Vaccination for Persons 65 Years and Older,

1971-72 Through 1977-78. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Price per Dose of Influenza Vaccines Paid by Selected Purchasers, 1977-78 Through 1980-81. 50

Guillain-Barre Syndrome Among 1976-77 A/New Jersey Influenza Vaccines.. .,... . . . . . . . . . . 51

Excess Mortality From All Causes Reported During Influenza Epidemics, 1970-71 Through

1977-78: Used in Base Case Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Estimated (Expected) Mortality From All Causes Reported During Influenza Epidemics,

1970-71 Through 1977-78: Used in Base Case Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Excess Mortality From All Causes Reported During Influenza Epidemics, 1970-71 Through

1977-78: Used insensitivity Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Estimated (Expected) Mortality From All Causes Reported During Influenza Epidemics,

1970-71 Through 1977-78: Used in Sensitivity Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Annual Individual Mean Earnings for Full-Time, Year-Round Workers, by Age and Sex,

1977-78 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Data Relating to Pneumonia Deaths in the 1950’s, by Age Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Age-Specific Death Rates From Pneumonia in the 1950’s, by Age Group . . . . . . . . . . . . . . . . . . . . . . 56

Probabilities of Dying From Pneumonia in the 1950’s, by Age Group . . . . . . . . . . . . . . . . . . . . . . . . 57

Increased Probability of a High-Risk Person’s Being Hospitalized for Pneumonia or Influenza

During an Influenza Epidemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Average Length of Stay for a Hospital Case of Pneumonia Among Persons With One or More

High-Risk Conditions, 1976. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Disability Days Caused by Selected High-Risk Conditions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
1. ●

Findings, Issues,

and Options
Findings, Issues, and Options

Influenza is an infectious disease that affects

the population of the United States to varying

degrees almost every year. In some years, influenza occurs in epidemic proportions in all

States. In 1957-58, for example, it contributed to

approximately 70,000 excess deaths. In other

years, such as 197&71, influenza occurs very infrequently and reportedly produces no excess

deaths. During the 7-year period from 1971-72

through 1977-78, there were an estimated

127,000 influenza-related excess deaths reported

in the United States, and Americans spent over

$1 billion on influenza treatment.

The preferred method of controlling influenza

is its prevention through vaccination. Inactivated influenza vaccines have been marketed

in the United States since the 1940’s. Because the

chemical (antigenic) makeup of prevalent influenza virus(es) changes almost yearly, the composition of influenza vaccine is reevaluated annually and in most years reformulated.

The Federal Government is responsible for

conducting influenza surveillance (monitoring

influenza occurrence and mortality) and establishing standards for influenza vaccine composition, purity, safety, and efficacy. In one year,

1976-77, the Federal Government supported a

nationwide effort to immunize virtually the entire U.S. population against the so-called swine

influenza virus. In two subsequent years, the

Federal Government gave assistance to State and

local health departments to purchase and distribute influenza vaccine.

Influenza vaccine has never enjoyed widespread acceptance or demand by either the public or health professionals. In each of the years

from 1971-72 through 1977-78, only about 10

percent of the Nation’s population received in-

‘ Excc+s death> (xc ur when the (ltwervcd number (lt death~ ex -

ctwi+ the expec t(d number (~t dr.]t h+ I n .] given t i mc peri(d.

fluenza vaccine. Further, in any given year,

only about 20 percent of the high-risk population (people at greater risk of dying from influenza if they contract the disease) received influenza vaccine. (In 1976-77, however, both of

these percentages doubled. )

The effectiveness of influenza vaccination has

been examined repeatedly. Its effectiveness can

vary from year to year because of changes in the

influenza virus. On the basis of data from clinical trials, OTA estimates that the clinical efficacy or effectiveness of influenza vaccine was

about 60 percent from 1971-72 through 1977-78

(see app. B).

In 1976-77, swine flu vaccinations were associated with about 500 cases of a rare paralytic

condition called Guillain-Barre Syndrome

(GBS). A S a result, the vaccine’s safety was seriously questioned. However, since 1976-77, influenza vaccinations have proven to be quite

safe. GBS may have been an adverse reaction

(side effect) peculiar to swine flu vaccine (see

app. D).

This OTA study evaluates influenza vaccination on the basis of another criterion-cost effectiveness. In this analysis, prevention of influenza by vaccination is compared to treatment

of the disease if it occurs. Changes in health effects and medical care costs produced by influenza vaccination from 1971-72 through 1977-78

are estimated. Costs and health effects are

viewed primarily from a societal perspective, although a medicare perspective is also included.

Using data obtained from selected Government

agencies and incorporating certain assumptions,

OTA developed a computerized cost-effectiveness model to generate the following findings

concerning influenza vaccinations. Details regarding the data and methods used in the costeffectiveness analysis are described in chapter 2

and appendix E.
FINDINGS

The findings below were generated by OTA’s

cost-effectiveness model and apply to influenza vaccinations administered from 1971-72

through 1977-78.

1.

2.

3.

4.

General and Productivity Effects

The medical care costs associated with influenza vaccination in the United States during

this 7-year period totaled $808 million; for

that cost, about 150 million doses of vaccine

were given, and those vaccinations yielded

approximately 13 million years of healthy

life, for a per vaccination cost of $63 per year

of healthy life gained.

Medically attended influenza-related illness

during this 7-year period accounted for an

average of 15 million days of self-reported

work loss each year. Productivity loss associated with that work loss totaled $764 million

each year.

Influenza vaccination prevented 5 million

days of self-reported work loss and saved

$253 million in productivity loss from medically attended influenza-related illness during

this 7-year period.

Influenza vaccination prevented 3.6 million

days of self-reported housekeeping loss with

an imputed economic value of $136 million

during this 7-year period.

Cost Effectiveness for the

General Population

Vaccination of a population may result in

added years of life for some members of the

population. These members will, on average,

incur typical medical care costs during the

added years. Analysis of the costs of a vaccination program, therefore, could include these

added medical care costs. Analysts disagree on

whether such inclusion is appropriate for a costeffectiveness analysis. Thus, OTA has calculated the cost effectiveness of vaccination both

ways: by excluding such added costs, and by including them.

5. When vaccinations are administered to the

general population and the medical cure costs

incurred during additional years of life

yielded by vaccination are excluded, the agespecific costs of generating a year of healthy

life through influenza vaccination are these:

Per uaccination cost/year of

Age in 1971-72 healthy life

<3 years $258

3-14 196

15-24 181

25-44 64

45-64 23

(cost saving)

All ages $63

The cost effectiveness of influenza vaccination improves with increasing age of the vaccinee at the time of vaccination.

6. When medical care costs incurred during additional years of life yielded by vaccination

are included, the age-specific costs of generating a year of healthy life are these:

Per vaccinaiton cost/year of

Age in 1971-72 healthy life

<3 years $1,745

3-14 1,880

15-24 2,010

25-44 2,027

45-64 2,084

1,782

All ages $1,956

Cost Effectiveness for Medically

High-Risk Populations Only

7. When vaccinations are administered to the

medically high-risk population (i. e., those

most susceptible to influenza morbidity and

mortality), and medical care costs during additional years of life yielded by vaccination

are excluded, the age-specific costs of generating a year of healthy life through influenza vaccination are these:

Per uaccination cost/year of

Age in 1971-72 healthy life

15-24 years $44

25-44 23

45-64 15

(cost savings)

All ages $10
Ch. l—Findings, Issues, and Options ● 5

8

With the assumptions about treatment costs Substantial alterations in vaccine efficacy

and health effects that are used in this anal- produce directly proportional, but smaller,

ysis, vaccination of high-risk persons within a changes in the cost-effectiveness ratio. For exgiven age appears more cost effective than ample, a 30-percent increase in vaccine efvaccination of the general population (see ficacy produces about a 17-percent drop in

app. E). the cost of gaining a year of healthy life for all

When estimated medical care costs in additional years of life are included, however, the

costs of generating 1 year of healthy life

among high-risk persons are these:

Per vaccination cost year of

Age in 1971-72 healthy life

15-24 years $3,050

25-44 3,620

45-64 4,150

4,040

All ages $3,880

Factors That Affect Cost Effectiveness

9 .

●

●

●

ages combined.

For the period 1971-72 through 1977-78,

the cost of vaccination (vaccine cost plus administration fee) substantially affects the cost

effectiveness of annual influenza vaccination.

For example, at a cost of $1.55, vaccination of

a person 65 years old produces net savings in

medical care costs, while at a cost of $9.39,

that same vaccination yields a net cost of $34

for each year of healthy life gained.

Including medical care expenditures in exThree factors substantially affect the cost ef- tended years of life substantially increases the

festiveness of influenza vaccination in both cost of gaining a year of healthy life through

the general and high-risk populations: 1) vac- influenza vaccination. This variable comcine efficacy, 2) cost of vaccination, and 3) in- pletely overshadows the changes produced by

eluding medical care expenditures in extended all other variables combined in the sensitivity

years of life. analysis.

ISSUES

To what extent, if any, should the Federal

Government promote the use of influenza

vaccine? ●

What mechanisms are available to the Federal

Government to promote influenza vaccination?

For whom should influenza vaccination be

promoted?

Prior to 1976-77, the Federal Government had

not extensively promoted the use of influenza ●

vaccine. Thus, for example, it did not purchase

influenza vaccine for distribution to Federal,

State, and local public health clinics (as it did ●

selected vaccines for childhood immunizations),

Prior to 1976-77, Federal activities related to influenza vaccine included the following:

●

● establishing the formula for, and evaluating the safety and efficacy of, each year’s

vaccine (Food and Drug Administration

(FDA));

disseminating to health professionals and

medical care institutions the recommendations of the Immunization Practices Advisory Committee (ACIP)—a governmentally

financed outside advisory group that establishes nationally recognized standards for

the use of all marketed vaccines in the

United States (Centers for Disease Control

(CDC));

conducting annual surveillance of influenza

virus activity and influenza-related mortality (CDC);

occasionally mounting public educational

programs to encourage the use of influenza

vaccine by selected groups identified by

ACIP (Public Health Service (PHS)); and

attempting to develop more effective influenza vaccines (National Institutes of

Health (NIH)).
6 ● Cost Effectiveness of influenza Vaccination

In 1976-77, the Federal Government mounted

the National Influenza Immunization Program,

the so-called swine flu immunization program.

For that initiative, the Federal Government took

the following actions to help ensure that virtually every person in the United States received

the swine flu vaccine:

●

●

●

●

purchased almost the total 1976-77 influenza vaccine production from vaccine manufacturers;

indemnified vaccine manufacturers from

selected types of product liability (86,88);

launched massive public education programs to encourage the use of influenza

vaccine by most of the U.S. population;

and

strongly encouraged State and local public

health departments to participate in the National Influenza Immunization Program.

The swine flu immunization program received

much derogatory press coverage, primarily for

the following reasons:

● the targeted influenza virus—A/New Jersey/76 (Hsw1N1 )—never occurred in epidemic proportions; and

● vaccination was associated with GBS.

In spite of its problems, the swine flu program

demonstrated a Federal capability to increase

the rate of influenza vaccination throughout the

United States. During the 1976-77 season, influenza vaccination rates for all age groups combined were twice the rates from previous years.

Since 1976-77, Federal activities related to the

promotion and distribution of influenza vaccine

have been sporadic. During the years 1977-80,

the Department of Health, Education, and Welfare (HEW), now the Department of Health and

Human Services (DHHS), sponsored a series of

at least eight conferences in which the Nation’s

leading experts on several aspects of influenza

(e.g., surveillance, diagnosis, prevention, and

treatment) discussed how the Federal Government could best use its resources to detect and

control influenza (97-104). In addition, in

1978-79 and 1979-80, the Federal Government

either: 1) purchased influenza vaccine directly

from manufacturers at a fixed nationwide price

and distributed it to State and local public health

departments, or 2) provided financial assistance

to State and local health departments (for the

purchase of influenza vaccine. There was no

such Federal support in 1977-78 or 1980-81. In

1978, former HEW Secretary Joseph Califano

unsuccessfully attempted to persuade Congress

to finance a continuing federally sponsored influenza vaccination program.

At present, there is no federally financed program to influence the use of influenza vaccine.

Existing Federal policy regarding influenza vaccination appears to be laissez-faire. In the absence of Federal support, the use of influenza

vaccine is primarily determined by private sector physicians, State and local health departments, employers, and self-initiated public

demand.

The results of this OTA study indicate that influenza vaccination is a low-cost preventive

medicine intervention that yields health benefits

among all age groups. Influenza vaccination appears to be most cost effective among high-risk

populations.

In addition to generating the costs and savings

included in the cost-effectiveness calculations,

influenza vaccination improves productivity in

the economy. Using historical rates of vaccination from 1971-72 through 1977-78, OTA calculated the value of work loss prevented by influenza vaccination to be $253 million and the

value of housekeeping loss prevented to be $136

million during that 7-year period.

These results relate to decisions regarding

which groups in the population should be targeted to receive the vaccine. If work loSS a nd

housekeeping loss are taken into account, the

benefits to be gained from vaccinating adults

age 17 to 64 increase. When the economic gains

from reductions in work loss are included, and

the medical care costs incurred during extended

years of life are excluded, the cost of gaining a

year of healthy life falls to $134 for ages 17 to

24, $32 for ages 25 to 44, and $11 for ages 45 to

64.

Present ACIP recommendations for recipients

of influenza vaccination do not explicitly include

healthy working-age adults in the general population. Some employers, including Federal
Ch. 1—Findings, Issues, and Options ● 7

agencies, provide voluntary annual influenza

vaccination, usually at low cost. Vaccination

rates for working age groups are low, i.e., about

10 percent, as one would expect in light of current ACIP recommendations.

It appears that without strong Federal support, the use of influenza vaccine remains at a

level too low for society to fully reap the potential benefits—in terms of health benefits and prevention of productivity losses—of the vaccine.

For example, in the period from 1971-72 through

1977-78, approximately 70 percent of influenzarelated work loss occurred in the 25- to 64-yearold age group; yet, on the average only 10 percent of that age group received influenza vaccine

during the 1970’s.

Likewise, only about 20 percent of the medically high-risk population in the United States

receives influenza vaccine in any given year.

OPTIONS

The information contained in the findings and

issues presented above has certain implications

for the future of influenza vaccination and the

Federal role related to it. Based on the findings

and issues, the following discussions lay out

some of the implications that may follow from

various Federal actions.

If the Federal Government decides to retain its

laissez-faire approach to influenza vaccination,

then neither Congress nor DHHS would need to

enact any new programs. If funding for the Bureau of Biologics (BOB) and CDC remains a t current levels, adjusted for inflation, then the following Federal influenza activities would likely

remain intact. Influenza investigators within

DHHS could continue to meet once or twice

yearly to: 1) assess which strains of influenza

virus(es)—if any—are likely to invade the

United States and 2) formulate the subsequent

year’s vaccine makeup. BOB would continue to

evaluate the safety and efficacy of each year’s

vaccine formulation, CDC could continue its

surveillance of influenza occurrence and mortality. The availability of Federal funds to purchase, distribute, and promote the use of influenza vaccine would be quite limited unless

Congress were to specifically appropriate funds

for this use. Reductions in funding for these two

agencies could easily jeopardize current Federal

influenza-related activities.

If the Federal Government instead decides to

consistentl y promote the use of influenza vaccine for selected target populations, it could take

one or more of several actions. Three possible

options and their implications follow (the three

actions are not mutually exclusive; in fact, taking all three simultaneously would maximize the

immunization status of the population).

1. The Public Health Service (PHS), if funded

to do so, could mount a continuing national campaign to increase the awareness

of practicing health professionals, employers, labor unions, and the public about the

benefits and costs associated with influenza

vaccination among selected target populations.

It has long been stated that health care consumers have insufficient knowledge to evaluate

the use of medical technologies (4,39). Because

of their greater expertise in health matters, physicians are considered to act as patients’ agents.

Studies in the area of medical technology during

recent years have dramatically illustrated that

physicians themselves sometimes lack knowledge about appropriate technology use. Moreover, once evaluations of technology have been

performed, they are rarely disseminated in an

effective way to physicians and other users (87).

This option would promote the dissemination

of information concerning the economic and

health benefits of influenza vaccination. Potential users of the information include physicians,

consumers, employers, labor unions, and thirdparty payers. Each of these groups would have

an interest in knowing the effects of vaccination

on health benefits, medical care costs, and productivity losses.

The dissemination of information about medical technologies is a legislated function of the
8 . Cost Effectiveness of Influenza Vaccination

National Center for Health Care Technology

(NCHCT). NCHCT has arranged for certain information to be published in major medical

journals. In addition, a subcommittee of its National Advisory Council is considering the generic issue of dissemination of medical technology information.

Other areas of PHS are also concerned with

vaccination information. CDC and its ACIP, as

well as the Office of Health Promotion and Disease prevention, could undertake special information dissemination efforts.

This option is consistent with the perceived

need by providers, consumers, and others for

better information about the appropriate use of

preventive technologies. Information could be

provided to groups within the private sector

who could then take whatever action they considered appropriate. This approach does not involve Federal financing of influenza vaccination, although it would be compatible with doing so (see below). An assumption behind the

strategy of disseminating information is that potential vaccine users in the private sector have

incomplete information about influenza vaccination and will act themselves on better information.

If the private sector does not accept the responsibility of using information about influenza vaccination, then any Federal effort to disseminate information would not by itself be

likely to alter existing influenza vaccination

rates. A 1979 study commissioned by CDC, for

example, illustrated that although most physicians are aware that certain groups of high-risk

patients should receive influenza vaccine each

year, they do not routinely administer it to such

groups (90). In that study, 92 percent of 1,000

participating physicians believed that annual influenza vaccinations are necessary for persons

with chronic diseases and the elderly. Yet, those

same physicians reportedly administered influenza vaccine to only 54 percent of their elderly

patients with chronic disease and to only onethird of their elderly patients without chronic

illness. If validated by results from other studies,

these data indicate that educational efforts may

need to be combined with other incentives to

promote influenza vaccinations.

The Federal Government could expand the

scope of its traditional influenza vaccination

strategies by encouraging vaccination of all persons in the work force, not just those with highrisk medical conditions. OTA estimates that influenza caused a productivity loss of approximately $764 million each year from 1971-72

through 1977-78. The Federal Government

could encourage employers to help prevent such

productivity losses by creating work site immunization programs, educating employees about

the benefits of immunization, or reimbursing

employers for incurred costs associated with immunization.

2. Congress could authorize and appropriate

Federal support for a continuing (annual)

publicly assisted nationwide influenza immunization program analogous to federally

supported childhood immunization efforts.

There are four potentially beneficial implications of such an influenza immunization program. First, if the Federal Government negotiated a vaccine selling price with manufacturers

that applied to public sector sales nationwide (as

it did in 1979-80), then vaccination costs would

likely be lower than private sector costs.

Second, by using participating State and local

public health clinics, the Federal Government

would have a readily accessible and experienced

network for distributing vaccine and information to health professionals. In general, when

the Federal Government finances the purchasing

and distribution of a vaccine, the rate of use for

that vaccine is higher than when its use is determined solely by the private sector. Third, by

controlling the public sector distribution of influenza vaccine, the Federal Government could

conceivably improve its capability to monitor

the occurrence of vaccine side effects. Fourth,

supplying the vaccine would probably encourage physicians to provide it to their patients.

There are two possible disadvantages of such

a program. First, if public clinics were relied on

too heavily for influenza vaccine distribution,

such a program could provide disincentives for
Ch. 1—Findings, issues, and Options ● 9

private sector physicians to administer influenza

vaccine. Private sector physicians could send

their patients to public health clinics for their

“flu shots” and interrupt their patients’ normal

pattern of receiving medical care. Second, the

adoption of this program would raise the issue

of Federal liability for adverse vaccine reactions

under certain conditions.

As to the first disadvantage, CDC believes, as

a result of its experiences with childhood immunization programs, that public immunization

programs do not significantly disrupt patients’

patterns of health care (26). About 50 percent of

all children still receive their immunizations

from private physicians.

The second potential disadvantage may be

more serious. At present, when the Federal Government purchases and distributes a vaccine, it

assumes from the vaccine manufacturers the responsibility of warning potential vaccinees

about the inherent risks of vaccination, i.e.,

rare, unpreventable, adverse reactions. The

Federal Government in turn passes this responsibility on to State and local government agencies that accept and administer federally purchased vaccines. The legality of such contractual

transfers of responsibility has not been tested in

court; as a result, the Federal Government’s liability for adverse reactions that occur in public

immunization programs is unclear. This issue

has been discussed at length in two prior OTA

reports (86,88).

3. Congress could amend the Social Security

Act of 1965 to authorize medicare to pay

for influenza vaccination.

Until recently, Title XVIII of the Social Security Act explicitly prohibited medicare reimbursement for all preventive vaccinations (42 USC

1395(y)). On December 28, 1980, President

Carter signed Public Law 96-611, which authorized medicare payment for vaccinations to prevent pneumococcal pneumonia. At present,

medicare pays for the treatment of influenza,

but not for its prevention through vaccination.

Adoption of this option by itself would affect

only about 45 percent of the population over 20

years old that is at high risk of being seriously

afflicted by influenza. Approximately 55 percent of this high-risk population is between 20

and 65 years old.

The impact of reimbursement on medicare

beneficiaries’ demand for influenza vaccination

is difficult to project. The effect of third-party

coverage on the use of preventive services is not

clear. To date, results of such analyses have

been conflicting (41,108). Consumers’ demand

for vaccines can also be influenced by their attitudes regarding personal susceptibility to disease, likelihood of disease occurring locally, and

vaccine safety and efficacy (86).

It is possible that medicare payment for vaccination would not increase the total number of

vaccine recipients among persons over age 65.

Payment could simply transfer the cost of vaccination to medicare from those who currently

pay for influenza vaccinations among the elderly (e.g., State and local health departments,

employers, individual consumers, and in some

years, CDC).

In a 1979 study commissioned by CDC, 4 3

percent of 1,000 participating physicians believed that more patients would receive influenza vaccination if it were covered by medicare

or medicaid (90).

Congress could amend the medicare law to

permit reimbursement for influenza vaccination

by using the same provision regarding pneumococcal vaccination in Public Law 96-611. Alternatively, Congress could approach the reimbursement of influenza vaccination with a

broader perspective and could establish criteria

for preventive health services to be included in

the medicare benefit package. Examples of such

criteria include:

● services/ technologies that help prevent disease that particularly affect the elderly; and

 services/technologies that have proven safe

and efficacious, and possibly cost effective,

when used by individuals 65 years and

older.

Special payment mechanisms, for example,

waiver of copayment (deductibles and coinsurance) requirements, could be used to encourage beneficiaries’ use of selected preventive

health services, especially low-cost items such as

vaccinations.

84-329 0 - 81 - 3
In this analysis, the economics of medicare reimbursement for influenza vaccination would

be as follows:

● When the medical care costs in extended

years of life are included, each influenza

vaccination administered to a person 6 5

years or older (in the general population)

yields an additional month of healthy life

for about $60.

● When the medical care costs in extended

years of life are excluded, each influenza

vaccination administered to a person 65

years or older (in the general population)

yields an additional month of healthy life

for about $2.

In either case, influenza vaccination generates

a notable health benefit at a reasonably low cost

to the medicare program.
2.

The Cost-Effectiveness Analysis:

Data, Methods, and Results
2.

The Cost= Effectiveness Analysis;

Data, Methods, and Results

INFLUENZA

Clinical Description

Influenza is an acute infectious disease caused

by influenza viruses. A case of influenza usually

begins abruptly with fever and usually includes

frequently recurring short chills; headache; malaise; pain behind the eye; a hacking, irritating

cough; and severe muscle aches and pains (75).

The manifestations of influenza can vary widely. In up to 25 percent of influenza infections,

there is no clinical evidence of illness. However,

in some cases, the disease can rapidly progress to

overwhelming pneumonia and may cause death

within hours to days.

Other potential complications of influenza include middle ear infections (94), acute encephalopathy (inflammation of the brain) (22), Reye’s

Syndrome (a rare, potentially life-threatening

syndrome occurring in children) (61), renal failure (32), and rejection of kidney transplants

(58). Further, influenza can lead to a deterioration of an existing disease (e. g., heart disease)

that can be fatal.

The extent to which influenza leads to such

complications is not known. In general, however, those individuals with certain types of

chronic illnesses (e. g., lung, heart, or kidney disorders) and those with selected major illnesses

(e.g., certain cancers) appear to be at greatest

risk of incurring severe medical complications

including death as a result of influenza.

Diagnosis and Treatment

A case of influenza is often diagnosed on the

basis of clinical and epidemiologic information

and the laboratory-confirmed absence of bacterial infections. When presented with a case of

upper respiratory tract infection (URI), physicians may order laboratory tests (e. g., a throat

culture) to help rule out bacterial causes. When

bacterial causes are ruled out, on the basis of a

patient’s medical history, physical examination,

or laboratory findings, viruses are generally assumed to be the cause of infection. During an influenza epidemic, validated by surveillance data

reported by the Centers for Disease Control

(CDC) or local public health laboratories, a case

of viral URI is likely to be diagnosed as influenza. Outside of an epidemic period, e.g., during summer months, a viral URI is usually not

attributable to influenza, although such infections are often referred to as “the flu. ”

Influenza is treated largely through supportive

measures. Clinical relief is obtained by resting in

bed, drinking lots of liquids, and taking drugs

that relieve symptoms of the disease (e.g., pain

relievers, fever reducers, and decongestants).

Unless a case of influenza leads to a secondary

bacterial infection, antibiotics have no role in

treatment of influenza. However, evidence demonstrates that the drug amantadine can help prevent certain types of influenza, help reduce the

severity of a case of influenza, as well as serve as

effective treatment for influenza in some cases

(82) .

Influenza Morbidity and Mortality

CDC has recently estimated that influenza

contributed to approximately 127,000 excess

deaths during the period from 1970-71 through

1977-78 (see app. E).

13
INFLUENZA VACCINE

The preferred method of reducing the incidence, morbidity, and mortality of influenza is

by preventing the disease through vaccination.

Various forms of inactivated (killed) influenza

virus vaccines have been used for this purpose in

the United States since the 1940’s. Many factors

affect the impact of such vaccines on influenza,

including:

● vaccinees’ prior exposures to influenza

viruses and their antibody response to such

exposures;

● the efficacy and duration of immunity acquired from vaccination;

● the percentage of individuals (especially

those at high risk) vaccinated (see table 1,

table 2); and

● the degree to which the virus(es) in the vaccine matches the virus(es) causing disease.

The influenza viruses present a peculiar problem for those who formulate, develop, produce,

and distribute influenza vaccine. The extent to

which these viruses circulate varies from year to

year, and the composition of antigens (chemicals) on the virus surface changes with irregular

frequency to unpredictable new forms (27).

Within the 6 to 9 months needed to manufacture influenza vaccine, influenza viruses can

change their surface chemicals faster than vaccine manufacturers can change their product’s

formulations. As a result, in some years, the

producers and promoters of influenza vaccinations have distributed vaccines that contained

viruses that did not exactly match the circulating

influenza viruses (see app. C). However, small

changes in the circulating viruses do not appear

to have substantially altered the efficacy of the

vaccine (see app. B).

The safety of influenza vaccine became a major issue during the 1976-77 swine flu vaccination program (see app. D). Approximately 500

recipients of swine flu vaccine developed a disorder characterized by paralysis called GuillainBarre Syndrome (GBS) (112). Although there is

a strong correlation between GBS and the swine

flu vaccine, such a relationship has not been

documented between the use of other influenza

Table I.–Size of the General and High-Risk

Populations Vaccinated With influenza Vaccine,

1970-71 Through 1977-78 (by age group)

Size of

Size of general population high-risk

(in thousands) population

1-19 20-64

Year years years years Total years

1970-71 . . . . 5,319 10,374 3,399 19,092 NA

1971 -72.... 4,951 9,320 3,300 17,571 NA

1972.73 . . . . 4,050 8,608 3,210 15,868 3,316

7973-74 . . . . 4,511 8,975 3,628 17,114 3,964

1974 -75.... 3,469 10,616 4,601 18,686 5,003

1975-76 . . . . 3,426 9,055 4,621 17,102 4,764

1976.77 . . . . 4,678 30,120 8,436 43,234 10,151

1977 -78.... 3,872 11,170 5,381 20,423 5,975

Total . . . . . . 34,276 98,238 36,576 169,090 33,173

Average

(excluding

1976-77). ., 4,228 9,731 4,020 17,979 4,604

NA = not available.

SOURCE: US. /mmunization Survey, 1970-78 (124).

Table 2.—Percentage of the General and High.Risk

Populations Vaccinated With influenza Vaccine,

1970.71 Through 1977-78 (by age group)

Percent of

Percent of high-risk

general population population

Year years years years Total years

1970-71 . . . . . . . . . . 6.6% 9.80/0 17.5% 9.60/0 NA

1971-72 . . . . . . . . . . 6.8 8.6 16.5 8.7 NA

1972-73 . . . . . . . . . . 5.6 7.8 15.8 7.8 16.40/,

1973-74 . . . . . . . . . . 6.3 8.0 17.4 8.4 17.7

1974-75 . . . . . . . . . . 4.9 9.3 21.5 21.0

1975-76 . . . . . . . . . . 4.9 7.8 21.1 19.6

1976-77 . . . . . . . . . . 6.8 25.5 37.7 20.9 36.4

1977-78 . . . . . . . . . . 5.7 9.3 23.5 9.7 20.8

Average/year

(weighted) . . . . . . . 6.0% 10.9°/0 21.6% 10.3% 22.50/o

Average/year

(excluding

1976-77) . . . . . . . . . 6.09% 9.00/0 19.1 0/0 9.0 ”/0 19.3%

NA = not available.

SOURCE: U.S. Immunization Survey, 1970-78 (124)

vaccines and GBS in subsequent years, notwithstanding relatively intense surveillance of GBS

cases by CDC (66). GBS might have been an

adverse reaction peculiar to swine flu vaccine.

Aside from GBS, influenza vaccines produce

mild to moderate local reactions (e. g., pain,

swelling, and redness at the injection site) as well

as systemic reactions (e. g., fever and malaise)

and rare allergic reactions (see app. B).
Ch 2— The Cost-Effectiveness Analysis: Data, Methods, and Results ● 15

INFLUENZA VACCINATION STRATEGIES

There are three basic strategies used to prevent influenza through vaccination. Each strategy—medical risk, socioeconomic risk, school

children—is distinguished by the target population intended to be vaccinated.

Medical Risk Strategy

People with certain demographic characteristics and medical conditions are at the greatest

risk of being seriously affected (either dying or

becoming severely ill) by influenza during an

epidemic. People over 45 years of age, for example, tend to be at greater risk of dying from influenza than do those under 45. Other so-called

risk factors include selected chronic diseases

(e.g., selected ailments of the heart, lungs, and

kidney) and possibly certain types of cancer (l).

The premise of the medical risk strategy is that

those persons most vulnerable to influenza mortality and severe morbidity should be protected

through vaccination. This strategy is employed

in the United States (56,57) and has been used in

the United Kingdom (116).

Socioeconomic Risk Strategy

This strategy is designed to prevent influenza

among those persons who are deemed to be esCOST-EFFECTIVENESS ANALYSIS

In this cost-effectiveness analysis, influenza

vaccination is compared to treatment of the disease if it occurred. Changes in health effects and

medical care costs produced by influenza vaccination during 1971-72 through 1977-78 were estimated. The analysis is limited to events within

the medical care sector. Quantification of health

effects and costs was based on data relating to

the morbidity, mortality, and medical care costs

associated with influenza and on data relating to

the safety, effectiveness, use, and cost of influenza vaccine. Costs incorporate both medical

sential to either the social or economic life of a

country or community. This strategy targets in

general the working population, and in particular, persons in selected occupations such as

health professionals, armed forces personnel,

and certain public servants (e. g., police ,

firemen, and postal workers). In the United

States, this strategy has been combined to a

minor extent with the medical risk strategy.

School Children Strategy

This strategy is designed to vaccinate school

children as the primary method of preventing influenza epidemics. It is based on the premise that

school-age children comprise a large, susceptible

segment of the population and regularly have a

high influenza-attack rate (52,74). School children also appear to be responsible for bringing

influenza into the home, and therefore are important disseminators of influenza viruses

(6,20,73).

The Government of Japan has sponsored a national program for immunizing school children

as a public health measure for more than 15

years (28).

care expenditures and savings. Effects consist of

changes in years of healthy life.

Costs and health effects are viewed primarily

from a societal perspective, which includes all

medical care costs and health effects, regardless

of who paid for them. They are viewed in a later

section from the perspective of the medicare program.

In addition, the effects of vaccination on influenza-related work, school, and housekeeping

losses were calculated separately.
16 ● Cost Effectiveness of Influenza Vaccination

MEASUREMENT OF HEALTH EFFECTS AND MEDICAL CARE COSTS

ASSOCIATED WITH INFLUENZA VACCINATION

Simulating the Effects of Influenza

Vaccinations for Years 1971-72

Through 1977=78

OTA constructed a computerized simulation

model that quantified the health effects and

medical care costs associated with influenza for

years 1971-72 through 1977-78. The health effects of influenza measured were:

. restricted activity:

—bed disability days,

—nonbed disability days; and

● premature deaths.

The primary factors calculated to determine

the health effects associated with influenza vaccine

●

●

●

●

were:

mortality from influenza;

morbidity from influenza;

vaccine effectiveness rate; and

incidence of vaccine side effects.

The medical care costs measured were:

● hospitalization expenditures;

● expenditures for ambulatory cases (including physician visits, ancillary services, and

drugs);

. vaccination costs (including treatment of

vaccine side effects); and

 costs of treating GBS associated with vaccination.

In determining the effects and costs associated

with influenza, it was assumed that excess morbidity and mortality occurred only in the unprotected (i.e., unvaccinated plus the not effectively

vaccinated) portion of the population. Higher

than average morbidity and mortality rates were

estimated for the unprotected population, but

the overall average values for the entire general

population were not altered from those observed

each year.

The changes in health effects and medical care

costs were then calculated between two closed

populations: one vaccinated and the other unvaccinated. Cost-effectiveness ratios based on

these changes were developed for each epidemiologic year (July l-June 30), for an average year,

and for all 7 years combined.

Quantifying Morbidity and Mortality

Related to Influenza

Quantifying the degree of morbidity and mortality caused by influenza is a difficult task, primarily because influenza is seldom diagnosed

definitively in routine medical practice. Over

100 types of viruses have been associated with

URI. At least for the last 4 years, in a given geographical location, there have been either none,

one (influenza A (H1N1 or H3N2) or influenza

B), or a combination of these viruses causing influenza. Diagnostic technologies are either not

available or not commonly used in general medical practice to differentiate which virus is causing a person’s URI. It is common medical practice to differentiate between certain bacterial and

viral infections, but not to differentiate among

viral URIS. Techniques currently available to

diagnose influenza (e.g., isolating influenza

viruses from nasal secretions or measuring

serum antibodies to influenza viruses) are usually reserved for research and” surveillance purposes, such as the reporting of influenza viruses

by certain laboratories to CDC.

Because of the lack of definitive diagnostic

criteria, influenza, as reported in surveys of

physicians and the lay public, can become a

“catch-all” term used to identify several types of

viral URIS. In the absence of clinical diagnostic

criteria, physicians often base their diagnosis of

influenza on indirect evidence. For example, a

person’s URI may be diagnosed as influenza

when the following situations exist:

●

●

URI occurs during an influenza epidemic

validated by CDC’s influenza surveillance

system;

the patient exhibits influenza-like symptoms, e.g., fever and generalized muscle

aches; and
Ch. 2—The Cost-Effectiveness Analysis: Data Methods, and Results ● 17

. a bacteria] infection has definitely been

ruled out by laboratory findings or clinical

diagnosis.

To attribute morbidity to influenza, OTA

used a technique developed by Kavet (55). OTA

selected 1970-71 to serve as a nonepidemic influenza year—i.e., a year in which there was no

influenza epidemic, were few reports of either

influenza A or B viruses in circulation, and was

no excess mortality attributed to influenza. During that year, however, influenza was reported

as a cause of morbidity in surveys conducted by

the National Center for Health Statistics

(NCHS). OTA subtracted all influenza and

pneumonia morbidity (measured in terms of

hospitalization, physician visits, days of disability, work loss, and school loss) reported in

1970-71 from each of the following years, i.e.,

1971-72 through 1977-78 (see app. E). The

amount of excess morbidity remaining was attributed to influenza.

OTA selected influenza (ICDA codes’

470-474) and pneumonia (ICDA codes 480-486)

combined as the primary diagnostic category by

which to measure morbidity. Most illness attributed to influenza during an epidemic would be

reported in these two diagnostic categories by

physicians, hospitals, and patients. Because influenza leads to increases in pneumonia rates,

data concerning the two illnesses are difficult to

separate.

Mortality was measured in “excess deaths”

due to all causes as calculated by CDC. Excess

deaths are calculated by subtracting “estimated”

or “expected” mortality from observed mortality

during an influenza epidemic period (see app. E).

Health Effects

Changes in health effects from influenza vaccination are expressed in years of healthy life,2

an index that incorporates days of illness and

‘Eighth Revision, International Classification of Disease.

2The entity “years of healthy life” has been used for over a decade by several researchers, including Bush and associates (16,18,

19,54), Zeckhauser and Shephard (127), and Weinstein and Stason

(126).

days of death related to influenza and to side effects of influenza vaccine. Different disability

states are assigned rankings in terms of their

relationship to the extremes of full functioning,

on the one hand, and death, on the other. For

example, on a scale where a year of full functioning is 1 and a year of death is O, a year with a

minor health problem might rank as 0.9, and a

year with a major health problem might rank as

only 0.2. Rankings of different degrees of health

can be thought of as representing preferences

between more years of unhealthy life and fewer

years of healthy life (86).

For purposes of this analysis, degrees of health

were divided into four categories: death, disability days with confinement to bed, disability days

without confinement to bed, and full functioning. Weighings for these different states were

drawn from an analysis by Kaplan, Bush, and

Berry: O for a year of death, 0.4 for a year of bed

disability, 0.6 for a year of nonbed disability,

and 1.0 for a year of full functioning (54).

This scale of weights was applied to years of

life at whatever age changes in health status

might be expected to occur. Thus, a year of

health or life gained by a 5-year-old was

weighted the same as a year gained by a 65-yearold. This simplifying assumption was made

despite the fact that individuals and society may

well value years of extra health or life differently

depending on the age at which the additional

years occur.

Medical Care Costs

In this analysis, costs, expressed in 197 8

dollars, measure changes in medical care expenditures that likely resulted from influenza

vaccination. Included as costs are increases or

decreases in the medical expenditures incurred

by all payers—patients, private third-party payers, and governments—for the treatment of influenza, the cost of influenza vaccine, the treatment of vaccine side effects, and (in the sensitivity analysis) total medical care expenditures in

extended years of life yielded by influenza vaccination (see app. E).
18 . Cost Effectiveness of Influenza Vaccination

Health Effects and Medical Care Costs

Over Time

Influenza vaccination not only affects illness

and medical costs related to influenza, but also

has implications for other health effects and

medical costs over time. Some vaccinees, for example, avoid death from influenza and gain extended years of life. These added years, adjusted

for disability, are included in this model, as

described previously.

The health benefits gained—added years of

life and reduced disability—have implications

that reach beyond the medical care sector, but

such implications are not included in this

analysis. Added years of life, for example, may

imply increased production and income as employed survivors continue their occupations, or

increased social welfare as survivors continue

their personal and family relationships. The

cost-effectiveness ratios do not include such effects because they lie outside the medical care

sector. Some productivity changes are calculated separately.

Another implication for a person who gains

extended years of life is that the person will incur

substantial medical expenses in each additional

year. As secondary effects of vaccination, medical care costs in extended years of life do not

appear in the base case because including one

secondary and costly financial effect of vaccination, while excluding other secondary and beneficial financial effects, such as improvements in

production, could be confusing. For example, in

1978, a person age 65 or older had average medical expenditures of about $2,000. If medical

care costs in extended years of life were included

in the cost-effectiveness analysis, the addition of

an extra year to that person’s life would worsen

(increase) the cost-effectiveness ratio by increasing annual medical care costs by $2,000. T h e

sensitivity analysis shows the effect of including

these medical costs. Some previous cost-effectiveness studies have included medical costs in

extended years of life (86,126).

All health effects and medical care costs were

discounted in the base case using a S-percent rate

(see app. E.)

Work, Housekeeping, and School Loss

Days lost from work, housekeeping, and

school because of influenza were calculated.

These three measures of influenza morbidity

were not included in the cost-effectiveness analysis of influenza vaccination; however, the impacts of influenza vaccination on these measures

were calculated separately. These lost days are

already included as disability days in the costeffectiveness model. A 1978 dollar value was

assigned to work and housekeeping losses (see

app. E).

COST-EFFECTIVENESS EQUATION AND

Cost-effectiveness ratios (C/E) for influenza

vaccination, expressing the net medical expenditure per year of healthy life gained by vaccina-

@ tion, were computed with the following model:3

Em

net medical costs = c = (Cp - ct + Cse + c,) Ese

net health effects E (El Y + Em – Ese – E,) E,

C p 

=

Expenditure for vaccination

Ct = Saving in costs of treating influenza

vaccination among vaccinees whose lives are

prolonged as a result of vaccination (in sensitivity analysis only)

Increased years of life from vaccination

Increased health from preventing influenza morbidity

Reduced health from vaccine side effects

Reduced health from future illness not prevented

by vaccination among vaccinees whose lives are

prolonged as a result of vaccination.

Cse = Cost of treating vaccine side effects Separate cost-effectiveness ratios were calcuC, = Cost of treating future illnesses not prevented by lated for vaccinating people in each of six different age groups: under 3, 3 to 14, 15 to 24, 25 to

‘The model used in this analysis is similar to that used by Weins- 44, 45 to 64, and 65 years and older. The model tein and Stason in their analysis of a hypertension treatment program. One difference is that the term Ei has been added to account is applied to high-risk groups in a subsequent

for illnesses in extended years of life (see 126). section of this chapter.
Ch. 2— The Cost-Effectiveness Analysis: Data, Methods, and Results ● 19

BASE CASE AND SENSITIVITY ANALYSIS

In the base case, values assigned to all vari- Assumptions used in both the base case and

ables were based on the best estimates available. the sensitivity analysis are listed in table 3.

A sensitivity analysis was used to test the impor- Values altered for the following variables in the

tance of values assigned to selected variables and sensitivity analysis are displayed in table 4:

hence to identify those variables that significantly affect the cost-effectiveness ratio of influenza

●

●

vaccination. The sensitivity analysis is partic- ●

ularly useful in determining the importance of ●

those variables for which data are uncertain or ●

missing. The sensitivity analysis is also helpful in

identifying important topics for future biomedical research and policy analysis.

cost of vaccination,

vaccine efficacy rate,

discount rate,

excess deaths, and

medical care costs for treatment of illnesses

(other than influenza) in extended years of

life.

Table 3.—Assumptions Employed in Both the Base Case and Sensitivity Analysis

1, Duration of immunity from vaccination was 1 year.

2. An ambulatory case of influenza-related illness consisted of 1.10 to 3.66 physician office

visits (depending on patient’s sex and age); during each visit, 0.16 clinical lab test, 0.17

X-ray, and 0.75 prescription were ordered. The total cost per ambulatory case ranged from

$23.38 to $51.60 (depending on patient’s sex and age). (See app. E.)

3. For persons 65 years and older, medicare paid for 55.6 percent of all physician charges,

74.6 percent of all hospital expenditures, and 44.1 percent of all medical care expenditures

(37, 24).

4. A hospitalized case of influenza-related illness consisted of 3.92 to 12.5 days of hospitalization (depending on patient’s sex and age and year of illness), one initial comprehensive

physician visit, and subsequent daily routine followup brief hospital visits. The cost of a

hospital case ranged from $657 to $2,031 (depending on patient’s sex and age).(See app.E.)

5. The incidence of adverse reactions other than Guillain-Barre Syndrome (GBS) was as

follows: (See app. D and E.)

● Local or mild systemic reactions which resulted in a physician visit (at $10.36/visit):

— 5 percent of vaccinees 18 years and over,

— 13 percent of vaccinees under 18 years;

● Severe systemic allergic reaction (anaphylaxis) (at $725/case):

— 1 case per 4 million vaccinees.

6. Guillain-Barre Syndrome (GBS) occurred as a statistically significant side effect of influenza vaccination only in 1976-77. The effects of GBS were quantified according to data

generated from 1976-77 and 1977-78. (See app. D and E.)

7. A day of nonbed disability was weighted at 0.6 and a day of bed disability was weighted at

0.4 (54).

8. The vast majority of treated influenza was reported to the National Center for Health

Statistics as either influenza (ICDA codes 470-474) or pneumonia (ICDA codes 480-486) (unduplicated, all listed diagnoses).

SOURCE: Off Ice of Technology Assessment
20 ● Cost Effectiveness of lnfluenza Vacccination

Table 4.—Values Assigned to Uncertain Variables in the Base Case and

Sensitivity Analysisa

Sensitivity analysis

Base case

Variable value Low value High value

Cost of vaccination:

$6.00

$11.09

Vaccine efficacy rate , . . . . . . . . 600/0

Discount rate . . . . . . . . . . . . . . . . 5%

Excess deaths . . . . . . . . . . . . . . . Excess deaths

calculated by CDC

Medical care costs for

treatment of illnesses not

prevented in extended

years of life . . . . . . . . . . . . . . . Not included

$1.55 $9.39

$4.50 $19.60

30 ”/0 90 ”/0

o —

Based on excess —

deaths calculated by NIH

(Ailing, et al.)

Included

aFor explanations of the data sources, calculations, and assumptions used to derive these values, see aPP. E

SOURCE: Office of Technology Assessment.

RESULTS

Most of the results are presented as “per vaccination. ” Costs and effects per vaccination are

not affected by the number of people vaccinated. This relationship reflects the following

two

●

●

assumptions made in the analysis.

The price of vaccination is not changed by

the number of vaccinees.

Vaccination rates during the period 1971-72

through 1977-78 were below those necessary for unvaccinated people to derive herd

immunity from vaccinees.

Base Case

Cost-effectiveness ratios for influenza Vaccination, derived using base case assumptions, are

represented in table 5. With base case assumptions (see table 4), influenza vaccination would

result in a net improvement in health for vacciTable 5.—Base Case Analysis: Per Vaccination Cost Effectiveness of Annual

Influenza Vaccination,1971 -72 Through 1977-78a

(by age groupb)

Under 3-14 15-24 25-44 45-64

3 years years years years years years All ages

Per vaccination costs

and health effects of

vaccination

Net cost . . . . . . . . . . . . . . . . $ 10 $ 11 $ 8 $ 5 $ 3 —c —d

Net health effect

(days of healthy life

gained). . . . . . . . . . . . . . . 15 days 20 days 17 days 30 days 49 days 28 days —d

Cost-effectiveness

ratio

(cost per year of

healthy life) . . . . . . . . . . . $258/ $196/ $181/ $64/ $231 —c $63/

year of year of year of year of

healthy healthy

year of year of

healthy healthy healthy healthy

life life life life life life

aAverage ~05t.effectivene55 ratio5 per vaccination are based on data from years 1970-71 throu9h 1977.78; the impact$ of

annual vaccination from 1971-72 through 1977-78 were calculated over the lifetimes of vaccinees.

bAge5 a5 of Ig71.72, Vaccinated and unvaccinated populations were followed as a cohort over time.

Cln these instances, vaccination resulted in negative costs — or savings. However, because they can be misleading, such

savings are not displayed.

dper Vaccination net co5t5 and net health effects were not calculated for all ages combined.

SOURCE: Office of Technology Assessment.
Ch. 2–The Cost-Effectiveness Analysis: Data, Methods, and Results ● .? I

nees of all ages, and would result in savings in

medical expenditures (associated with influenza)

for vaccinees 65 years and older.

In general, the cost-effectiveness of influenza

vaccination, expressed in net medical costs (or

savings) per year of healthy life gained, improves with increasing age of the vaccinee at the

time of vaccination. Net medical cost per year of

healthy life gained for a vaccinee under 3 years

old is about $258. This ratio drops to $196 for

ages 3 to 14, $181 for ages 15 to 24, $64 for ages

25 to 44, and $23 for ages 45 to 64. For vaccinees

aged 65 years and older, vaccination produces a

net savings. The net cost per vaccination ranges

from a high of about $11 for vaccinees aged 3 to

14 years to an actual savings for vaccinees over

65 years. The gain in net health effects ranges

from a low of 15 days of healthy life for vaccinees aged less than 3 to a high of 49 days of

healthy life for vaccinees aged 45 to 64.

For all ages combined, the overall cost-effectiveness ratio per vaccination is about $63 per

year of healthy life gained. This overall ratio

illustrates by contrast the difference in the cost

effectiveness of a vaccination program that can

be achieved by targeting vaccination to specific

subgroups of the population—namely, the lower

cost-effectiveness ratio for vaccinating the elderly (a net savings per year of healthy life gained)

and the higher cost-effectiveness ratio for vaccinating the very young ($258 per year of

healthy life gained among vaccinees less than 3).

It should be noted that even the highest ratio,

i.e., $258, is a very low price to pay for a year of

healthy life.

Even when a program is not actually cost saving, it may be deemed cost effective. The determination that a program or intervention is cost

effective is a value judgment that can be made

by either an individual or by society at large. A

majority of people would be willing to pay

something to gain a year of healthy life, and

there exists a consensus that most people would

willingly spend several thousand dollars for each

healthy year gained (126). In terms of their

economic efficiency, alternative programs or interventions with low cost-effectiveness ratios

might be more easily justified than those with

high ratios (e.g., those costing over $50,000 p e r

year of healthy life gained) (126).

Net costs and effects of influenza vaccination

for the total population are shown in table 6 .

Total population costs and effects depend on the

number of people vaccinated. The results shown

in table 6 are based on actual influenza vaccination rates from years 1971-72 through 1977-78

(124). Influenza vaccination generally is targeted

to high-risk people (see app. E) and generally

confers protection for a single year.

The numbers in table 6 demonstrate the degree to which per vaccination costs and health

effects of an influenza vaccination program are

magnified when considered for the population as

a whole. Results in table 6 are based on the agespecific vaccination rates shown in tables 1 and

2.

For all ages combined, influenza vaccinations

administered between 1971-72 and 1977-78 generated net medical costs (associated with influenza vaccination and medical treatment) totaling

$808 million and yielded a net gain of 12.9 million years of healthy life.

Sensitivity Analysis

The importance of five variables in the costeffectiveness model is shown by the results of the

sensitivity analysis in table 7. Except for the

“best case” and “worst case” analyses, the values

of the five variables were altered one at a time;

the variables that were not being tested were assigned their base case values. In the “best case”

and “worst case” analyses, the values of four

variables, (i. e., vaccine efficacy rate, vaccination costs, medical costs in extended years of

life, and influenza mortality rates) were altered

simultaneously. In both analyses, the discount

rate remained at the base case value of 5 percent.

An influential variable for the cost-effectiveness ratio is the cost of vaccination (see table 7).

The cost per dose used in the base case was $6.00

for vaccinees age 25 and older and $11.09 for

vaccinees under age 25 (see app. E). These costs

represent the estimates of vaccination costs

when influenza vaccine was administered in the
Table 6.—Base Case Analysis: Cumulative Population Costs and Health Effects of Annual Influenza Vaccination,

1971.72 Through 1977-78a (by age groupb)

Under 3-14 15-24 25-44 45-64

3 years years years years years years All ages

Population costs

and health effects

of vaccination

Net costs . . . . . . . . . . . . . . . . . . $41,800,000

Net health effects

$205,300,000 $229,400,000 $200,600,000 $112,600,000 –C $807,800,000

(years of healthy life

gained) . . . . . . . . . . . . . . . . . . 160,000 1,000,000 1,300,000 3,100,000 4,800,000 2,000,000 12,900,000

years years years years years years years

Coat-effectiveness

ratio

(cost per year of healthy

life) . . . . . . . . . . . . . . . . . . . . . $258/ $196/ $181/ $64/ $23/ —c

year of

$63/

year of year of year of year of year of

healthy life healthy life healthy life healthy life healthy life healthy life

aThe Population costs and effects of annual influenza vaccination were calculated based on the age-specific vaccination ratea reported for years 1971-72 throu9h

1977-78 in the U.S. /rrrrnun/zat/orr Survey (see table 2, app. E) (124). It was assumed there would be no economies of SCale In costs and no herd immunity

bAges as of 1971.72, Vaccinated and unvaccinated populations were followed as a cohort Over time.

cln these instances, vaccination resulted in negative COStS — or Savin9S

SOURCE: Office of Technology Assessment.

private sector. Using lower vaccination costs

—i. e., $1.55 for vaccinees age 25 and older and

$4.50 for vaccinees under age 25 (low public sector estimates), improves the cost effectiveness of

vaccination for every age group. Using higher

private sector vaccination cost estimates—i.e.,

$9.39 for vaccinees age 25 and older and $19.60

for those under age 25—however, reduces the

cost effectiveness of vaccination for every age

group; and among vaccinees aged 65 and older,

vaccination generates a small net cost.

The variable with the most profound impact

on the cost effectiveness of influenza vaccination

is the inclusion of medical care costs in extended

years of life (see table 7, app. E). These medical

care costs are incurred by people whose lives are

saved as a result of influenza vaccination. Such

costs were left out of the base case for conceptual reasons. When such costs are included,

the y completely overshadow the importance of

changes in all other variables combined in the

sensitivity analysis. Their inclusion elevates the

cost of gaining a year of life to a minimum of

$1,745 (age group less than 3 years) to a maximum of $2,084 (age group 45 to 64). For all ages

combined, the cost of gaining a year of life

becomes $1,956.

When no discount rate is used, the costeffectiveness ratios improve for vaccinees of all

ages.

Altering the vaccine efficacy rate had minimal

effect on the cost-effectiveness ratios for any age

group (see table 7). Among vaccinees over age

65, influenza vaccination generated medical care

savings when the vaccine efficac y rate was

varied between 30 percent and 60 percent.

The use of excess influenza death estimates

generated by Ailing and associates at the National Institute of Allergy and Infectious Diseases (2), instead of those estimates calculated

by Chow and Thacker at CDC had virtually n o

effect on the cost-effectiveness ratio for all ages

combined (see table 7). Vaccination still yielded

net savings in costs per year of healthy life (associated with influenza vaccination and medical

treatment) for vaccinees aged 65 and over. The

cost of gaining a year of healthy life was somewhat less among younger age groups, because of

the allocation of excess influenza deaths to the

lower age groups.

In the “best case” analysis—i.e., lowest vaccination cost, highest vaccine efficacy rate, exclusion of medical care costs in extended years of

life, and NIH mortality rates—the overall cost of

gaining a year of healthy life for all ages combined is $1.00. Under these conditions, influenza

vaccination yields cost savings for age groups 45

and older,

In the “worst case” analysis—i.e., highest vaccination cost, lowest vaccine efficacy rate, inclusion of medical care costs in extended years of
Ch. 2– The Cost-Effectiveness Analysis: Data, Methods, and Results . 23

life, and CDC mortality rates—the overall cost enza vaccination does not yield cost savings for

of gaining a year of healthy life for all ages com- any age group.

bined is $2,018. Under these conditions, influtable 7.—Sensitivity Analysis: Per Vaccination Cost Effectiveness of Annual Influenza Vaccination, 1971-72

Through 1977-78

Per vaccination cost per year of healthy life by age groupa, 

c

Under 3-14 15-24 25-44 45-64 All

Variable Assigned valuesb

3 years years years years years years ages

cost of Public sector - Low

vaccination

Vaccinees < age 25-$1.55 $ 118 $ 90 $ 73 $ 18 –d –d

● private sector - Low

$ 11

Vaccinees < age 25-$6,00 $ 258 $ 196 $ 181 $ 64 $ 23 –d

$ 63

Private sector - High

Vaccinees < age 25-$9.39 $ 439 $ 332 $ 306 $ 99 $ 45 $ 34 $ 1 1 2

Vaccine 30 percent. . . . . . . . . . . . . . . . . . $ 262 $ 198 $ 183 $ 66 $ 33 $ 7 4 $ 74

efficacy ● 60 percent. . . . . . . . . . . . . . . . . . $ 258 $ 196 $ 181 $ 64 $ 23 $ 63

rate 90 percent. . . . . . . . . . . . . . . . . . $ 253 $ 194 $ 178 $ 61 $ 14 –d

$ 52

Discount rate No discount rate . . . . . . . . . . . . $ 9 $ 9 $ 13 $ 9 $ 7 –d $ 8

applied to

costs and

effects

occurring

after 1971-72 ● 5 percent. . . . . . . . . . . . . . . . . . . $ 258 $ 196 $ 181 $ 64 $ 23 –d

$ 63

Excess NIH (Ailing, et al,). . . . . . . . . . . . $ 187 $ 146 $ 146 $ 58 $ 26 –d

$ 61

death ● CDC ... , . . . . . . . . . . . . . . . . . . . $ 258 $ 196 $ 181 $ 64 $ 23 –d

$ 63

rate

Medical care Included . . . . . . . . . . . . . . . . . . . $1,745 $1,880 $2,010 $2,027 $2,084 $1,782 $1,956

costs in

extended

years of life ● Not included. ., . . . . . . . . . . . . . $ 258 $ 196 $ 181 $ 64 $ 23 –d

$ 63

Best case —Excess deaths - NIH (Allsituation ing, et al.)

(5 percent —Vaccine efficacy rate -90

discount) percent

—Medical care costs in

extended years of life -

not included

—Vaccination costs - low

public sector . . . . . . . . . . . $ 83 $ 66 $ 57 $ 14 –d –d $ 1

Worst case —Excess deaths - CDC

situation —Vaccine efficacy rate -30

(5 percent percent

discount) —Medical care costs in

extended years of life -

included

—Vaccination costs - high

private sector . . . . . . . . . . . $1.937 $2,022 $2,143 $2,068 $2,118 $1,842 $2,018

“ Base case values aAge~ are !h~~e ,n 1971.72 vaccinated and unvaccinated populations Were followed as a cohort over time

bFor ,nformatlon regardtng the data sources and calculation of the values used In this sensltivltY analYsls, see aP!J E

cActual calculated values were rounded off to the nearest $1.00

dln these instances, Vacclnatlon resulted ,n negative Costs—or savings such Savings are not displayed, however, because they can be misleading

SOURCE Off Ice of Technology Assessment.
24 ● Cost Effectiveness of Influenza Vaccination

EFFECT OF INFLUENZA VACCINATION ON PRODUCTIVITY

An implication of illness from influenza is the ing people in the general population in order to

inability of those affected to carry on their usual reduce productivity losses (100).

major activities in the workplace, in housekeeping activities, or in school. Work days lost be- Table 8 shows self-reported medically atcause of influenza reduce productivity in the tended excess work loss from 1971-72 to

economy. In fact, often raised in policy discus- 1977-78. During this period, such work loss

sions is the question of whether or not influenza averaged 15 million days per year—7 million

vaccination should be recommended for work- days for females and 8 million for males, Almost

Table 8.—Self-Reported Excess Work Loss Related to Medically Attended

Influenza, 1971-72 Through 1977.78°

Work loss in days by age group

17-24 25-44 45-64

Year years years years years All ages

1971.72

Male . . . . . . . . . . . 566,560 2,527,748 2,513,321 1,145,913 6,753,542

Female. . . . . . . . . 1,638,361 5,979,464 3,867,125 610,412 12,095,362

Total. . . . . . . . . 2,204,921 8,507,212 6,380,446 1,756,325 18,848,904

1972.73

Male . . . . . . . . . . . 2,425,252 4,813,922 4,352,705 1,753,318 13,345,197

Female. . . . . . . . . 3,503,367 2,608,446 1,097,946 325,628 7,535,387

Total. . . . . . . . . 5,928,619 7,422,368 5,450,651 2,078,946 20,880,584

1973.74

Male . . . . . . . . . . . 1,914,235 3,105,884 530,791 1,038,803 6,589,713

Female. . . . . . . . . 1,139,066 3,874,346 0 284,252 5,297,664

Total. . . . . . . . . 3,053,301 6,980,230 530,791 1,323,055 11,887,377

1974-75

Male . . . . . . . . . . . 2,192,063 950,182 1,196,434 409,319 4,747,998

Female. . . . . . . . . 3,440,273 4,195,904 0 0 7,636,177

Total. . . . . . . . . 5,632,336 5,146,086 1,196,434 409,319 12,384,175

1975.76

Male. , . . . . . . . . . 552,808 6,693,126 1,689,008 204,613 9,139,555

Female. . . . . . . . . 3,017,422 4,645,739 2,010,055 0 9,673,216

Total. . . . . . . . . 3,570,230 11,338,865 3,699,063 204,613 18,812,771

1976-77

Male. . . . . . . . . . . 0 0 0 413,241 413,241

Female. ... , . . . . 1,942,255 4,336,791 298,460 0 6,577,506

Total. . . . . . . . . 1,942,255 4,336,791 298,460 413,241 6,990,747

1977.78

Male. . . . . . . . . . . 4,898,327 6,806,237 3,966,569 0 15,671,133

Female. . . . . . . . . 85,763 882,767 0 0 968,530

Total. . . . . . . . . 4,984,090 7,689,004 3,966,569 0 16,639,663

Average number of excess

days of work Ioss/year

Male . . . . . . . . . . . 1,792,749 3,556,728 2,035,547 709,315 8,094,340

Female. . . . . . . . . 2,109,501 3,789,065 1,039,084 174,327 7,111,977

Total. . . . . . . . . 3,902,250 7,345,793 3,074,631 883,642 15,206,317

aTheSe data Were based on unpublished work loss data related to influenza [8th Revision ICDA Codes 470-474) and

pneumonia (8th Revision ICDA Codes 480-486) supplied by the Health Interview Survey at the National Center for Health

Statistics (see app E). “Excess” work loss was derived by subtracting days of work loss (due to influenza and pneumonia) in

1970-71 from work loss (due to Influenza and pneumonia) for each subsequent year through 1977.78.

SOURCE: Office of Technology Assessment.
Ch. 2– The Cost-Effectiveness Analysis: Data, Methods, and Results .25

half of

million

44.

this work loss, an annual average of 7 Table

days, is reported by workers aged 25 to cination

fluenza

10 reports the effect that influenza vachad on reducing work loss related to infrom 1971-72 through 1977-78. With

ing to age- and sex-specific

1971-72 to 1977-78, average

lost was about $764 million.

Table 9 reports productivity lost from these vaccination rates that existed, about 5 million

work days were gained for the overall work work days. Productivity loss was valued accord- force, and these productivity gains were valued earnings (15). From at about $250 million during that 7-year period. annual Productivity

The age group from Table 11 reports comparable figures for peo25 to 44 years experienced the greatest produc- ple who reported housekeeping as their major

tivity loss in each year, an annual average of activity. The reduction in housekeeping days

almost $400 million. lost was also substantial. The gains rose with inTable 9.—Productivity Loss Related to Self-Reported Excess Work Loss From

Medically Attended Influenza, 1971-72 Through 1977-78a

Productivity loss by age group (thousands of dollars)

17-24 25-44 45-64

Year years years years years All ages

1971.72

Male . . . . . . . . . . . 22,100 174,400 183,500 68,800 448,800

Female. . . . . . . . . 49,200 236,200 150,800 18,300 454,500

Total. . . . . . . . . $71,300 $410,600 $334,300 $87,100 $ 903,300

1972.73

Male . . . . . . . . . . . 94,600 329,800 317,700 105,200 847,300

Female. . . . . . . . . 105,100 103,000 42,800 10,094 260,994

Total. . . . . . . . . $199,700 $432,800 $360,500 $115,294 $1,108,294

1973-74

Male . . . . . . . . . . . 74,700 212,800 38,700 62,300 388,500

Female. . . . . . . . . 34,200 153,000 0 8,800 196,000

Total. . . . . . . . . $108,700 $365,800 $38,700 $71,100 $ 584,500

1974-75

Male . . . . . . . . . . . 85,500 65,100 87,300 24,600 262,500

Female. . . . . . . . . 103,200 165,700 0 0 268,900

Total. . . . . . . . . $188,700 $230,800 $87,300 $24,600 $ 531,400

1975.76

Male . . . . . . . . . . . 21,600 458,500 123,300 12,300 615,700

Female. . . . . . . . . 90,500 183,500 78,400 0 352,400

Total. . . . . . . . . $112,100 $642,000 $201,700 $ 12,300 $ 968,100

1976-77

Male. . . . . . . . . . . 0 0 0 24,800 24,800

Female. . . . . . . . . 58,300 171,300 11,600 0 241,200

Total. . . . . . . . . $58,300 $171,300 $11,600 $24,800 $ 266,00 0

1977-78

Male. . . . . . . . . . . 191,000 466,200 289,600 0 946,800

Female. . . . . . . . . 2,600 34,900 0 0 37,500

Total. . . . . . . . . $193,600 $501,100 $289,600 $ 0 $ 984,300

Average income loss/year

Male . . . . . . . . . . . 69,900 243,800 148,600 42,600 504,900

Female. . . . . . . . . 63,300 149,700 40,500 5,300 258,800

Total. . . . . . . . . $133,200 $393,500 $189,100 $47,900 $ 763,700

ap~~du~tl”lt~ 10~~ ~~~ ~~l~ul~t~d by m“ltlply,ng excess days of self. reportecl work IOSS (see table 8) by age-specific dally earnings for full-time workers as reported by the Bureau of the Census (see app. E) (15)

SOURCE: Off Ice of Technology Assessment.
Table 10.—Base Case Analysis: Effects of Vaccination on Reduction in Work Loss and Productivity Loss

From Influenza, 1971-72 Through 1977-78° (by age groupb

)

3-14 15-24 25-44 45-64

years years years years Total

Per vaccination

Work days gained. . . . . . . . 0.01 0.05 0.05 0.03 0.02 –

Productivity gained. . . . . . . $ .36 $2.10 $2.60 $1.60 $1.20 –

For work force

Work days gained. . . . . . . . 198,100 1,452,000 1,922,000 945,000 576,200 5,093,300

Productivity gained. . . . . . . $6,965,000 $57,030,000 $101,000,000 $56,340,000 $31,520,000 $252,855,000

ac~ange~ in ~Ork IOSS and ~roductlvlty ICIW for the work force were based on influenza vaccination rates reported for 1971-72 through 1977-78 In the u,S /mrrrurrizat/orr

Survey (124).

bAges as of Ig71.72, Vaccinated and unvaccinated populations were followed as a cohofi over time.

SOURCE: Office of Technology Assessment.

Table 11.—Base Case Analysis: Effects of Vaccination on Reduction in

Housekeeping Loss and Imputed Productivity Loss Related to Influenza,

1971-72 Through 1977=78 (by age groupa)

3-14 15-24 25-44 45-64

years years years years Total

Per vaccination

Housekeeping days

gained. . . . . . . . . . . . . . 0.003 0.01 0.02 0,02 0.06

Imputed productivity

—

gained. . . . . . . . . . . . . . —b —b —b —b $1.86

For general population

—

Housekeeping days

gained. . . . . . . . . . . . . . 57,300 296,000 824,600 899,300 1,490,000 3,567,200

Imputed productivity

gained. . . . . . . . . . . . . . —b —b —b —b $46,190,000 $135,553,600

aAges as of Ig71.72. vaccinated and unvaccinated populations were followed as cohorts over time. Productivity loss was imputed on basis of average female earnings.

bNot imputed.

cBased on influenza vaccination rates reported for 1971-72 through 1977-78 in the U.S. //7rfr7ur7/Za(/Orr Survey (124).

SOURCE: Office of Technology Assessment.

creasing age at the time of vaccination. From Vaccination also reduced school loss. An esti1971-72 through 1977-78, housekeeping days mate based on actual vaccination rates is that

gained totaled about 3.5 million, with an im- about 780 thousand school days were gained.

puted value of about $135.5 million based on

average earnings for women.

MODIFICATION OF THE MODEL FOR THE HIGH-RISK POPULATION

Influenza vaccination is most often recom- ditions or characteristics are deemed to be at

mended for those persons with certain medical “high risk” and should receive influenza vaccinaconditions or demographic characteristics that tions annually (l):

render them at greater risk of complications if

they contract the disease. Such persons are re- ●

ferred to as the influenza “high-risk” population. ●

According to the Immunization Practices Advisory Committee, formerly the Advisory Committee on Immunization Practices, which ad- ●

vises the Federal Government on national vaccination policies, persons with the following con- ●

65 years of age or older;

selected types of acquired or congenital

heart disease;

any chronic disorder with compromised

pulmonary function;

chronic renal disease;
Ch. 2—The Cost-Effectiveness Analysis: Data, Methods, and Results ● 27

●

●

●

diabetes mellitus or other metabolic diseases

with increased susceptibility to infection;

chronic, severe anemia, such as sickle cell

disease; and

other conditions which compromise the immune mechanism, including certain malignancies and immunosuppressive therapy.

The following analysis compares the cost effectiveness of influenza vaccination among highrisk persons to the cost effectiveness of vaccination among the general population.

Size of Vaccinated High-Risk

Population

On the basis of data collected by the Bureau of

the Census, CDC estimates the size of the highrisk populations. During each year from 1972-73

through 1977-78, there were an estimated 24.5

million persons over 20 years old in the influenza high-risk population (see app. E, table 12).

Forty percent of all persons over 65 years old reportedly had one or more medical conditions

that represent an influenza risk factor (124).

Each year, an estimated 19 percent of the highrisk population (all ages combined) received influenza vaccine; during 1976-77, the year of the

swine flu program, about 36 percent of the highrisk persons were vaccinated (see app. E, table

12 for age-specific rates).

Alteration of Selected Characteristics

Describing the High-Risk Population

The values of the following variables were

altered in the cost-effectiveness analysis for influenza vaccination among high-risk persons

(see app. E):

●

●

●

●

probability of a person’s dying—from all

causes as well as from influenza or pneumonia—within a given year,

probability of a person’s either being hospitalized or visiting a physician’s office for

influenza or pneumonia,

the length-of-stay of a hospitalized influenza case and the number of physician visits

per ambulatory influenza case,

total medical care costs per person in any

extended years of life,

●

●

probability of a person’s encountering bed

or nonbed disability days from all causes

and from influenza, and

probability of a person’s receiving influenza

vaccine.

Results

With the assumptions in the base case, vaccination of high-risk groups is more cost effective at any given age than vaccination of individuals in the general population (see table

13). Vaccination of high-risk individuals 6 5

years and older is cost saving. Again, cost effectiveness improves with increasing age at the time

of vaccination. Cost per year of healthy life

gained drops from $44 for ages 15 to 24 to $15

for ages 45 to 64.

The inclusion of medical costs in extended

years of life substantially changed the results for

the high-risk population, as it did the results for

the general population. The magnitude of the

difference for the high-risk population, however, is relatively much greater. For example,

when additional medical costs are included, the

per vaccination cost per year of healthy life is

$4,040 for a high-risk person 65 years or older.

When additional medical care costs are excluded, vaccination of a high-risk person 65

years or older is cost saving. If medical care costs

in extended years of life are included, the highest

cost per year of healthy life gained occurs for a

high-risk person aged 45 to 64, i.e., $4,150.

Thus, cost per year of healthy life for a high-risk

person 45 years or older is about twice the cost

for the general population—about $4,000 compared to about $2,000, These differences stem

from the greater probability that a high-risk person will become ill and from the higher medical

costs in any extended years of life.

It is noteworthy that vaccination of high-risk

people of a certain age may be more cost effective than vaccination of an older age group in

the general population. For example, cost per

year of healthy life gained for a high-risk person

aged 15 to 24 is $44, a lower cost than the $64 for

an average-risk person aged 25 to 44. Although

these cost differences are small, they illustrate

a point that has been made about the differences

among members of a certain age group or
28 . Cost Effectiveness Of Influenza Vaccination

Table 12.—Size and Percent of High-Risk Population 20 Years and Older

Vaccinated During Fiscal Years 1973-78a (by age group)

20-29 30-39 40-49 50-64 All ages

Fiscal year years years years years years

1973

Size of high-risk population

(000’s) . . . . . . . . . . . . . . . . . . . . . . . . . 1,878 1,647 2,665 6,938 7,131 20,259

Percent of total relevant

population. . . . . . . . . . . . . . . . . . . . . 5.71% 6.970/o 11.60/0 22.60/o 35.1% 15.50/0

Percent of high-risk population

vaccinated. . . . . . . . . . . . . . . . . . . . . 10.1% 8.9 ‘/0 10.7% 16.1 ‘/0 22.2% 16.40/o

1974

Size of high-risk population

(000’s). . . . . . . . . . . . . . . . . . . . . . . . . 1,995 1,928 2,848 7,601 7,964 22,336

Percent of total relevant

population. . . . . . . . . . . . . . . . . . . . . 5.93% 7.880/o 12.4% 24.40/o 38.20/o 16.8%

Percent of high-risk population

vaccinated. . . . . . . . . . . . . . . . . . . . . 10.5% 11.0 ‘J/o 12.70/o 17.1% 23.60/o 17.70!0

Size of high-risk population

(000’s) . . . . . . . . . . . . . . . . . . . . . . . . . 2,098 2,179 3,192 8,029 8,321 23,819

Percent of total relevant

population. . . . . . . . . . . . . . . . . . . . . 6.000/0 8.690/o 14.1% 25.50/o 38.90/o 17.60/o

Percent of high-risk population

vaccinated. . . . . . . . . . . . . . . . . . . . . 10.5% 12.1% 15.0’?!0 20.0%0 29.20/o 21.0%

1976

Size of high-risk population

(000’s) . . . . . . . . . . . . . . . . . . . . ., . . . 2,222 2,260 3,183 8,108 8,549 24,322

Percent of total relevant

population. . . . . . . . . . . . . . . . . . . . . 6.1 70/0 8.760/o 14.1% 25.50/o 39.0% 17.6%

Percent of high-risk population

vaccinated. . . . . . . . . . . . . . . . . . . . . 7.40% 10.8 ‘/0 11 .80/0 1 9.0%0 28.60/o 19.60/o

1977

Size of high-risk population

(000’s) . . . . . . . . . . . . . . . . . . . . . . . . . 2,313 2,636 3,676 9,171 10,089 27,885

Percent of total relevant

population. . . . . . . . . . . . . . . . . . . . . 6.360/o 9.650/o 16.40/o 28.70/o 45.1 %0 19.80/o

Percent of high-risk population

vaccinated. . . . . . . . . . . . . . . . . . . . . 24.2 ‘/0 26.0 ‘/0 29.90/o 36.70/o 44.00/0 36.40/o

1978

Size of high-risk population

(000’s) . . . . . . . . . . . . . . . . . . . . . . . . . 2,383 2,672 3,570 9,603 10,432 28,660

Percent of total relevant

population. . . . . . . . . . . . . . . . . . . . . 6.440/o 9.380/o 15.9% 29.80/o 45.60/o 20,00/0

Percent of high-risk population

vaccinated. . . . . . . . . . . . . . . . . . . . . 10.0% 10.4% 1 4.7% 19.40!0 29.50/o 20.80/o

Total high-risk population

(000’s), fiscal years,

1973-1978 . . . . . . . . . . . . . . . . . . . . . . 12,889 15,200 19,137 49,450 52,486 147,281

Average high-risk population

per year(000’s) . . . . . . . . . . . . . . . . . 2,148 2,533 3,189 8,242 8,748 24,547

Average percent of total

population 20 years and older

considered to be high-risk . . . . . . . . 6.11 ‘/0 9.820/o 14.1% 26.1 ‘/0 40.50/0 1 7.9%0

Average percent of high-risk

population vaccinated per year . . . 12.3 0/0 12.0% 16.30/o 23.80/o 30.20/o 22.50/o

Average percent of high-risk

population vaccinated per year

excluding 1976-77 ......, . . . . . . . . 9.65% 9.11% 13.1% 20.90/o 26.90/o 19.3%

aThe high-risk population comprises persons with one or more of the following medical conditions: diabetes, selected tYPeS of iung disease, selected tYPes of head

disease.

SOURCE: U.S. /mrnurrIzat/orr Survey, 1973-78 (124).
Ch. 2–The Cost-Effectiveness Analysis: Data, Methods, and Results . 29

Table 13.—Per Vaccination Cost-Effectiveness Ratios for Annual Influenza

Vaccination Among High-Risk Persons Compared to Ratios Among the

General Population, 1971-72 Through 1977-78

Cost per year of healthy life gained by age groupa

15-24 25-44 45-64 All ages

years years years years combined

High-risk population

Base case. . . . . . . . . . . . . . . . . . $ 44 $ 23 $ 15 –b $ 10

Including medical care costs

in extended years

of life. . . . . . . . . . . . . . . . . . . . $3,050 $3,620 $4,150 $4,040 $3,880

General population

Base case. . . . . . . . . . . . . . . . . . $ 181 $ 64 $ 23 —b $ 63c

Including medical care costs

in extended years

of life. . . . . . . . . . . . . . . . . . . . $2,010 $2,027 $2,084 $1,782 $1 ,956c

aAge~ as of 1971.72 vaccinated and unvaccinated populations were followed as a cohort over time

bln these ,nstances, Vacclnatlon resulted (n savings, However, because they can be misleading, such SaVit7fJS are flOt

displayed.

CAll ageS for the general ~Opulatlon includes children < 15 yeaC3,

SOURCE: Office of Technology Assessment.

among members of the general population (114).

High-risk people may experience greater benefits

from vaccination than others, because the incidence and severity of the disease and the costs

of treating it are higher for those at high risk.

Therefore, the inclusion of high-risk people in

the general population raises the average level of

benefits to be obtained from vaccinating the general population. In fact, a non-high-risk member

of the general population would realize a lower

level of benefit and have a higher cost-effectiveness ratio than the average, which includes highrisk people.

tional years of life are included. Medical care

costs in extended years of life may be so much

greater for high-risk people that their cost per

year of healthy life gained may be greater than

the same calculation for average-risk people.

These differences in results for high-risk people and for the general population indicate that

efforts should be made to identify heterogeneity

within a population. Analyses are most valuable

that, to the extent that is feasible and manageable, take the differences in risk status into

account.

As shown in table 13, the relationship is not so

predictable when medical care costs in addiMODIFICATION OF THE MODEL FOR MEDICARE

From a societal perspective, influenza vaccination for persons 65 years or older is cost saving in the base case. Even with worst case assumptions, notably the inclusion of medical

costs in extended years of life, the net cost per

year of healthy life gained was only about

$1,800 for those 65 or older. These results for the

elderly raise the issue of medicare coverage for

influenza vaccination. The Social Security Act

now prohibits medicare payment for influenza

vaccination.

The societal model was modified to evaluate

the effect on medicare expenditures of covering

influenza vaccination. After copayments and deductibles, medicare insures about 75 percent of

the hospital costs and about 56 percent of the

physician costs for the treatment of influenza

(37). In addition, it was estimated that medicare

pays about 44 percent of medical costs in extended years of life (37). It was assumed that

medicare would pay 100 percent of vaccination

costs.
30 ● Cost Effecyiveness of Influenza Vaccination

As shown in table 14, full coverage of influenza vaccination from 1971-72 through 1977-78

would have cost medicare $791 per year of

healthy life gained by vaccinees 65 years and

older. Per vaccination costs to medicare would

have totaled $61: $6 for the original vaccination

and treatment of any side effects; a negligible

amount for treating GBS; $4 saving in reduced

influenza treatment costs; and $60 for additional

medical costs in extended years of life. A vaccination improved the health of an elderly person

by 28 additional days of healthy life. In summary, every influenza vaccination among medicare beneficiaries would have generated about 1

month of healthy life at a cost of about $60 to

the medicare program.

With the vaccination rates that existed from

1971-72 through 1977-78, coverage of influenza

vaccination by medicare for that entire period

would have cost the program about $1.6 billion

for vaccinations that yielded about 2 million

years of healthy life. Of this cost, $145 million

would have been spent for vaccinations and

treatment of their side effects, while savings

from reduced influenza treatment costs would

have been about $104 million. The additional

medical costs due to survivors’ living longer lives

would total approximately $1.5 billion and thus

represent the major costs.

Other effects of influenza vaccination on the

Social Security program were not quantified in

this analysis. Such effects would include:

Table 14.—Effect on Medicare Costs of Annual

influenza Vaccination for Persons 65 Years and

Older,” 1971-72 Through 1977-78

Per vaccination

costs Health benefits

Cost of vaccination and Days of healthy

and side effects ... ... ... ... ... .$ 6 life gained . .......28

Cost of treating GuillainBarre Syndromeb . . . . . . . . . . . . . . . —c

Reduced influenza treatment

costs . . . . . . . . . . . . . . . . . . . . . . . . . – 4

Medical costs in extended

years of life . . . . . . . . . . . . . . . . . . . . 60

Total cost . . . . . . . . . . . . . . . . . . . . .$61d

Cost/year of healthy life = $791

For population

costs Health benefits

Cost of vaccination and Years of healthy

side effects ... ... ... .$ 145,000,000 life gained . .2,003,000

Cost of treating GuiliainBarre Syndrome. . . . . . . 296,000

Reduced influenza

treatment costs. . . . . . . – 103,800,000

Medical costs in extended

years of life . . . . . . . . . . 1,541,800,000

Total costs ... ... ... . .$1,583,226,000

Cost/year of healthy life = $797

aThose persons 65 years and older in 1971-72.

bAss umes medicare pays 44 percent of total medical costs (37).

cCost is about $0.01.

d

eColumn does not sum because of rounding.

Based on vaccination rates reported for 1971-72 through 1977-78 in the US /rrrmunizaflon Survey (124).

SOURCE: Office of Technology Assessment.

●

●

increased payments to Social Security by

vaccinees remaining in the work force

longer as a result of reduced morbidity and

mortality, and

increased payments to beneficiaries resulting from people’s living longer.
Appendixes
Appendix A.— Relationship of Serum Antibody

Concentration to Incidence of Influenza Illnesses*

by Gary R. Noble, M.D.

Chief, Respiratory Virology, Bureau of Laboratories

Center for Disease Control, Atlanta, Ga.

June 5, 1980

The most instructive period for studying the relationship between immunity to influenza and levels of

antibody produced by inactivated vaccines occurs on

those rare occasions when vaccine produced from a

major new antigenic subtype of influenza A is administered to individuals before their first infection with

this new pandemic subtype, This opportunity has occurred only three times in over 40 years, i.e. in 1957

(H2N2 virus), in 1968 (H3N2 virus), and in 1978

(when H1N1 strains of influenza caused illnesses primarily among individuals born after 1957). Much

useful information also may be obtained during interpandemic periods, but primed individuals respond

better to vaccine than do unprimed subjects. The

study of artificially induced infections of human volunteers may also yield useful information, but the virus challenge may not resemble that which occurs

naturally, and thus interpretation of results is difficult.

The relationship between the concentration of influenza serum antibody and immunity to influenza

infection or illness may be influenced by a number of

variables. Serum antibody formed after a first infection with an antigenically new subtype of influenza A

may be quantitatively and qualitatively different

from antibody produced after several sequential infections with the same subtype of influenza A. The

initial infection may produce a relatively low concentration of serum antibodies, but subsequent infections may boost antibody concentrations which may

persist at measurable levels for a longer period of

time. Repeated infections with familiar strains of influenza virus may stimulate some antibodies which

are specific for the current infecting strain, and other

antibodies which are more cross-reactive with earlier

strains infecting the same individual. The method of

measuring antibody in serum is also an important

variable, since hemagglutination-inhibition (HI) and

neutralization tests, and other tests such as single

radial hemolysis of ELISA, may measure antibodies

having somewhat different specific reactivities with

● NOTE: Reference citations for app. A refer to the list of references at the

end of app A.

influenza viral antigens. While both HI and neutralization tests primarily measure the biological function of hemagglutinin attachment to cell receptors,

the single-radial hemolysis tests and enzyme immunoassay (EIA) measure antibodies against both

hemagglutinin and neuraminidase, and in the case of

EIA, common internal antigens as well. Although the

HI test is the most universally accepted for measurement of serum antibodies in influenza, the actual

dilution of serum which will cause complete inhibition of red blood cell (RBC) hemagglutination may

vary somewhat depending on the avidity of the

hemagglutinin-antibody interaction, as well as other

variables such as the method used for removal of

serum inhibitors and the type of RBC used.

When examining the relationship between serum

antibody and immunity to influenza, it is important

to specify whether antibody has been produced by

parenteral administration of inactivated vaccine or

by natural infection. While serum antibody induced

by parenteral vaccination may reflect systemic immunity to virus infections of the lower respiratory

tract (lung), resistance to the initiation of influenza

virus infection at the mucosal surface of the upper

respiratory tract may correlate better with the presence in secretations of virus-specific IgA, induced by

replication of the virus at these sites during natural

infection.

In 1957, one dose of 200 or 500 chick cell agglutination (CCA) units of inactivated A/Japan/305/57

vaccine was given to volunteers, and 2 to 4 weeks

later an A/Japan/305/57-like live virus challenge

(diluted nasal washings of infected boys) was given

to both vaccinated and unvaccinated volunteers (1).

of 33 unvaccinated individuals, 23 (78 percent)

developed febrile influenza-like illness while 14 (44

percent) of those given vaccine developed similar illness, Attack rates varied inversely with HI antibody

titers induced by vaccination, with rates of febrile illness of 60, 43, and 25 percent, respectively, in 10 individuals with titers <10, 14 individuals with titers

flicting data were obtained by Rose and Fukumi in

1957. Rose demonstrated that 200 or 750 CCA units

33
34 ● Cost Effectiveness of lnfluenza Vaccination

of monovalent A/Japan/305/57 vaccine provided

some immunity to infection during an Asian influenza outbreak (60 to 78-percent efficacy), yet he was

unable to demonstrate a serum HI response to the

vaccine; a CF antibody rise did occur (2). Fukumi, on

the other hand, reported that vaccines induced good

HI antibody responses, and infections occurred rarely among individuals with HI titers of 32 or greater

(although it is not entirely clear if he refers to antibody induced by vaccination or prior infection)(3).

In 1968, Dowdle, et al., demonstrated that 3,000

CCA, but not 300 CCA, units of inactivated influenza A/Hong Kong/68 vaccine conferred a protective

effect against natural challenge with homologous

virus (4). Although febrile influenza-like illness occurred among individuals with HI titers of 80 to 160,

illness severe enough to cause patients to remain in

bed occurred in only approximately 11 percent of

those with HI titers of 80 to 160, compared with an

incidence of illness requiring bed rest of about 32 perboth HI and neuraminidase-inhibiting (NI) antibody

were present at any titer, illness requiring bed rest

was seen even less frequently. )

During an epidemic of A/Brazil /11/ 78( HlNl)-like

virus infections among university students in Georgia

during early 1979, Noble, et al., found that

A/USSR/77 vaccine produced a protective effect.

Two doses of inactivated vaccine containing 7 mcg of

hemagglutinin were given to October and November

1978, and an epidemic occurred in January and February 1979. Among vaccinated individuals with HI

cidence of influenza-like illness (fever or feverishness

and chills with respiratory symptoms and a significant rise of HI antibody to H1N1 virus) was 20 percent (19 of 97), whereas among individuals with titers

The incidence of illness among placebo recipients, all

179).

From the preceding review it is apparent that great

variation is seen in different situations between the

level of serum antibody and evidence of immunity.

However, approximately a 60- to 80-percent reduction in typical influenza-like illnesses is generally seen

when serum HI antibody titers of 40 to 80 are

achieved by vaccination during the first wave of a

new major antigenic variant, when attack rates of a

placebo group or individuals with titers of 20 or less

after vaccination are used for comparison. Additional data have been generated by investigators who

have examined serum antibody tiers and the resistance to an artificial challenge with intranasally administered live influenza virus. Hobson, et al., reviewed experience at the Common Cold Unit, Salisbury, England (570 volunteers challenged with influenza “A2 viruses” and 462 volunteers challenged

with influenza B viruses) and found that serological

evidence of infection occurred rarely among individuals with prechallenge HI titers of 100 to 200 (5). At

titers of 48, serological evidence of infection was reduced approximately 60 to 80 percent when compared with infection rates in those with prechallenge

homologous HI serum antibody titers of 6 to 12.

During interpandemic periods, a similar correlation between serum HI antibody titers and protection

has also been observed. Among vaccinated and unvaccinated individuals, the incidence of influenzalike illness was approximately 15 to 20 percent

were 3.5 percent or lower in those with titers of

a good correlation between serum HI antibody titer

and the probability of clinical infection with

A/FM/l/47-like viruses (7). The estimated incidence

of infection among those with titers <8 was 18.3 percent, compared to a 1.6-percent infection rate among

individuals with titers of 32; no influenza-like illOthers have reported generally similar findings

(8,9,10), although the method of expressing serum dilutions in early papers may result in titers higher than

titers obtained with methods now in use, and thus a

comparison of actual titers may be misleading (6).

It is clear from the review of existing data that no

single titer of serum influenza HI antibody can be

chosen to indicate any specific index of immunity to

natural challenge. This is particularly true during the

first appearance of a new major antigenic variant of

influenza A, because the data available are limited, It

is clear, however, that an increasing concentration of

homologous serum HI antibody confers an increasing

degree of protection against typical influenza illness.

This appears to be true whether the antibody is induced by vaccination or by natural infection. Thus,

HI antibody titers of 40 to 80 (or 32 to 64) have generally been found to provide a reduction in the incidence of typical influenza-like illness of 60 to 80

percent, when compared with the incidence of illness

The question of what concentration of serum antibody is to be considered ideal following vaccination

is, therefore, a matter of judgment, as stated by Salk

20 years ago (11):

The incentive for achieving the highest levels that

are practicably attainable is clear. In answer to the

question as to how high the level should be, it might

be said that the higher the better; the higher the level
●

Appendix A—Relationship of Serum Antibody Concentration to incidence of influenza Illness ● 35

attained, the greater the persistence at the more effective levels.

The limiting factors in attaining the highest level

are clinical and economic. If one eliminates the economic considerations, the upper limit attainable,

using a single dose of vaccine, is set by the frequency

Appendix A References

1.

2.

3.

4.

5.

6.

J. A. Bell, T. G. Ward, A. Z. Kapikian, A. Shelokov, T. E. Rechelderfer, and R. J. Huebner, “Artificially Induced Asian Influenza in Vaccinated

and Unvaccinated Volunteers, J. Amer. Med.

ASSOC. 165:1366-1373, 1975.

H. M. Rose, in “International Conference on

Asian Influenza, ” Bethesda, Md., 2/17-19/60,

Amer. Rev, Resp. Dis. 83(2):152-153, 1961 .

H. Fukumi, in “International Conference on

Asian Influenza, ” Bethesda, Md,, 2/17-19/60,

Amer. Rev. Resp. Dis. 83(2):156, 1961.

W. R. Dowdle, S. R. Mostow, M. T. Coleman,

H. S. Kaye, and S. C. Schoenbaum, “Inactivated

Influenza Vaccines. 2. Laboratory Indices of Protection,” Postgrad. Med. ]. 49:159-163, 1973.

D. Hobson, R. L. Curry, A. S. Beare, and A.

Ward-Gardner, “The Role of Serum Haemagglutination-Inhibiting Antibody in Protection

Against Challenge Infection With Influenza A2

and B Viruses, ” ]. Hyg, (Carob.) 70:767-777,

1972.

J. Salk and D. Salk, “Control of Influenza and

Poliomyelitis With Killed Virus Vaccines, ” Science 195;837-847, 1977.

or severity of systemic reactions that accompany the

use of concentrated virus preparations; in infants and

young children the “severity” of the reaction is perhaps of greater consequence, and in the adult population the “frequency” of reactions is of first importance.

7.

8<

9.

10,

11,

G. Meiklejohn, C. H. Kempe, W. G. Thalman,

and E. H. Lennette, “Evaluation of Monovalent

Influenza Vaccines. II. Observations During an

Influenza A-Prime Epidemic, Amer. ]. Hyg.

55:12-21, 1952.

M. D. Eaton and G. Meiklejohn, “Vaccination

Against Influenza. A Study in California During

the Epidemic of 1943-44, Amer. ]. Zfyg. 42:28-44,

1945.

E. R. Rickard, F. L. Horsfall, Jr., G. K. Hirst, and

E. H. Lennette, “The Correlation Between Neutralizing Antibodies in Serum Against Influenza

Viruses and Susceptibility to Influenza in Man,

Publ. Hlth Rep. 56:1819-1834, 1941.

W. Henle, G. Henle, and J. Stokes, Jr., “Demonstration of the Efficacy of Vaccination Against

Influenza Type A by Experimental Infection of

Human Beings, ” ]. lmmuno]. 46:163-175, 1946.

J. Salk, in “International Conference on Asian Influenza, ” Bethesda, Md., 2/17-19/60, Amer.

Rev. Resp. Dis. 83(2):153-156, 1961.
Appendix B.—Safety and Efficacy of

Inactivated Influenza Vaccine

Description of Inactivated Influenza

Virus Vaccine

Influenza vaccines can be categorized in two basic

groups—live, which contain small amounts of live,

attenuated (weakened) influenza viruses, and inactivated, which contain either whole influenza viruses

or subunits of viruses. Only inactivated influenza viruses are licensed for general use in the United States;

therefore, this discussion of vaccine safety and efficacy pertains exclusively to inactivated vaccines.

Inactivated influenza virus vaccines have been

manufactured and used in the United States since the

1940’s (64). Early development of influenza vaccines

was spearheaded by the Armed Forces Epidemiological Board and its Commission on Influenza (12). The

early vaccines have undergone several improvements.

Influenza virus vaccine production procedures

have been described elsewhere (33,71).

Today, there are two types of inactivated influenza

virus vaccine commercially available in the United

States, whole virus and subunit. The antigenicity of

whole virus vaccine has been demonstrated more extensivel y than that of subunit vaccines (91). On the

basis of evidence generated from clinical trials conducted in 1976, however, subunit vaccines are now

considered by some researchers to be equally antigenic with whole virus vaccines in adults with prior

influenza virus antibody production and less antigenic in either children or adults with no prior influenza virus antibody production (51). In some

studies, administration of a booster injection of subunit vaccine yielded antibody levels comparable to

those produced by whole virus vaccines (21,44). In

other studies, however, a second injection yielded no

“booster” effect among those responding poorly to

an initial injection (25). Subunit influenza vaccines

tend to cause fewer adverse reactions than whole

virus vaccines (30,51,65).

Vaccine Efficacy

There are two major types of investigations used to

evaluate the efficacy of influenza vaccines. First,

clinical trials—in which vaccinated subjects are exposed, either by design or by chance, to influenza

organisms —can be used to determine a vaccine’s protective efficacy. Second, antibody response studies—in which prevaccination and postvaccination

serum antibody levels are measured in vaccinated

subjects—are used to determine the capacity of a vaccine to induce antibody information. It can be difficult to conduct clinical trials involving influenza

vaccine, because the occurrence of influenza epidemics caused by specific strains of viruses is often

difficult to predict, and because intentional exposure

of subjects raises ethical concerns. Antibody response studies by themselves are not usually relied on

to assess a vaccine’s efficacy; rather, they provide

data from which efficacy or protection be inferred.

Often, data from antibody studies are obtained from

vaccinated subjects not subsequently exposed to influenza virus; therefore, achievement of a certain

postvaccination serum antibody level, for example, a

fourfold increase over prevaccination level, is sometimes used to help assess a vaccine’s clinical efficacy.

Antibody responses can also be described in terms of

the percentage of a vaccinated population with postperiences document a correlation between a particular level of serum antibody rise and clinical efficacy.

A few of these experiences are discussed briefly

below. Others have been described previously

(23,44,95).

Numerous factors affect a vaccinated person’s antibody response to an inactivated influenza vaccine,

and thus affect a vaccine’s effectiveness. First, and

obviously, the vaccine’s potency (amount of

antigen), purity (freedom from contaminating material), and other measures of quality are important.

Second, the degree to which the antigenic components of the virus(es) in a vaccine match the antigenic components of the virus(es) circulating in the

environment greatly affects the effectiveness of the

vaccine (see app. C). Third, a vaccinated person’s antibody response to a given vaccination is influenced

by his or her prior exposures to influenza viruses

either through vaccination or acquisition of disease

(natural immunity) (21,29,36,49). Fourth, the duration of immunity conferred by influenza vaccination

tends to be short (i.e., usually 1 year, possibly 3

years, and perhaps longer); further, the duration of

immunity varies substantially with age and other

host factors.

Usually, inactivated influenza vaccines contain

either whole cells or antigenic subunits (neuraminidase and hemagglutinin) from two or more strains of

influenza viruses. Ever since 1943, in the United

States, vaccines have been marketed with at least one

type of influenza A virus and one type of influenza B

virus. In recent years, trivalent vaccines, containing

36
Appendix B—Safety and Efficacy of Inactivated Influenza Vaccine ● 37

two types of influenza A viruses and one type of influenza B virus, have been marketed. Much more

data are available concerning the safety and efficacy

of influenza A virus vaccines than influenza B virus

vaccines.

The type(s) of influenza virus(es) (e.g., type A or

B) that circulate in the United States can easily

change, sometimes from year to year (27), Furthermore, even in subtypes within a particular type of

virus (e. g., H3N2 or H1N1 type A influenza viruses),

the antigenic components can change in a fashion

that alters the virus’s susceptibility to a person’s antibodies. Because the manufacturing and distribution

processes for influenza vaccine take from 6 to 9

months, the type(s) of influenza virus selected to be

represented in a vaccine for a given year may not be

in circulation at the time the vaccine is actually used.

As a result, in a given year, the vaccine being administered may not stimulate antibodies to—and therefore not help protect against—the type(s) of influenza

virus(es) producing disease. Evidence of the protective efficacy of a current vaccine formulation is therefore often difficult or sometimes impossible to obtain

before a vaccine is released by the Bureau of Biologics for general use. There can be, however, some

degree of overlapping protection among different

types of influenza viruses (70,118).

Clinical Studies

The clinical efficacy of inactivated influenza vaccines has been debated virtually since their development in the 1940’s. Clinical studies have yielded

clinical efficacy rates ranging from O to 90 percent

(104). (Note: The clinical efficacy rate refers to the

precentage decline in the incidence of clinical influenza among a group of vaccinated subjects as compared to the incidence of clinical influenza among a

group of unvaccinated subjects. )

The following studies are used to illustrate clinical

efficacy rates for inactivated influenza A virus vaccines:

1. Ferry, et al., in Australia conducted three clinical trials of a trivalent subunit influenza vaccine containing 250 international units (IU) of

A/Victoria/3/75 virus, 250 IU of A/Scotland/840/74 virus, and 300 IU of B/Hong

Kong/8/73 virus (36). The first trial involved

698 vaccinees and 2,034 unvaccinated controls; all subjects were members of a hospital

staff. Although the difference in the incidence

of respiratory tract infection (RTI) between the

two groups was not significant, the incidence

of influenza (diagnosed on the basis of clinical

and serological determinations) was 81 percent

lower among vaccinees.

In the second trial, the same vaccine was administered to 480 laboratory workers; another

583 laboratory workers in the same institution

served as controls. There were no statistically

significant differences in either incidence of

RTI (47 cases among vaccinees v. 51 cases

among controls) or isolation of influenza

viruses (24 isolates among vaccinees v. 24 controls) between the two groups. However, the

vaccinated group lost only 493 days of work

compared to 837 days for the unvaccinated.

The differences in work loss between the two

groups might be attributable to a less severe

type of influenza among the vaccinated.

In the third trial, involving patients in a

geriatric home, 154 vaccinated volunteers were

compared with 63 unvaccinated controls.

There was no statistically significant difference

in the incidence of influenza between the two

groups, but the severity of influenza cases was

deemed by the investigators to be less in the

vaccinated group.

The authors attributed the difference in vaccine efficacy in these three trials to possibly differences in prevaccination antibody levels;

those with lower prevaccination antibody levels and those being vaccinated for the first time

experienced less postvaccination influenza.

2. Hoskins, et al., in England studied the protective efficacy of inactivated influenza vaccines

among 375 school boys who experienced three

epidemics: 1972 (A/England/42/72), 1974

(A/Port Chalmers), and 1976 (A/Victoria)

(49). During the three epidemics collectively,

the cumulative case-rates were approximately

the same (i. e., 40 to 50 percent) among all

boys, regardless of their vaccination status.

Those boys who were vaccinated before each

epidemic experienced influenza at the same

rate as those who received no vaccine at all

when evaluated retrospectively over the three

epidemics. Boys vaccinated for the first time

were partially protected against the strain of

influenza causing the next outbreak.

In 1976, the year A/Port Chalmers virus

caused the influenza outbreak, the attack rate

among boys who received no relevant vaccination was similar to that among boys who received A/Port Chalmers vaccine that year and

who in adddition had been vaccinated against

other strains in earlier years. Boys vaccinated

with A/Port Chalmers that year only (with no

prior influenza history) experienced a substantially lower attack rate. Also in 1976, immunity derived from natural infection (A/Port

Chalmers/1974 or A/England/1972) appeared
3.

4.

5.

to provide better protection than did any vaccination.

Hoskins concluded that “when a new antigen subtype, e.g., A/Port Chalmers, first appears and a population is completely susceptible, a vaccine will have its maximum effect and

may be expected to protect 50 percent or more

of those vaccinated . . . However, this benefit

is short-lived. As a strain undergoes antigenic

drift, subjects previously protected from natural infection by vaccination will be at risk and

cannot be effectively protected by further vaccination with either the same or a later strain. ”

On the basis of his findings, Hoskins questioned the effectiveness and wisdom of annual

influenza vaccination within a population.

Sparks, in another English school, reported

findings similar to those of Hoskins’ (117). He

claimed that influenza vaccination only postpones an attack and that transient protection

provided by vaccination can prevent the development of the long-term immunity resulting

from an attack of influenza.

During the 1977-78 influenza season, Couch

and coworkers in Houston, Tex., compared

the clinical protective efficacy of two successive annual influenza vaccinations among 129

elderly subjects (51 to 78 years old; median, 65

years) (21). In 1976, all subjects received bivalent influenza vaccine containing A/Victoria/75 (H3N2) and A/New Jersey/76

(Hsw1N1) antigens. In October 1977, 74 of

those subjects received another bivalent vaccine containing A/Victoria/75 and B/Hong

Kong/72 antigens. Vaccinees voluntarily submitted information about their history of respiratory illnesses, which were classified according to severity. Vaccinated subjects’ sera

samples were also analyzed for antibody content. Among the 74 subjects who received the

second vaccination, there was no statistically

significant reduction on the incidence of mild

illness, but there was a 60-percent reduction in

severe illness.

At the Surgeon General’s Meeting on Influenza

Immunization held on January 22, 1980, several vaccine efficacy studies were reviewed (104).

In one of these studies, 169 college students in

Atlanta, Ga., were given 2 doses of a vaccine

containing an A/U.S.S.R.-like (H1N1) antigen

and 181 students were given a placebo vaccine.

An epidemic of A/Brazil/78-like (H1N1) influenza followed in Atlanta 7 to 10 weeks after

the students were vaccinated. The use of this

vaccine in this study reduced the incidence rate

of laboratory-confirmed influenza illness by

nearly 50 percent.

Reviews of influenza vaccine safety and efficacy are contained in the written summaries

of conferences on influenza sponsored by the

Department of Health and Human Services between 1977 and 1980 (97-104).

Vaccine Efficacy During Years of Inexact

Antigenic Match Between Vaccine Virus(es)

and Circulating Virus(es)

As described in appendix A, influenza viruses

sometimes change their chemical makeup from

season to season and even within a single season.

Small changes—i.e., those within a given type of

virus such as H3N2 influenza A virus—are collectively referred to as “antigenic drift. ” Larger

changes—such as a replacement of an H3N2 influenza A virus by an H1N1 influenza A virus—are called

“antigenic shifts. ”

During the 8-year period from 1970-71 through

1977-78, there were four episodes of antigenic drift in

the predominate H3N2 influenza A virus circulating

in the United States. These drifts occurred in 1972-73

(Hong Kong to England), 1973-74 (England to Port

Chalmers), 1975-76 (Port Chalmers to Victoria), and

1977-78 (Victoria to Texas).

The degree to which antigenic drift affects the effectiveness of a given H3N2 influenza A virus vaccine

creates yearly public debates (97-104). Because’ antigenic drift can occur within the 6 to 9 months between vaccine formulation and vaccine distribution,

in some years the influenza A virus contained in the

distributed vaccine somewhat differed antigenically

from the circulating viruses causing disease. In three

clinical trials (70,85, 118) and one retrospective

epidemiologic investigation (8), researchers have attempted to assess the clinical effectiveness of vaccines

containing an H3N2 virus that differed from the predominant circulating H3N2 virus causing disease in a

distinct geographical location.

Clinical Evidence.—In 1977, Meiklejohn and coworkers assessed the efficacy of a trivalent inactivated influenza vaccine (400 chick cell agglutinating

(CCA) units of A/Victoria/3/75, 400 CCA units of

A/New Jersey/76 and 500 CCA units of B/Hong

Kong/72 viruses) against a variant of A/Victoria

virus (A/Texas/l /77-like virus) among military personnel in Colorado (70). In November 1976, approximately 4,200 military students at Lowry Air Force

Base (AFB) were given this vaccine; subsequently,

this population was continually altered by the arrival

of approximately 200 new students and the departure
Appendix B—Safety and Efficacy of inactivated influenza Vaccine ● 39

of a similar number of students each week. The newly arrived students intermingled extensively with the

remaining ones. An influenza outbreak (caused by an

A/Texas/l/77-like virus) occurred at Lowry AFB in

February 1977, causing 87 cases of influenza. During

the first and second weeks of the outbreak, the attack

rates among the unvaccinated students were 20.0 and

23.6 cases per 1,000 persons per week, and the attack

rate among the vaccinated never exceeded 2.3 cases

per 1,000 persons per week. For the remaining 3

weeks of the outbreak, attack rates were 1.4, 4.7, and

1.2 cases per 1,000 among the unvaccinated and 2.2,

2.3, and 1.2 among the vaccinated. The investigators, using three different methods of calculation,

estimated the clinical efficacy rate of the vaccine to

range from 69.0 to 83.1 percent,

During the winter of 1974-75, CDC conducted

among university students an open field trial of vaccines containing either inactivated or live influenza

A/England/42/72 (H3N2) virus (85). Influenza

A/Port Chalmers/1/73 (H3N2) which differed antigenically from A/England/42/72, however, was

the predominant H3N2 influenza virus causing disease among volunteer participants in this study. The

influenza attack rate among placebo recipients (unvaccinated control group) was 69 cases per 1,000 persons, whereas the attack rate among inactivated vaccine recipients was 25 cases per 1,000 persons, and 36

cases per 1,000 persons among live vaccine recipients. Using the following formula, OTA calculated

the clinical effectiveness rate of the inactivated influenza vaccine during this trial to be 64 percent (l):

Vaccine effectiveness =

(attack rate in unvaccinated group –

—attack rate in vaccinated group) X I@) ”/o —

attack rate in unvaccinated group

Retrospective Epidemiologic Investigation.—In

1972, Stiver and associates studied the clinical effectiveness of a vaccine containing Hong Kong influenza

virus antigen (A2Aichi/2/68) during an outbreak of

A2England/72 influenza among air force recruits in

Colorado (118). Among 979 vaccinees, the influenza

attack rate was 18.4 cases per 1,000 persons. Among

2,955 unvaccinated subjects, the influenza attack rate

was 46.0 cases per 1,000 persons. The vaccine’s clinical effectiveness rate was calculated to be 60 percent

(p < 0.01 by chi-square test).

Barker and Mullooly attempted to assess the impact of the A/Hong Kong/68 (H3N2) influenza virus

vaccine on the rates of pneumonia-influenza associated hospitalization and mortality among a defined

population 65 years and older at Kaiser-Permanente

Hospital in Portland, Oreg., during the 1972-73

epidemic caused by A/England/42/72 (H3N2) influenza virus (8). These researchers retrospectively reviewed the medical records of a 5-percent sample of

Kaiser-Permanente patients 65 years and older. Prior

to this epidemic, 20 to 30 percent of the chronically ill

elderly Kaiser-Permanente patient population was

vaccinated; vaccinees and nonvaccinees were comparable in age and distribution of chronic disease.

Among those vaccinated, there was a 72 percent reduction in hospitalizations associated with pneumonia or influenza during the 1972-73 influenza epidemic. Further, no deaths were recorded among the

vaccinated, while death rates among the unvaccinated were 6 out of 10,000 non-high-risk individuals

and 35 out of 10,000 high-risk individuals.

These researchers conducted a similar analysis of

the impact of the A/Taiwan/l/64 (H2N2) virus (8).

There were no statistically significant differences in

either hospitalization or mortality rates between the

vaccinated and unvaccinated groups. The authors attributed the lack of vaccine impact during the

1968-69 epidemic to the major shift from an H2N2 to

an H3N2 antigenic configuration in the circulating

virus.

On the basis of the findings of these three clinical

trials and one epidemiologic investigation, OTA

assumed that the clinical effectiveness rate of the inactivated influenza virus vaccines used in three years

involving antigenic drift of H3N2 virus (i. e., 1972-73,

1974-75, and 1977-78) was at least 60 percent.

Antibody Response to Influenza Vaccine

Among Specialized Populations

The following studies illustrate variations in antibody response to influenza vaccine among selected

subpopulations who are likely to receive influenza

vaccine. Several studies of influenza vaccines in

special populations were published previously in the

December 1977 (supplement) issue of the Journal of

Infectious Diseases.

Neoplastic Diseases.—Shild and coworkers demonstrated an adequate antibody response to a trivalent influenza vaccine (A/New Jersey 1976

(Hsw1N1), B/Hong Kong/5/72, and A/Victoria/

3/75 (H3N2)) among 36 patients with solid tumors

and a less-than-favorable response in 46 patients with

Iymphomas (110).

Ganz, et al., demonstrated a fourfold rise in antibody titers to a bivalent influenza vaccine (A/New

Jersey /76( HswlNl) and A/Victoria/ 75( H3N2)) in 41

to 47 percent of 17 patients with various types of

cancer and on various types of chemotherapy (40).

Ortbals, et al., found that 71 percent of 42 cancer patients (21 with lymphoreticular neoplasms and 21

with solid tumors) demonstrated a fourfold or

greater increase in serum antibody titers to A/New
40 ● Cost Effectiveness of Influenza Vaccination

Jersey/1976 influenza vaccine as compared to 91 percent of control subjects (92). Also, immunization at

the time of chemotherapy administration lowered the

incidence of seroconversion from 93 percent to 5O

percent.

Silver and Weinerman administered a bivalent influenza vaccine (A/Port Chalmers/1/73 (H3N2) and

B/Hong Kong/5/72) to 44 patients with cancer and

27 healthy controls (115). Against the A antigen, 16

of the cancer patients and 25 of the controls yielded a

fourfold or greater increase in antibody titer. Against

the B antigen, 14 of the cancer patients and 20 of the

controls yielded a fourfold increase in serum antibodies. Nineteen of the cancer patients had lymphomas, and only four of these patients demonstrated a fourfold increase in antibody level.

Neoplasms in Children. —In 1978, Douglas and

associates gave one or more of the following antigens

to 54 children with malignancies: A/U.S.S.R./77

(H1N1), A/Texas/77( H3N2), and B/Hong Kong/72

(25). By the end of the study, the percent of subjects

(indicative of a good antibody response) was as

follows:

 49 percent of those given A/U.S.S.R./77 vaccine,

● 59 percent of those given A/Texas/77 vaccine,

and

● 24 percent of those given B/Hong Kong/72 vaccine

Systemic Lupus Erythematosus.—Ristow, et al.,

found a fourfold or greater antibody response to

A/New Jersey/76 (Hsw1N1) vaccine in 14 of 29 patients with systemic lupus erythematosus, compared

to 18 out of 29 control subjects (109).

Herron, et al., studied the safety and efficacy of an

influenza vaccine (A/New Jersey/76 and A/Victoria/75) among 62 patients with rheumatic diseases,

including systemic erythematosus, rheumatoid arthritis, and degenerative joint disease and among 32

healthy control subjects (46). Among the patients

with rheumatic diseases, 62 to 87 percent

seroconverted to A/New Jersey/76 and 62 percent

seroconverted to A/Victoria/75. Thirteen of the

rheumatic disease patients experienced a flare up of

their disease.

Tecson and Bornstein have cautioned against

repeated yearly influenza vaccination because of

potential complications (121).

Pregnancy .—Sumaya and Gibbs administered

A/New Jersey/76 influenza vaccine to 56 pregnant

women and found no significant difference in the antibody responses between pregnant and nonpregnant

adults (120). Further, no significant immediate

maternal reactions or increased fetal complications

were observed.

Murray and associates studied the antibody

responses to A/New Jersey/8/76 (Hsw1N1), A/

Japan/305 /57( H2N2), and A/Hong Kong/8/68

(H3N2) influenza vaccine in 59 pregnant and 27 nonpregnant women (77). There were no significant differences in antibody responses between pregnant and

nonpregnant subjects.

Geriatric Population. —Serie and coworkers administered a trivalent influenza vaccine (A/Pasteur

P 24.R (H3N2), A/Port Chalmers/73 (H3N2) and

B/Hong Kong/73)) to 523 geriatric hospitalized patients with an average age of 83 years (113), Serologic

and virologic investigations were performed in 110

patients. The incidence of clinical influenza caused

by type A/Victoria was roughly twice as high among

the unvaccinated as that among the vaccinated. The

mortality rate among all vaccinees was 0.19 percent

compared to 3.90 percent of those unvaccinated.

When 80 percent of patients in a particular hospital

section was immunized, the incidence of influenza

was reduced by as much as three times.

Howells and associates have also assessed the

value of this vaccine among the elderly (so).

Multiple Sclerosis. —Banford, et al., administered

a bivalent influenza vaccine (A/New Jersey and

A/Victoria) to 65 patients with multiple sclerosis and

compared the incidence of adverse neurological conditions among vaccinees with that among 62 unvaccinated control multiple sclerosis patients (7). Sixtyone of the vaccinated patients tolerated the vaccine

well, and four developed new necrologic complications. Among the 62 unvaccinated control patients,

four also developed new necrologic symptoms. The

authors concluded that influenza vaccine posed no

excessive risk of necrologic symptoms among multiple sclerosis patients. Vaccine efficacy was not

evaluated in this study.

Chronic Renal Failure, Renal Dialysis, and Transplant Populations.—McMillen and associates administered a bivalent influenza vaccine (A/New

Jersey/76 and A/Victoria/75 by Wyeth Laboratories) to 23 chronic dialysis patients (age 30 to 72

years), 18 renal transplant patients (age 18 to 64

years), and 10 pediatric patients (6 on chronic dialysis and 4 with renal transplants) (68). Seroconversion was observed in 67 percent of all 29 dialysis patients and in 50 percent of all 22 renal transplant patients. Among the transplant group, patients 18 to 25

years old had a much lower seroconversion response

(12.5 percent) than either those under 18 (75 percent)

or over 25 (90 percent).

Osanloo and coworkers administered a bivalent
Appendix B—Safety and Efficacy of lnactivated Influenza Vaccine ● 41

influenza vaccine (A/Victoria/75 and A/New Jersey/76) to 10 azotemic, undialyzed males, 19 hemodialyzed males, and 17 control subjects (93). Fiftyfour percent of the control subjects, 53 percent of the

hemodialysis patients, and 60 percent of the azotemic

patients developed a fourfold greater increase in antibody levels to A/Victoria antigen. Against the

A/New Jersey antigen, 92 percent of the controls, 89

percent of the dialyzed patients, and 90 percent of the

azotemic patients developed a fourfold or greater rise

in serum antibody levels. The authors noted that

severe azotemia and/or immunosuppressive or corticosteroid therapy may

responses.

Vaccine Safety

The safety of influenza

depress certain antibody

vaccine, like that of all vaccines, is evaluated on the basis of the incidence of

adverse reactions to the vaccine that: 1) investigators

in clinical trials report, or 2) practicing health professionals voluntarily report to CDC, FDA, or the vaccine manufacturer (86). Adverse reactions to vaccines can be classified as follows:

Local Reactions: These reactions include pain,

redness, and swelling at the vaccine injection

site. Such reactions occur commonly, do not

involve other areas of the body, and are usually minor and self-limiting.

Systemic Reactions: These reactions include

perturbations in one or more organ systems

and can affect one or more areas of the body.

Such reactions range from fevers to allergic

reactions; their severity can be mild and shortlived, severe and long-lasting, or sometimes

even fatal.

A recent study commissioned by the Department

of Health and Human Services (DHHS) describes in

detail the clinical and economic profiles of several

selected types of adverse reactions to commonly used

vaccines (4).

The safety of influenza vaccines became quite

topical during the National Influenza Immunization

Program of 1976, the so-called swine flu program.

Unexpectedly, approximately 1 out of every 100,000

persons who received swine flu vaccine (A/New Jersey/76 Hsw1N1] virus) developed Guillain-Barre

Syndrome (GBS), a neurological disorder that results

in varying degrees of disability, ranging from temporary paralysis of extremities (arms and legs) to death

(112). The relationship between influenza vaccines

and GBS has received much publicity and the safety

of influenza vaccines has been studied extensively

during the past 4 years. The following descriptions of

each type of adverse reaction associated with influenza vaccine are based largely on such studies.

During the 1976-77 influenza immunization program, CDC coordinated a nationwide surveillance

program to detect adverse reactions following influenza vaccination. CDC received a total of 4,733

voluntarily submitted reports of such reations, including reports of 233 deaths, for the estimated 48

million persons vaccinated against influenza during

the season (107). This surveillance program was the

early warning system that led to the discovery of an

association between GBS and influenza vaccination.

Limitations to data collected in this system, however,

are noted by CDC investigators (107):

Reports of illness that depend on voluntary reporting during a time of varying publicity are inappropriate for retrospectively developing rates of illness in a

target population. . . . The passively reported data

gathered through this surveillance system are of such

a nature that they cannot be compared with data

gathered from monitored defined populations.

According to a 1979 survey conducted by Opinion

Research Corp. for the Bureau of Health Education,

CDC, approximately 13 percent of all children and 5

percent of all adults receiving influenza vaccine in

1978 had an adverse reaction that resulted in a visit

to a doctor, hospital, or clinic (123).

Local Reactions

Noble and associates investigated among University of Georgia students the safety and efficacy of two

trivalent inactivated influenza virus vaccines (both

the vaccines contained 7 micrograms of hemagglutinin from A/Texas/l/77 (H3N2) and from A/Brazil/

11/78 (H1N1) viruses. One vaccine (Vaccine No. 1)

also contained 7 micrograms of B/Hong Kong/8/73

while the other (Vaccine No. 2) contained 50 micrograms of B/Hong Kong/8/73 (104). The vaccine with

7 micrograms of each virus (Vaccine No. 1) was administered to 394 volunteers. The vaccine with 50

micrograms of B/Hong Kong/8/73 virus (Vaccine

No. 2) was given to another 386 subjects. A placebo

vaccine was given to another 396 volunteers. About

20 percent of those subjects receiving Vaccine No. 1

and 36 percent of those receiving Vaccine No. 2 developed sore arms at the vaccination site.

Eastwood and associates studied the reactions of

49 children (aged 4 to 11 years) to a surface-antigenabsorbed influenza virus vaccine containing 8.4

micrograms HA (hemagglutinin) of A/Victoria/3/75

(H3N2) and 12.7 micrograms HA of B/Hong Kong/

8/73 per dose (30). Eighteen (37 percent) of the vaccinees experienced mild local reactions (slight soreness and aching at the inoculation site) during the 3
days following immunization. Two children (4 percent) also had local swelling, two had redness, and

one developed a bruise.

Systemic Reactions

Systemic reactions to influenza vaccine can be

classified as follows (1):

minor (fever, malaise, myalgia [muscle aches])

—all such reactions usually subside within 48

hours);

immediate—presumably allergic—responses

(breathing difficulties, certain skin eruptions,

rarely severe allergic reactions [anaphylaxis]);

Guillain-Barre Syndrome (GBS) (a paralytic disorder that usually starts in a person’s extremities

and moves up the body; approximately 50 percent of the cases recover completely within 1

year; 10 percent result in moderate to severe permanent disability; and 5 percent die); and

miscellaneous.

Minor: In the study cited above, Noble and

associates found a 2-percent incidence of fever

(>100° F), a 5-percent incidence of malaise and

myalgia, and a 6-percent incidence of headache

among those subjects receiving Vaccine No. 2.

Vomiting occurred in 6 recipients of Vaccine No. 2

(104).

Dr. William S. Jordan from the National Institute

of Allergy and Infectious Diseases (NIAID) prepared

an analysis of clinical trials involving the administration of inactivated influenza vaccine containing the

A/U.S.S.R./77 (H1N1) antigen to approximately

2,000 subjects (100). Among nearly 1,000 subjects 13

years of age or older given two doses of either split or

whole virus vaccine, only 18 developed fever ( > 100°

F). Twelve (36 percent) out of 33 subjects under 13

years old who received a placebo vaccine, however,

also developed fevers.

In Eastwood's study cited above, one diabetic child

experienced raised levels of urinary sugar and

ketones which subsided in 2 days. No fevers were reported (30).

Dolin, et al., administered inactivated influenza

A/New Jersey/76 virus vaccine in doses of 200, 400

or 800 CCA units to 199 adult health volunteers (23).

All fevers subsided within 48 hours. Malaise—usually gone in 48 hours—occurred in 50 to 60 percent of

vaccinees receiving 400 to 800 CCA units. Headache

persisted beyond 48 hours in 9 to 19 percent of vaccinees.

Parkman, et al., summarized adverse reactions

data from clinical trials involving 3,900 adults who in

1976 received various doses of A/New Jersey/76,

A/Victoria/75, and B/Hong Kong/72 influenza virus

vaccines (95). At doses below 800 CCA units, mild

fever ( <100° F) occurred in 0.6 to 12.8 percent of

vaccinees. About 3.7 percent of recipients of a vaccine containing 800 CCA units developed fevers of

102° F.

2. Immediate Reactions: According to Dr. Kenneth

McIntosh, University of Colorado, the incidence rate

of severe allergic reactions (anaphylaxis) to influenza

vaccine is 1 case per 4 million vaccinees (100).

Gross, et al., reported a case of meningoencephalitic syndrome following influenza vaccination in a

60-year-old woman allergic to chicken meat and eggs

(45).

Horowitz reported a case of urticaria occurring in

an n-year-old girl with asthma (48).

In the studies summarized by Parkman, et al., 2 of

the 3,900 vaccinees experienced allergic reactions and

both survived with no sequelae (95).

3. Guillain-Barre_ Syndrome: (See app. D.)

4. Miscellaneous: Perry and associates reported a

case of reversible blindness from optic neuritis associated with influenza vaccination (96).
Appendix C.—Summary of Medical Literature Review of

Effectiveness of Inactivated Influenza Virus Vaccines*

by Robert Couch, M.D.

Baylor College of Medicine

For purposes of analysis, vaccines were characterized by populations used for testing, type of vaccine,

dose, number of doses, whether the vaccine was

proven to be immunogenic, the interval between vaccination and challenge, whether the naturally occurring challenge was with homologous or heterologous

virus, the clinical attack rate of illness in the population, and the calculated efficacy.

Seventy-seven trials reporting effectiveness against

naturally occurring influenza were identified, 60 for

type A and 17 for type B influenza. Three trials were

rejected; in two of these, no protection was seen but

the attack rate was low and influenza virus was not

shown to be a cause of illness, and in one, protection

was 23 percent but vaccine was given during the outbreak. Two of these were type A trials and one was a

type B trial. Two type A and four type B trials were

with adjuvenated vaccine, a type of vaccine never

distributed for general use in this country. These

were also excluded from this analysis.

The range of reported effectiveness for each virus

type was O to 96 percent. The effectiveness for

aqueous inactivated vaccines varied according to

virus type and relationship of challenge virus to vaccine virus. A designation of homologous challenge

indicates that vaccine virus and epidemic virus were

identical, whereas heterologous indicates the natural

challenge was with a virus that exhibited minor

(drift) or major (shift) antigenic differences from vaccine virus. The majority of trials reported effectiveness greater than 60 percent for homologous virus

challenge, but protection against heterologous virus

was more variable. Only six trials in the elderly were

reported and these were for type A. No trials involving infants and small children were identified.

Effectiveness was also summarized by population

group and vaccine dose among those experiencing

challenge with homologous virus. Greater protection

● NOTE This report was presented at a Workshop on Influenza B Viruses

and Reye’s Syndrome, National Institute of Allergy and Infectious Diseases,

National Institutes of Health, Bethesda, Md., July 30-31, 1979. It is based on

a search of the English language literature, Eighty-five percent of possible

references identified were obtained. Sources used were as follows: C G

Loosli, International Bibliography of lnfluenza, 1930-1959; Medlars Service

of the National Library Medicine; and Cumulative lndex Medicus. The

author’s bibliography appears a t the end of this appendix.

was reported for studies involving military personnel

than civilian, and this was most notable for type B

vaccines. This may be partly explained by the fact

that early trials involved the military primarily and

higher doses of vaccine were used than in later trials.

Two of the civilian trials with type B vaccine were in

remote populations (South Pacific natives and

Alaskan Eskimos) who experienced very high attack

rates of illness; the vaccines failed to exhibit any protective effect. No studies in remote populations were

identified for type A virus.

Only eight trials used two doses of vaccine, although three others involved persons who had received either one or two doses. No difference in protection occurring in these trials compared to those

using one dose was noted. Immunogenicity of the

vaccine was proven in the majority of trials. In one

trial, the vaccine was proven not to be immunogenic,

and this resulted in 13-percent protection of an elderly population against a heterologous virus. Clinical

attack rates of illness in the population appeared

unrelated to degree of effectiveness. Only four

reports involved very high attack rates (70 to 90 percent), the two noted above for type B with no protection and two with type A in the military with

reported effectiveness of 57 and 77 percent. Protection against antigenically novel viruses (shift) with

homologous vaccine virus was generally low in 1947

and 1968 but good in 1957.

Protection 14 to 16 months after vaccination was

O, 35, 80, and 85 percent in four studies and 60 percent after 3 years in one study. All other studies involved challenge in 1 to 9 months after vaccination.

Thus, factors evaluated that might relate to degree

of effectiveness of vaccine were remoteness of

population studied, attack rates of illness and age

and health status of given populations, dose of vaccine (particularly for type B), interval between vaccination and challenge, and antigenic novelty of the

virus. Any one or more of these factors may be more

important for one type of vaccine than for another,

but the relative significance of each could not be

discerned. Clearly, the most significant factor identified in this review that influences degree of effectiveness is the antigenic relationship between the vaccine and challenge (epidemic) virus.

4 3
44 ● Cost Effectiveness of Influenza Vaccination

Conclusion: Review of the medical literature on effectiveness of aqueous inactivated influenza virus

vaccines provided support for the belief that these

vaccines are generally effective for prevention of

clinical influenza, particularly if the epidemic virus is

antigenically similar to the vaccine virus and if vaccine is given in the immediate few months preceding

Appendix C Bibliography*

Bashe, W. J., Jr., Stegmiller, H., Leonida, D., and Greenwald, P., “Failure of Polyvalent Vaccine To Provide

Clinical Protection Against Asian Influenza, ” N. ~ng. ].

Med. 270:870-874, 1964.

Blake, F. G., “An Evaluation of Vaccination Against

Epidemic Influenza in Man, ” Bull. N, Y. Acad. Med.

24:308-328, 1948.

Briscoe, J. H. D., “The Protective Effect of Influenza Vaccine in a Mixed Influenza A and B Epidemic in a Boys’

Boarding School,” ]. Royal CoIl. Gen. Prac. 27:28-31,

1977.

Brown, P., Felta, E. T., List-Young, B., Ritter, D. G., and

Noble, G. R., “An Influenza B Epidemic Within a Remote Alaska Community: Serologic, Epidemiologic, and

Clinical Observations,” ). A.M.A. 214:507-512, 1970.

D’Allessio, D. J., Cox, P. M., and Dick, E. C., “Failure of

Inactivated Influenza Vaccine To Protect an Aged Population,” J. A.M.A. 210:485-489, 1969.

Davenport, F. M., Hennessy, A. V., Houser, H. B., and

Cryns, W. F., “An Evaluation of an Adjuvant Influenza

Vaccine Tested Against Influenza B in 1954-1955,” Am,

]. I-Iyg. 64:304-313, 1956.

Fey, H. M., Cooney, M. K,, and McMahan, R., “A/Hong

Kong Influenza Immunity Three Years After Immunization,” /. A,M.A, 226:758-761, 1973.

Fey, H. M., Cooney, M. K., McMahon, R., Bor, E., and

Grayston, J, T., “Single-Dose Monovalent A2/Hong

Kong Influenza Vaccine, ” ]. A.M.A. 217:1067-1071,

1971.

Francis, T., Jr., Salk, J. E., and Brace, W. M., “The Protective Effect of Vaccination Against Epidemic Influenza B,”

]. A.M.A. 131:146-156, 1946.

Gundelfinger, B. F., Stille, W. T., and Bell, J. A., “Effectiveness of Influenza Vaccines During an Epidemic of

Asian Influenza,” N. Eng. ]. Med. 259:1005-1009, 1958.

Hammond, M. L. Ferris, A. A., Faine, S. and McAvan, T.,

“Effective Protection Against Influenza After Vaccination With Subunit Vaccine, ” Med. ]. Aust. 1:301-303,

1978.

Hennessy, A. V., Minuse, E., Davenport, F. M., and

Francis, T., Jr., “An Experience With Vaccination

Against Influenza B in 1952 by Use of Monovalent Vaccine, ” Am. ]. Hyg. 58:165-173, 1953.

● Prepared 9 months after search; four additional references could not be

located.

exposure. The commonly quoted figure of 70-percent

protection against illness in this circumstance seems

reasonable. Deficiencies in present knowledge exist

regarding effectiveness of aqueous vaccines in elderly

and chronically ill persons, on duration of effectiveness, on the mechanism of protection, and on

type B vaccines in general.

Hirst, G. K., Vilches, A., Rogers, O., and Robbins, C. L.,

“The Effect of Vaccination on the Incidence of Influenza

B,” Am. J. Hyg. 45:96-101, 1947.

Hoskins, T. W., Davies, J. R., Allchin, A., Miller, C. L.,

and Pollock, T. M., “Controlled Trial of Inactivated Influenza Vaccine Containing the A/Hong Kong Strain

During an Outbreak of Influenza Due to the A/

England/42/72 Strain, ” ,1.ancet, 116-122, 1973.

Knight, V., Couch, R. B., Douglas, R. G., and Tauraso, N.

M., “Serological Responses and Results of Natural Infectious Challenges of Recipients of. Zonal Ultracentrifuged

Influenza A2/Aichi/2/68 Vaccine, ” Bull. W.H. O.

45:767-771 ,

Leibovitz, A., Coultrip, R. L., Kilbourne, E. D., Legters, L.

J., Smith, D. C., Chin. J., and Schulman, J. L., “Correlated Studies of a Recombinant Influenza Virus Vaccine.

IV. Protection Against Naturally Occurring Influenza in

Military Trainees, ” ]. Infect. Dis. 124:481-487, 1971.

Mascoli, C. C., Leagus, M. B., and Hilleman, M. R., “Influenza B in the Spring of 1965,” Proc. Soc. Exp. Biol.

Med. 123:952-960, 1966.

Maynard, J. E., Dull, H. B., Feltz, E. T., Berger, R., and

Hammes, L., “Evaluation of Monovalent and Polyvalent

Influenza Vaccines During an Epidemic of Type A2 and

B Influenza,” Am. J. Epid. 148-157, 1967.

McDonald, J. C., and Andrews, B. E., “Influenza in the

United Kingdom, 1953-1956. Report to the Medical Research Council Committee on Clinical Trials of Influenza

Vaccine by the Public Health Laboratory Service, ” Brit.

Med. ]. 5035:8-10, 1957.

Medical Research Council Committee on Influenza and

Other Respiratory Virus Vaccines, “Trials of an Asian Influenza Vaccine: Fourth Progress Report,” J3rit. Med. ].

1:415-418, 1958.

Meiklejohn, G., “Effectiveness of Monovalent Influenza

A-Prime Vaccine During 1957 Influenza A-Prime Epidemic,” Am. J. Hyg. 67:237-249, 1958.

Mogabgab, W. J., and Leiderman, E., “Immunogenicity of

1967 Polyvalent and 1968 Hong Kong Influenza Vaccines,” ]. A.M.A. 211:1672-1676, 1970.

Nelson, A. J., “Evaluation of Asian Influenza Vaccine in an

Industrial Population, ” Can, Med. Assn. ]. 79:888-891,

1958.

Newnham, C. T., ‘Evaluation of an Influenza Vaccine Program in Industry,” Brit. J. C]in. Prac. 16:778-779, 1962 .

Norwood, W. D., and Sachs, R. R., “The Protective Effect
— ——

Appendix C—Summary of Medical Literature Review of Effectiveness of inactivated influenza Virus Vaccines ● 45

of Vaccination Against Epidemic Influenza B in an Industrial Plant, ” lndus. Med. 16:1-3, 1947.

Pavilanis, V., Frappier, A., Isomlo, F., Boudreault, A., and

Claveau, P., “Evaluation of the Effectiveness of Anti-Influenza Vaccination,” Can. Med. Assn. ]. 79:527-532,

1958.

Philip, R. N., Bell, J. A., Davis, D. J., Beem, M. O.,

Beigleman, P. M., Engler, J. I., Mellin, G. W., Johnson,

J. H., and Lerner, A. M., “Epidemiologic Studies on Influenza in Familial and General Population Groups,

1951 -1956,” Am. ]. Epid. 90:471-483, 1969.

Ruben, F. L., DeKalb, I., Akers, L. W., Stanley, E. D., and

Jackson, G. G., “Protection With Split and Whole Virus

Vaccines Against Influenza, ” Arch. ]ntern. Med.

132:568-571, 1973.

Salk, J. E., and Suriano, P. C., “Importance of Antigenic

Composition of Influenza Virus Vaccine in Protecting

Against the Natural Disease: Observations During the

Winter of 1947-1948,” Am. ]. Pub. Health 39:345-355,

1949.

Salk, J. E., and Rapalski, A. J., “Evaluation of Influenza

Vaccine in an Explosive Epidemic of Mixed Etiology, ”

U. S.A. F. Med. ]. 9:469-478, 1958.

Salk, J. E., and Suriano, P. C., “Importance of Antigenic

Composition of Influenza Virus Vaccine in Protecting

Against the Natural Disease: Observations During the

Winter of 1947-1948, ” Am. ]. Pub. Health 39:345-355,

1949.

Smith, J. W. G., and Pollard, R., “Vaccination Against Influenza: A Five-Year Study in the Post Off ice.,” ]. Hyg.

Carob. 83:157-170, 1979.

Stiver, H. G., Graves, P., Eickoff, T. C., and Meiklejohn,

G., “Efficacy of ‘Hong Kong’ Vaccine in Preventing

‘England’ Variant Influenza A in 1972, ” AJ’. Eng. ). Med.

289:1267-1271, 1973.

Stuart, W. H., Dull, H. B., Newton, L. H., McQueen, J.

L., and Schiff, E. R., “Evaluation of Monovalent Influenza Vaccine in a Retirement Community During the

Epidemic of 1965-1966, ]. A.M.A. 209:232-238, 1969.

Sugiura, A., Yanagawa, H., Enomoto, C., Ueda, M.,

Tobita, K., Matsuzaki, N., Suzuki, D., Nakaya, R., and

Shigematsu, I, “A Field Trial for Evaluation of the Prophylactic Effect of Influenza Vaccine Containing Inactivated A2/Hong Kong and B Influenza Viruses, ” ]. Infect, Dis. 122;472-478, 1970.

Tyrrell, D. A. J., Buckland, R., and Rubenstein, D., “Vaccination Against Hong Kong Influenza in Britian,

1968-1969,” ]. Hyg. Carob. 68:359-368, 1970.

Van Ravenswaay, A. D., “Prophylactic Use of Virus Vaccine: Instance of Inadequate Protection Against Influenza, ]. A.M.A. 136:435-437, 1948.

Waldman, R. H., and Coggins, W. J., “Influenza Immunization: Field Trial on a University Campus, ” ]. ]nfect.

Dis. 126:242-248, 1972.

Waldman, R. H., Mann, J. J., and Small, P. A., Jr., “Immunization Against Influenza: Prevention of Illness in

Man by Aerosolized Inactivated Vaccine, ” J. A.M.A.

207:520-524, 1969.

Warburton, M. F., Jacobs, D. S., Langsford, W. A., and

White, G. E., “Herd Immunity Following Subunit Influenza Vaccine Administration, ” Med. ]. Aust. 2:67-70,

1972.
Appendix D. —A Description of Guillain=Barre Syndrome

Due to Influenza Vaccine*

Reprinted from Arthur D. LittIe,

Estimated Economic Costs of Selected Medical Events Known or Suspected To Be Related

to the Administration of Common Vaccine,

written for the Office of Health, Research, Statistics, and Technology,

National Center for Health Services Research,

DHEW contract No. 233=78-3013, appendix C, Dec. 31, 1979, pp. 157=161.

Clinical Profile

Etiology

The Guillain-Barre Syndrome (GBS) was first

described by Landry in 1859 (l), then by Guillain,

Barre, and Strohl in 1919 (2). It is also known as

acute postinfectious neuritis, acute ascending

paralysis and polyradiculoneuritis. The etiology has

not been definitively established, although it has

been associated with a variety of viral, bacterial, and

other infections, as well as endocrine, hematologic,

dermatologic, allergic and neuropsychiatric disorders, various toxins and drugs, and with vaccines

for rabies, tetanus, typhoid, pertussis, diptheria,

smallpox, polio, and influenza (3).

Clinical Manifestations

Although the clinical presentation is fairly

uniform, numerous diagnostic criteria have been proposed without universal acceptance. In addition to

the original descriptions, detailed criteria have been

outlined by Osler and Sidell (4), Marshall (5), Wiedenholt, et al (6), McFarland and Heller (7), Ravn (8)

and Masucci and Kurtzke (9). In 50 to 75 percent of

nonvaccine-related cases, a history of mild respiratory or gastrointestinal infectious illness, within the

preceding 4 weeks, can be elicited. In vaccine associated cases, there is no preceding acute infectious illness in 75 percent of cases (10). There is usually an

asymptomatic afebrile period of 1 to 3 weeks, then

vague pains or paresthesia of the hands and feet are

reported in 75 to 90 percent of cases. The first symptom of prominence is muscle weakness, involving the

proximal or distal muscles of the legs, then the arms,

but this ascending progression is by no means constant. This involvement is usually bilateral (95 percent) but may be asymmetric. The progression of

sensory and other symptoms is gradual and usually

complete within 2 weeks, but occasionally can continue for months. Facial weakness and involvement

● NOTE: Reference citations for app. D refer to the list of references at the

end of app. D .

4 6

of any or all cranial nerves occur in 50 to 80 percent

of cases. Cranial nerves are more often involved in

vaccine-associated cases (10). Urinary incontinence

or retention may occur in 20 percent but is transient.

From 10 to 25 percent of patients may have paralysis

of breathing and require artificial respiratory support. Pulmonary complications, anoxia and seizures,

and residual neurological deficits may occur, but

complete recovery is gradually achieved in one year.

Mortality, usually from respiratory involvement, is

approximately 5 percent. Residual paralysis occurs in

10 to 30 percent of cases.

Physical examination is marked by bilateral motor

weakness of the lower extremities, upper extremities,

and trunk. Muscle atrophy and fasciculations may be

noted. Sensory deficits may involve position, vibration pain, and light touch. Deep tendon reflexes are

depressed or absent; superficial reflexes may be absent, but are usually intact. As noted, cranial nerves

may be involved, and papilledema may be found.

Some patients, especially children, may have neck

stiffness as a sign of meningeal irritation (11). Autonomic dysfunction with hypertension, postural hypotension, facial flushing, and tachycardia may

occur.

Laboratory abnormalities are few, but CSF findings are diagnostic. CSF protein should be elevated

(above 60 mg/dl), but may be within normal limits

early in the illness. The CSF cell count is usually less

than 20 WBC/cmm. Peripheral white blood cell

count, differential, and erythrocyte sedimentation

rates are usually normal. Serum calcium may be elevated in patients immobilized for prolonged periods

and electrolyte imbalances with inappropriate secretion of antidiuretic hormone have been reported.

Electromyography is usually diagnostic (fasciculations), and motor nerve conduction is delayed.

Epidemiology

In February 1976, an influenza virus was isolated

during an epidemic at Fort Dix, N. J., antigenically

similar to the virus implicated in the 1918 influenza

pandemic. The Federal Government then initiated a
Appendix D—A Description of Guillain-Barre Syndrome Due to Influenza Vaccine ● 47

project to immunize much of the population of the

United States. Between October 1, 1976, and

December 16, 1976, nearly 43 million doses of killed

influenza A/New Jersey/1976 vaccine were administered. The program was abruptly halted when an

increasing number of reports of GBS (associated with

vaccine inoculation) were reported. By January 10,

1977, a total of 581 cases of GBS had been reported,

of which 295 had received the vaccine. 11 percent of

the patients who received vaccine were less than 3

years of age. Fifty-eight percent were between 30 and

59 years, and 31 percent were 60 years or older. Of

266 unvaccinated patients, 4 percent were less than

30 years, 39 percent between 30 and 59, and 17 percent were 60 or older. There was no differences between sexes. Cases were noted in 49 of 50 States (12).

The clinical states of vaccinated and non-vaccinated patients as reported by the Center for Disease

Control were remarkably similar, significantly differing only in history of previous acute (27 v. 62 percent) or chronic illness (44 v. 27 percent), involvement of cranial nerves (64 v. 47 percent), and sensory

symptoms (87 v. 74 percent). Of the vaccinated patients, there were 41 percent with respiratory involvement, 23 percent placed on a respirator and 5

percent of 299 cases died. Within 8 to 28 days following vaccination, 75.2 percent had onset of paralysis,

3.3 percent within 7 days after vaccination, and 21.5

percent more than 28 days following vaccination

(lo).

The relative risks of GBS in influenza vaccinated

persons was approximately 12 times greater than in

unvaccinated persons (10). The risk was similar for

monovalent or bivalent vaccine. Age-specific attack

rates per million population per month were 2.48 for

vaccinated v. 0.34 for unvaccinated in ages O to 17

years, 3,45 and 0.70 for ages 18 to 24, 9.21 and 0.56

for ages 25 to 44, 6.49 and 0.81 for ages 45 to 64, 7.22

and 0.76 for over 65, and 6.99 and 0.58 for all ages.

Thus, all ages were at risk.

Pathology

Pathological examination varies with the stage of

disease progression. There are no significant pathologic changes in the cerebrum, brain stem, or spinal

cord, except for severe changes in the anterior horn

cells and motor nuclei of the brain stem. Acutely,

there is marked edema of the spinal roots and cranial

nerves. Later, demyelination and degeneration of the

spinal and cranial nerve axons are seen. Lymphocytic

inflammatory cells invade the myelin sheath and

Schwann cell proliferation follows. Chromatolysis of

dorsal root ganglia and anterior horn cells may be

observed (13).

Diagnosis

Diagnostic criteria are those outlined under clinical

manifestations and include:

1.

2.

3.

4.

5.

6.

acute or subacute onset of muscle weakness

and/or sensory symptoms (i. e., paresthesia,

numbness or pain);

usually ascending spread (may be descending,

or variable) with progression over 1 to 2 weeks

(up to 2 months);

bilateral (may be asymmetric) muscle involvement;

deep tendon reflexes absent or diminished;

cranial nerves may be involved; and

CSF protein elevated ( >60 mg/dl), CSF WBC

count < 20/cmm.

Differential Diagnosis

The differential diagnosis of influenza-vaccineassociated GBS includes:

1.

2.

3.

4.

5.

GBS secondary to other causes, including viral

infections (infectious mononucleosis, measles,

hepatitis, upper respiratory and gastrointestinal

infections, etc. ), bacterial infections (strep tococcal, etc.), other vaccinations, (rabies, tetanus

toxoid, etc.), autoimmune disorders (lupus erythematosis, polyarteritis nodosa, etc. ) malignant diseases (Hodgkin’s disease, etc.), endocrine disorders (diabetes mellitus, etc.), poisons

and toxins and antibiotic therapy (penicillin,

etc.). Only a complete history, appropriate viral

cultures and serologies, toxic screens, and

search for underlying disease can implicate these

disease etiologies.

Poliomyelitis, which is differentiated by epidemic occurrence, meningeal symptoms, biphasic course (aseptic meningitis then

paralysis), fever, asymmetric muscle involvement, CSF pleocytosis without cytoalbumin dissociation and positive viral cultures.

Acute myelitis, which is marked by sensorimotor paralysis below a specific spinal level.

Diphtheric polyneuropathy characterized by

weakness or paralysis of limbs and muscles innervated by cranial nerves associated with loss

of position and vibratory sensation. This can be

easily diagnosed by the obvious symptoms of

laryngeal, pharyngeal or nasal diptheria, i.e.,

fever, pseudomembrane, proteinuria and positive culture for Corynebacteria diptheriae.

Porphyric polyneuropathy, a rapidly advancing

severe, symmetric polyneuropathy with or

without psychosis or convulsions. Diagnosis of

underlying porphyria is accomplished by usual

serum and/or urine tests.
Outcomes

Few prognostic data are available regarding influenza vaccine associated cases of GBS. Prognosis of

other cases is usually good. Death occurs in approximately 5 percent of cases (5,6,10,14).

In vaccine associated cases, 3 to 4 extremities are

involved in 85 percent of cases, cranial nerves in 47

percent, respiratory impairment occurs in 41 percent,

and ventilator assistance is required in 25 percent

(lo).

The duration of hospitalization ranges from weeks

to years depending upon the eventual outcome. Of

97 patients from the Mayo Clinic (6), 50 made complete recovery with a year, 7 more in 2 years, and 4

more after 2 years. Twelve patients made incomplete

recovery, five had moderate incapacity, four marked

incapacity, and three respiratory insufficiency. FifAppendix D References

1.

2.

3.

4.

5.

6.

7.

8.

9.

Landry, O., “Note sur las Paralysie Ascendance

Aigue, ” Gaz. Hebd. Med. 6:472:474, 486-488, 1859,

Guillain, G., Barr@, J. A., and Stronhl, A., “Sur un

Syndrome de Radiculo-Nevrite avec Hyperalbiminose

du Liquide Cephalorachidien saris Reaction Cellulaire:

Remarques sur Ias Caracteres Linques et Graphiques

des Refexes Tendineux, ” Bull. SOC. Med. Hop. Paris

40:1462-1470, 1916.

Leneman, F., “The Guillain-Barr@ Syndrome, ” Arch.

lnt. Med. 118: 139-144, 1966.

Osler, L. D., and Side] D. “The Guillain-Barr6_ Syndrome,” N. Eng. ], Med. 262:964-969, 1960.

Marshall J., “The Landry-Guillain-Barr{ Syndrome,”

Brain 86:55-56, 1963.

Wiederholt, C., Mulder W., and Lambert H., Mayo,

C/in. Proc. 39:427-451, 1964.

McFarland, H., and Heller, L., “Guillain-BarrE Disease

Complex,” Arch, Neurol. 14:196-201, 1966.

Ravn, H. , “The Landry-Guillain-Barre Syndrome, ”

AC’TA Neurol. Scan. Suppl, 30, 43:1-64, 1967.

Masucci, E. F., and Kurtzke, J. F., “Diagnostic Criteria

teen patients were improved when last seen, four unchanged 3 or more years after diagnosis, and five

dead. From Columbia Presbyterian Medical Center,

49 of 81 patients were reexamined at least 2 years

after onset of GBS. Of these, 8 had marked distal

weakness, and 8 mild distal weakness (14).

Impairment may range from mild weakness of one

or more extremities to marked paralysis and respiratory insufficiency requiring ventilator assistance,

and constant nursing care. Relapses may occur weeks

or years after resolution’ of symptoms (14,15). Influenza vaccination of persons who have previously

suffered from GBS may precipitate a second attack

(16). From 50 to 60 perceni of patients should be able

to return to their normal routine within 1 year of

onset. Approximately 15 percent will be completely

disabled (6,14).

10

11

12

13.

14,

15.

16.

17.

for the Guillain-Barr{ Syndrome, ” ]. Neurol. Sci.

13:483-501, 1971.

Center for Disease Control, Handout #4, Jan. 7, 1977.

Paulson, G. W., “The Landry-Guillain-Barr6-Strohl

Syndrome in Childhood,” Devel. Med. Child. Neurol.

12:604-607, 1970.

Center for Disease Control, Morbidity & Mortality

Weekly Report, 26:7, 1977.

Haymaker, W., and Kernohan, W., “The Landry-Guillain-Barr@ Syndrome, ” Medicine 28:59-141, 1949.

Pleasure, E., Lovelace, E., and Duvoisin, R. C., “The

Prognosis of Acute Polyradiculoneuritis, ” Neurol.

18:1143-1148, 1968.

Bolin, T. D., and DeCarle, D. J., “Recurrent GuillainBarr6 Polyneuritis,” Med. J. Aust. 2: 263-264, 1972.

Thomas, P. K., Lascelles, R. G., Hallpike, J. F., and

Hewer, R. L., “Recurrent and Chronic Relapsing Guillain-Barre Polyneuritis, Brain 92: 589-606, 1968.

Seyal, M., Ziegler, K., and Couch, R., “Recurrent

Guillain-Barr@ Syndrome Following Influenza Vaccine, ” Neurol. 28:725-726, 1978.
Appendix E.—Values Assigned

to Selected Variables

This appendix describes the sources of data, methods, and assumptions that OTA used to assign values

to the following variables in its analysis of the cost effectiveness of influenza vaccination: 1) vaccination

cost, 2) vaccine effectiveness rate, 3) duration of vaccine-induced immunity, 4) vaccine side effects and

their treatment costs, S) hospitalization related to influenza, 6) ambulatory care related to influenza,

7) excess mortality related to influenza, 8) the cost of

treating illnesses in extended years of life, 9) medicare

expenditures, 10) work loss, 11) values assigned to

selected characteristics of the influenza high-risk population, and 12) the discount rate.

Vaccination Cost

Base Case: Adult: $6.00 Child: $11.09

Sensitivity Analysis: Adult: $155 to $9.39

Child: $4.50 to $19.60

There are two components to vaccination cost—

purchase price of the vaccine and the cost of administering the vaccine. Both components can vary substantially each year. The price of the vaccine is determined by such factors as these:

●

●

●

●

●

●

●

●

●

manufacturers’ production and distribution

costs;

manufacturers’ desired profit margin;

level of competition among manufacturers;

number of doses being purchased (purchasers of

large quantities usually pay a lower price per

dose);

type of vaccine (whole virus v. split product;

monovalent v. polyvalent);

type of purchases—public v. private;

number of doses administered per person (children and young adults in some years require two

doses per season; adults usually require one

dose);

type and size of product container purchased

(e.g., prefilled syringes v. multiple-disc vial);

and

the “returned goods” policy of manufacturers

(i.e., a manufacturer’s willingness to purchase

back unused portions of vaccine).

Factors that affect the cost (or the price) of administering the vaccine include these:

. number of doses administered per person;

● type of place or person administering the vaccine (e.g., private physician’s office v. public

health clinic);

● geographical location of vaccination; and

● type of vaccination procedure used (e. g., “jet”

gun v. syringe and needle).

The estimates of influenza vaccination costs in

OTA’s study were based on the following data and

observations. First, data on vaccine selling prices

were obtained from an OTA survey of selected vaccine manufacturers. Overall, selling prices for the

whole virus influenza vaccine—when purchased in

lo-dose (5CC) vials—ranged from $0.45 to around

$1.70/dose over the period from 1977 through 1980.

The cost of split virus vaccine most often was higher

than that of whole virus and ranged from about $1 to

$2/dose. Whole virus vaccine sold in prefilled

syringes from one company ranged from about

$1.65/dose to approximately $2.00/dose in 1978-79.

Second, the vaccine purchase prices paid during

the years 1977-78 through 1980-81 were obtained

from selected public and private vaccine purchasers

(see table E-1). The purchase price of influenza vaccine varied substantially from year to year (e.g., a

private sector purchaser experienced a 50-percent increase in 2 years). Further, in all years, public sector

purchasers commanded a lower price than private

sector purchasers. In 1979-80, the Federal Government through the Centers for Disease Control (CDC)

negotiated with manufacturers a purchase price that

applied to all State government vaccine consumption. In that year, public sector purchasers bought a

dose of whole virus vaccine for $0.29, while some

private sector purchasers paid $1.07. In 1980-81,

CDC did not negotiate a uniform purchase price, but

some State health departments are paying a price up

to 20 percent lower than some private sector purchasers.

Third, the cost incurred or the price charged for

administering influenza vaccine was solicited from

selected private and public sector sources. The six

public health clinics surveyed do not charge a fee for

administering the vaccine. Some, however, are contemplating charging $1 to $2 per person. On the basis

of data generated from the 1976 swine influenza program, Tolsma and Millar estimated that vaccine was

administered in that program for about $1/dose, exclusive of the cost of vaccine (122). The use of “jet

gun” vaccine administration undoubtedly contributed to low vaccine costs. Updated for inflation, that

$1.00 cost would be $1.25 in 1978,

In the private sector, surveyed clinics charged

$3.00 to $8.00 to administer the vaccine. In some

4 9
Table E-1 .—Price per Dose of Influenza Vaccines Paid by Selected Purchasers,

1977-78 Through 1980.81

Purchaser and type of vaccine 1977-78 1978-79 1979-80a

1980-81

Public sector

West coast State health department:

Whole virus . . . . . . . . . . . . . . . . . . . . $ .65 $ .29 $1.00

Split virus . . . . . . . . . . . . . . . . . . . . . $.65 $1.80 $.99 –

Southern State health department:

Whole virus . . . . . . . . . . . . . . . . . . . . — — $ .29 $1.18

Split virus . . . . . . . . . . . . . . . . . . . . . — — $ .99 $1.95

Center for Disease Control:

Adult formula . . . . . . . . . . . . . . . . . . — $.34 to $ .49 – –

Youth formula. . . . . . . . . . . . . . . . . . — $.77 to $1.66

Whole virus . . . . . . . . . . . . . . . . . . . . — — $ .29 _ 

Split virus . . . . . . . . . . . . . . . . . . . . . — — $ .99 –

Private sector

West coast university hospital:

Whole virus . . . . . . . . . . . . . . . . . . . . $ .82 $1.07 $1.12

Split virus . . . . . . . . . . . . . . . . . . . . . $.78

Syringes . . . . . . . . . . . . . . . . . . . . . . — $1.15 $1.38 -

Northeast university hospital:

Whole virus . . . . . . . . . . . . . . . . . . . . — $ .82 $1.07 $1.20

aln 1 gTg.f30 the Fe@ral Government negotiated a Set price with manufacturers for the price Of lnft UenZa vaccine. State

governments participating in federally sponsored influenza immunization programs received vaccines at those negotiated

prices

SOURCE” Office of Technology Assessment.

cases, vaccine was supplied by State health departments free of charge to practicing physicians who can

charge patients their normal vaccine administration

fees, exclusive of the cost of vaccine. When persons

require 2 doses of vaccine (e.g., those under 25

years), some physicians reportedly reduce their administration fees somewhat to yield a “package cost”

per person.

Fourth, the vaccine administration fee charged by

physicians was also calculated with data from three

other sources. First, it was determined from the 1969

California Relative Value Scale that vaccine administration is valued at one-half the value of a brief examination followup visit for an established patient

(17). Second, it was determined from an article by

Muller and Otelsburg (76) that in 1977 the mean physician charge for such a visit for a medicare patient

was $9.56. Third, one-half of this charge, i.e., $4.78,

was then adjusted for inflation for years 1977-78 by

multiplying it by the physician services component of

the consumer price index (CPI). The vaccination

charge thus calculated for 1978, for example, was

$5.18.

For the past 3 to 4 years, the Immunization Practices Advisory Committee (ACIP), the official vaccination advisory body to the Federal Government,

has recommended that children and young people receive two doses of split virus vaccine instead of one

dose of whole virus vaccine. Therefore, OTA derived

special vaccination costs for those vaccinees under 25

years of age.

For public and private sector provision of influenza vaccination in 1978, OTA derived the following

costs:

Public Sector Vaccine price + Administration = Total vaccination

cost

Low Estimate

cost per person

per year

$0.30/dose + $1 25/dose = $1.55

Child/young adult <25 $2.00/2 doses + $2,50/2 doses = $4.50

High Estimate

$0.65/dose + $1 25/dose = $190

Child/young adult <25 $3.60/2 doses + $2 50/2 doses = $6.10

Private Sector

Low Estimate

$0.82/dose + $5.18/dose = $6.00

Child/young adult <25 $3.32/2 doses + $77712 doses = $1109

High Estimate

$1.39/dose + $8.00/dose = $9.39

Child/young adult <25 $3.60/2 doses + $16.00/2 doses = $1960

Vaccine Effectiveness Rate

As described in appendix B, the effectiveness of influenza vaccine is measured in terms of either: 1) its

documented ability to reduce in clinical trials the incidence—and perhaps the morbidity and mortality—of influenza among vaccinated subjects; or 2) its

ability to stimulate the production of antibodies

which are presumed to provide protection against influenza among vaccinated subjects. In OTA’s analysis, the effectiveness rate of inactivated influenza
Appendix E–Values Assigned to Selected Assumptions and Variables ● 51

virus vaccine was based only on data relating to the

vaccine’s ability to reduce clinical disease. Such data

are difficult to find and, in some cases, quite difficult

to interpret and extrapolate to populations beyond

the clinical trial setting. Based on data outlined in

appendix B, a vaccine effectiveness rate of 60 percent

was used for all years in the base case analysis; that

rate was varied from 30 to 90 percent in the sensitivity analysis.

Duration of Vaccine-Induced Immunity

As explained in appendix A (by Dr. Gary Noble,

CDC), the duration of immunity provided by a particular influenza vaccine can vary substantially.

Because there is no reliable indicator of the population’s influenza antibody status—especially concerning antibodies to an upcoming variant of an influenza

virus, ACIP recommends yearly influenza vaccinations for selected high-risk groups. On the basis of

ACIP’s recommendation, it was assumed in OTA’s

analysis that the effective duration of immunity of influenza vaccination would be 1 year. Undoubtedly,

for some individuals, vaccine-induced immunity

against some influenza viruses exceeds 1 year; however, on the basis of existing data, it is not possible to

quantify differences in duration of immunity beyond

1 year among populations.

Vaccine Side Effects and Their

Treatment Costs

The incidence, health effects, and costs of treating

adverse reactions to influenza vaccines were quantified as described below.

Mild Local and Systemic Reactions

(see app. B for description of reactions)

The following data were used to quantify mild

local and systemic vaccine side effects in the base case

and in the sensitivity analysis.

Adults (18 years and older)

Incidence: 5 percent of all vaccinees (90)

Treatment costs: 1 physician visit = $10.36

Health effects: 1 day of nonbed disability

Children (under 18 years)

Incidence: 13 percent of all vaccinees (90)

Treatment costs: 1 physician visit = $10.36

Health effects: 1 day of nonbed disability

Guillain-Barre Syndrome (GBS)

In the base case, it was assumed that,

(in 1978) (76)

(in 1978) (76)

in all years

except 1976-77, no excess GBS was attributable to influenza vaccine. For 1976-77, the incidence and

nature of GBS occurring during the swine flu immunization program were used, The types, incidence,

and treatment costs of GBS during 1976-77 are displayed in table E-2 (4,112),

Table E.2.—Guillain Barre Syndrome Among 1976-77 A/New Jersey Influenza Vaccinees

Severe (respiratory

5 % 00/0 365 – $33,181 $30,241 $30,319 $29,865

($1,832 for the 2nd year)

($1,552 for each added year of life)

Severe (paralysis of

5 % 0 % 365 – $43,659 $37,779 $36,129 $37,040

($5,140 for the 2nd year)

($3,661 for each added year of life)

Death. . . . . . . . . . . . . . . . . . — 5 % 1000/0 60 – $23,685 $20,689 $20,839 $22,734

aT~ ~btaf” age.~peclflc Incldences, these estimates were multlpl!ed by the fOl10Wln9 attack rates (1 12):

Age Attack rate (casesJmilllon vacclnees) ——

0-17 yeari 1.1

18-24 years . . 3.3

25-44 years . . 9.1

45-64 vears 7.5

z 65 ‘years 7.3

bBecj days are equivalent to total number of days spent In a hospital Or Iong.term car@ facllltY

cNonbed days are equivalent t. the difference between bed days and either 180 or 365, dependln9 on tYPe of GBS case

SOURCE Based on data from Estimated Econorn/c Costs of Selected Medical Events Known or Suspected TO Be Related to the Admmlstratlon of Common Vacc/nes

(4)
52 . Cost Effectiveness of Influenza Vaccination

Anaphylaxis

It was assumed in the base case and in the sensitivity analysis that the incidence of severe anaphylaxis

(severe allergic reaction) associated with influenza

vaccination for any year was 1 case per 4 million vaccinees (107). The assigned treatment costs (in 1978

dollars) and health effects of such a reaction were the

following.

costs

3 days of hospitalization

6 inpatient physician visits

1 outpatient physician visit

Total cost per case

Health Effects

3 days of bed disability

2 days of nonbed disability

= $581.43

= 132.72

. 10.36

$724.51

Hospitalization Related to Influenza

The content and cost of a hospitalized case of influenza/pneumonia were constructed with data obtained from the Hospital Discharge Survey of the National Center for Health Statistics (NCHS), an article

by Muller and Otelsberg (76), and the Blue Cross/

Blue Shield option of the Federal Employee Health

Benefits Program.

The construction of a hospitalized case is as described below.

Length of Stay

The length of stay for a hospitalized case of influenza/pneumonia was calculated from data provided

by the Hospital Discharge Survey. The total number

of days of hospitalization assigned to 8th Revision

ICDA Codes 470-474 (all influenzas) and 480-486 (all

pneumonias) as a first-listed diagnosis was divided

by the total number of hospital discharges assigned

to the same ICDA codes. The average length of stay

(ALOS) ranged from 3.92 to 12.5 days per case, depending on patients’ sex, age, and year of hospitalization.

Hospital Cost per Day

Hospital costs were obtained from the Blue

Cross/Blue Shield option of the Federal Employees

Health Benefit Program. In 1977, the average cost per

day for a nonsurgical inpatient admission for influenza was $112.88. This figure includes charges for

room and board, intensive care unit, treatment

‘ These figures were based on data from references (4) and (76).

rooms, drugs and medication, oxygen, blood and ancillary services such as lab tests, X-rays, and other

tests if billed by the hospital. It does not include

physician-billed care.

The average cost per day for a nonsurgical inpatient admission for pneumonia in 1977, again based

on data from Blue Cross/Blue Shield, was $140.12.

According to data from the Hospital Discharge Survey of NCHS, approximately 80 percent of all hospital discharges with a diagnosis of either influenza

or pneumonia (all listed-unduplicated) was attributed

to pneumonia, in epidemic as well as nonepidemic

years. In order to calculate the average cost per day

for a nonsurgical inpatient admission for influenzapneumonia (as a combined group), a weighted average cost was calculated as follows:

$112.88 (.20) + $140.12 (.80) = $134.68

By using the CPI for hospital service charges, this

$134.68 hospital cost per day was updated for inflation to yield a 1978 cost per day of $149.63 ($134.68

x 1.111).

Physician Hospital Visits and Costs

It was assumed that each hospitalized patient

would receive one initial comprehensive physician

visit ($39.62 in 1978) and subsequently receive daily

routine followup brief hospital visits ($10.51 per visit

in 1978) throughout the hospital stay.

Ambulatory Care Related to Influenza

The content and cost of an ambulatory case of influenza/pneumonia were constructed with data obtained from the National Ambulatory Medical Care

Survey (NAMCS), an article by Muller and Otelsberg (76), and CPI data from the Department of

Commerce.

The construction of a case is described below.

Number of Visits per Case

Calculated on the basis of data from NAMCS, the

average number of physician office visits per case of

influenza/pneumonia ranged from 1.10 to 3.65, depending on patient’s age and sex and the year of the

case. To calculate this number, the total number of

visits for influenza/pneumonia (listed as the first diagnosis) as reported in NAMCS was divided by the

number of new visits for influenza/pneumonia (listed

as the first diagnosis). The number of new visits

served as a proxy for the number of ambulatory

cases.
Appendix E—Values Assigned to Selected Assumptions and Variables ● 53

Procedures Ordered or

Performed per Visit

Again based on NAMCS data, the following estimates were derived concerning the frequency with

which selected procedures were either ordered or

performed:

Percent of influenza ‘pneumonia

visits during which procedure was

Procedure ordered or performed ordered or performed

Limited physical examination 72

History/general examination 15

Clinical laboratory test 16

X-ray 17

Drug prescribed recommended. 75

A limited physical examination and a history/general

examination were interpreted to be a limited office

visit for a new condition in an established patient

(17,76). NAMCS’s categories for examinations

changed during the early 1970’s.

Cost per Case

Cost estimates for each of the visits and procedures

included in an ambulatory case of influenza/pneumonia were based on 1977 medicare data (76), which

were updated for inflation using the relevant medical

care index from CPI data.

Physician cost of an ambulatory visit. —It was

assumed that each case would include one initial limited office visit for an established patient at $13.78 in

19782 and 0.10 to 2.65 routine followup brief office

visits (depending on sex and age of patient and year

of case) at $10.36 per visit in 1978. Physician costs

ranged from $14.82 to $41.23 in 1978.

Cost of procedures ordered during an office visit in

1978. —

Number o f

procedures Cost per procedure cost

per visit procedure per visit

Clinical lab test

(e.g., complete

blood count) 0.16 X $ 7.68 = $1.2 3

X-ray

(e.g., chest) 0.17 X $15.8 6

= $2.7 0

Drug ordered

(e.g., antibiotic,

decongestant) 0.75 X $4.923 = $3.69

Total cost of procedures

per visit $7.62

2 The cost of an initial limited visit for an established patient was calculated in the following manner:

● Calculating the average charge for a routine followup brief office visit a s

billed by general practitioners and specialists (weighted evenly) to medicare in 1977 (76) and updating that charge to 1978 prices using CPI

data; i.e.:

$8.63 + $10.48 = $9.56

$9.56 X2

$10.84 = $10.3 6

● Multiplying $10.36 by 16/12 (the ratio of values between a limited examination and a brief examination in the 1969 California Relative Value

Studies (17), i.e., $1036 x 16/12 = $13.78

3

This estimated cost per drug order was based on data from Out-of-Pocket

Total cost per ambulatory case. —The total costs

per ambulatory case (age-, sex-, and year-specific)

were derived by combining the cost of an initial visit

with the cost of followup visits (0.10 to 2.65 followup

visits per case).

Cost of initial visit Cost of each followup visit

Physician fees. $13.7 8 $10.3 6

Procedures . . . . 7.6 2 7.6 2

Total . . . . . $21.40 $17.98

Total costs per case ranged from $23.20 to $56.71,

depending on patient’s sex, age, and year of illness.

Excess Mortality Related to Influenza

The number of excess deaths used in the base case

analysis were recently derived by CDC for this report

(see tables E-3 and E-4). Excess mortality includes

deaths from all causes during CDC-defined influenza

epidemics. CDC estimates are calculated from NCHS

mortality data.

In the sensitivity analysis, the number of total excess deaths due to all causes among all age groups

combined for each year from 1970-71 through 1975

was derived by Dr. David Ailing and his associates at

the National Institute of Allergy and Infectious DisCost and Acquisition of Prescribed Medicines United States 1973 (79). In

1973, the average price of a prescribed medicine for conditions of the respiratory system (including influenza) was $3 80; that figure was inflated to

1978 prices by using the CPI for drugs and prescriptions.

Table E-3.—Excess Mortality From All Causes

Reported During Influenza Epidemics, 1970-71

Through 1977.78: Used in Base Case Analysisa

(by age group)

Under 1 1-44 45-64

Year year years years years All ages

1970-71 . . . . . . . . . . — — —

1971 -72 . . . . . . . . . . 359 1,640 7,580

1972-73 . . . . . . . . . . 844 606 3,250

1973 -74 . . . . . . . . . . — — —

1974 -75 . . . . . . . . . . 173 676 1,270

1975-76 ...., . . . . . 508 903 4,850

1976-77 . . . . . . . . . . — — —

1977 -78., . . . . . . . . 578 1,173 5,200

22,100

24,542

5,371

22,471

22,851

31,67 9

29,24 2

7,489

28,73 2

29,80 3

Total deaths

by age group . . . . 2,462 4,997 22,150 97,335 126,945

Average excess

deaths/year . . . . . 308 625 2,769 12,167 15,868

Average excess

deaths/year with

excess mortality 492 999 4,430 19,467 25,389

Average percent

of total deaths

by age groups . . . 2.0 ”/0 4.0 ”/0 17.0% 77.00/o 100 ”/0

a Estimates for each age group for years 1970-71 through 1975-76 were derived

by the Center for Disease Control (CDC). The estimates for all ages In 1976-77

and 1977-78 were calculated by CDC In a different fashion (100); the agespeciflc estimates for those 2 years were calculated by the Office of

Technology Assessment.
54 . Cost Effectiveness of Influenza Vaccination

Table E-4.—Estimated (Expected) Mortality From

All Causes Reported During Influenza Epidemics,

1970-71 Through 1977-78: Used in Base Case

Analysisa (by age group)

Under 1 1-44 45-64

Year year years years years All ages

1970-71 . . . . . . . . . — — — —

1971-72 . . . . . . . . . 10,140 28,573 80,234 210,960 329,907

1972-73 . . . . . . . . . 18,783 59,800 165,614 428,628 672,825

1973-74 . . . . . . . . . — — — — —

1974-75 . . . . . . . . . 12,801 41,989 117,881 332,386 505,057

1975-76 . . . . . . . . . 11,540 40,610 111,466 326,382 489,998

1976-77 . . . . . . . . — — — — —

1977-78 . . . . . . . . . 17,244 55,353 153,846 420,347 646,791

aEstimated deaths for 1970-71, 1973-74, and 1976-77 were not used since

there was no excess mortality calculated for those years. Estimates for each

age group for years 1970-71 through 1975-76 were calculated by the Center

for Disease Control. Estimates for 1977-78 were calculated by the Office of

Technology Assessment,

ease. CDC’s estimates of excess mortality were used

for 1976-77 and 1977-78 (see tables E-5 and E-6).

From these data, “excess mortality rates” for

deaths from all causes within four age groups—under

1 year, 1 to 44, 45 to 64, and over 65—were derived.

A baseline “force of mortality” was calculated for

each year, and an additional force of mortality —varied in accordance with the degree of excess

mortality—was programmed for the influenza season

in each epidemiologic year from 1970-71 through

1977-78.

Table E-5.—Excess Mortality From All Causes

Reported During Influenza Epidemics, 1970.71

Through 1977.78: Used in Sensitivity Analysisa

(by age group)

Under 1 1-44 45-64 All

Year year years years years ages

1970-71 ...., . . . . . — — — — —

1971 -72 . . . . . . . . . . 42 188 870 6,800 7,900

1972 -73 . . . . . . . . . . 1,508 1,083 5,809 19,000 27,400

1973-74 ..., . . . . . 49 191 360 800 1,400

1974 -75 . . . . . . . . . .

1975-76 . . . . . . . . . . 849 – – – – 1,500 8,056 8,600 19,000

1976-77 ......., . — — — — —

1977 -78 . . . . . . . . . . 1,307 1,585 8,077 18,834 29,803

Total deaths

by age group . . . . 3,755 4,547 23,172 54,034 85,503

Average excess

deathly ear . . . . . . 469 568 2,897 6,754 10,688

Average excess

deaths/year with

excess mortality . 751 909 4,634 10,807 17,101

Average percent

of total deaths

by age groups . . . 4.0 ”/0 5.0 ”/0 270/o 630/0 1000/0

aEstlmates for the 4,65” age group and for “all ages” for all years 1970-71

through 1975-76 were derwed by Dr. David Ailing and associates at the

National Institute of Allergy and Infectious Diseases (2). The estimates for all

ages for years 1976-77 and 1977-78 were derwed by the Center for Disease

Control (100). Age+peciflc estimates for age groups <1, 1-44, and 45-64 were

calculated by the Office of Technology Assessment

Table E-6.—Estimated (Expected) Mortality From

All Causes Reported During Influenza Epidemics,

1970-71 Through 1977-78: Used in

Sensitivity y Analysisa (by age group)

Under 1 1-44 45-64

Year year years years years All ages

1970-71 . . . . . . . . . – – – – –

1971-72 . . . . . . . . . 9,986 28,140 79,017 207,760 324,902

1972-73 . . . . . . . . . 18,140 57,754 159,947 413,962 649,804

1973-74 . . . . . . . . . 8,186 26,851 75,383 212,554 322,974

1974-75 . . . . . . . . . — — — — —

1975-76 . . . . . . . . . 11,069 38,953 106,917 313,062 470,001

1976-77 . . . . . . . . . — — — _ —

1977-78 . . . . . . . . . 17,244 55,353 153,846 420,348 646,791

aAlling and associates calculated no excess mortality in 19?’0-71 and 1974-75

(2), and the Center for Disease Control calculated no excess mortality for

1976-77; therefore, no estimated deaths were used for those years. Estimated

deaths for the “all ages” category for years 1970-71 through 1975-76 were

calculated by Ailing and associates (2). The Office of Technology Assessment

calculated estimated mortality for the age-specific groups in all years.

Cost of Treating Illnesses in

Extended Years of Life

To calculate the cost of treating other illnesses

(those not prevented by influenza vaccination) in extended years of life gained by individuals who avoid

death from influenza, per capita annual total medical

care costs were multipled by the number of years of

life generated by vaccination.

Data used to calculate total medical care costs per

person were those published by the Health Care Financing Administration (HCFA) (37,42). According

to HCFA, in 1978, the average age-specific per capita

total medical care expenditures were the following.

Age Total per capita expenditure

Under 19. ., . . . . $ 286

19-64. . . . . . 764

65 and over, ., . . . . 2,026

All ages. . . . . . . 753

These averages were weighted for persons 19 years

and over to assign higher costs to more specific age

groups. Thus, for example, individuals aged 64 were

assigned higher costs than individuals aged 20.

Medicare Expenditures

Medicare’s portion of expenditures for the treatment of influenza, as well as for all other illnesses,

was based on data from (37). In 1977, for persons 65

and older, after copayments, medicare paid for 74.6

percent of all hospital expenditures, 55.6 percent of

all physician expenses, and overall 44.1 percent of all

medical care expenditures.

Work Loss

“Excess” days of work loss caused by medically attended influenza (8th Revision ICDA codes 470-474)
Appendix E—Values Assigned to Selected Assumptions and Variables ● 55

and pneumonia (8th Revision ICDA codes 480-486)

were calculated by subtracting work loss reported in

1970-71 from work loss reported in each subequent

year through 1977-78. Age- and sex-specific work

loss data were obtained from the Health Interview

Survey at the NCHS. Age- and sex-specific individual mean earnings data were obtained for years

1975, 1976 and 1977 from the Bureau of the Census

(15). Earnings for 1978 were derived by multiplying

1977 earnings data by the ratio of the 1978 GNP

deflator/1977 GNP deflator, i.e., 152.05/141.70 =

1.0730 (see table E-7). Daily earnings were derived by

dividing annual earnings for full-time year-round

workers by 260 working days per year. Days of work

loss were multiplied by 1978 daily earnings to obtain

age- and sex-specific productivity losses.

Values Assigned to Selected

Characteristics of the Influenza HighRisk Population

Increased Probability of Dying Within a

Given Year

Age-specific probabilities of a high risk person’s

dying from any cause within a given year were calculated with the following equation:

‘ P I

= 1 – exp [In(l - me.) X 2.2]

where

mpI is the mortality for poor-risk patients at age 1 and

mGI is the mortality for good-risk patients at age I.

This is a modified version of an equation developed by Fitzpatrick and associates based on increased

probabilities of dying among persons with chronic

bronchitis (38).

These probabilities were multiplied by the age-specific estimated death rates (for all causes) for the general population.

Probability of Dying From Influenza or

Pneumonia Within a Given Year

Age-specific probabilities of a high-risk person’s

dying from influenza or pneumonia within a given

year were derived from data displayed in table E-8.

From these data, age-specific death rates for pneumonia in persons with medically attended heart disease were calculated (see table E-9). Heart disease

was used as a proxy for all influenza high-risk conditions. Age-specific probabilities and relative risks of

dying from influenza or pneumonia are displayed in

table E-10. To derive high-risk mortality rates, these

relative risk values were multiplied by the excess

mortality rates for influenza and pneumonia calculated for the general population.

Although the mortality rates for both pneumonia

and heart disease have changed since the 1950’s, it

was assumed that the ratio between the pneumonia

mortality rate in the general population and the

pneumonia mortality rate for those persons with

heart disease has remained fairly constant over the

past 25 years.
56 ● Cost Effectiveness of Influenza Vaccination

Table E.8.—Data Relating to Pneumonia Deaths in the 1950’s, by Age Group

45-64

years years years All ages

Number of pneumonia deaths

(underlying cause) in the

general population . . . . . . . . . . . . 13,166 6,590 22,417 42,173

Estimated population of U.S. . . . . . . 116,865,000 33,359,000 14,079,000 164,303,000

Number of pneumonia deaths

(underlying cause) among

persons with medically

attended heart disease. . . . . . . . . 580 1,651 6,602 8,833

Estimated population with

medically attended heart

disease . . . . . . . . . . . . . . . . . . . . . . 579,000 1,341,000 1,677,000 3,598,000

Number of pneumonia deaths

(underlying cause) in

persons without medically

attended heart disease. . . . . . . . . 12,586 4,939 15,815 33,340

Estimated population without

medically attended heart

disease . . . . . . . . . . . . . . . . . . . . . . 116,286,000 32,018,000 12,402,000 160,705,000

SOURCES: (1) Vital Statistics of the United States 1955. National Office of Vital Statistics, Washington, DC.: U.S. Department of Health, Education, and Welfare. Volume 1, p, LIX, table L,, 1957 (82).

(2) Ibid. Supp/ernerrt, p. 110, table 8, 1965 (83).

(3) Heart Conditions and High Blood Pressure United States, Ju/y 1957-Jwre 1958. U.S. National Health Survey,

Series B-No.13. Washington, DC.: U.S. Department of Health, Education, and Welfare, Table 5, p. 17, February

1980 (78),

Table E-9.—Age-Specific Death Rates (Deaths/100,000) From Pneumonia

in the 1950’s, by Age Group

45-64

years years years All ages

Death rate from pneumonia (as underlying cause)

among the general population . . . . . . . . . . . . . . . . . . . 11.27 19.75 159.22 25.67

Death rate from pneumonia (as underlying cause)

among persons with medically attended heart

disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100.2 123.1 393.7 245.5

Death rate from pneumonia (as underlying cause)

among persons without medically attended

heart disease . . . . . . . . . . . . . . . . . . . . ., . . . . . . . . . . . 10.82 15.43 127.52 20.75

SOURCES: (1) Vita/ Statistics of the United States 1955. National Office of Vital Statistics, Washington, D. C.: U.S. Department of Health, Education, and Welfare. Volume 1, p, LIX, table L,, 1957 (82).

(2) Ibid. Supp/errrerrt, p. 110, table 6, 1965 (83).

(3) Heart Conditions and H/gh Blood Pressure: United States, Ju/y 1957-Jurre 1958, U.S. National Health Survey,

Series B-No.13. Washington, D. C.: U.S Department of Health, Education, and Welfare. Table 5, p. 17. February

1960 (78),

Increased Probability of Either Being

Hospitalized or Visiting a Physician’s

Office for Influenza/Pneumonia

Barker and Mullooly calculated age-specific

hospitalization rates among the general population

and among high-risk populations during two epidemic and one nonepidemic periods in a large health

maintenance organization in Portland, Ore. (9).

Using these data, OTA compared age-specific excess

hospitalization rates among high-risk persons to rates

among the general population during an epidemic

(see table E-II).

It was assumed in OTA’s analysis that the excess

probability of a high-risk person’s visiting a physician’s office for influenza or pneumonia was the same

as the excess probability of a high-risk person’s being

hospitalized for influenza or pneumonia. To derive
Appendix E–Values Assigned to Selected Assumptions and Variables ● 57

Table E-10.—Probabilities of Dying From Pneumonia in the 1950’s, by Age Group

45-64

years years years All ages

Probability of dying from pneumonia

among persons with medically attended

heart disease. . . . . . . . . . . . . . . . . . . . . . . . . . . 0.00100 0.00123 0.00394 0.00245

Probability of dying from pneumonia

among the general population . . . . . . . . . . . . 0.00011 0.00020 0.00159 0.00026

Probability of dying from pneumonia

among persons without medically

attended heart disease. . . . . . . . . . . . . . . . . . . 0.00011 0.00015 0.00128 0.00021

Increased probability of dying from

pneumonia for persons with medically

attended heart disease over the

general population . . . . . . . . . . . . . . . . . . . . . . 0.00089 0.00103 0.00235 0.00219

Increased probability of dying from

pneumonia for persons with medically

attended heart disease over those

without medically attended heart

disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0.00089 0.00108 0.00266 0.00224

Relative risk of dying from pneumonia

in persons with medically attended

heart disease over the general

population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.09 6.15 2.48 9.42

Relative risk of dying from pneumonia

in persons with medically attended

heart disease over persons without

medically attended heart disease. . . . . . . . . . 9.09 8.20 3.08 11.67

SOURCES: (1) V/ta/ Statist/cs of the Un/fed States 1955 National Off Ice of Vltd Statistics VV=hwton, D c us Dwartment of Health, Education, and Welfare Volume 1, p LIX, table L., 1957 (82).

(2) Ibid Supplement, p 110, table 6, 1965 (83)

(3) Heart Corrd/f/ons and H/g/r 8/ood Pressure Un/fed States, July 1957-Jurre 1958 U.S. Nat!onal Health Survey,

Series B-No. 13. Washington, DC U S. Department of Health, Education, and Welfare Table 5, p. 17 February

1960 (78).

Table E-n .—Increased Probability of a High-Risk

Person’s Being Hospitalized for Pneumonia or

Influenza During an Influenza Epidemic

Excess hospitalization

rates a (persons Increased probability

hospitalized/100,000) of a high-risk

person’s being

Within the Within the hospitalized eve-r a

high-risk general person in the general

Age group population population population

15-44 years . . . . 83 26 83)26 = 3.19

45-64 years . . . . 514 95 514195 = 5.41

556 481 556/481 = 1.16

aExcess hospltaljzatlon rates are derived by subtracting hospitalization ‘ates

during a nonepldemlc Influenza year (1970-71) from average rates during two

epldemlc Influenza years (1968-69 and 1972-73)

SOURCE. The Office of Technology Assessment’s Interpretation of data from

Barker and Mullooly (9).

Average Length of Hospital Stays and Number

of Physician Office Visits/Ambulatory Case

The Hospital Discharge Survey of NCHS supplied

length-of-stay data for persons hospitalized with

pneumonia (any listed) who also had one or more of

the following types of medical problems: cardiovascular, bronchopulmonary, renal, diabetes, or sickle

cell disease. For high-risk populations, age-specific

ALOS were calculated and compared to ALOS for a

hospital case of pneumonia among the general population (see table E-12).

Likewise, the age-specific numbers of physician

office visits per ambulatory case of influenza/pneumonia in the general population were multiplied by

the age-specific ratios of:

ALOS for high risk persons

rates of hospitalization and ambulatory cases among

high-risk populations, these probabilities were multiplied by the hospital discharge rate and the ambulatory case rate (for influenza or pneumonia) in the

general population.

ALOS for the general population

Total Medical Care Costs

It was assumed that the total medical care costs in

any extended year of life for a high-risk person were
58 . Cost Effectiveness of Influenza Vaccination

Table E-12.—Average Length of Stay (ALOS) for

a Hospital Case of Pneumonia Among Persons

With One or More High-Rlsk Conditions,’ 1976

Total ALOS for highnumber of risk persons/

Number of hospital ALOS ALOS for general

Age group discharges days (in days) population

0-1 years . . . 8,663 62,527 — 7 . 2 1.22

2-24 years . . 11,143 69,424 6.2 1.15

25-44 years . 16,615 130,886 7.9 1.00

45-64 years . 44,528 489,264 11.0 1.12

119,324 1,564,430 13.1 1.08

All ages . . . . 202,293 2,316,553 11.5 1.30

a High.risk conditions include the following types of medical problems: cardiovascular, bronchopulmonary, renal, and diabetes.

b ALOS for a hospital case of pneumonia (first-listed diagnosis) for the general

population:

Age ALOS

0-1 years, . . . . . . 5.9

2-24 years. . . . . . 5.4

25-44 years . . ... 7.9

45-84 years ., . . 9.8

>=65 years. 1 2,1

All ages ., ... . . . . 8.9

SOURCE: Unpublished data, Hospital Discharge Survey, t976, National Center

for Health Statistics, Hyattsville, Md.

twice those for a person in the general population.

No known data exist regarding the extent to which

total expenditures for medical care of a high-risk person exceed those of an average person.

The sensitivity analysis tested the effect of including total medical costs in extended years of life.

Treatment Costs for a Case of

Influenza/Pneumonia

The cost of a day of hospitalization for influenza/pneumonia was not increased for high-risk persons. Total hospitalization costs related to influenza/pneumonia in the high-risk population increased, however, because of the steps described

above, which increased the probability of being hospitalized and the average length of stay.

Likewise, the cost of a physician office visit for influenza/pneumonia was not increased for high-risk

persons. Total ambulatory care costs related to influenza/pneumonia in the high-risk population, increased, however, because of the steps described

above.

Disability Days

Bed and nonbed days of disability among high-risk

persons were calculated in the following manner.

First, restricted activity days and bed disability

days related to selected high-risk conditions were obtained from publications of NCHS (see table E-13).

Nonbed disability days were calculated by subtracting bed disability days from restricted activity days.

Weighted averages for all selected types of conditions

combined were calculated.

Second, total days of bed and nonbed disability

among high-risk persons were calculated by using the

following equation:

[population’ X percent with high-risk conditions X

disability days for high-risk person’] +

[low-risk population’ X disability days forlow-riskperson] =

[population’ X disability days for average-risk person]

Discount Rate

It is generally accepted that streams of costs occurring over time should be discounted (86,89). The

process of discounting involves the application of a

rate—i. e., the discount rate—to outcomes to be realized over time. The magnitude of future outcomes is

thereby changed to a present value.

Discounting has two theoretical bases. One is the

fact that funds can be invested in alternative ways.

‘Any age- or sex-specific population.

‘Disability days are those calculated in table E-13.

Table E-13.—Disability Days Caused by Selected High-Risk Conditions

Type of Restricted activity Bed days Non bed days

high-risk days per condition per condition per condition

condition Prevalence per year per year per year

Heart condition . . . . . . . 10,291,000 30.2 12.6 17.6

Chronic

bronchitis. . . . . . . . . . 6,526,000 7.5 3.6 3.9

Emphysema. . . . . . . . . . 1,313,000 35.8 14.5 21.3

Asthma. ., . . . . . . . . . . . 6,031,000 15.0 5.8 9.2

Total . . . . . . . . . . . . . . . . 24,161,000 — — —

Average . . . . . . . . . . . . . — 20.6 8.57 12.0

SOURCES: (1) Prevalerrce of Chronic Circulatory Comditions: United States, 1972, Washington, D. C.: National Center for

Health Statistics, 1975 (80).

(2) Prevalence of Selected Chronic Respiratory Conditions: United States, 1970, Washington, D. C,: National

Center for Health Statistics, 1973 (81).
Appendix E—Values Assigned to Selected Assumptions and Variables . 59

The discount rate approximates the yield that is foregone by investing in the project under consideration

instead of using the funds in other ways. The other

reason for discounting is that people prefer to realize

benefits now rather than to postpone them to some

future date. OTA’s analysis of influenza vaccination

discounts health effects, as well as costs, occurring

over time (86,126).

It is important to note that discounting concerns

time and is distinct from inflation, which concerns

the level of prices. OTA’s analysis takes account of

changes in the price level by expressing all costs in

terms of 1978 dollars.

The discount rate used in the base case is 5 percent,

the rate generally used in recent analyses of medical

programs (125). The rate considered appropriate for

society’s perspective is lower than that considered appropriate for an individual’s perspective, because

society would likely value more highly than an individual programs yielding benefits that stretch into

the future, perhaps across generations. Although actual money market rates are the result of many factors and do not represent true discount rates, it is

noteworthy that U.S. bond yields during the 1950’s

and early 1960’s, when inflation rates were low,

ranged from 2 to 4 percent (34). The sensitivity

analysis substitutes a discount rate of zero to test the

direction of the effect of a lower rate.
Appendix F. —Acknowledgments

Appreciation is expressed to the following individuals, who generously gave advice and support during

the course of the study: Joel Kavet, Office of the

Assistant Secretary for Health, Department of Health

and Human Services (DHHS); John LaMontagne,

National Institutes of Health, DHHS; Keewhan

Choi, Centers for Disease Control, DHHS; Stephanie

Hadley, Office of the Assistant Secretary for Health,

DHHS; Jeffrey Koplan, Centers for Disease Control,

DHHS; Gary Noble, Centers for Disease Control,

DHHS; and William Barker, University of Rochester.

Appreciation is also expressed to the following

staff of the National Center for Health Statistics,

DHHS, who provided data necessary for the study:

James Dolozier, Ethyl Black, Mary Moien, Thomas

Drury, Nelma Keen, and Ronald Wilson.

Finally, appreciation is expressed to the individuals

listed below, who along with members of the Health

Program Advisory Committee and many of the individuals listed above, provided reviews of drafts of

the report:

John Adams

Pharmaceutical Manufacturers Association

David Ailing

National Institutes of Health

Jacob Brody

National Institutes of Health

James Chin

State of California

Robert Couch

Baylor College of Medicine

Dack Dalrymple

Lederle Laboratories

Walter Dowdle

Centers for Disease Control

David Fedson

University of Chicago School of Medicine

Capt. Peter Flynn

Department of the Navy

Rhonda Friedman

Senate Committee on Labor and Human Resources

Michael Gregg

Centers for Disease Control

Alan Hinman

Centers for Disease Control

Robert Hutcheson

Physician, Franklin, Term.

William Jordan

National Institutes of Health

Alexander Langmuir

Public Health Physician, Chilmark, Mass.

Helene Lipton

University of California, San Francisco

Tim McCormack

General Accounting Office

Donald Millar

Centers for Disease Control

Elena Nightingale

Institute of Medicine

Tim Nolan

Centers for Disease Control

Claudia Sanders

Health Care Financing Administration

Steven Schoenbaum

Harvard Medical School

Donald Shepard

Harvard School of Public Health

Ira Tager

Harvard Medical School

Stephen Thacker

Centers for Disease Control

Hugh Tilson

State of North Carolina

E. A. Timm

Warner-Lambert Co.

Kenneth Warner

University of Michigan School of Public Health

60
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