Background Although influenza causes substantial morbidity andmortality in all age groups, current recommendations emphasizeannual immunization for people at high risk for complicationsof influenza. We conducted a double-blind, placebo-controlledtrial of vaccination against influenza in healthy, working adults.
Methods In the fall of 1994, we recruited working adults from18 to 64 years of age from in and around the Minneapolis–St.Paul area and randomly assigned them to receive either influenzavaccine or placebo injections. The primary study outcomes includedupper respiratory illnesses, absenteeism from work because ofupper respiratory illnesses, and visits to physicians' officesfor upper respiratory illnesses. The economic benefits of vaccinationwere analyzed by estimating the direct and indirect costs associatedwith immunization and with upper respiratory illnesses.
Results We enrolled a total of 849 subjects. Base-line characteristicswere similar in the two groups. During the follow-up period,consisting of the 1994–1995 influenza season (December1, 1994, through March 31, 1995), those who received the vaccinereported 25 percent fewer episodes of upper respiratory illnessthan those who received the placebo (105 vs. 140 episodes per100 subjects, P<0.001), 43 percent fewer days of sick leavefrom work due to upper respiratory illness (70 vs. 122 daysper 100 subjects, P = 0.001), and 44 percent fewer visits tophysicians' offices for upper respiratory illnesses (31 vs.55 visits per 100 subjects, P = 0.004). The cost savings wereestimated to be $46.85 per person vaccinated.
Conclusions Vaccination against influenza has substantial health-relatedand economic benefits for healthy, working adults.
Although most deaths from influenza occur among elderly people,all age groups are affected by this illness. Annual attack ratesaverage 10 to 20 percent and are higher during severe epidemics.1Symptoms include the abrupt onset of fever, myalgia, sore throat,nonproductive cough, headache, and malaise. Influenza is sometimesassociated with malaise persisting for several weeks and oftenresults in restriction of activity.2 Influenza accounts formillions of days lost from work each year.3
The current recommendations of the Advisory Committee on ImmunizationPractices target persons at increased risk for complicationsof influenza for annual immunization, although all people whowish to avoid illness are encouraged to consider vaccination.4We undertook this trial to clarify the benefits of immunizationin a population not at high risk for complications. The effectsof vaccination on the frequency of upper respiratory illness,sick leave from work, and use of health care services were assessedin healthy, working adults.
Methods
Subjects
Subjects were recruited from the Minneapolis–St. Paularea through advertisements at work sites and in local newspapersand through recruitment sessions at shopping malls. People wereeligible if they were 18 to 64 years old, were employed full-time,and had no medical conditions, such as chronic cardiopulmonarydisease, diabetes mellitus, or other serious medical conditions,that would place them at high risk for complications of influenza.The criteria for exclusion were a history of immediate hypersensitivityreactions to eggs (because the vaccine may contain small amountsof residual egg protein), thimerosal (a preservative in thevaccine), or previous vaccination against influenza, and pregnancyor planned pregnancy within three months. Informed consent wasobtained from all participants. The study was approved by theHuman Studies Committee of the Minneapolis Veterans AffairsMedical Center.
Study Design and Data Collection
The study was a randomized, double-blind, placebo-controlledtrial. Subjects received injections of vaccine (trivalent subvirioninfluenza vaccine containing 15 µg of antigen from thecomponent strains A/Texas/36/91, A/Shangdong/9/93, and B/Panama/45/90;Fluzone, Connaught Laboratories, Swiftwater, Pa.) or placebo(vaccine diluent) according to a computer-generated randomizationschedule. Ten-unit blocks were used to ensure balanced allocationof subjects to the two groups. Accountability logs in whichinvestigators documented subjects' group assignments were completedto ensure adherence to the randomization schedule. Vaccine andplacebo were available in preloaded syringes that were identicalin appearance and labeled only with the study code. Blindingwas maintained until all study data were collected.
Base-line data on demographic and health-related characteristicswere collected by means of a questionnaire administered at thetime of enrollment. Follow-up data were obtained through structuredtelephone interviews. Most telephone surveys were conductedwith a computerized, interactive-response telecommunicationsystem (Posit, Health Outcomes Technologies, Doylestown, Pa.).Subjects who required assistance were interviewed by an operator.Five interviews were completed during the follow-up period.The first call was initiated 7 to 14 days after the study injectionto collect information on side effects during the week afterthe injection, and the second through fifth calls were madeduring January, February, March, and April to identify occurrencesof upper respiratory illness, use of sick leave, and visitsto physicians' offices in the preceding month. Subjects werealso encouraged to record information about these outcomes in"illness logs" and were asked to refer to the logs during theirfollow-up interviews. During the final interview, subjects werealso asked whether they had received an influenza vaccinationin addition to the study injection at any time during the studyand which study injection they thought they had received.
Study Outcomes and Statistical Analysis
An upper respiratory illness was defined as a sore throat associatedwith either a fever or a cough that lasted at least 24 hours.On the basis of previous experience with influenza seasons inMinnesota, the follow-up period was defined as December 1, 1994,through March 31, 1995 (the influenza season). The primary outcomeswere the totals during four months for episodes of upper respiratoryillness, days of work lost because of respiratory illness, andvisits to physicians' offices for respiratory illness. Secondaryoutcomes included the proportion of subjects with any upperrespiratory illness, days of respiratory illness, days of worklost because of all illnesses, and estimates of the economicbenefits associated with vaccination. Information was also collectedon side effects during the week after the study injection.
Bivariate analyses to compare vaccine and placebo recipientsincluded chi-square tests for categorical variables and Student'st-tests for continuous variables. The kappa statistic was usedto assess the adequacy and maintenance of blinding.5 The effectivenessof the vaccine was calculated as follows: [(rate of the outcomevariable in placebo recipients - rate in vaccine recipients)/ratein placebo recipients] x 100 percent. All statistical testswere performed with SPSS 6.1 for Windows software (SPSS, Chicago).
Estimates of the economic benefits of vaccination were basedon the primary study outcomes of sick leave and visits to physicians'offices related to respiratory illness. Costs were calculatedfrom the social perspective as combined direct and indirectcosts, as follows6: net costs = direct costs + indirect costs;direct costs = costs of vac-cination + costs of medical carefor side effects - costs of medical care for disease averted;indirect costs = costs of work time lost for vaccination + costsof work loss due to side effects - costs of work loss averted.
The numbers of visits to physicians' offices and days of worklost that were avoided because of vaccination were taken fromthe point estimates for the primary study outcomes. A vaccinationwas estimated to take 30 minutes of work time and cost $10,on the basis of a survey of public and work-site immunizationprograms (Nichol KL: unpublished data). The estimate of twodays of work lost per 100 vaccinations because of side effectsof the vaccine was based on the observed, though statisticallynonsignificant, differences between vaccine and placebo recipientsduring the week after the study injection. We estimated thathalf the people with side effects would see a physician. Work-losscosts were estimated at $93.40 per day, based on the 1994 medianweekly earnings of full-time U.S. workers.7 The cost for a visitto a physician's office was estimated to be $69.51, on the basisof the mean fee for a visit to a physician's office for an establishedpatient in the 1994 American Medical Association SocioeconomicMonitoring System Core Survey,8 a list of diagnostic tests andmedications associated with visits to physicians for upper respiratoryillnesses from the 1992 National Ambulatory Medical Care Surveyof the National Center for Health Statistics, payments to physiciansfor diagnostic tests from the 1993 Physician Payment ReviewCommission Multipayer Database, and the costs of generic medicationsfor the treatment of upper respiratory illnesses in a surveyof three local branches of national franchise pharmacies (NicholKL: unpublished data). All costs were adjusted to 1994 dollarswith use of the Consumer Price Index. More detailed explanationsof these estimates are available elsewhere (*).
Sample-size calculations were based on the expected proportionsof subjects with respiratory illnesses. For an event rate of50 percent in the placebo group with 30 percent of these eventsbeing due to influenza (two-sided alpha, 0.05; beta, 0.20),at least 410 subjects per group were needed to enable us todetect differences, assuming a vaccine efficacy of 70 percent.Sample-size calculations were performed with Power software(Epicenter Software, Pasadena, Calif.).
Results
A total of 849 subjects were enrolled between October 10 andNovember 30, 1994. The characteristics of the subjects accordingto treatment assignment are shown in Table 1. Randomizationresulted in an even distribution of all base-line measures,including characteristics that might be independently relatedto the study outcomes, such as health status, number of childrenin the household, smoking status, and sick leave during thepast six months.
Table 1. Base-Line Characteristics of the Study Subjects.
After enrollment, 3 subjects were dropped from the study becauseof incorrect addresses and telephone numbers, leaving 424 placeboand 422 vaccine recipients. Follow-up interviews to ascertainside effects were completed for 841 subjects (99 percent). Therewere no significant differences between vaccine and placeborecipients with regard to specific systemic symptoms, althoughvaccine recipients were more likely to report local symptoms(Table 2). The mean number of days of sick leave during theweek following the injection was 4.5 per 100 for the placeborecipients and 6.5 per 100 for the vaccine recipients (P = 0.34).
Table 2. Side Effects Associated with Vaccination.
After the interview focusing on side effects, five additionalsubjects were withdrawn. The reasons included a refusal to continuewith the study (two subjects in the vaccine group) and incorrectaddresses or telephone numbers (two subjects in the placebogroup and one in the vaccine group). Complete follow-up datawere obtained for 416 of 422 placebo recipients (99 percent)and 409 of 419 vaccine recipients (98 percent; P = 0.44).
During the study period, 69 percent of the placebo recipientsand 61 percent of the vaccine recipients had at least one upperrespiratory illness (P = 0.018). Cumulative rates of respiratoryillness, sick leave, and visits to physicians' offices for respiratoryillnesses and associated rates of vaccine effectiveness aresummarized in Table 3. For each outcome, vaccination was associatedwith significantly fewer events, with the greatest reductionsin the more severe outcomes: days of work lost and visits tophysicians' offices.
Table 3. Health-Related Benefits Associated with Vaccination.
The original treatment assignments were well maintained throughoutthe study. Only one person in the placebo group (0.2 percent)and two in the vaccine group (0.5 percent) received influenzavaccine from another source. Blinding was also well maintained.When asked during the final interview which type of injectionthey thought they had received, only 60.3 percent of the placeborecipients and 54.3 percent of the vaccine recipients correctlyidentified their injection, with an overall rate of agreementof 57 percent. This correlated with a kappa of 0.15, indicatingagreement only slightly better than would have resulted fromchance alone.
The results of the economic analysis are shown in Table 4. Onthe basis of the outcomes observed in the trial, direct savingsin medical costs were estimated to be $5.99 per person vaccinated($599 per 100 persons), and indirect cost savings were estimatedto be $40.86 per person vaccinated ($4,086 per 100 persons).Combined cost savings were estimated to be $46.85 per personvaccinated ($4,685 per 100 persons).
Table 4. Economic Benefits Associated with Vaccination.
Discussion
The results of this placebo-controlled trial show the benefitsthat vaccination against influenza offers for healthy, workingadults. Immunization decreased the frequency of upper respiratoryillnesses by 25 percent, absenteeism from work due to upperrespiratory illness by 43 percent, absenteeism due to all illnessesby 36 percent, and visits to physicians' offices for upper respiratoryillness by 44 percent. On the basis of the observed decreasesin sick leave and visits to physicians for upper respiratoryillness, we estimate that vaccination was associated with costsavings of $46.85 per person vaccinated.
Previous studies of the clinical effectiveness of the influenzavaccine in working adults have had varying results. Trials inthe 1950s and 1960s in the United Kingdom,9,10,11 United States,12and Australia,13 using early monovalent or bivalent formulationsof the vaccine, demonstrated a reduction in absenteeism duringsome but not all influenza seasons. The years in which the vaccinewas found to be ineffective were generally those in which therewas a poor match between the virus strains in the vaccine andcirculating strains. A five-year study in the early 1970s amongpostal workers in the United Kingdom also suggested benefit.14The findings of that study, however, are unreliable becauseof base-line differences in absenteeism between the interventionand control groups. More recent trials in the United Stateshave confirmed the efficacy of the vaccine among healthy adults,as indicated by the frequency of laboratory-confirmed infection.15,16In one study, rates of clinical illness were also decreased,16but absenteeism from work was not evaluated. Another recenttrial that assessed rates of clinical illness and absenteeismfailed to demonstrate a benefit.17 That study had a small sample,however. Furthermore, during the 1985–1986 study year,there was a poor match between the vaccine strains and circulatingviruses.
The present study extends these observations. Our trial hada sample of adequate size; the study year was characterizedby an excellent match between the strains in the vaccine andthe predominant circulating virus strains, as has been the casefor seven of the past nine years (Cox N, Centers for DiseaseControl and Prevention: personal communication); and we evaluateda broad range of outcomes including clinical illness, absenteeismfrom work, use of health care services, and economic benefits.
The benefits observed in this study probably represent a low-to-intermediateestimate of the benefits that might be seen in other years.Influenza activity was at low-to-moderate levels in Minnesotain 1994–1995.18 During seasons with higher levels of activity,such as years when there are severe epidemics, the benefitsof vaccination would undoubtedly be greater.
Our study was not designed to detect differences between vaccineand placebo recipients with regard to serious complicationsof influenza, including hospitalization and death. Influenzaepidemics are, however, associated with increased rates of hospitalizationfor acute respiratory disease in all age groups.19,20,21 Furthermore,influenza — together with pneumonia — accounts for6000 to 7000 deaths each year among persons 18 to 64 years ofage.22,23 A substantial proportion of these deaths probablyrepresent mortality associated with influenza epidemics.21 Vaccinationagainst influenza markedly decreases the numbers of hospitalizationsand deaths due to complications of influenza among the elderly.24,25,26,27It is probable that vaccination is of similar benefit in youngerpersons.
In our study, vaccination was associated not only with a reductionin days of work lost because of upper respiratory illness butalso with a reduction in absenteeism due to all illnesses. Upperrespiratory infections accounted for approximately 65 percentof sick-leave days during the study period. Because only halfthe people with influenza have classic symptoms,1 it is likelythat some subjects with influenza did not have upper respiratorysymptoms. This would have resulted in a misclassification oftheir illnesses into a non–upper-respiratory category.Episodes of influenza may also have predisposed subjects tosecondary illnesses.
Vaccination of the elderly against influenza clearly saves money.3,26,27,28Analyses of the influenza vaccine in healthy, younger adultsalso suggest that vaccination is cost effective and possiblycost saving.3,29,30,31 Our estimates of direct and indirectcost savings corroborate these findings and indicate that theeconomic benefits of vaccinating working adults may be greaterthan previously estimated. Our figures may underestimate theactual savings associated with vaccination in this populationfor several reasons. We did not, for example, include in ouranalysis savings associated with decreases in nonrespiratoryillnesses or decreases in the rates of hospitalization and deathdue to influenza and its complications. The economic benefitsfor a particular population depend, of course, on the actualcosts of illness in that population, the type and severity ofinfluenza, the clinical attack rate, and the effectiveness ofthe vaccine during the season in question.
Concern about side effects is a barrier to immunization. Tworecent trials have shown that the vaccination of elderly peopleagainst influenza is not associated with higher rates of systemicside effects than placebo injections.32,33 In our study we observedvirtually identical results among younger, low-risk subjects.
We relied on subjects' own reports as the measure of clinicaloutcomes in this study. Such reports of sick leave have beenshown to be reliable and accurate.34 In our study, we minimizedthe recall period (and the possibility of recall bias) for subjectsby conducting monthly follow-up interviews. Blinding was alsowell maintained despite the higher rate of local reactions amongvaccine recipients. Therefore, the subjects' reports of outcomesshould have provided a valid and unbiased estimate of the effectsof vaccination in the study.
The group of participants in this study was broadly representativeof the general population. Exclusion criteria were kept to aminimum, recruitment was conducted in a variety of settings,and participation was made as convenient as possible. The resultsof this study should therefore be generalizable to other workingadults and have important implications for the 87 million full-timeworkers in the United States.7
Supported in part by grants from the Blue Cross Blue Shieldof Minnesota Foundation and Connaught Laboratories.
We are indebted to the participating employers and the manyother people who supported our recruitment efforts for thisstudy.
* See NAPS document no. 05247 for three pages of supplementarymaterial. To order, contact NAPS c/o Microfiche Publications,248 Hempstead Tpk., West Hempstead, NY 11552.
Source Information
From the Veterans Affairs Medical Center (K.L.N., A.L., M.M., M.H.), Hennepin County Medical Center (K.L.M., R.M.), and the University of Minnesota Medical School (K.L.N., A.L., K.L.M., M.M., R.M., S.M.), Minneapolis; Blue Plus, an affiliate of Blue Cross Blue Shield of Minnesota, Eagan (S.M.); and the American Lung Association of Minnesota, St. Paul (M.D.).
Address reprint requests to Dr. Nichol at the Section of General Internal Medicine (111O), Veterans Affairs Medical Center, One Veterans Dr., Minneapolis, MN 55417.
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