Context Data are limited and conflicting regarding the
effectiveness of influenza vaccine in health care professionals.
Objective To determine the effectiveness of trivalent influenza
vaccine in reducing infection, illness, and absence from work in young,
healthy health care professionals.
Design Randomized, prospective, double-blind, controlled trial
over 3 consecutive years, from 1992-1993 to 1994-1995.
Setting Two large teaching hospitals in Baltimore, Md.
Participants Two hundred sixty-four hospital-based health care
professionals without chronic medical problems were recruited; 49
participated for 2 seasons; 24 participated for 3 seasons. The mean age
was 28.4 years, 75% were resident physicians, and 57% were women.
Intervention Participants were randomly assigned to receive either
an influenza vaccine or a control (meningococcal vaccine, pneumococcal
vaccine, or placebo). Serum samples for antibody assays were collected
at the time of vaccination, 1 month after vaccination, and at the end
of the influenza season. Active weekly surveillance for illness was
conducted during each influenza epidemic period.
Main Outcome Measures Serologically defined influenza infection
(4-fold increase in hemagglutination-inhibiting antibodies), days of
febrile respiratory illness, and days absent from work.
Results We conducted 359 person-winters of serologic
surveillance (99.4% follow-up) and 4746 person-weeks of illness
surveillance (100% follow-up). Twenty-four (13.4%) of 179 control
subjects and 3 (1.7%) of 180 influenza vaccine recipients had
serologic evidence of influenza type A or B infection during the study
period. Vaccine efficacy against serologically defined infection was
88% for influenza A (95% confidence interval [CI], 47%-97%;
P=.001) and 89% for influenza B (95% CI,
14%-99%; P=.03). Among influenza vaccinees,
cumulative days of reported febrile respiratory illness were 28.7 per
100 subjects compared with 40.6 per 100 subjects in controls
(P=.57) and days of absence were 9.9 per 100
subjects vs 21.1 per 100 subjects in controls
(P=.41).
Conclusions Influenza vaccine is effective in preventing infection
by influenza A and B in health care professionals and may reduce
reported days of work absence and febrile respiratory illness. These
data support a policy of annual influenza vaccination of health care
professionals.
The effectiveness
of influenza vaccine in reducing morbidity and mortality in children,
elderly, or debilitated patients has been demonstrated in several
studies.1-7 Influenza epidemics can also exact a heavy toll
among younger, healthy adults.8-11 While vaccine efficacy
of 70% to 90% has been documented in young adults, particularly
military recruits, cost-effectiveness has not been demonstrated
conclusively in this population.12-15
Since 1981, the Advisory Committee on Immunization Practices of the US
Public Health Service has suggested influenza vaccine for health care
professionals who care for patients at high risk for significant
morbidity following influenza infection.16 Among the
presumed benefits are a reduction in infection and absenteeism among
health care professionals and a reduction in transmission of influenza
from health care professionals to high-risk patients.12,17
Although published data support the hypothesis that infected health
care professionals can serve as a vector to spread
influenza among hospitalized patients, causing a
variety of adverse effects from increased hospital costs to
death,18,19 there are conflicting data on whether influenza
vaccine decreases the rate of influenza infection or sick leave among
health care professionals.20-25 However, compliance with
the Advisory Committee on Immunization Practices recommendations by
physicians and nurses has been poor, with rates of influenza
vaccination among health care professionals reported to range from 16%
to 51%.19,26,27
We undertook a prospective randomized, double-blind, controlled study
to determine the benefits of influenza vaccination in young, healthy
health care professionals. We assessed the effectiveness of vaccine in
the reduction of serologically proven influenza infection, reported
respiratory illness, and days absent from work.
Hospital-based physicians, nurses, and respiratory therapists from
departments of pediatrics, medicine, and emergency medicine agreed to
participate in the study. Subjects were eligible if they were younger
than 50 years, were in good health, and were willing to report illness
during the epidemic period. Exclusion criteria included history of
allergic reaction to influenza vaccine or egg products, allergy to the
control vaccines, pregnancy, or medical conditions that would place the
subject at high risk for complications from influenza infection such as
chronic pulmonary, renal, or metabolic disease, severe cardiac disease,
immunosuppression, or diabetes mellitus. Informed consent was obtained
from all participants. This study was approved by the Joint Committee
for Clinical Investigation at the Johns Hopkins University Hospital and
School of Medicine, Baltimore, Md.
Study Design and Measurements
The study was a prospective, randomized, double-blind, controlled trial
conducted at the Johns Hopkins Hospital and at Sinai Hospital in
Baltimore (Figure 1). All vaccines and
the saline placebo were administered in volumes of 0.5 mL as
intramuscular injections in October and November of 1992, 1993, and
1994, with control vaccines including meningococcal vaccine,
pneumococcal vaccine, or placebo, respectively.
Four-unit block randomization was used to allocate subjects to
vaccine or control groups. The pharmacy was responsible for the
randomization process and for labeling and dispensing vaccines and
controls. The list of assignments was kept in the pharmacy until the
end of the study to ensure allocation concealment. The syringes
containing the vaccine or control were packaged and labeled identically
and were identified only by a study number, thus keeping the assignment
hidden to both subject and investigator.
A baseline blood sample was collected at the time of enrollment and
vaccination in October-November, a postvaccination blood sample was
drawn 1 month later to determine the serologic response to the vaccine,
and a final blood sample was obtained 1 month after local influenza
activity had ended to identify subjects who were infected by the
influenza type A(H3N2) or type B strains during each influenza season.
Blood samples were centrifuged and frozen within 6 hours, coded, and
sent to a reference laboratory for analysis. All 3 samples from each
study subject were analyzed simultaneously. Hemagglutination inhibition
assays were performed on all serum samples, using the appropriate
influenza A(H3N2) and influenza B vaccine antigens for each annual
epidemic and previously described techniques.28
At the time of enrollment and vaccination, demographic information was
collected from all participants to establish their eligibility to
participate. Participants were contacted by telephone 3 days after
vaccination to determine the occurrence of adverse reactions. Subjects
were also asked to guess which vaccine they had received but were not
informed of group assignment until the code was broken after the
epidemic.
Local onset of the influenza epidemic was determined through active
monitoring by the hospital virology laboratory as well as through
epidemiologic data obtained from local, state, and national surveys.
During the influenza season, the study nurse conducted weekly telephone
interviews with participants to inquire about illnesses during the
previous week. Specific symptoms of respiratory illness and absences
from work due to illness were recorded.
Vaccine response was defined as a 4-fold increase in
hemagglutination-inhibiting antibodies between the preimmunization and
postimmunization specimens. Influenza infection during the yearly
epidemic period was defined as a 4-fold increase in
hemagglutination-inhibiting antibodies between the postimmunization and
postepidemic specimens. For the purposes of this study, respiratory
illness was defined as report of 2 or more of the following symptoms
for 2 or more days: rhinorrhea, cough, or sore throat. Febrile
respiratory illness was defined as respiratory illness with a report of
fever (with or without documentation by
thermometer). Vaccine effectiveness was calculated as
1−(rate in vaccine group/rate in control group). The rate ratio was
also used to estimate vaccine effectiveness in reducing cumulative days
of illness or absence, and the difference in rates to estimate the
magnitude of vaccine effect per 100 vaccine doses.
The primary outcome was serologic evidence of infection during the
influenza season; secondary outcomes included days of respiratory
illness, days of febrile respiratory illness, and days absent from work
due to illness.
Each winter, we randomized all participants without regard
to previous vaccine assignment experience. Because some study
participants volunteered for more than 1 winter, our 264 volunteers
were observed for a total of 361 person-winters. The vaccine strains
and circulating influenza viruses were different each winter, and our
data showed no effect of previous vaccine experience on protection. For
these reasons, we analyzed our data as 361 subjects (person-winters);
hence, several volunteers are represented for 2 or 3 winters.
Comparisons between influenza vaccine recipients and controls were made
on an intention-to-treat basis; influenza vaccine recipients who did
not demonstrate a 4-fold increase in antibody titers after vaccination
remained in the influenza vaccine group for data analysis.
Data were analyzed using STATA statistical software (STATA Corp,
College Station, Tex) release 5.0 for Windows 95. The significance
level chosen for all analyses was .05. A 2-sided Wilcoxon rank sum test
was used to compare continuous variables between vaccine recipients and
controls. Nominal or categorical variables were compared using
χ2 tests of association (Yates corrected) or Fisher exact
test, as appropriate. Serum titers were log transformed, and 2-sided
t and Wilcoxon rank sum tests were used to compare postvaccine
and postinfluenza season titers among vaccine recipients and controls.
Mantel-Haenszel estimates of rate ratios were used to compare the 2
groups.29 We estimated that at least 105 subjects were
needed in each group to detect a true vaccine efficacy of 80%,
assuming an α level of .05, power of 80%, and an influenza attack
rate of 20%.
A total of 264 health care professionals were studied during a 3-year
period; 49 subjects participated for 2 seasons and 24 for 3 seasons.
The characteristics of the study subjects are provided in
Table
1. There were no differences in baseline
characteristics between the influenza vaccine recipients and the
control recipients. Fifty-seven percent of the participants were women.
Eighty-six percent of participants were white, 4% were black, 9% were
Asian/Pacific Islander, and 1% were Hispanic. Resident physicians
represented 75% of the study population, 2% were attending
physicians, 18% were nurses, and 5% were medical students and
respiratory therapists.
Vaccines and Surveillance
Influenza vaccine components are shown in Table
2. Because some subjects participated for
more than 1 winter season, control vaccines were changed each year. To
encourage study participation, we used vaccines with proven benefit for
the control subjects for the first 2 years. The surveillance during the
3 winter periods included 361 person-winters or 4746 person-weeks of
illness surveillance. Clinical follow-up was obtained for all subjects.
Serologic data were obtained for 99.4% of the subjects, including 180
vaccine recipients and 179 control recipients, for 359 person-winters
of serologic surveillance.
There were no absences due to vaccine adverse effects during the
observation period 3 days after vaccination. Three significant adverse
events were attributed to study participation, 1 case each of serum
sickness and cellulitis in recipients of pneumococcal vaccine and 1
case of lymphangitis in a saline-control recipient. Other than mild
pain or swelling at the injection site, the rest of the subjects
reported no significant adverse effects.
Three days after receipt of vaccine or control, subjects were asked
about adverse effects. They were also asked to guess whether they had
received influenza vaccine or control. Successful masking of subjects
was achieved in 2 of 3 years. Subjects in the first 2 seasons could not
predict their correct vaccine assignment (κ=−0.19,
−0.05, respectively; P>.69 for both years). However,
saline-control recipients in 1994-1995 did predict their correct
assignment at a statistically significant rate
(κ=0.32; P<.01).
National and local virology labs reported influenza A(H3N2) in
substantial numbers in all 3 years, type B was active
in 2 years, and A(H1N1) was essentially absent. A
good match was achieved between the epidemic influenza subtypes and the
vaccine components in year 2 of the study. There was a partial match in
years 1 and 3 (Table 2).
Vaccine response to influenza A(H3N2), measured by a 4-fold increase in
hemagglutination inhibition titers after vaccination was demonstrated
in 41% to 78% of subjects and to influenza B in 33% to 52%
of subjects. Overall, vaccine response was noted in 57% of subjects
for A(H3N2) and in 40% of subjects for influenza B.
The number and rate of influenza type A and B infection in study
subjects each year is shown in Table
3. The rate of influenza A(H3N2) infection
per 100 person-winters was 1.1 in influenza vaccinees and 8.9 in
controls, for an effectiveness of 88% (95% confidence interval
[CI], 47%-97%; P=.001). The rate of
influenza type B infection per 100 person-winters was 0.6 in influenza
vaccinees and 5.0 in controls, for an effectiveness of 89% (95% CI,
14%-99%; P=.02). Overall incidence of
influenza infection was 1.7% among vaccine recipients vs 13.9% among
controls.
Only 1 (2.3%) of 43 consecutive year influenza vaccine recipients
became infected with influenza compared with 2 (1.5%) of 138 receiving
the vaccine for the first time. Control subjects who had received the
vaccine during the previous season were infected at the same rate
(15%) as controls who had not been vaccinated during the prior year
(13.6%).
Among the 179 unvaccinated subjects with serological
follow-up, those with serologic evidence of infection with influenza A
or B (n=24, 13.3%) were more likely than those without
evidence of infection (n=155) to have febrile
respiratory illness (58% vs 14%, respectively; P<.001),
had longer mean duration of febrile respiratory illness (1.67 vs 0.20
days; P<.001), had absence from work (29% vs 7.7% of
subjects; P=.006), and had higher mean number
of days absent (0.67 vs 0.14 days; P=.001).
The definition of febrile respiratory illness used in this study had a
sensitivity of .58, specificity of .86, and positive predictive value
of .37 for influenza infections. The mean number of reported febrile
days actually exceeded the mean number of absence days, suggesting that
these health care professionals reported for work during febrile
respiratory illnesses. In contrast to control subjects, none of the 3
persons vaccinated for influenza who were infected reported any febrile
respiratory illness or work absence.
The estimates of clinical effectiveness of influenza immunization
are based on 264 subjects over 361 person-winters. Most subjects had no
days of illness or work absence; the range for absence was 0 to 7 days
per subject. The mean absence from work for the vaccinated group was
0.1 days (SD, 0.35) and for the control group, it was 0.21 days (SD,
0.75). The median absence for both groups was 0 days. The mean febrile
respiratory illness for the vaccinated group was 0.29 days (SD, 0.68)
and for the control group, it was 0.41 days (SD, 1.0). The median
absence due to febrile respiratory illness was 0 days for both groups.
Subjects who were vaccinated (n=181) had fewer
cumulative days of febrile respiratory illness than controls
(n=180) (52 days [28.7 days per 100 subjects] vs 73
days [40.6 days per 100 subjects], respectively;
P=.57, Mantel-Haenszel test). The observed
29% reduction (95% CI, −22% to 59%) was not statistically
significant. Subjects in the vaccinated group also had fewer cumulative
days of work absence than those in the control group (18 days [9.9
days per 100 subjects] vs 38 days [21.1 days per 100 subjects];
P=.41, Mantel-Haenzel test). The observed 53%
reduction (95% CI, −56% to 86%) was not statiscally significant.
The results from this 3-year study of health care professionals
indicate that influenza
vaccine is effective in preventing infection and
may help to reduce cumulative days absent from work during the
influenza epidemic. To our knowledge, ours is the first study of health
care professionals to assess the effect of influenza vaccine in a
randomized, double-blind, controlled trial over 3 successive epidemic
seasons. We used results of serological studies to assess response to
vaccine, to document infection by influenza A(H3N2) or B, and to define
the association of our clinical outcome with objective data on
infection. We closely monitored illness by directly contacting study
participants by telephone each week during the influenza season and
achieved 100% clinical and 99.4% serological follow-up. Our overall
vaccine effectiveness of 88% is similar to results from previous
studies in young adults14,30 as is the cumulative influenza
attack rate of 14% in controls.8,31,32 The variation in
matching between the vaccine and the epidemic influenza strains for
each of the 3 years suggests our effectiveness estimates are
generalizable to programs of annual vaccination during periods of
antigenic drift.
Prior studies in healthy adults have shown a decreased rate of absence
from work among those vaccinated with influenza
vaccine.13,33 In a randomized controlled trial of healthy
adults, Nichol et al13 showed a 0.5-day reduction in
absenteeism during a study period with an unusually high apparent
influenza attack rate.12 Studies conducted specifically
among health care professionals have shown mixed results with regard to
work absence.22,23,25 The health care professionals in our
study seem unlikely to be absent from work even when they experience a
febrile respiratory illness, a characteristic that may differ from that
of the general adult working population. Although the rates of work
absence in the health care professionals in our group are only one
third of those of working adults in the study by Nichol et al (41 days
vs 122 days per 100 subjects, respectively), the 2 studies show similar
estimates of effectiveness of influenza vaccine in reducing cumulative
work absence (53% and 43%, respectively).13 Direct
comparison of respiratory illness experience in the 2 studies is not
possible because our definition included fever, which was not required
in the definition made by Nichol et al. However, the estimated
influenza vaccine effectiveness against either clinical definition was
similar: 29% in our study and 35% in the study by Nichol et al.
Although similar to other studies, the point estimates in our subjects
do not reach statistically significant levels; a larger study is needed
to confirm these estimates.
Our data show a 14% risk of developing influenza type A or B infection
for the individual health care professional who remains unvaccinated
and show that influenza infection will increase the risk of
experiencing a febrile respiratory illness or work absence by 4-fold.
Moreover, among subjects in our study, influenza infection was
associated with experiencing an additional 1.5 days of febrile
respiratory illness and 0.5 days of absence from work during each
influenza season. Our data also provide a point estimate of an absolute
vaccine effect of 11 work absence days that were averted per 100
vaccinees and confirm the relative effect of 88% reduction in
infection.
One criticism of annual influenza vaccination for young, healthy adults
is that it may be counterproductive, both in the short-term and in the
long-term.34 Data from a study of British schoolboys
vaccinated in 3 consecutive years in the 1970s suggested there was less
protection from influenza infection, as defined by either culture or
serological results, if the vaccine had been received the previous
year.35 In 1983, Gill and Murphy36 showed that
previous infection conferred long-term immunity to the homologous
influenza virus; subjects who had been alive during the previous H1N1
epidemics of 1947-1957 had a lower attack rate than subjects exposed to
H1N1 for the first time when it reappeared in 1977. Subsequent studies
have shown that while 4-fold seroconversion to the vaccine components
is much lower among subjects who have been vaccinated in prior years,
effectiveness in preventing culture or serologically proven infection
was better after repeated annual vaccination.14,15 In a
matched case-control study. Ahmed et al37 showed a
reduction in mortality in an elderly population for those who had
received repeated annual vaccination compared with a single-season
vaccination.
Sixty-five percent of the subjects in our study who did not have
a history of influenza vaccination in the previous year seroconverted
to the H3N2 component after vaccination, whereas only 30% of those
receiving the vaccine for the second consecutive year seroconverted.
These rates are consistent with the previous studies.14,15
However, protection within those groups was equivalent; we found no
significant influenza vaccine carryover effect. The influenza infection
rate in influenza vaccine recipients and in controls was not altered by
the vaccine experience in the previous year, which supports the
recommendation for yearly influenza vaccination. Although we did not
study it, nosocomial influenza infection has been well documented as a
cause of increased hospital days and mortality among
inpatients.11,18,38,39 Influenza infection in 10% to 20%
of a hospital staff per season has major implications for nosocomial
transmission, particularly given prolonged shedding of the virus from
infected persons38-40 and poor vaccine efficacy in
vulnerable elderly patients.4 Two recent studies have shown
a reduction in nosocomial infection after large-scale vaccination of
health care professionals, including a 1997 study that showed a
decrease in total mortality rates from 17% to 10% among nursing home
patients.19,20 These facts, coupled with our data showing
that hospital employees report to work despite having a febrile
illness, lend support to institutional efforts to vaccinate health care
professionals.
Our study has several limitations. First, previous studies have shown
that serological analysis may fail to detect up to 20% to 30% of
culture-proven cases of influenza infection in adults.15,41
We may not have detected all influenza infections, although it is not
clear if this effect is likely to be greater in the influenza vaccine
group or the control group. Analysis of serologic response using the
adjustment suggested by Govaert et al5 did not increase the
number of
infections detected. Second, the majority of our
subjects were resident physicians in a large teaching hospital, a
subset of health care professionals that tends to be highly motivated
and may be loath to miss any time from work. Although a study
focusing on nonphysician health care professionals might yield
different results in the rates of absenteeism, there is little reason
to believe that rates of reported febrile illness would be different.
Third, our study was not specifically designed to examine a vaccine
carryover effect, and our subjects were not randomized for this
purpose; our findings about the lack of a vaccine carryover effect
should be confirmed in a prospective study.
In conclusion, influenza vaccine is effective in preventing
serologically proven influenza infection in young, healthy
hospital-based health care professionals and may reduce cumulative days
of illness and absence. These data suggest that a policy of annual
immunization with influenza vaccine in health care professionals will
reduce influenza infections and can reduce associated illness.
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