Download Smallpox vaccination and all-cause infectious disease

Published by Oxford University Press on behalf of the International Epidemiological Association
ß The Author 2011; all rights reserved. Advance Access publication 4 May 2011
International Journal of Epidemiology 2011;40:955–963
doi:10.1093/ije/dyr063
INFECTIOUS DISEASES
Smallpox vaccination and all-cause infectious
disease hospitalization: a Danish
register-based cohort study
Signe Sørup,1,2*y Marie Villumsen,1,2*y Henrik Ravn,1 Christine Stabell Benn,1
Thorkild I A Sørensen,2 Peter Aaby,1,3 Tine Jess2,4 and Adam Roth3,5
1
Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark, 2Institute of Preventive Medicine, Copenhagen
University Hospital, Copenhagen, Denmark, 3Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau, 4Department of
Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark and 5Department of Medical Microbiology, Lund University
Hospital, Malmö, Sweden
*Corresponding authors. Bandim Health Project, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark.
E-mail: [email protected]; [email protected]
y
These authors contributed equally to this work.
Accepted
9 March 2011
Background There is growing evidence from observational studies and randomized trials in low-income countries that vaccinations have nonspecific effects. Administration of live vaccines reduces overall child
morbidity and mortality, presumably due to protection against
non-targeted infections. In Denmark, the live vaccine against smallpox was phased out in the 1970s due to the eradication of smallpox.
We used the phasing-out period to investigate the effect of smallpox vaccination on the risk of hospitalization for infections.
Methods
From the Copenhagen School Health Records Register, a cohort
of 4048 individuals was sampled, of whom 3559 had information
about receiving or not receiving smallpox vaccination. Infectious
disease hospitalizations were identified in the Danish National
Patient Register.
Results
During 87 228 person-years of follow-up, 1440 infectious disease
hospitalizations occurred. Smallpox-vaccinated individuals had a
reduced risk of all-cause infectious disease hospitalization compared
with smallpox-unvaccinated individuals [hazard ratio (HR) 0.84;
95% confidence interval (CI) 0.72–0.98]. The reduced risk of hospitalizations was seen for most subgroups of infectious diseases. The
effect may have been most pronounced after early smallpox vaccination (vaccination age <3.5 years: HR 0.81; 95% CI 0.69–0.95; vaccination age 53.5 years: HR 0.91 95% CI 0.76–1.10). Among the
smallpox-vaccinated, the risk of infectious disease hospitalization
increased 6% with each 1-year increase in vaccination age (HR
1.06; 95% CI 1.02–1.10).
Conclusion Smallpox vaccination is associated with a reduced risk of infectious
disease hospitalization in a high-income setting.
Keywords
Immunization, smallpox vaccine, infection, hospitalization, cohort
studies, proportional hazards models, Denmark
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Introduction
Our current vaccination policy is based on the assumption that vaccines have a specific effect on the
immune system resulting in protection against the
targeted infection. Apart from adverse events following shortly after vaccinations, the possible impact of
vaccinations on overall health has scarcely been studied. There is, however, growing evidence from
studies in low-income countries that vaccinations
may have non-specific effects on child mortality and
these non-specific effects seem to be most pronounced for girls.1–8 The live vaccines against measles
and tuberculosis [Bacille Calmette-Guérin (BCG)]
have beneficial non-specific effects reducing child
mortality more than what can be explained by specific
prevention of the targeted infections.1,4–6 On the other
hand, inactivated vaccines against diphtheria, tetanus,
pertussis and hepatitis B may increase mortality unrelated to the target disease.2,3 Though initially based
on observational studies, these unexpected findings
are now being reproduced in randomized controlled
trials designed to investigate the non-specific effects
of vaccination.4,5,7 For example, in a randomized controlled trial from Guinea-Bissau, children who had not
received vitamin A at birth and were randomized to
receive an additional measles vaccination at
4.5 months of age had a lower mortality rate than children randomized to no additional measles vaccination
when measles cases were censored [hazard ratio (HR)
0.65; 95% confidence interval (95% CI) 0.43–0.99].5
Smallpox vaccination was withdrawn worldwide
following the declared eradication of smallpox in
1980. However, smallpox vaccination is associated
with long-lasting immunity9 that may still affect
the health of smallpox-vaccinated individuals. Two studies from Guinea-Bissau showed that smallpox vaccination, as identified by a vaccination scar, was associated
with reduced mortality many years after vaccination.10,11 Such an assessment is important in highincome countries also; especially considering that
smallpox vaccination was re-introduced in the US military in 2002 to meet the possible threat of bioterrorism
and that the vaccinia virus used in smallpox vaccines
are being used as vectors in vaccines against other
infections.12,13
Reduced severity of and susceptibility to infections
are the likely causes of reduced mortality in lowincome countries.4,5,8 The aim of the present study
was to test the a priori hypothesis that smallpox vaccination reduces the risk of all-cause infectious disease hospitalizations in the birth cohort born from
1965 to 1976 in Copenhagen experiencing the gradual
phasing out of smallpox vaccination.
Methods
Vaccination history
In Denmark, smallpox vaccination was free-of-charge
and mandatory before school entry until 1 April 1977.14
A few years before the repeal of the law of smallpox vaccination, the vaccination practice resulted in
a gradual phasing out of smallpox vaccination. Since
vaccination could be administered at any age before
school entry, some individuals from the same year
of birth were smallpox vaccinated, whereas others
were not. To reduce potential confounding normally present when comparing vaccinated with
unvaccinated individuals, we focused on the birth
cohorts experiencing the phasing out of smallpox
vaccination since the change in vaccination policy—
rather than parental choice—determined vaccination
status.
Study population
The present study was based on the Copenhagen
School Health Records Register (CSHRR), which contains computerized data on a part of the information
from school health records of children who attended
public and private primary schools in the municipality
of Copenhagen, the capital of Denmark.15 Since
1968, a unique central person registration number
(CPR number) has been assigned to all citizens of
Denmark and this number is available in the
CSHRR.15 Information about vaccinations along with
general information about the child and its family
was retrievable from the original school health records stored in the Copenhagen Municipal Archives
of School Health Records. A total of 47 622 individuals born from 1965 to 1976 were registered in the
CSHRR. The present study of vaccinations was based
on the vaccination cohort of 4048 individuals
obtained from two slightly overlapping samples
(Figure 1); the 5% sample (n ¼ 2391) was obtained
by random sampling of 5% of the individuals within
strata of sex and year of birth and the first-day
sample included all individuals born the first day of
every month (n ¼ 1755).
Information on exposure and potential
confounders
In addition to the data already available in CSHRR,
information on vaccination status and potential confounders was computerized for the individuals in the
vaccination cohort. The accuracy of the vaccination
data was secured by double entry. The information
about smallpox vaccination and potential confounders
was originally collected and recorded by the school
medical officers in connection to the school entry
health examination at 5–7 years of age.15
The school medical officer gathered the information
about vaccinations from the pupil’s standardized vaccination card on which all vaccinations were recorded
at the time of administration. Individuals were regarded as smallpox unvaccinated if the smallpox vaccination field was empty and the school health record
had information on other early childhood vaccinations. Information was regarded as missing if all
SMALLPOX VACCINATION AND ALL-CAUSE INFECTIOUS DISEASE HOSPITALIZATION
47 622 individuals in CSHRR born 1965–76
Five-percent sample:
2391 individuals
randomly sampled
within strata of sex
and year of birth
First-day sample:
1755 individuals born
the first day of every
month
Vaccination cohort:
4048 individuals of whom:
2293 individuals only in the five-percent cohort
1657 individuals only in the first-day cohort
98 individuals in both cohorts
Exclude 63 individuals with
non-valid and 134 individuals
with missing CPR number
(unknown no. of
hospitalizationsa)
3851
Exclude 37 individuals with
missing school health records
(18 hospitalizationsa)
3814
Exclude 23 individuals with
no observation time
(0 hospitalizationsa)
3791
Exclude 2 individuals with
cystic fibrosis
(103 hospitalizationsa)
3789
Exclude 230 individuals
without information on
smallpox vaccination
(90 hospitalizationsa)
3559 individuals from the vaccination cohort
included in the analyses
Figure 1 Overview of exclusion and inclusion from the
vaccination cohort
a
Number of hospitalizations with all-cause infections
other fields of early childhood vaccinations were left
empty.
Potential confounders examined in the analyses
were sex, year of birth (1-year groups), eczema (yes
or not reported), BCG vaccination (yes, no or unknown), child immigrated to Denmark (yes or no),
number of siblings (none, one, two or more and unknown), day care before school entry (yes, no or unknown), the presence of a relative at the child’s first
school health examination (yes, no or unknown) and
family social class [I (highest) to V (lowest) or
unclassifiable]. Family social class was coded as the
highest individual social class of the parents based on
information on the parents’ occupation and/or
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education at school entry of the child. The unclassifiable group included unemployed, housewives, students and individuals with uncertain or unknown
occupation information.
Identification of outcome
Infectious disease hospitalizations were identified
in the Danish National Patient Register (DNPR),
which contains computerized patient information
about all hospitalizations in Denmark since 1977.
Diagnoses were coded with the Danish version of
the International classification of diseases (ICD).
Until 1993, the 8th revision (ICD-8) was used, and
in 1994 the 10th revision (ICD-10) was introduced.
Codes describing diseases or categories of diseases
that are always or almost always due to infections
were included in the group of all-cause infectious disease hospitalization. We subdivided diagnoses into
groups based on the type of infection and organ infected. The category ‘other infections’ includes infectious diseases without a specified site or too rare to
constitute a separate group (Supplementary Table S1,
available as Supplementary Data at IJE online).
Multiple hospitalizations with the same type of
infections were included in the analyses, except for
hospitalizations for the following chronic infectious
diseases, which were only counted once per individual: chronic otitis media, chronic sinusitis, chronic
laryngitis, chronic tonsillitis, tuberculosis, chronic
gastritis, hepatitis A, hepatitis B, hepatitis C and
other subtypes of hepatitis.
Included individuals
Individuals with missing or invalid CPR number were
excluded along with individuals with inaccessible
school health records, individuals with no observation
time and individuals with cystic fibrosis (Figure 1).
The latter category included two cases with 103 infectious disease hospitalizations that might exert a disproportionate influence on the results. Finally,
individuals with missing information about smallpox
vaccination were excluded. Consequently, 3559 individuals from the vaccination cohort were included
in the analyses from the date of first school health
examination or the date of initiation of DNPR
(1 January 1977), whichever event occurred latest.
Information on emigration and death was obtained
through linkage to the Danish Civil Registration
System. Five smallpox-vaccinated and three smallpox-unvaccinated individuals were excluded from further analysis after the first diagnosis of HIV/AIDS
because HIV and AIDS are risk factors of hospitalization with other types of infections.16 Thus, individuals
were followed up until first HIV/AIDS diagnosis in
DNPR, emigration, death or last available update of
the Danish Civil Registration System (11 August
2004), whichever event occurred first.
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Statistical methods
For descriptive purposes, risk ratios (RRs) of being
smallpox vaccinated according to potential confounders were estimated by Poisson regression with robust
variance.17
In the main analyses, HRs and 95% CIs were estimated using Cox proportional hazards model with
age as the underlying time scale and with smallpox
vaccination as time-varying variable. If another hospitalization occurred within 30 days of the latest discharge, this hospitalization would be defined as part
of the previous hospitalization, since the readmission
was most likely due to a persisting infection. Wald
test statistics were used to examine the association
between smallpox vaccination and hospitalization
with all-cause infection and with each of the identified subgroups of infections. The P-values of the interactions between smallpox vaccination and sex and
year of birth were also determined by Wald test
statistics.
All analyses were stratified for year of birth and
adjusted for sex, family social class and eczema as
time-fixed variables and BCG vaccination as a
time-varying variable. Year of birth influenced vaccination status, sex may have influenced the vaccination
effect, family social class at school entry might have
influenced vaccination status, eczema was a contraindication against smallpox vaccination14 and BCG
vaccination was phased out in the same period as
smallpox vaccination. The other potential confounders
were non-obligatory and considered for inclusion in
the final model by performing backward elimination
based on the change-in-estimate method with a 10%
threshold for a relevant change in the HR estimate.
However, all the other potential confounders were
<10% threshold and thus, not included in the final
analyses.
To validate our results, we included fractures identified in the DNPR as an outcome, since these diagnoses were expected to be independent of vaccination
status. We examined the assumption of proportional
hazards using Schoenfeld residuals and compared the
estimates of the vaccination effect in different age
groups (<15, 15–25 and 425 years). To examine a
possible effect of age at vaccination, we divided the
smallpox-vaccinated into two groups according to the
median age at vaccination. We also included vaccination age as a continuous variable. All analyses were
performed in Stata version 9.2.
Results
Background information
During 87 228 person-years of follow-up, there were
1440 hospitalizations with infections. Among the 3559
individuals included in the analyses, 29.6% had registered one or more hospitalizations with an infectious
disease. Smallpox-vaccinated individuals comprised
Figure 2 Coverage of smallpox vaccination by year of birth
in the vaccination cohort
57.0% of the studied individuals. Smallpox vaccination
was primarily administered before school entry
(90.3%) at a median age of 3.5 years and the coverage
of smallpox vaccination declined over the period of
the study (Figure 2). Immigration was associated
with lower vaccination coverage (RR 0.80; 95% CI
0.67–0.96) and was the only non-obligatory potential
confounder that had an unequal distribution between
smallpox-vaccinated and smallpox-unvaccinated when
controlling for sex and year of birth (Table 1).
Infectious disease hospitalization
Smallpox-vaccinated individuals had a reduced risk of
hospitalization for infectious diseases (HR 0.84; 95%
CI 0.72–0.98) (Table 2). The estimates were similar for
males (HR 0.81; 95% CI 0.67–0.98) and females (HR
0.87; 95% CI 0.73–1.03) (Supplementary Table S2,
available as Supplementary Data at IJE online).
There was also no interaction between smallpox vaccination and year of birth (Supplementary Table S2,
available as Supplementary Data at IJE online). With
the exception of infections during pregnancy and
puerperium, the estimates for all other subgroups of
infections were <1 for the smallpox-vaccinated
(Figure 3). There was no interaction between smallpox vaccination and sex for any of the subgroups
(data not shown).
The assumption of proportional hazards was fulfilled for smallpox vaccination (PSchoenfeld ¼ 0.305).
However, the effect of smallpox vaccination was
strongest before 25 years of age (Table 3). The analyses of the effect of age at smallpox vaccination
SMALLPOX VACCINATION AND ALL-CAUSE INFECTIOUS DISEASE HOSPITALIZATION
Table 1 Distribution of background factors among the
smallpox-vaccinated and smallpox-unvaccinated at the
end of follow-up
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Table 2 Incidence rates and HRs of all-cause infectious
disease hospitalization
Incidence rate
Smallpox
vaccinationa
Variables
No
Yes
(n ¼ 1530) (n ¼ 2029)
Variables
RR
(95% CI)b
P-valuec
707 (40) 1043 (60)
1.00 (reference)
Male
823 (45)
0.91 (0.88–0.95)
986 (55)
535 (67)
259 (33)
1.00 (reference)
Yes
884 (34) 1743 (66)
1.23 (1.14–1.33)
Missing
111 (80)
27 (20)
0.87 (0.67–1.11)
Not reported 1416 (42) 1958 (58)
1.00 (reference)
Yes
0.85 (0.73–0.98)
71 (38)
Yes
1409 (42) 1958 (58)
121 (63)
1.00 (reference)
71 (37)
0.80 (0.67–0.96)
Number of siblings
0
226 (46)
270 (54)
1.00 (reference)
1
703 (42)
967 (58)
1.01 (0.95–1.08)
52
511 (42)
704 (58)
0.98 (0.91–1.04)
90 (51)
88 (49)
0.91 (0.80–1.02)
Missing
1138 (49) 1192 (51)
)
0.329
252 (33)
522 (67)
1.02 (0.98–1.07)
Missing
140 (31)
315 (69)
0.91 (0.86–0.96)
No
Missing
1155 (42) 1618 (58)
Female
1.96 (842/43 039)
1.00 (reference)
Male
1.35 (598/44 190)
0.68 (0.61–0.75)
No
1.76 (345/19 568)
1.00 (reference)
Yes
1.58 (1026/65 094)
1.00 (0.87–1.14)
Missing
2.69 (69/2567)
1.45 (1.12–1.89)
Not reported 1.65 (1369/82 902)
1.00 (reference)
Yes
0.96 (0.76–1.23)
1.64 (71/4327)
9
>
>
1.24 (0.94–1.65)=
I
1.30 (73/5627)
II
1.55 (154/9914)
1.00 (reference) >
III
1.35 (191/14 113)
1.09 (0.83–1.43)
IV
1.67 (498/29 857)
V
1.77 (332/18 711)
>
1.36 (1.06–1.74)>
>
;
0.003
1.46 (1.13–1.88)
1.63 (1.24–2.14)
HRs and 95% CIs are derived from mutually adjusted Cox
proportional hazards model stratified by year of birth.
b
P-value of Wald test statistics.
c
The highest social class of the parents. The highest social class
is I and the lowest is V.
1.00 (reference)
287 (47)
322 (53)
0.96 (0.90–1.02)
88 (50)
89 (50)
0.94 (0.84–1.06)
Family social class at school entryd
0.84 (0.72–0.98)
a
Relative attended first school health examination
Yes
1.00 (reference)
1.49 (777/52 150)
Unclassifiable 2.13 (192/9607)
1.00 (reference)
No
1.89 (663/35 078)
Yes
Family social class at school entryc
Day care outside the home before school entry
Yes
No
Eczema
Child immigrated to Denmark
No
P-valueb
BCG vaccination
Eczema
114 (62)
HR
(95% CI)a
Sex
BCG vaccination
No
(Hospitalizations/
person-years)
Smallpox vaccination
Sex
Female
%
9
>
>
=
1.00 (0.89–1.12) >
I
115 (49)
120 (51)
1.00 (reference)
II
185 (44)
233 (56)
III
229 (41)
336 (59)
0.96 (0.86–1.06)
IV
467 (40)
714 (60)
0.94 (0.85–1.04)
V
299 (40)
457 (60)
0.91 (0.82–1.01)
Unclassifiable
235 (58)
169 (42)
0.78 (0.68–0.88)
>
>
>
;
0.078
a
Figures are number of participants (%).
RRs and 95% CIs for being smallpox vaccinated are estimated
by Poisson regression with robust estimation of variance and
adjusted by sex and year of birth.
c
P-value derived from Wald test of the difference between the
specified groups.
d
The highest social class of the parents. The highest social class
is I and the lowest is V.
b
included 3423 individuals who had 1383 hospitalizations during 84 481 years at risk. The beneficial effect of smallpox vaccination may have been most
pronounced among individuals vaccinated early
in life. Individuals vaccinated before the median vaccination age (3.5 years) were less likely to be hospitalized with infectious diseases than unvaccinated
individuals (HR 0.81; 95% CI 0.69–0.95), whereas
those vaccinated at or after 3.5 years of age were
more similar to the smallpox-unvaccinated (HR
0.91; 95% CI 0.76–1.10) (P ¼ 0.120 for same effect
among those vaccinated before and after 3.5 years
of age). Among the smallpox-vaccinated, the risk of
being hospitalized increased 6% with each 1-year increase in vaccination age (HR 1.06; 95% CI 1.02–1.10).
We analysed 613 fractures occurring during followup and smallpox-vaccinated had an HR 0.93 (95% CI
0.73–1.18) for fractures compared with smallpoxunvaccinated [the assumption of proportional hazards
was fulfilled (PSchoenfeld ¼ 0.595)].
Discussion
In the present study, smallpox-vaccinated individuals
had a reduced risk of all-cause infectious disease
hospitalization compared with smallpox-unvaccinated
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Figure 3 Estimated HRs (dot) of subgroups of infectious disease hospitalization with 95% CIs (lines) for smallpoxvaccinated vs smallpox-unvaccinated (HR ¼ 1).
a
HRs are derived from Cox proportional hazards model stratified by year of birth and adjusted for sex, eczema, family
social class and BCG vaccination. All-cause infections: HR 0.84 (95% CI 0.72–0.98); respiratory infections: HR 0.95 (95% CI
0.72–1.26); gastrointestinal infections: HR 0.87 (95% CI 0.66–1.14); urinary tract infections: HR 0.81 (95% CI 0.41–1.59);
sexually transmitted infections: HR 0.91 (95% CI 0.55–1.53); skin infections: HR 0.66 (95% CI 0.43–1.03); infections during
pregnancy: HR 1.22 (95% CI 0.67–2.22); other infections: HR 0.57 (95% CI 0.37–0.88). The subgroup ‘other infections’
includes infections of unspecified site or too rare to constitute a separate group (Supplementary Table S1, available as
Supplementary Data at IJE online)
Table 3 Incidence rates and HRs of all-cause infectious disease hospitalization according to age at hospitalization
Incidence rate of
smallpox-unvaccinated
Age at hospitalization
(years)
<15
Incidence rate of
smallpox-vaccinated
%
1.77
(Hospitalizations/
person-years)
(202/11 435)
%
1.48
(Hospitalizations/
person-years)
(165/11 143)
HR (95% CI)a
0.73 (0.55–0.97)
15–25
1.98
(291/14 702)
1.32
(259/19 670)
0.78 (0.61–1.00)
425
1.90
(170/8942)
1.65
(353/21 338)
1.02 (0.79–1.32)
Pequalb
0.168
a
HRs and 95% CIs are derived from Cox proportional hazards model stratified by year of birth and adjusted for sex, eczema, family
social class and BCG vaccination with smallpox-unvaccinated as reference (HR ¼ 1) within each category of age.
b
P-value for equality of the HRs in the different age groups.
individuals. The beneficial effect of smallpox vaccination was similar for females and males and in most
subgroups of infectious diseases. Those who were
youngest when vaccinated had the lowest risk of
all-cause infectious disease hospitalization.
Strengths and weaknesses
The Copenhagen Municipal Archive of School Health
Records covers an unselected population of school
children attending public or private primary schools
and is a unique source of information about vaccination. Owing to the Danish smallpox vaccination legislation, recording in the school health record has
been meticulous; parents were asked to present the
child’s vaccination card. Access to the Danish healthcare system was free-of-charge in the period under
study and socio-economic conditions are unlikely
to influence the access to hospital care. The unique
Danish personal identification number enabled
linkage between the nationwide DNPR, in which all
hospitalizations are identified, and the Danish Civil
Registration System, ensuring information on
follow-up. Exact dates of vaccination and hospitalization secured temporality.
Smallpox vaccination did not substantially influence
the risk of fractures, which indicates that bias in the
general likelihood of hospitalization by vaccination
status is unlikely to have affected the results. The
potential for confounding was limited by focusing
SMALLPOX VACCINATION AND ALL-CAUSE INFECTIOUS DISEASE HOSPITALIZATION
on the cohort experiencing the phasing out of smallpox vaccination. This created a situation resembling a
natural experiment in which external forces, rather
than social selection biases, explained who were
vaccinated. This was supported by the backwards confounder selection analysis leaving none of the potential confounders in the final model.
The reason for being smallpox unvaccinated may have
changed for the birth cohorts from 1965 to 1976.
Contraindication to smallpox vaccination may be the
main reason to be smallpox unvaccinated for individuals belonging to the oldest birth cohorts, whereas the
main reason for the youngest may be the phasing out of
smallpox vaccination. However, all analyses were
stratified by year of birth and no interaction between
smallpox vaccination and year of birth was observed.
Eczema is a contraindication against smallpox vaccination14 and regarded as a risk factor for skin infections.18 We have adjusted all analyses for eczema to
control for possible confounding from eczema.
However, eczema did not seem to be a confounder
since exclusion of individuals with eczema from the
analyses did not change the estimates and CIs for
either all-cause infectious diseases or skin infections
(data not shown). Furthermore, eczema cases did
not have a higher risk of all-cause infectious disease
hospitalization or skin infections than those with unreported eczema (data not shown). In this study,
eczema was defined as eczema before school entry.
Unreported cases of eczema before school entry are
likely to be less severe, because parents are more
likely to remember and report more severe cases to
the school medical officer. Considering that less
severe cases have better prognosis19 and that the reported cases did not seem to confound the results, we
do not find it likely that unreported eczema cases
confounded the results.
Consistency with previous studies
A few studies from high-income countries have suggested that smallpox vaccination may have had a beneficial effect on chronic conditions including Crohn’s
disease,20 multiple sclerosis21 and asthma.14 A beneficial effect of smallpox vaccination on cancers has
also been reported for lymphomas,22,23 rhabdomyosarcoma24 and malignant melanoma.25 Studies from a
low-income country have suggested that having a
smallpox vaccination scar is significantly associated
with lower adult mortality more than 20 years after
the last smallpox vaccination was administered.10,11
One recent study26 could be said to contradict our
observation on smallpox vaccination and reduced infectious disease hospitalization rate. For the purpose
of detecting possible adverse events of smallpox vaccination, a study among US military personnel compared hospitalization rates of one group in the year
following smallpox vaccination (post-vaccination)
with the hospitalization rates of another group
1 year prior to smallpox vaccination (pre-vaccination).
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The post-vaccination group had an HR of hospitalization of 1.12 (95% CI 1.04–1.20) compared with the
pre-vaccination group. However, there was no excess
hospitalization with ‘infections and parasitic diseases’,
which is the category presumably closest to our
definition of ‘infectious disease hospitalizations’.
Furthermore, there are aspects that make the studies
incomparable. The US military study provided smallpox vaccination to adults, whereas smallpox vaccination was given in childhood in our cohort and the
risk of infectious disease hospitalization was lower for
those vaccinated at a younger age. There may also
have been some inherent incomparability between
the pre-vaccination group and the post-vaccination
group in the US military study. The post-vaccination
group also had a higher risk of hospitalization than
the pre-vaccination group in the year preceding the
period of observation for both groups (RR 1.20; 95%
CI 1.12–1.27; calculation based on the results presented in Table 1 of the US military study).
Possible explanations and implications
In the present study, it was presumably only the most
severe cases of infections that were hospitalized,
whereas milder infections would have been treated
by the general practitioners or received no treatment.
Hence, the observed effects of smallpox vaccination
could be due to both reduced incidence of infection
and reduced severity of disease. There is some evidence from studies of other vaccines that the effect
may be due to change in susceptibility since the incidence of non-targeted infections was modified.27–29
It is worth noting that the beneficial effect of smallpox vaccination was particularly strong for children
vaccinated early. For measles vaccination, we have
also observed a much stronger beneficial nonspecific effect if the vaccine is administered before
9 months of age, the currently recommended age of
vaccination.5,30
The possible immunological explanations behind
our findings remain speculative and include crossreactivity between antigens, shift in the relationship
between Th1 and Th2 cytokine profiles and effects on
regulatory T cells.8,31 The live smallpox vaccines
induce a Th1 response with pro-inflammatory cytokines including interferon-g.8 Further investigations
into the immunological mechanisms behind the
non-specific effects of vaccinations are needed.
In conclusion, the present study suggests that smallpox vaccination conferred protection against all-cause
infectious disease hospitalization later in life. The
health and economic implications of stopping smallpox vaccination may, therefore, have been huge.
Cost–benefit analyses of disease eradication usually
indicate large savings since all future spending on
vaccination can be removed. In future eradication
campaigns, cost–benefit analyses may look very different if non-specific beneficial effects of vaccination
have to be considered.
962
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Today, smallpox vaccination is only administered in
a modified version to certain groups for biodefence. It
is unlikely that smallpox vaccination will be reintroduced for the general population. However, if our
findings of possible non-specific beneficial effects of
smallpox vaccination hold true, this may open
new fields within vaccine research and immunology.
In a society with increasing access to information,
further research into non-specific effects of vaccination in both low- and high-income countries is
necessary to promote and optimize vaccination programmes. To the extent vaccination has beneficial
non-specific effects, these should clearly be used to
support public health and popular acceptance of
some vaccinations and they would need to be investigated in detail to optimize vaccination policy with
regard to timing of vaccination, simultaneous administration of different vaccines and when deciding to
terminate a specific vaccination.
Supplementary Data
Supplementary Data available at IJE online.
Funding
This work was supported by the Danish Medical
Research Council (FSS 9588-2291 to S.S. and M.V.);
the Health Insurance Foundation (2009B132 to S.S.);
Rosalie Petersens Foundation (to S.S.); the Lundbeck
Foundation (R34-A3862 to M.V.); Dagmar Marshalls
Foundation (to M.V.); the Danish Graduate School in
Public Health Science and University of Copenhagen
(scholarship to M.V.); and the Novo Nordisk
Foundation (research professorship grant to P.A.).
Conflict of interest: None declared.
KEY MESSAGES
Smallpox vaccination was found to be associated with a reduced risk of all-cause infectious disease
hospitalization in a population-based Danish cohort.
Among the smallpox-vaccinated, the reduced risk of infectious disease hospitalization was most
pronounced among those vaccinated early in life.
Non-specific effects of vaccination should be considered at introduction, discontinuation of vaccinations and as part of post-licensure surveillance.
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