CI indicates confidence interval; DT-IPV, diphtheria, tetanus, and inactivated
poliovirus; DTaP-IPV, diphtheria, tetanus, acellular pertussis, and inactivated
poliovirus; Hib, Haemophilus influenzae type b; MMR,
measles-mumps-rubella; OPV, oral poliovirus. Pertussis alone indicates whole-cell
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Hviid A, Wohlfahrt J, Stellfeld M, Melbye M. Childhood Vaccination and Nontargeted Infectious Disease Hospitalization. JAMA. 2005;294(6):699–705. doi:https://doi.org/10.1001/jama.294.6.699
Author Affiliations: Department of Epidemiology
Research (Mssrs Hviid and Wohlfahrt and Dr Melbye); Medical Department (Dr
Stellfeld), Statens Serum Institut, Copenhagen, Denmark.
Context It has been hypothesized that multiple-antigen vaccines, such as measles-mumps-rubella
vaccine, or aggregated vaccine exposure could lead to immune dysfunction,
resulting in nontargeted infectious diseases as a result of an “overload”
Objective To evaluate the relationship between routinely administered childhood
vaccines (Haemophilus influenzae type b; diphtheria-tetanus-inactivated
poliovirus; diphtheria-tetanus-acellular pertussis-inactivated poliovirus;
whole-cell pertussis; measles-mumps-rubella; oral poliovirus) and hospitalization
for nontargeted infectious diseases.
Design, Setting, and Participants Population-based cohort comprising all children born in Denmark from
1990 through 2001 (N = 805 206). Longitudinal information was
collected on type and number of vaccine doses received and hospitalization
with infectious diseases, specifically acute upper respiratory tract infection,
viral and bacterial pneumonia, septicemia, viral central nervous system infection,
bacterial meningitis, and diarrhea.
Main Outcome Measures Rate ratios for each type of infectious disease according to vaccination
Results During 2 900 463 person-years of follow-up, 84 317 cases
of infectious disease hospitalization were identified. Out of 42 possible
associations (6 vaccines and 7 infectious disease categories), the only adverse
association was for Haemophilus influenzae type b
vaccine and acute upper respiratory tract infection (rate ratio, 1.05; 95%
confidence interval, 1.01-1.08 comparing vaccinated participants with unvaccinated
participants). This one adverse association of 42 possible outcomes was within
the limits of what would be expected by chance alone and the effect was not
temporal or dose-response. When considering aggregated vaccine exposure, we
found no adverse associations between an increasing number of vaccinations
and infectious diseases.
Conclusion These results do not support the hypotheses that multiple-antigen vaccines
or aggregated vaccine exposure increase the risk of nontargeted infectious
During the last 2 decades, more vaccinations have become available and
routine vaccination schedules have become increasingly complex. This has led
to concern among some that multiple antigen vaccines, such as the measles-mumps-rubella
vaccine, or aggregated vaccine exposure could lead to immune dysfunction,
resulting in infectious diseases not targeted by vaccination, occurring as
a result of an “overload” mechanism. In a 2002 safety review of
multiple immunizations and immune dysfunction, the US Institute of Medicine
concluded that there was strong evidence for the existence of biological mechanisms
by which multiple vaccinations could influence the risk of nontargeted infectious
diseases.1 However, epidemiological and clinical
support for the effect was lacking, and some studies even favored a beneficial
effect on nontargeted infectious diseases.2-6
To test the hypotheses that multiple-antigen vaccines or aggregated
vaccine exposure increase risk of nontargeted infectious diseases, we evaluated
the relationship between routinely administered childhood vaccines and nontargeted
infectious diseases in a large population-based cohort study comprising all
children born in Denmark from 1990 through 2001. Our study included longitudinal
information on type and number of vaccine doses received and hospitalization
with infectious diseases, specifically acute upper respiratory tract infection,
viral and bacterial pneumonia, septicemia, viral central nervous system infections,
bacterial meningitis, and diarrhea. Included vaccines were Haemophilus influenzae type b (Hib); diphtheria-tetanus-inactivated
poliovirus; diphtheria-tetanus-acellular pertussis-inactivated poliovirus;
whole-cell pertussis; measles-mumps-rubella (MMR); and oral poliovirus vaccine–the
majority of these being multiple-antigen vaccines.
Since April 1968, people living in Denmark have been given a unique
identification number in the Danish Civil Registration System.7 This
registry keeps daily updated information regarding demographic features on
all residents including dates of birth, death, emigration, and change of address.
From this registry we constructed a cohort of all children born in Denmark
from January 1, 1990, through December 31, 2001. Using the unique personal
identification number, we were able to link information on all childhood vaccinations,
infectious disease hospitalization, and potential confounders to the children
in the cohort. Since our study was registry-based with no active participation
from study subjects, no approval from an ethics committee was required according
to Danish law. The use of registry data on individual subjects was approved
by the Danish Data Protection Agency.
During the study period of 1990 through 2001, the Danish childhood vaccination
program included vaccinations against pertussis, measles, mumps, rubella,
diphtheria, tetanus, polio, and Haemophilus influenza type
b. A detailed overview of the childhood vaccines used in the Danish program
in this period to 5 years of age is given in Table 1. The dates of vaccination with the first, second, or third
dose of vaccines were obtained from the National Board of Health, as previously
described.8,9 In Denmark, only
general practitioners administer childhood vaccinations and they are reimbursed
when reporting these to the National Board of Health. The National Board of
Health has kept a registry of these reports since 1990. Data on MMR has only
been available since September 1991, and thus, children born in 1990 were
classified as having unknown MMR status.
Information on hospitalization with infectious diseases in the period
January 1, 1990, to December 31, 2001, was obtained from the Danish National
Hospital Register.10 During 1990 to 1993, ICD-8 (International Classification of
Diseases, 8th Revision) was used, and during 1994 to 2001, ICD-10 (International Classification of Diseases,
10th Revision). We included the following categories of infectious
diseases in our study: acute upper respiratory tract infection (ICD-8: 460.xx, 461.xx, 462.xx, 463.xx, 464.xx, 465.xx, 466.xx; ICD-10: J00.x, J01.x, J02.x, J03.x, J04.x, J05.x, J06.x);
viral pneumonia (ICD-8: 480.xx; ICD-10: J12.x); bacterial pneumonia (ICD-8:
481.xx, 482.xx; ICD-10: J13.x, J14.x, J15.x); septicemia
(ICD-8: 038.xx, 036.10; ICD-10: A40.x, A41.x, A39.2); viral central nervous system infections (ICD-8: 040.xx, 041.xx, 042.xx, 043.xx, 044.xx, 045.xx,
046.xx; ICD-10: A8x.x); bacterial meningitis (ICD-8: 036.09, 320.00, 320.09, 320.19, 320.80; ICD-10: A39.0, G00.x, G01.x); and diarrhea (ICD-8: 009.xx; ICD-10: A09.x).
Children in the cohort contributed person-time to follow-up from birth
until hospitalization with any of the infectious diseases, death, disappearance
or emigration, 5 years of age, or December 31, 2001, whichever occurred first.
The resulting incidence rates for infectious disease hospitalization were
analyzed with Poisson regression (log-linear regression on the incidences
using the logarithm to the follow-up time as offset), producing estimates
of incidence rate ratios (RRs) according to vaccination status.11 Vaccination
status was considered a time-varying variable, ie, children could contribute
person-time as both unvaccinated and vaccinated. The time following receipt
of a vaccine was subdivided into 3 periods: within 14 days, 14 days after
until 3 months after, and more than 3 months after. To eliminate confounding
resulting from vaccination being postponed for acutely ill children, the within-14-days
period was considered a lag period; follow-up time and case activity from
this period was not attributed to either the vaccinated or unvaccinated group
in any analyses unless stated explicitly. We estimated the dose-response relation
between the vaccines and infectious disease hospitalization as the increase
in RR per dose (per 0.5 mL in the case of the whole-cell pertussis vaccine)
and only among vaccinated children. Thus, we estimated the possible effect
of vaccination on infectious disease hospitalization through: (1) RRs comparing
vaccinated with unvaccinated children; (2) increases in RRs per vaccine dose
among vaccinated children; (3) RRs comparing children in the period 14 days
after to 3 months after any vaccine dose with unvaccinated children; and (4)
RRs comparing children in the period more than 3 months after any vaccine
dose with unvaccinated children. These RRs were always adjusted for age (<1
year of age, 1-month intervals; 1-2 years of age, 3-month intervals; 2-4 years
of age, 1 year intervals), calendar period (1-year intervals), and receipt
of other vaccines when estimating the previously stated RRs. Furthermore,
to take into account a possible change in the distribution of age at infectious
disease hospitalization from ICD-8 to ICD-10, we included an age and calendar period interaction (0 months
of age, 1-5 months of age, 6-11 months of age, 1 year of age, and 2-4 years
of age for the periods 1990-1993 and 1994-2001). All analyses were conducted
using SAS statistical software version 8.2 (SAS Institute Inc, Cary, NC).
Information on possible confounding factors was obtained from the Danish
Civil Registration System, the Danish Medical Birth Registry,12 and
the National Hospital Register: child’s sex, child’s place of
birth (Copenhagen, Copenhagen suburbs, area with at least 100 000 population,
area with population of 10 000-99 999, area with population <10 000),
child’s birth weight (<2500 g, 2500-2999 g, 3000-3499 g, 3500-3999
g, ≥4000 g), mother’s country of birth (Denmark or other), mother’s
age at birth of child (<20 years, 20-24 years, 25-29 years, 30-34 years,
35-39 years, ≥40 years), and birth order (1, 2, 3, ≥4). Month of follow-up
was also considered as a potential confounding variable. The percentage of
missing values for the variables birth weight, child’s place of birth,
and mother’s country of birth were 4.06%, 0.03%, and 0.82% respectively.
Variables were identified as confounders for the association between vaccination
and infectious disease hospitalization and included in the regression models
if they changed the RR comparing vaccinated with unvaccinated children by
more than 10% for a given vaccine. When adjusting for the potential confounding
effect of variables with missing values, we used the method of single imputation,
replacing a missing value with the most common value.
A total of 805 206 children were included in the cohort. During
2 900 463 person-years of follow-up, 84 317 cases of infectious
disease hospitalization were identified. The follow-up of 12 552 children
was prematurely terminated because of death (n = 4681), emigration
(n = 7710), or disappearance (n = 161).
Table 2 presents the person-years
of follow-up time and number of cases of infectious disease hospitalization
according to age, calendar period, sex, and vaccination status.
Figure 1 displays the RRs for
infectious disease hospitalizations comparing vaccinated with unvaccinated
children and increases in RRs for infectious disease per dose of vaccine among
vaccinated children. The confounding effects of sex, place of birth, birth
weight, mother’s country of birth, mother’s age at birth, birth
order, and season were negligible. Figure 2 presents
RRs comparing vaccinated children in the period from 14 days to 3 months after
vaccination with unvaccinated children, and RRs comparing vaccinated children
in the period more than 3 months after vaccination with unvaccinated children.11 The only statistically significant adverse association
between any combination of vaccine type and infectious disease hospitalization
was between the Hib vaccine and acute upper respiratory tract infection (RR
comparing vaccinated with unvaccinated children, 1.05; 95% confidence interval
[CI], 1.01-1.08; RR comparing children >3 months after any vaccine dose with
unvaccinated children, 1.07; 95% CI, 1.03-1.12 with no dose-response association).
Thus, of the 42 possible associations between the 6 vaccines and the 7 nontargeted
infectious disease outcome categories, only 1 indicated an adverse effect.
At the 5% level of statistical significance, 1 adverse association of 40 possible
would be expected by chance alone.
Of the RRs estimated for children in the within-14-days lag period relative
to unvaccinated children, the only adverse association was between MMR vaccine
and acute upper respiratory tract infection (RR, 1.10; 95% CI, 1.01-1.21).
We reestimated RRs comparing vaccinated with unvaccinated children for all
associations including this period in the vaccinated group. No RR comparing
vaccinated with unvaccinated children was increased more than 10%.
In our main analyses, children were censored when hospitalized with
any of the infectious disease categories. In a further analysis, we reestimated
RRs comparing vaccinated with unvaccinated children in which other infectious
disease categories than the one under analysis did not result in censoring
but were instead a time-varying exposure. Including this previous infectious
disease hospitalization exposure as a possible confounding variable increased
only 2 RRs comparing vaccinated with unvaccinated children by 10% or more:
oral poliovirus vaccine and viral central nervous system infection (RR comparing
vaccinated with unvaccinated children, 0.93; 95% CI, 0.53-1.62 increased to
1.16; 95% CI, 0.68-1.97), oral poliovirus vaccine and diarrhea (RR comparing
vaccinated with unvaccinated children, 0.88; 95% CI, 0.82-0.95 increased to
0.99; 95% CI, 0.72-1.34).
A minor group of the unvaccinated children consists of children whose
parents have chosen not to have their children vaccinated at all. To evaluate
the impact of this group, we focused on the effect of vaccination after the
age of 12 months and compared RRs of vaccinated with unvaccinated children
with and without excluding completely unvaccinated children. None of the RRs
comparing vaccinated with unvaccinated children were increased by more than
We evaluated the association between the total number of vaccine doses
received (aggregated vaccine exposure, N = 0 . . . 13)
and infectious disease hospitalization as the increase in RR per dose. These
dose-responses were RR, 0.99 (95% CI, 0.99-0.99) for acute upper respiratory
tract infection; RR, 0.94 (95% CI, 0.93-0.95) for viral pneumonia; RR, 0.96
(95% CI, 0.95-0.97) for bacterial pneumonia; RR, 0.98 (95% CI, 0.96-1.00)
for septicemia; RR, 0.99 (95% CI, 0.96-1.02) for viral central nervous system
infections; RR, 1.00 (95% CI, 0.98-1.02) for bacterial meningitis; and RR,
0.99 (95% CI, 0.98-0.99) for diarrhea. Furthermore, we compared children vaccinated
at least once with completely unvaccinated children. These RRs were 0.82 (95%
CI, 0.78-0.86) for acute upper respiratory tract infection; RR, 0.70 (95%
CI, 0.64-0.77) for viral pneumonia; RR, 0.79 (95% CI, 0.64-0.98) for bacterial
pneumonia; RR, 0.53 (95% CI, 0.41-0.67) for septicemia; RR, 1.47 (95% CI,
0.90-2.40) for viral central nervous system infections; RR, 0.84 (95% CI,
0.60-1.18) for bacterial meningitis; and RR, 0.90 (95% CI, 0.83-0.99) for
We evaluated the relationship between routinely administered childhood
vaccines and nontargeted infectious disease hospitalizations in a large population-based
cohort study. We specifically tested 2 hypotheses: whether multiple-antigen
vaccines increase the risk of nontargeted infectious diseases, and whether
aggregated vaccine exposure increases the risk of nontargeted infectious diseases.
Of the associations between specific vaccines and nontargeted infectious disease
hospitalizations, we found an adverse association between the Hib vaccine
and acute upper respiratory tract infections. This association, if causal,
has limited clinical relevance because of the modest magnitude of the effect.
It also has no bearing on the specific hypothesis tested due to Hib being
a single-antigen vaccine. However, the association is unlikely to be causal
because it did not present as either a temporal effect or a dose-response
effect. Furthermore, this 1 adverse association of a possible 42 is within
the limits of what would be expected purely by chance in a study with multiple
comparisons at this level of statistical significance. Conversely, the 15
observed protective associations suggest that vaccination may have nontargeted
protective effects. When considering aggregated vaccine exposure, we found
no adverse associations between an increasing number of vaccinations and nontargeted
infectious disease hospitalizations. Overall, our results support neither
of the tested hypotheses. However, using only hospitalization, presumably
representing the more severe cases of infectious disease, as our study outcome
is a limitation. When evaluating the generalizability of our results, the
differences in schedule between Denmark and other countries (vaccinations
are administered later in Denmark) should be taken into consideration.
A major challenge in any study of vaccination and nontargeted infectious
diseases is the potential for bias and confounding. Our study methodology,
a nationwide cohort study with prospective follow-up, has effectively minimized
any concern over selection and information bias, particularly recall bias.
However, the comparability of vaccinated and unvaccinated children with respect
to factors influencing risk of infection other than the possible effect of
vaccination merits discussion. We included a number of factors (other than
age, calendar period, and receipt of other vaccines) typically associated
with risk of infection: sex, place of birth, birth weight, mother’s
country of birth, mother’s age at birth, birth order, and month of the
year. The confounding effect of these factors was negligible. In other studies,
few factors have been identified in Denmark as being associated with obtaining
vaccinations.13 A series of programmatic changes
(introduction of new vaccines and old vaccine types replacing new ones) in
the Danish childhood vaccination program during the study period also allayed
concern about comparability of the vaccinated and unvaccinated groups. For
the majority of the vaccines in the study, the unvaccinated group was primarily
composed of children vaccinated with other vaccines. Thus, for a given vaccine,
we compared 2 groups of vaccinated children differing only on receipt of that
vaccine. This eliminates concern over the comparability of an unvaccinated
group of children whose parents have chosen not to have their child vaccinated
at all. Furthermore, identifying and eliminating this small group of children
(defined by us as children still completely unvaccinated after the age of
12 months) had minimal impact on our results. Finally, transient confounding
by indication could potentially result in protective effects of vaccination
in the period after vaccination if vaccination of acutely ill children was
postponed. Consequently we introduced a 14-day lag period after vaccination
and adjusted for prior infectious disease hospitalization. Neither of these
measures changed our results, indicating little if any confounding by indication
affecting the overall results.
Few studies specifically examining the association between vaccination
and nontargeted infectious diseases exist. A number of US studies from the
early 1990s have examined the association between diphtheria, tetanus, whole-cell
pertussis vaccine and invasive bacterial disease.2-5 None
of these studies reported an increased risk of nontargeted infectious disease
after vaccination. However, the studies were small case-control studies2-4 and a cohort study without
an unvaccinated comparison group.5 Furthermore,
the majority of these studies only included the immediate postvaccination
period. Otto and colleagues conducted a randomized controlled trial comparing
vaccinated and unvaccinated children with respect to nonspecific morbidity,
such as coughing or signs of rhinitis, and found that nonspecific morbidity
was significantly more common among unvaccinated children.6 Despite
being a randomized controlled trial, this study had some methodological shortcomings;
the study was not blinded and nonspecific morbidity was self-reported through
a parent diary. A recent study by Miller and colleagues examined the association
between MMR vaccination and bacterial infection and found a protective effect
using the self-controlled case series method.14
Outside the United States and Europe, a study from a small West African
country examined the association between vaccination (BCG; polio; diphtheria,
tetanus, whole-cell pertussis; and measles) and childhood mortality and found
that diphtheria, tetanus, whole-cell pertussis vaccine was associated with
increased childhood mortality.15 Recent studies
commissioned by the World Health Organization16 have
not confirmed this effect.17-19
In conclusion, our results do not support the hypothesis of increased
risk of nontargeted infectious disease hospitalization after childhood vaccination.
Corresponding Author: Anders Hviid, MSc,
Department of Epidemiology Research, Statens Serum Institut, Artillerivej
5, DK-2300 Copenhagen, Denmark (firstname.lastname@example.org).
Author Contributions: Mr Hviid had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Hviid, Stellfeld,
Analysis and interpretation of data: Hviid,
Wohlfahrt, Stellfeld, Melbye.
Drafting of the manuscript: Hviid.
Critical revision of the manuscript for important
intellectual content: Wohlfahrt, Stellfeld, Melbye.
Statistical analysis: Hviid, Wohlfahrt.
Obtained funding: Hviid.
Study supervision: Wohlfahrt, Melbye.
Financial Disclosures: None reported.
Funding/Support: This study was supported by
grants from the Danish National Research Foundation and the Danish Medical
Role of the Sponsor: The funding organizations
did not participate in the design and conduct of the study, in the collection,
analysis, and interpretation of the data, or in the preparation, review, or
approval of the manuscript.
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