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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 955 956 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 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 957 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. 958 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 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 959 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 960 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 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). 961 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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