In low-income countries, live measles vaccine reduces mortality from causes other than measles infection. Such nonspecific effects of vaccines might also be important for the health of children in high-income settings.
To examine whether the live vaccine against measles, mumps, and rubella (MMR) is associated with lower rates of hospital admissions for infections among children in Denmark.
Design, Setting, and Participants
Population-based cohort study of Danish children born 1997-2006 and followed up from ages 11 months to 2 years (last follow-up, August 31, 2008). Nationwide Danish registers provided data on vaccinations and hospital admissions. The recommended vaccination schedule was inactivated vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) administered at ages 3, 5, and 12 months and MMR at age 15 months.
Main Outcomes and Measures
Incidence rate ratios (IRRs) of hospital admissions for any infection, comparing receipt of MMR vs DTaP-IPV-Hib as the most recent vaccine. Risks, risk difference, and number needed to vaccinate were calculated for receiving MMR on time.
The study included 495 987 children contributing with 56 889 hospital admissions for any type of infection during 509 427 person-years (rate, 11.2 per 100 person-years). For the 456 043 children who followed the recommended schedule and received MMR after the third dose of DTaP-IPV-Hib, MMR (rate, 8.9 per 100 person-years) vs the third dose of DTaP-IPV-Hib (rate, 12.4 per 100 person-years) as the most recent vaccine was associated with an adjusted IRR of 0.86 (95% CI, 0.84-0.88) for any admission for infection. There were 19 219 children immunized out of sequence. The adjusted IRR was 0.87 (95% CI, 0.80-0.95) for those receiving MMR (rate, 9.9 per 100 person-years) after the second dose of DTaP-IPV-Hib (rate, 15.1 per 100 person-years). However, in the 1981 children who subsequently received the third dose of DTaP-IPV-Hib (rate, 12.8 per 100 person-years) after MMR, the IRR for hospital admissions for infection was significantly greater (adjusted IRR, 1.62 [95% CI, 1.28-2.05]). The risk of admission for an infection between ages 16 months and 24 months was 4.6% (95% CI, 4.5%-4.7%) for receiving MMR on time and 5.1% (95% CI, 5.0%-5.2%) for not receiving MMR on time. The risk difference was 0.5 percentage point (95% CI, 0.4-0.6), and the number needed to vaccinate with MMR before age 16 months to prevent 1 admission for any infection was 201 (95% CI, 159-272).
Conclusions and Relevance
In a cohort of Danish children, receipt of live MMR vs inactivated DTaP-IPV-Hib as the most recent vaccine was associated with a lower rate of hospital admissions for any infections. These findings require replication in other high-income populations.
Childhood vaccines are recommended worldwide, based on their protective effect against the targeted diseases.1 However, observational studies and randomized trials from low-income countries show that vaccines may have nonspecific effects that affect morbidity and mortality from nontargeted diseases.2-8 These studies have found that live vaccines such as measles and BCG vaccines have beneficial nonspecific effects, ie, reducing nontargeted morbidity and mortality. In contrast, inactivated vaccines, such as diphtheria-tetanus-pertussis,9 inactivated polio vaccine,10 and hepatitis B vaccine,11 have been associated with increased morbidity and mortality in girls.
The specific disease-protective effects of different vaccines are additive, and they are not affected by the sequence in which the vaccines have been administered. However, the nonspecific effects are largely determined by the most recent vaccination. As summarized elsewhere, many studies from low-income countries have found that receipt of measles vaccine as the most recent vaccine after receipt of diphtheria-tetanus-pertussis vaccine is associated with decreased mortality, but receiving an inactivated vaccine as the most recent vaccination after measles vaccine is associated with increased mortality among girls.9,12
The mechanisms behind these consistent findings are not understood but may involve epigenetic modulation. Recent research has shown that BCG induces increased H3K4 trimethylation in circulating monocytes, leading to stronger proinflammatory responses and increased protection against unrelated pathogens in humans and animals; blocking the H3K4 methylation reverses this monocyte training.8,13 Other mechanisms may also be involved, but such epigenetic modifications have the potential to explain how the “most recent vaccine” shapes the nonspecific effects.
So far, most studies of nonspecific effects have been conducted in low-income countries with high infectious disease pressure. In the present study, conducted in a high-income setting (Denmark), we examined whether the rate of hospital admissions for infection in the second year of life differed for children who received live vaccine against measles, mumps, and rubella (MMR) as their most recent vaccination rather than inactivated vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib). Based on the experience from low-income countries, we hypothesized that the incidence of hospital admission for any infection would be lowest when MMR was the most recent vaccination.
The study included children born in Denmark from January 1, 1997, to August 31, 2006, when the recommended vaccination schedule until age 2 years consisted of 3 doses of DTaP-IPV-Hib at ages 3, 5, and 12 months and MMR (Enders-Edmonston, Jeryl Linn, Wistar RA 27/3) at age 15 months. In Denmark all recommended childhood vaccinations are noncompulsory and are administered free of charge by general practitioners. For the purpose of reimbursement, general practitioners report vaccinations along with information on the unique personal identification number of the recipient to the Danish National Board of Health.14 The personal identification number is used by all Danish registers, making linkage possible.15 Until 1996, all childhood vaccines were registered with the parent’s identification number. Occasionally, childhood vaccinations were reported for adults (4.3%). In these cases, we assigned the vaccinations to that adult’s child who was closest to the recommended age for that vaccine (eBox 1 in Supplement).
The Danish Data Protection Agency approved the study; no informed consent from the participants was required.
Hospital Admissions for Any Infection
The Danish National Patient Register contains information about discharge diagnoses, which are coded according to the International Statistical Classification of Diseases, Tenth Revision (ICD-10).16 We identified all inpatient contacts with a primary or secondary discharge diagnosis of any infection as defined in eTable 1 in Supplement. In Denmark, general practitioners have limited access to diagnostic tools such as acute blood tests and radiography. Hence, children with suspected severe infections are usually admitted to hospitals free of charge for further diagnostic testing; children with the mildest infections are often discharged the same day.
The Danish Civil Registration System contains information on births, deaths, and emigration, which we used to define inclusion and follow-up and to obtain information about the child’s parents and household.15 The Danish Medical Birth Register contains information about birth weight, cesarean delivery, gestational age, and maternal smoking.17 Information on household income18 and maternal education19 was obtained from Statistics Denmark.
We included children who had received 2 doses of DTaP-IPV-Hib before age 11 months to limit the possibility of bias attributable to factors related to low vaccination coverage. We used 2 cohorts with different sequences of vaccinations. The recommended-schedule cohort included children who received the third dose of DTaP-IPV-Hib after the second dose (and possibly MMR later), whereas the reversed-schedule cohort received MMR after DTaP-IPV-Hib2 (and possibly DTaP-IPV-Hib3 later). We excluded children with missing information on any of the potential confounders. The children were followed up from administration of DTaP-IPV-Hib3 (recommended-schedule cohort) or administration of MMR (reversed-schedule cohort) until age 2 years, administration of other vaccines, migration, death, whereabouts unknown to the Danish authorities, or uncertainty about vaccine allocation for twins. The latest date of follow-up was August 31, 2008, in the main analysis.
As a supplemental analysis to examine the rate of hospital admissions for infection among children receiving MMR after DTaP-IPV-Hib2, we included children who had received DTaP-IPV-Hib2 before age 11 months and provided follow-up from age 11 months until age 2 years or receipt of vaccines other than MMR.
We used a generalized linear model for the binomial family with log-link to estimate the risk ratios for entering the reversed-schedule cohort compared with the recommended-schedule cohort. This model was also used to examine the determinants of having received the next vaccine at age 16 months.
We used Cox regression to estimate the incidence rate ratios (IRRs) and 95% CIs of hospital admission for any infection according to the most recent vaccination. The assumption of proportional hazards for vaccination status was evaluated by Schoenfeld residuals,20 and no violations were detected. We used age as the underlying time scale and stratified by date of birth to control completely for any effect of age, season, and year. All hospital admissions for infection were included, so one child could have several admissions. However, several admissions within a short period could be attributable to the same infection; therefore, we defined admissions occurring less than 14 days after a previous discharge as 1 episode. To account for repeated admissions we used the Andersen-Gill model (counting process approach), for which each individual is allowed to be present only once in a particular risk set at a particular age, ensuring that a child will never be compared with him or herself.21 Vaccination was included as a time-varying variable changing at the date of vaccination; thus, we analyzed the association with the most recent vaccine.
We performed both unadjusted and adjusted analyses in Stata 12 (StataCorp) (variables and categorization are included in Table 1). All tests were 2-sided, and the threshold for statistical significance was P < .05 or, for IRRs, a 95% CI not overlapping 1.0.
In-Depth Examination of the Association With Vaccination
We analyzed the association with time since vaccination and tested for trend using the likelihood ratio test. We used a competing-risks analysis22 with Wald test statistics to test equality between different types of infections and duration of admission. We also examined whether the association differed according to background factors and tested for homogeneity with Wald test statistics.
We repeated the analyses including only those children for whom all vaccines had been registered with their own personal identification number. Vaccines are only registered with the week of vaccination; we therefore coded the date of vaccination as Wednesday of the specified week. This made some misclassification inevitable, and we examined the importance of this by excluding admissions and person-years occurring during the week of vaccination. We examined the results according to administration of MMR before and after age 15 months in the reversed-schedule cohort, because early MMR vaccination could be attributable to travel to low-income countries and related to a different hospital admission pattern.
We performed analyses of vaccinations and emergency department visits registered in the Danish National Patient Register as resulting from unintentional injury,16 because we do not believe vaccination is causally related to such events. Most such visits are diagnosed as injuries. We also examined the association between vaccination status and emergency department visits related to infectious diseases.
Risk Difference and Number Needed to Vaccinate
Two methods were applied. First, we estimated the risks for the first admission related to infection from age 16 to 24 months for children who received MMR before age 16 months and for those who had received DTaP-IPV-Hib3 as the most recent vaccine by age 16 months (received MMR later or never). The risks were calculated using estimates from an adjusted Cox regression analysis comparing the 2 groups. Based on these risks, the risk difference and the number needed to vaccinate with MMR to avoid 1 hospital admission for an infection were calculated. Confidence intervals were estimated based on nonparametric bootstrap method with 2000 bootstrap samples.23 This method provides a conservative (too high) estimate of the number needed to vaccinate, because it does not account for children receiving MMR after age 16 months and only includes first hospital admissions.
Second, an estimate of the risk difference between MMR and DTaP-IPV-Hib3 was calculated as [1 − exp(−IR)] − [1 − exp(−IR × adjusted IRR)], where the adjusted IRR is the estimate from the adjusted Cox regression for MMR vs DTaP-IPV-Hib3 as the most recent vaccine and IR is the crude rate of infectious disease admissions among those most recently vaccinated with DTaP-IPV-Hib3. We used the rate over the course of an 8-month period for comparability with the conservative method. The obtained risk difference was used to calculate the number needed to vaccinate. This method provides a liberal (too low) estimate, because it is based on the crude admission rate when DTaP-IPV-Hib3 was the most recent vaccine, ie, among the youngest children.
The study included 456 043 children in the recommended-schedule cohort and 19 219 in the reversed-schedule cohort (Figure). The characteristics of the 2 cohorts are reported in Table 1. The children were followed up until the first of the following events: age 2 years (n = 436 258 [91.8%]), administration of vaccines other than MMR and DTaP-IPV-Hib3 (n = 38 533 [8.1%]), migration (n = 413 [0.1%]), death (n = 39 [0.0%]), uncertain vaccine allocation for twins or triplets (n = 11 [0.0%]), and unknown whereabouts (n = 8 [0.0%]). The supplemental analysis examining MMR vs DTaP-IPV-Hib2 included 490 838 children. A total of 495 987 different children were included in at least 1 of the analyses.
The number of MMR-vaccinated children increased from ages 15 months to 16 months in both cohorts (eTable 2 in Supplement). The median age of MMR vaccination was 15.8 months (interquartile range, 15.2-17.0 months) in the recommended-schedule cohort and 15.9 months (interquartile range, 15.2-17.4 months) in the reversed-schedule cohort. In the reversed-schedule cohort, 1981 children (10.3%) received DTaP-IPV-Hib3 after MMR.
In the recommended-schedule cohort, most background variables were significantly associated with MMR vaccination by age 16 months, although most estimates were close to 1 (eTable 3 in Supplement). In the reversed-schedule cohort there were fewer significant determinants of vaccination status (eTable 3 in Supplement).
Hospital Admissions for Infections
In total the study included 56 889 admissions attributable to any type of infection during 509 427 person-years of follow-up in the recommended-schedule cohort, reversed-schedule cohort, and the supplemental analysis examining MMR vs DTaP-IPV-Hib2 (incidence rate, 11.2 admissions per 100 person-years); 39 670 children were admitted once, whereas 7187 children were admitted several times during follow-up. Generally, the rate of admissions declined with age (eTable 4 in Supplement).
In the recommended-schedule cohort, the rate of admission was significantly lower in the adjusted model for children who received MMR compared with those who still had DTaP-IPV-Hib3 as their most recent vaccination (IRR, 0.86 [95% CI, 0.84-0.88]) (Table 2 and eTable 5 in Supplement). When comparing children who received MMR after DTaP-IPV-Hib2 with those receiving DTaP-IPV-Hib2 as the most recent vaccine, the association was similar (adjusted IRR, 0.87 [95% CI, 0.80-0.95]) (Table 2). In the reversed-schedule cohort, DTaP-IPV-Hib3, compared with MMR as the most recent vaccination, was associated with a higher rate of admission (adjusted IRR, 1.62 [95% CI, 1.28-2.05]) (Table 2 and eTable 5 in Supplement).
There was no significant difference in the rate of admissions in the first 15 days following a new vaccination (Table 3). In the recommended-schedule cohort there was a significant trend toward lower IRRs with time since MMR vaccination.
Type and Severity of Infection
In adjusted analyses of the recommended-schedule cohort, receiving MMR as the most recent vaccination had the strongest association with lower respiratory tract infections (IRR, 0.80 [95% CI, 0.76-0.84]), significantly (P < .001) stronger than for other types of infection (Table 4). About one-third of admissions in the recommended-schedule cohort and the reversed-schedule cohort lasted less than 1 day (14 627 admissions [33.9%]); in the recommended-schedule cohort the adjusted IRR for admissions lasting less than 1 day was 0.86 (95% CI, 0.82-0.90), comparable with the estimate for admissions lasting at least 1 day (adjusted IRR, 0.86 [95% CI, 0.83-0-89]) (eTable 6 in Supplement). The adjusted IRR was 0.83 (95% CI, 0.79-0.86) for admissions lasting more than 1 day, 0.80 (95% CI, 0.76-0.84) for those lasting more than 2 days, and 0.80 (95% CI, 0.75-0.86) for those lasting more than 3 days (eTable 6 in Supplement). In the reversed-schedule cohort, there was no significant difference according to type of infection (Table 4) or duration of admission (eTable 6 in Supplement).
Variability According to Background Factors
There were statistically significant interactions between the most recent vaccination and the following variables in adjusted analyses in the recommended-schedule cohort: chronic diseases, hospital admission within the last 30 days, hospital admission for infection before age 11 months, parental origin, and other children in the household. Receiving MMR as the most recent vaccination was associated with a lower rate of admission for all groups except children admitted to the hospital within the last 30 days, those with chronic conditions, and those with both parents born outside Denmark (eTable 7 in Supplement). In the reversed-schedule cohort, the only significant interaction was between most recent vaccine and chronic diseases (eTable 8 in Supplement). There was no statistically significant interaction between the most recent vaccination and sex (eTable 7 and eTable 8 in Supplement).
Among the 410 872 children (90.1%) from the recommended-schedule cohort who had all vaccines registered with their own personal registration number, the adjusted IRR for MMR as the most recent vaccination was 0.86 (95% CI, 0.84-0.89; 38 022 admissions). In the reversed-schedule cohort 17 658 children (91.9%) had all vaccines registered with their own personal registration number; among these children the adjusted IRR for receiving DTaP-IPV-Hib3 after MMR was 1.68 (95% CI, 1.31-2.14; 1062 admissions). In the reversed-schedule cohort the results were similar for those receiving MMR before age 15 months (adjusted IRR, 1.79 [95% CI, 0.81-3.97]) and after age 15 months (adjusted IRR, 1.71 [95% CI, 1.22-2.38]). The results were similar with exclusion of admissions in the week of vaccination (eTable 9 and eTable 10 in Supplement), exclusion of 38 admissions because of the vaccine-targeted infections (eAppendix in Supplement), and exclusion of admissions because of chronic infections (eTable 11 in Supplement).
Emergency Department Visits
In the recommended-schedule cohort, the adjusted IRR of emergency department visits following unintentional injury was 0.97 (95% CI, 0.95-0.99) for MMR compared with DTaP-IPV-Hib3 as the most recent vaccination (eTable 12 in Supplement). The equivalent adjusted IRR of infections registered at emergency department visits was 0.84 (95% CI, 0.78-0.91) (eTable 13 in Supplement).
Risk Difference and Number Needed to Vaccinate
Children vaccinated with MMR before age 16 months had a 4.6% (95% CI, 4.5%-4.7%) risk of being admitted at least once for an infection between ages 16 and 24 months, whereas the risk for those not vaccinated with MMR before age 16 months was 5.1% (95% CI, 5.0%-5.2%). Hence, the conservative estimate of the risk difference was 0.5 percentage point (95% CI, 0.4-0.6), and the number needed to vaccinate with MMR before age 16 months to prevent 1 hospital admission for an infection before age 24 months was 201 (95% CI, 159-272). The liberal estimate of the risk difference was 1.1 percentage points (95% CI, 0.9-1.2) for DTaP-IPV-Hib3 vs MMR as the most recent vaccine, and the number needed to vaccinate with MMR to prevent 1 hospital admission for an infection during an 8-month period was 93 (95% CI, 82-109).
Receiving the live MMR vaccine after the inactivated DTaP-IPV-Hib vaccine was associated with a lower rate of hospital admissions for any infection. The association was particularly strong for lower respiratory tract infections and for longer hospital admissions. Children who received DTaP-IPV-Hib after MMR had a significantly higher rate of infectious disease admission.
Vaccinations were registered by general practitioners to obtain reimbursement; we therefore believe that the information is reliable, but there might have been some underreporting.24 Any misclassification or underreporting of vaccinations would bias the estimates toward no association. There was no possibility for residual confounding by age, because the Cox regression model was specified to compare children of the exact same age but who have received different vaccinations.
To observe nonspecific effects of vaccines it is necessary to go beyond measurement of protective antibody responses or protection against the specific disease and examine the overall effect on morbidity or mortality. Before measles vaccine was recommended, 2 community studies randomized some areas to receive measles vaccine or no vaccine, and the reduction in overall mortality was 30% to 50%.25,26 After measles vaccination at age 9 months became global policy, it was not possible to compare measles-vaccinated with measles-unvaccinated children, but randomized trials have measured the effect of introducing an additional dose of measles vaccine before age 9 months compared with the current policy. Reduction in overall mortality and hospital admissions was 30% to 50% and was not explained by prevention of measles infection.3,27-29 Our finding that MMR as the most recent vaccine was associated with lower risk of hospital admissions for nontargeted infections is consistent with these reports.
In high-income countries, some studies also found an association with MMR and lower risk of infectious diseases.30-32 However, these studies have not focused on the most recently administered vaccine and are therefore not directly comparable with the present study. It has been a consistent observation in low-income countries that the most recent vaccination most strongly influences susceptibility to unrelated infections.1,9,12,33 The immunological mechanisms for how different vaccinations induce such changes—from DTaP-IPV-Hib3 to MMR or from MMR to DTaP-IPV-Hib3 in the present study—have not been studied. Both cross-reactivity of T cells in the adaptive immune system and trained innate immunity have been suggested as potential explanations of nonspecific effects of vaccines.8
It might be speculated that our results were attributable to selection bias if the healthiest children received MMR first.34 However, many of our observations cannot be explained by selection bias. First, if the association was attributable to healthy children being vaccinated first, the association should have been apparent in the first 2 weeks. This was not the case. Second, the association should be similar for all types of infection; however, we observed a significantly lower rate of lower respiratory tract infections. Third, a similar association was seen when MMR was administered out of sequence after DTaP-IPV-Hib2. Fourth, MMR was only associated with a 3% reduction in emergency department visits following unintentional injury, which suggests that our results are not explained by a health-seeking bias.
Furthermore, when DTaP-IPV-Hib3 was given after MMR in the reversed-schedule cohort, vaccination was associated with an increase in admissions. In the reversed-schedule cohort, there was also no significant association in the first 15 days after DTaP-IPV-Hib3 vaccination, there was no association with emergency department visits following unintentional injury, and the association was also present among normal birth weight children and children without chronic conditions.
The high-quality data, the strict control for confounders, and the consistency with prior observations from low-income countries1,8,28 all support that vaccines also have nonspecific effects on susceptibility to infections in high-income countries.
The coverage with MMR is suboptimal in many high-income countries35; in the present study, about 50% of children were not vaccinated on time. Physicians should encourage parents to have children vaccinated on time with MMR and avoid giving vaccinations out of sequence, because the present study suggests that timely MMR vaccination averted a considerable number of hospital admissions for any infection between ages 16 and 24 months. The conservative estimate of the number needed to vaccinate to avoid 1 admission for an infection between ages 16 and 24 months was 201, whereas the liberal estimate was 93. The true number needed to vaccinate probably lies somewhere between these 2 estimates. The estimates are affected by the rate of admissions, which is higher in Denmark than in many other countries, including the United States, because of different organization of health care, including free hospital care and limited diagnostic options in primary care.36-38
In a nationwide cohort of Danish children, receipt of the live MMR vaccine vs inactivated DTaP-IPV-Hib as the most recent vaccine was associated with a lower rate of hospital admissions for any infections. The findings require replication in other high-income populations.
Corresponding Author: Signe Sørup, PhD, CVIVA, Bandim Health Project, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark (email@example.com).
Author Contribution: Dr Sørup had full access to all 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: All authors.
Acquisition of data: Sørup, Ravn.
Analysis and interpretation: All authors.
Drafting of the manuscript: Sørup.
Critical revision of the manuscript for important intellectual content: Benn, Poulsen, Krause, Aaby, Ravn.
Statistical analysis: Sørup, Ravn.
Obtained funding: Sørup, Benn, Aaby, Ravn.
Administrative, technical, and material support:
Study supervision: Benn, Poulsen, Krause, Aaby, Ravn.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE form for Disclosure of Potential Conflicts of Interest. Dr Ravn reported owning a private statistical consultancy. No other authors reported disclosures.
Funding/Support: This work was supported by the Health Foundation (2009B132 [Dr Sørup]); the Rosalie Petersen Foundation (Dr Sørup); and the Novo Nordisk Foundation (research professorship grant [Dr Aaby]). Dr Benn holds a European Research Council (ERC) Starting Grant (ERC-StG-243149). The Danish National Research Foundation (DNRF) supports the Research Center for Vitamins and Vaccines (DNRF108).
Role of the Sponsors: The funders had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
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