Highlights
-
•
MMR vaccination is given to protect against measles, mumps and rubella.
-
•
RSV is an important cause of acute lower respiratory infections in young children.
-
•
MMR vaccination was associated with 22% lower rate of RSV hospital contacts.
-
•
MMR vaccination may reduce the rate or severity of RSV infection.
Abbreviations: CI, Confidence interval; DTaP-IPV-Hib, Inactivated vaccine against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b; GP, general practitioner; IRR, incidence rate ratio; MMR, Live vaccine against measles, mumps, and rubella; OPV, Oral polio vaccine; RSV, Respiratory syncytial virus
Keywords: Heterologous immunity, Immunization, Non-specific effects, Non-targeted effects, Measles–mumps–rubella vaccination, Respiratory syncytial virus
Abstract
Background
The live measles vaccine has been associated with lower non-measles mortality and admissions in low-income countries. The live measles–mumps–rubella vaccine has also been associated with lower rate of admissions with any type of infection in Danish children; the association was strongest for admissions with lower respiratory infections.
Objective
To examine whether measles, mumps, and rubella (MMR) vaccination was associated with reduced rate of hospital contact related to respiratory syncytial virus (RSV) in a high-income country.
Methods
Nationwide cohort study of laboratory-confirmed RSV hospital contacts at age 14–23 months in all children born in Denmark 1997–2002 who had already received the vaccine against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) at the recommended ages of 3, 5, and 12 months.
Results
The study included 888 RSV hospital contacts in 128,588 person years of follow up (rate 6.8/1000 person years). Having MMR as the most recent vaccine was associated with a reduced rate of RSV hospital contacts compared with having DTaP-IPV-Hib as the most recent vaccine (Incidence rate ratio (IRR), 0.75; 95% confidence interval (CI), 0.63–0.89). After adjustment for potential confounders including exact age in days the IRR was 0.78 (95% CI, 0.66–0.93). The adjusted IRR was 0.74 (95% CI, 0.60–0.92) in males and 0.84 (95% CI, 0.66–1.06) in females (P Interaction, 0.42). There was no association in the first month after MMR vaccination (adjusted IRR, 0.97; 95% CI, 0.76–1.24) but the adjusted IRR was 0.70 (95% CI, 0.58–0.85) from one month after MMR vaccination.
Conclusions
MMR vaccination was associated with reduced rate of hospital contacts related to laboratory-confirmed RSV infection. Further research on the association between MMR vaccination and other unrelated pathogens are warranted.
1. Introduction
Besides the disease-targeted effects, vaccines may affect morbidity and mortality to unrelated infections by changing the general level of resistance toward infections, the so-called nonspecific effects of vaccines [1], [2], [3]. In low-income countries, live vaccines like bacille Calmette–Guérin (BCG) against tuberculosis and measles vaccine have beneficial effects on all-cause child mortality [4], [5], [6], [7], [8]. In contrast, inactivated vaccines including diphtheria–tetanus–pertussis (DTP) vaccine may increase all-cause child mortality [9], [10], [11]. The nonspecific effects are often most marked in females [2], [8], [10], [11], [12]. Most findings from low-income countries relate to all-cause mortality. However, nonspecific effects of vaccinations on the incidence of infectious diseases and admission rates have been reported from both low-income [13], [14], [15], [16], [17] and high-income countries [18]. Recently, we found that the rate of admissions related to infections and particularly lower respiratory infections was reduced for Danish children following vaccination with the live MMR vaccine against measles, mumps, and rubella [19].
One of the most common causes of acute lower respiratory tract infections in infants is respiratory syncytial virus (RSV) [20], [21], [22]. Worldwide, an estimated 33.8 million new cases occur each year leading to 3.4 million hospital admissions of children under 5 years of age [21]. A study from Guinea-Bissau found that BCG vaccination reduced the risk of severe RSV infection [16]. The aim of the present study was to examine the association between MMR vaccine and the rate of hospital contacts resulting from RSV infection in a high-income setting. In the study period, the Danish recommendations were to administer MMR (Enders Edmonston, Jeryl Lynn, and Wistar RA 27/3) at 15 months of age after three doses of the inactivated vaccine against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) recommended at 3, 5 and 12 months of age (see Supplementary Fig. 1). The prespecified hypothesis was that children most recently vaccinated with MMR have a lower rate of RSV hospital contact compared with children vaccinated most recently with the third dose of DTaP-IPV-Hib (DTaP-IPV-Hib3).
Fig. 1.
Flowchart of the cohort. Abbreviations: RSV respiratory syncytial virus; DTaP-IPV-Hib vaccination against diphtheria tetanus pertussis (acellular) polio and Haemophilus influenzae type b; MMR vaccination against measles mumps and rubella. In the parentheses, number of hospital contacts related to RSV from 14 months and until date of censoring for the children included in the study or until 2 years of age for the children excluded from the study. a DTaP-IPV or Hib alone (N = 17,882; 63.0%), not recommended combination of vaccines (N = 5348; 18.8%), fourth dose of DTaP-IPV-Hib (N = 3371; 11.9%), whole cell pertussis vaccine (N = 1011; 3.6%), OPV (N = 435; 1.5%), booster dose against diphtheria and tetanus (N = 252; 0.9%), vaccine against hepatitis B (N = 87; 0.3%), and second dose of MMR (N = 10; 0.0%). b Children receiving MMR before DTaP-IPV-Hib3 were excluded.
2. Material and methods
The Danish Civil Registration System was established in 1968 and all Danish residents are assigned a unique personal identification number [23]. The personal identification number is used by all Danish national registers and was used to link the registers for the present study.
2.1. Vaccination register
In Denmark, all recommended childhood vaccinations are administered free-of-charge by the general practitioner (GP). For the purpose of reimbursement, the GPs report all vaccinations to the counties and from the counties the data are transferred to the Danish National Health Service Register [24]. Based on this information we created a database of childhood vaccinations. Most childhood vaccinations were registered in a child's name, but occasionally childhood vaccinations were registered in a parent's name (5.7%), particularly for young infants who only received their own medical card after they had been named [25]. The recommended childhood vaccinations were only reimbursed by the counties for persons below 18 years of age. Childhood vaccinations registered to an adult can therefore be assumed to have been administered to a child and we assigned such vaccinations to that adult's child, which was closest to the scheduled age of that vaccine. Vaccinations are only registered on a weekly basis. We coded date of vaccination as Wednesday of the registered week of vaccination.
2.2. RSV-database
Information on RSV-related hospital contacts was obtained from the Danish nationwide RSV-database, which was established for research purposes by collection of information from the 18 Danish laboratories testing for RSV among patients at the Danish hospitals, described in detail elsewhere [26]. The RSV-database covers the period 1 January 1996 to 1 June 2003 were RSV was examined by ELISA or immunofluorescence. During this period, all admitted children with symptoms consistent with RSV were tested for RSV to facilitate isolation of RSV cases from other admitted children to reduce the risk of transmission. In children born in Denmark and registered in the Danish Civil Registration System, the incidence rates of hospital contacts with RSV were 25.2, 27.5, 16.0, and 6.8 per 1000 person years among the age groups less than 6 weeks, 6 weeks-6 months, 6–14 months and 14–24 months, respectively. We only included information on children born on 1 January 1997 and onwards, because the vaccination schedule changed considerably from 1996 to 1997.
2.3. Other register information
The Danish Civil Registration System contains information on vital status and emigration which we used to define inclusion date and follow-up periods [23]. It was also possible to obtain information about the composition of each child's household, and age and country of birth of the parents. The Danish Medical Birth Register contains information about birth weight, mode of delivery, gestational age, and maternal smoking in pregnancy [27]. The Danish National Patient Register contains information about discharge diagnoses [28]; we used this register to obtain information on other types of hospital contacts, including accidents and chronic diseases. We obtained information on household equivalence income [29], maternal education [30], and public childcare from Statistics Denmark.
2.4. Design
The study was designed as a cohort study with retrospective identification of children born in Denmark during 1 January 1997 and 31 March 2002 and who were alive and living in Denmark at 14 months of age. In the main analysis we only included children who had followed the recommended vaccination schedule for the first three vaccination visits by receiving DTaP-IPV-Hib1 before 4 months of age, DTaP-IPV-Hib2 before 6 months of age, and DTaP-IPV-Hib3 before 13 months of age. The purpose of this selection was to include children who resemble each other with respect to determinants of vaccination and thereby reduce bias. Further details of the inclusion are given in Fig. 1. Follow-up was stopped at 2 years of age since oral polio vaccine (OPV) was scheduled at 2 years of age until July 1, 2001 (see Supplementary Fig. 1). The Danish Data Protection Agency approved the study.
2.5. Statistical methods
To describe determinants of MMR vaccination, we estimated the risk ratios (RRs) of being MMR-vaccinated at 16 months and 2 years of age according to different covariates using Poisson regression with robust variance [31].
To estimate incidence-rate-ratios (IRRs) and 95% confidence intervals (CIs) of RSV hospital contact according to most recent vaccination we used Cox proportional hazard regression analysis. Hence, the children changed vaccination status from DTaP-IPV-Hib3 to MMR on the date of MMR vaccination. We included all RSV hospital contacts, so one child could have several RSV hospital contacts. To minimize the risk that the same episode of RSV infection counted as two hospital contacts we defined the duration of one RSV infection to be 14 days based on the expected maximal period of shedding [32]. These 14 days were excluded from the count of person years.
We used age as the underlying timescale of the Cox regression model and stratified by date of birth such that cases were only compared with children born on the same date and at the same age; hence, we controlled completely for any potential confounding from age, season, and calendar year. Furthermore, the model was adjusted for: sex, birth weight in grams (≤2000, 2001–2500, 2501–3000, 3001–3500, 3501–4000, 4001–4500, or >4500), gestational age (<37 weeks or ≥37 weeks of gestation), caesarean section (no or yes), number of admissions for any cause between 1 month of age and date of DTaP-IPV-Hib3 vaccination (none, one, two, or ≥three), admission for any cause from date of DTaP-IPV-Hib3 vaccination until 14 months of age (no or yes), maternal age at birth of the child in years (≤19, 20–24, 25–29, 30–34, 35–39, or ≥40), parental place of birth (Denmark, Denmark-Foreign, or Foreign), adult composition of the household (two adults, single parent, or no parents), other children in the household (no or yes) and the time-varying variable chronic diseases (no or yes) coded according to Kristensen et al., 2012 [33]. In additional analyses described in the supplementary appendix further adjustment was made for maternal smoking in pregnancy, childcare, household income, and maternal education.
2.5.1. Interactions
Nonspecific effects of vaccines have previously been found to interact with sex and vitamin A supplementation [2], [3]; other interactions might also be important. For this reason and to assess the generalizability of the results, we introduced interaction terms between MMR and dichotomised forms of the variables adjusted for in the main analysis. The interaction terms were introduced in the model one at a time and statistical significance was examined with Wald test statistics.
2.5.2. Sensitivity
The assumption of proportional hazards between vaccination groups was evaluated by Schoenfeld residuals and no violation was detected. We examined if the effect of MMR was immediate by splitting the time period with MMR at 30 days after MMR vaccination. In addition we examined for trend in the association according to time since MMR vaccination. The stability of the results was examined by continuing follow-up until 3 years of age. In a subgroup analysis, we excluded children who had been admitted to hospital with RSV before inclusion in the study to limit the potential effect of immunity to RSV. We examined the generalizability of the results by using a cohort which also included the children who had not received the first three doses of DTaP-IPV-Hib on time.
We do not believe that accidents are related to vaccination and we therefore performed an analysis in which the outcome was accidents registered at emergency room visits to check for possible registration bias in our data material.
All analyses were performed in Stata 12.
3. Results
A total of 168,511 children were followed until the first of the following events: age 2 years (N = 129,333; 76.8%), 1 June 2003 (N = 25,475; 15.1%), administration of other vaccines than the first MMR (mainly OPV) (N = 13,370; 7.9%), migration (N = 296; 0.2%), death (N = 31; 0.0%), unknown whereabouts for the Danish authorities (N = 4; 0.0%), and uncertainty about vaccinations for twins (N = 2; 0.0%).
Overall 60.6% were vaccinated with MMR by 16 months of age and 91.8% at 2 years of age. There was little variation in the likelihood of being MMR-vaccinated, but children of single parents, younger mothers, and children who lived together with other children were less likely to be MMR-vaccinated, particularly at 16 months of age (Table 1).
Table 1.
Distribution of most recent vaccine and risk ratios of being MMR-vaccinated at 16 months and 2 years of age according to background factors.
| Characteristics | 16 months of age |
2 years of age |
||||||
|---|---|---|---|---|---|---|---|---|
| DTaP-IPV-Hib3% (N)a | MMR % (N)a | Adjusted RRb (95%-CI) | P valuec | DTaP-IPV-Hib3% (N)a | MMR % (N)a | Adjusted RRb (95%-CI) | P valuec | |
| Sex | ||||||||
| Male | 39.7% (33,700) | 60.3% (51,136) | 1 (Ref) | .03 | 8.3% (6486) | 91.7% (71,693) | 1 (Ref) | .10 |
| Female | 39.1% (32,328) | 60.9% (50,369) | 1.01 (1.00–1.02) | 8.0% (6147) | 92.0% (70,357) | 1.00 (1.00–1.01) | ||
| Birth weight, gram | ||||||||
| ≤2000 | 40.8% (834) | 59.2% (1208) | 1.02 (0.98–1.06) | .01 | 8.0% (152) | 92.0% (1738) | 1.01 (0.99–1.02) | .44 |
| 2001–2500 | 39.5% (2027) | 60.5% (3107) | 1.02 (1.00–1.05) | 8.3% (396) | 91.7% (4378) | 1.00 (0.99–1.01) | ||
| 2501–3000 | 38.3% (7978) | 61.7% (12,856) | 1.02 (1.01–1.04) | 8.2% (1568) | 91.8% (17,664) | 1.00 (1.00–1.01) | ||
| 3001–3500 | 39.5% (21,049) | 60.5% (32,298) | 1 (Ref) | 8.2% (4043) | 91.8% (45,178) | 1 (Ref) | ||
| 3501–4000 | 39.4% (22,254) | 60.6% (34,200) | 1.01 (1.00–1.02) | 8.2% (4264) | 91.8% (47,878) | 1.00 (1.00–1.01) | ||
| 4001–4500 | 40.1% (9634) | 59.9% (14,377) | 1.01 (0.99–1.02) | 8.0% (1781) | 92.0% (20,395) | 1.01 (1.00–1.01) | ||
| >4500 | 39.4% (2252) | 60.6% (3,459) | 1.03 (1.00–1.05) | 8.2% (429) | 91.8% (4819) | 1.01 (1.00–1.01) | ||
| Gestational age, weeks | ||||||||
| <37 | 40.3% (3465) | 59.7% (5139) | 0.99 (0.96–1.01) | .18 | 7.8% (622) | 92.2% (7366) | 1.01 (1.00–1.02) | .04 |
| ≥37 | 39.4% (62,563) | 60.6% (96,366) | 1 (Ref) | 8.2% (12,011) | 91.8% (134,684) | 1 (Ref) | ||
| Caesarean section | ||||||||
| No | 39.5% (56,015) | 60.5% (85,886) | 1 (Ref) | .60 | 8.2% (10,755) | 91.8% (120,192) | 1 (Ref) | .53 |
| Yes | 39.1% (10,013) | 60.9% (15,619) | 1.00 (0.99–1.01) | 7.9% (1878) | 92.1% (21,858) | 1.00 (1.00–1.01) | ||
| Chronic diseases | ||||||||
| No | 39.3% (64,154) | 60.7% (98,899) | 1 (Ref) | .03 | 8.1% (12,242) | 91.9% (138,144) | 1 (Ref) | .40 |
| Yes | 41.8% (1874) | 58.2% (2606) | 0.97 (0.95–1.00) | 9.1% (391) | 90.9% (3906) | 1.00 (0.99–1.01) | ||
| Number of admissions between 1 month of age and date of DTaP-IPV-Hib3 vaccination | ||||||||
| None | 39.1% (55,540) | 60.9% (86,521) | 1 (Ref) | <.001 | 8.0% (10,439) | 92.0% (120,777) | 1 (Ref) | <.001 |
| One | 40.8% (7858) | 59.2% (11,393) | 0.98 (0.97–0.99) | 9.1% (1617) | 90.9% (16,127) | 0.99 (0.98–0.99) | ||
| Two | 42.5% (1747) | 57.5% (2367) | 0.96 (0.93–0.99) | 10.3% (392) | 89.7% (3400) | 0.98 (0.97–0.99) | ||
| Three or more | 41.9% (883) | 58.1% (1224) | 0.98 (0.94–1.02) | 9.6% (185) | 90.4% (1746) | 0.99 (0.98–1.00) | ||
| Admission from date of DTaP-IPV-Hib3 vaccination until 14 months of age | ||||||||
| No | 39.3% (64,073) | 60.7% (98,879) | 1 (Ref) | <.001 | 8.1% (12,212) | 91.9% (138,262) | 1 (Ref) | .001 |
| Yes | 42.7% (1955) | 57.3% (2626) | 0.95 (0.92–0.97) | 10.0% (421) | 90.0% (3788) | 0.98 (0.97–0.99) | ||
| Maternal age at birth of the child, years | ||||||||
| ≤19 | 41.4% (1027) | 58.6% (1452) | 0.94 (0.91–0.98) | <.001 | 11.9% (277) | 88.1% (2043) | 0.95 (0.94–0.97) | <.001 |
| 20–24 | 37.1% (8509) | 62.9% (14,411) | 1.01 (1.00–1.02) | 8.9% (1858) | 91.1% (19,077) | 0.98 (0.98–0.99) | ||
| 25–29 | 38.1% (24,434) | 61.9% (39,708) | 1.01 (1.00–1.02) | 7.5% (4443) | 92.5% (54,593) | 1.00 (0.99–1.00) | ||
| 30–34 | 40.7% (22,732) | 59.3% (33,069) | 1 (Ref) | 8.0% (4132) | 92.0% (47,519) | 1 (Ref) | ||
| 35–39 | 42.0% (8231) | 58.0% (11,357) | 0.99 (0.98–1.01) | 9.1% (1673) | 90.9% (16,635) | 0.99 (0.99–1.00) | ||
| ≥40 | 42.1% (1095) | 57.9% (1508) | 0.99 (0.95–1.02) | 10.3% (250) | 89.7% (2183) | 0.98 (0.96–0.99) | ||
| Parental place of birth | ||||||||
| Denmark | 39.2% (55,129) | 60.8% (85,372) | 1 (Ref) | .004 | 8.2% (10,583) | 91.8% (119,060) | 1 (Ref) | <.001 |
| Denmark and foreign | 40.5% (5539) | 59.5% (8150) | 0.98 (0.96–0.99) | 8.4% (1063) | 91.6% (11,629) | 1.00 (0.99–1.00) | ||
| Foreign | 40.2% (5360) | 59.8% (7983) | 1.01 (0.99–1.02) | 8.0% (987) | 92.0% (11,361) | 1.01 (1.01–1.02) | ||
| Adult composition of the household | ||||||||
| Two adults | 39.2% (61,640) | 60.8% (95,795) | 1 (Ref) | <.001 | 7.9% (11,517) | 92.1% (133,767) | 1 (Ref) | <.001 |
| Single parent | 43.5% (4293) | 56.5% (5573) | 0.92 (0.91–0.94) | 11.9% (1089) | 88.1% (8088) | 0.96 (0.95–0.97) | ||
| No parents | 40.9% (95) | 59.1% (137) | 1.03 (0.92–1.15) | 12.2% (27) | 87.8% (195) | 0.98 (0.93–1.03) | ||
| Other children in the household | ||||||||
| No | 34.9% (27,558) | 65.1% (51,327) | 1 (Ref) | <.001 | 6.7% (4892) | 93.3% (67,715) | 1 (Ref) | <.001 |
| Yes | 43.4% (38,470) | 56.6% (50,178) | 0.87 (0.86–0.88) | 9.4% (7741) | 90.6% (74,335) | 0.97 (0.96–0.97) | ||
Abbreviations: RR—risk ratio; MMR, vaccination against measles, mumps, and rubella.
The number of children do not add to the total number of children in the study, because some children were censored before the specified age.
RR of being MMR vaccinated at the specified age estimated by Poisson regression with robust variance and adjusted for all variables in the table.
P values for the test of the association between the specified variable and vaccination status.
In 128,588 person years of follow-up 888 RSV hospital contacts occurred (rate, 6.8/1000 person years); 886 children had one RSV hospital contact each, while one child had two RSV hospital contacts during follow-up. The rate of RSV hospital contact according to the vaccination status and age are given in Supplementary Table 1. The median duration of RSV hospital contacts was 3 days (inter quartile range, 2–5 days) in both DTaP-IPV-Hib3 and MMR-vaccinated children.
Compared with children having DTaP-IPV-Hib3 as the most recent vaccination, having MMR as the most recent vaccination was associated with a reduced rate of RSV hospital contacts (IRR, 0.75; 95% CI, 0.63–0.89; Table 2); the adjusted IRR was 0.78 (95% CI, 0.66–0.93; Table 2). Further adjustment for maternal smoking in pregnancy, childcare, household income, and maternal education did not alter the results (Supplementary Table 3). In males, the adjusted IRR of RSV hospital contacts for MMR compared with DTaP-IPV-Hib3 as the most recent vaccine was 0.74 (95% CI, 0.60–0.92), while the adjusted IRR for females was 0.84 (95% CI, 0.66–1.06; P Interaction, 0.42; Table 3). Also, none of the other examined interactions were statistically significant (Table 3).
Table 2.
Incidence and incidence-rate-ratios of RSV hospital contact according to vaccination status.
| Characteristics | RSV hospital contacts per 1000 person years (RSV hospital contacts/person yearsa) | Unadjusted IRRb (95%-CI) | P Valuec | Adjusted IRRd (95%-CI) | P Valuec | |
|---|---|---|---|---|---|---|
| Vaccination status | ||||||
| DTaP-IPV-Hib3 | 8.9 | (320/35,995) | 1 (Ref) | .001 | 1 (Ref) | .006 |
| MMR | 6.1 | (568/92,593) | 0.75 (0.63–0.89) | 0.78 (0.66–0.93) | ||
Abbreviations: RSV—respiratory syncytial virus; IRR—incidence-rate-ratio; DTaP-IPV-Hib3—vaccination with the third dose against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b; MMR, vaccination against measles, mumps, and rubella.
The distribution of person years for each category indicates the demographic features of the included children.
Cox proportional hazards model with age as underlying time and stratified by date of birth thereby controlling for age and season.
P values for the test of the association between the most recent vaccine and RSV hospital contacts.
Cox proportional hazards model with age as underlying time, stratified by date of birth and adjusted for sex, birth weight, gestational age, caesarean section, chronic diseases, number of admissions between 1 month of age and date of DTaP-IPV-Hib3 vaccination, admission from date of DTaP-IPV-Hib3 vaccination until 14 months of age, maternal age at birth of the child, parental place of birth, adult composition of the household, and other children in the household (the IRR estimates for these variables are given in Supplementary Table 2).
Table 3.
Results for two-way-interactions between vaccination status and dichotomised forms of the variables included in the main analysis.
| Characteristics | RSV hospital contacts per 1000 person years (RSV hospital contacts/person years) | Unadjusted IRRa (95%-CI) | Adjusted IRRb (95%-CI) | |
|---|---|---|---|---|
| Female | ||||
| DTaP-IPV-Hib3 | 7.7 | (136/17,637) | 1 (Ref) | 1 (Ref) |
| MMR | 5.8 | (265/45,774) | 0.82 (0.65–1.04) | 0.84 (0.66–1.06) |
| Male | ||||
| DTaP-IPV-Hib3 | 10.0 | (184/18,358) | 1 (Ref) | 1 (Ref) |
| MMR | 6.5 | (303/46,819) | 0.70 (0.57–0.87) | 0.74 (0.60–0.92) |
| P interactionc | .28 | .42 | ||
| No other children in the household | ||||
| DTaP-IPV-Hib3 | 8.5 | (132/15,580) | 1 (Ref) | 1 (Ref) |
| MMR | 6.0 | (270/44,896) | 0.78 (0.61–0.99) | 0.82 (0.65–1.04) |
| Other children in the household | ||||
| DTaP-IPV-Hib3 | 9.2 | (188/20,415) | 1 (Ref) | 1 (Ref) |
| MMR | 6.2 | (298/47,696) | 0.74 (0.60–0.91) | 0.76 (0.61–0.94) |
| P interactionc | .70 | .57 | ||
| No single parenthood | ||||
| DTaP-IPV-Hib3 | 8.7 | (294/33,604) | 1 (Ref) | 1 (Ref) |
| MMR | 5.9 | (519/87,445) | 0.74 (0.62–0.89) | 0.77 (0.64–0.92) |
| Single parenthood | ||||
| DTaP-IPV-Hib3 | 10.9 | (26/2391) | 1 (Ref) | 1 (Ref) |
| MMR | 9.5 | (49/5148) | 0.96 (0.59–1.57) | 1.00 (0.61–1.63) |
| P interactionc | .30 | .30 | ||
| Only Danish born parents | ||||
| DTaP-IPV-Hib3 | 9.7 | (294/30,157) | 1 (Ref) | 1 (Ref) |
| MMR | 6.4 | (502/77,870) | 0.72 (0.60–0.86) | 0.75 (0.63–0.90) |
| At least one parent born outside Denmark | ||||
| DTaP-IPV-Hib3 | 4.5 | (26/5838) | 1 (Ref) | 1 (Ref) |
| MMR | 4.5 | (66/14,723) | 1.11 (0.69–1.77) | 1.12 (0.70–1.80) |
| P interactionc | .08 | .10 | ||
| Maternal age <30 years | ||||
| DTaP-IPV-Hib3 | 8.9 | (168/18,871) | 1 (Ref) | 1 (Ref) |
| MMR | 6.3 | (313/50,078) | 0.76 (0.61–0.94) | 0.79 (0.64–0.98) |
| Maternal age ≥30 years | ||||
| DTaP-IPV-Hib3 | 8.9 | (152/17,124) | 1 (Ref) | 1 (Ref) |
| MMR | 6.0 | (255/42,514) | 0.74 (0.59–0.93) | 0.77 (0.62–0.97) |
| P Interaction c | .86 | .88 | ||
| Normal birth weight (>2500 g) | ||||
| DTaP-IPV-Hib3 | 8.5 | (294/34,484) | 1 (Ref) | 1 (Ref) |
| MMR | 5.9 | (522/88,670) | 0.75 (0.63–0.90) | 0.79 (0.66–0.94) |
| Low birth weight (≤2500 g) | ||||
| DTaP-IPV-Hib3 | 17.2 | (26/1511) | 1 (Ref) | 1 (Ref) |
| MMR | 11.7 | (46/3923) | 0.69 (0.42–1.13) | 0.73 (0.44–1.22) |
| P interactionc | .71 | .79 | ||
| Term (gestational age≥37 weeks) | ||||
| DTaP-IPV-Hib3 | 8.6 | (293/34,173) | 1 (Ref) | 1 (Ref) |
| MMR | 5.8 | (512/87,914) | 0.74 (0.62–0.88) | 0.77 (0.64–0.92) |
| Premature (gestational age<37 weeks) | ||||
| DTaP-IPV-Hib3 | 14.8 | (27/1822) | 1 (Ref) | 1 (Ref) |
| MMR | 12.0 | (56/4679) | 0.87 (0.54–1.40) | 0.94 (0.58–1.52) |
| P interactionc | .53 | .42 | ||
| No caesarean section | ||||
| DTaP-IPV-Hib3 | 8.5 | (260/30,582) | 1 (Ref) | 1 (Ref) |
| MMR | 5.6 | (441/78,714) | 0.72 (0.60–0.87) | 0.75 (0.62–0.90) |
| Caesarean section | ||||
| DTaP-IPV-Hib3 | 11.1 | (60/5413) | 1 (Ref) | 1 (Ref) |
| MMR | 9.2 | (127/13,879) | 0.88 (0.63–1.22) | 0.94 (0.67–1.31) |
| P interactionc | .25 | .21 | ||
| No chronic diseases | ||||
| DTaP-IPV-Hib3 | 8.6 | (301/34,985) | 1 (Ref) | 1 (Ref) |
| MMR | 5.9 | (528/90,110) | 0.74 (0.62–0.89) | 0.77 (0.65–0.93) |
| Chronic diseases | ||||
| DTaP-IPV-Hib3 | 18.8 | (19/1010) | 1 (Ref) | 1 (Ref) |
| MMR | 16.1 | (40/2483) | 0.90 (0.51–1.57) | 0.94 (0.53–1.67) |
| P interactionc | .52 | .50 | ||
| No admissions between 1 month of age and date of DTaP-IPV-Hib3 vaccination | ||||
| DTaP-IPV-Hib3 | 7.4 | (225/30,285) | 1 (Ref) | 1 (Ref) |
| MMR | 4.9 | (385/78,784) | 0.72 (0.59–0.88) | 0.74 (0.60–0.90) |
| Admissions during 1 month of age and date of DTaP-IPV-Hib3 vaccination | ||||
| DTaP-IPV-Hib3 | 16.6 | (95/5710) | 1 (Ref) | 1 (Ref) |
| MMR | 13.3 | (183/13,809) | 0.86 (0.65–1.12) | 0.89 (0.68–1.17) |
| P interactionc | .28 | .23 | ||
| No admission from date of DTaP-IPV-Hib3 vaccination until 14 months of age | ||||
| DTaP-IPV-Hib3 | 8.5 | (298/34,936) | 1 (Ref) | 1 (Ref) |
| MMR | 5.8 | (523/90,193) | 0.74 (0.62–0.88) | 0.76 (0.64–0.91) |
| Admission from date of DTaP-IPV-Hib3 vaccination until 14 months of age | ||||
| DTaP-IPV-Hib3 | 20.8 | (22/1059) | 1 (Ref) | 1 (Ref) |
| MMR | 18.7 | (45/2400) | 1.06 (0.62–1.80) | 1.12 (0.66–1.92) |
| P interactionc | .19 | .16 | ||
Abbreviations: RSV—respiratory syncytial virus; IRR—incidence-rate-ratio; DTaP-IPV-Hib3—vaccination with the third dose against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b; MMR, vaccination against measles, mumps, and rubella.
Cox proportional hazards model with age as underlying time and stratified by date of birth thereby controlling for age and season.
Cox proportional hazards model with age as underlying time, stratified by date of birth and adjusted for sex, birth weight, gestational age, caesarean section, chronic diseases, number of admissions between 1 month of age and date of DTaP-IPV-Hib3 vaccination, admission from date of DTaP-IPV-Hib3 vaccination until 14 months of age, maternal age at birth of the child, parental place of birth, adult composition of the household, and other children in the household.
P value for the interaction term between vaccination status and the specified variables. This corresponds to testing if the IRR for MMR varies between categories of the other variables; for example, if the IRR for MMR differs between females and males.
The main results of the sensitivity analyses are given here; further data is available on request. In the first month after MMR vaccination, the adjusted IRR for MMR compared with DTaP-IPV-Hib3 was 0.97 (95% CI, 0.76–1.24) but this changed significantly after one month to an adjusted IRR of 0.70 (95% CI, 0.58–0.85). There was a significant trend for lower IRRs with longer time since MMR vaccination (Table 4). In the sensitivity analysis in which the children were followed to 3 years of age, an additional 129 cases of RSV hospital contacts were included and the estimate was unchanged (adjusted IRR, 0.78; 95% CI, 0.66–0.93). The adjusted IRR of RSV hospital contact was 0.75 (95% CI, 0.63–0.90) when the 3243 children who had been admitted with RSV before 14 months of age were excluded. The results were also stable when all children were included in the analysis irrespective of whether they had DTaP-IPV-Hib at the recommended ages (adjusted IRR, 0.79; 95% CI, 0.71–0.89).
Table 4.
Results according to time since MMR vaccination.
| Characteristics | RSV hospital contacts per 1000 person years (RSV hospital contacts/person years) | Unadjusted IRRa (95%-CI) | Adjusted IRRb (95%-CI) | |
|---|---|---|---|---|
| Vaccination status | ||||
| DTaP-IPV-Hib3 | 8.9 | (320/35,989) | 1 (Ref) | 1 (Ref) |
| Days since MMR vaccination | ||||
| 0–30 | 8.7 | (105/12,107) | 0.98 (0.77–1.25) | 1.01 (0.79–1.28) |
| 31–90 | 7.0 | (164/23,469) | 0.78 (0.62–0.97) | 0.82 (0.65–1.03) |
| 91–210 | 5.6 | (239/42,461) | 0.62 (0.49–0.79) | 0.64 (0.50–0.82) |
| >210 | 4.1 | (60/14,546) | 0.40 (0.27–0.60) | 0.43 (0.29–0.64) |
| P trend | <0.001 | <0.001 | ||
Abbreviations: RSV—respiratory syncytial virus; IRR—incidence-rate-ratio; DTaP-IPV-Hib3—vaccination with the third dose against diphtheria, tetanus, pertussis (acellular), polio, and Haemophilus influenzae type b; MMR, vaccination against measles, mumps, and rubella.
Cox proportional hazards model with age as underlying time and stratified by date of birth thereby controlling for age and season.
Cox proportional hazards model with age as underlying time, stratified by date of birth and adjusted for sex, birth weight, gestational age, caesarean section, chronic diseases, number of admissions between 1 month of age and date of DTaP-IPV-Hib3 vaccination, admission from date of DTaP-IPV-Hib3 vaccination until 14 months of age, maternal age at birth of the child, parental place of birth, adult composition of the household, and other children in the household.
There was no statistically significant association between MMR vaccination and emergency room visits resulting from accidents (adjusted IRR, 1.02; 95% CI, 0.98–1.06).
4. Discussion
As hypothesised children who had received MMR as their most recent vaccine had a lower rate of RSV hospital contacts compared with children who had DTaP-IPV-Hib3 as their most recent vaccination. The association was only apparent from 1 month after MMR vaccination. The association was similar for females and males and did not vary significantly according to any other background factors.
The main analyses of the present study included only children who had been vaccinated on time with DTaP-IPV-Hib to limit the possibility for confounding by factors related both to delayed vaccination and RSV hospital contact. There were too few RSV hospital contacts among children reversing the sequence of DTaP-IPV-Hib3 and MMR to perform an analysis in this group. It is important to emphasize that the statistical model had age in days as the underlying time scale securing elimination of any potential confounding by age by comparing the incidence of RSV hospital contacts between children of the exact same age but with different vaccination status. Inclusion of a wide range of additional potential confounders did not change the main estimate appreciably, indicating that confounding was limited in the present study.
Since there was no association between MMR vaccination and accidents, it seems unlikely that the association between MMR vaccination and RSV hospital contacts can be explained by a bias in health-seeking behavior.
Vaccinations were registered by GPs to obtain reimbursement; this provides an economic incentive to report all vaccines [24]. However, there might have been some underreporting of vaccines [34] and travel vaccines are not reimbursed and therefore not reported [24], but we believe travel vaccines are limited before two years of age. Any misclassification or underreporting of MMR vaccinations would bias the estimates toward no association. The outcome was RSV detected by ELISA or immunofluorescence and included in the RSV database, which cover 96% of RSV hospital contacts in Denmark [26]. RSV tests performed by ELISA or immunofluorescence are not as specific and sensitive as tests performed by PCR [35] indicating that some misclassification is present in the current study. However, there is no reason to believe that the sensitivity and specificity is affected by vaccination status; any misclassification would bias the results toward no association. There was a minimum of loss to follow-up because of the high quality of the Danish population-based registries [23].
Our previous observation of reduction in the rate of all-cause lower respiratory infections following MMR vaccination [19] can now partly be explained by a reduced rate of RSV hospital contacts. However, reduction in hospital contacts related to bacterial pathogens might also be important; a British self-controlled case-series study reported the risk of lobar pneumonia to be reduced 0–90 days following MMR vaccination [36]. In a similarly designed study of premature children from the US, the risk of wheezing lower respiratory disease in the first 30 days following MMR vaccination was reduced compared with 45–90 days after MMR vaccination [37]. These studies indicate a short-lived association. However, in the present study the association between MMR vaccination and RSV hospital contacts was only present from 30 days after MMR vaccination and continued throughout the third year of life.
In contrast to studies from West Africa of measles vaccination [38], [39], we did not find any statistically significant interaction between MMR vaccination and sex. MMR was associated with significant reduction in RSV hospital contacts in boys but not in girls. Boys have a higher risk of severe RSV infection [40], [41] as also seen in the present study; therefore there is greater statistical power to detect differences in boys. Furthermore, MMR vaccination may benefit boys more because of their higher risk of severe RSV infection. Also, there are numerous differences between high and low-income settings that might interact with the nonspecific and sex-differential effects of vaccinations, including family size, nutritional status, micronutrient supplementation, sex-differential access to care, the presence of atopic disease, exposure to infections in public child care institutions, and genetic differences.
The present study suggests that the MMR vaccine may have beneficial nonspecific effects by reducing the rate of hospital contacts related to RSV in a high-income setting. Only the most severe cases of RSV are cared for at the hospital, so the reduction in hospital contacts could be related to a reduction in the severity of RSV infection, enhanced resistance to RSV infection or both. The finding contradicts the current perception of vaccines as an intervention with a disease-specific effect only. Our observation might be interpreted as a chance finding or a finding resulting from uncontrolled confounding of factors related to delay in vaccination and the risk of RSV hospital contact. However, there were hardly any difference in characteristics between children who were and were not MMR-vaccinated at 16 and 24 months of age (Table 1). Furthermore, if the beneficial effect of MMR resulted from confounding, the same benefit should have been observed in the first month after vaccination. Several randomized trials from low-income countries have documented that nonspecific effects of vaccines are indeed possible [1]. In one of these trials from Guinea-Bissau [5] measles vaccine was particularly effective in reducing hospital admissions related to respiratory infections [17].
Nonspecific effects of vaccines have often been dismissed as biologically implausible. However, immunological studies have shown that a pathogen encounter may alter the subsequent resistance toward other infections [2], [3]. These changes can occur at the level of the innate immune system; for example, BCG may enhance the nonspecific innate resistance through epigenetic reprogramming of monocytes [42]. Numerous animal studies have shown that pathogens can also induce nonspecific alterations of the adaptive immune system, through cross-reacting T-cell epitopes [43]. Notably, measles virus, mumps virus, and RSV all belong to the family paramyxoviridae and one study in mice found T-cell cross reactivity between these viruses [44] and a study in children found that prior RSV infection was related to higher antibody titres against measles, mumps, and rubella following vaccination with MMR [45]. Further studies on the biological mechanisms are clearly needed, in particular whether antigen-specific responses or non-specific inflammatory/innate mechanisms are more important for the protection we observed in the present study.
The current WHO recommendations do not consider nonspecific effects of vaccines. However, WHO's Strategic Advisory Group of Experts has recently recommended further research into nonspecific effects of vaccines [46]. Ideally, the age schedule for vaccinations should be evaluated in trials testing both the specific effect and the nonspecific effects on overall morbidity and mortality. In high-income countries it might reduce the risk of hospital contacts and reduce health care costs to lower the age of MMR vaccination or introduce an additional dose of MMR vaccination at an earlier age, particularly bearing in mind that the greatest burden of RSV occurs in children below 12 months of age [21]. If confirmed in further studies in high-income settings, the nonspecific beneficial effect of MMR vaccination could be used as an additional incentive for parents to have their children vaccinated on time.
In conclusion, the present nationwide cohort study showed that the rate of RSV hospital contact was reduced in Danish children who had received MMR rather than DTaP-IPV-Hib3 as their most recent vaccination. The finding has major public health implications. Further studies are needed to test this observation and to examine whether earlier administration of MMR might be beneficial.
Funding
This work was supported by the Health Foundation [2009B132 to S.S.]; Rosalie Petersens Foundation [to S.S.]; Danish National Research Foundation [DNRF108 to S.S., C.S.B., L.G.S. and H.R.]; European Research Council [ERC-2009-StG, grant agreement no. 243149 to C.S.B.]; and the Novo Nordisk Foundation [research professorship grant to P.A.]. The funders had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication
Author's contributions
S.S. conceptualized and designed the study, acquired the vaccination and confounder data, analyzed and interpreted the data, drafted the initial manuscript. C.S.B. and P.A. conceptualized and designed the study, interpreted the data and reviewed and revised the manuscript. L.G.S. conceptualized and designed the study, acquired the RSV hospital contact data, interpreted the data, reviewed and revised the manuscript. H.R. conceptualized and designed the study, acquired the vaccination and confounder data, interpreted the data, reviewed and revised the manuscript, All authors read and approved the final manuscript.
Acknowledgements
The authors thank Tyra G Krause from Department of Infectious Disease Epidemiology, Statens Serum Institut, Denmark, for her valuable comments on the draft for this article.
Conflict of interest statement
All authors have no conflicts of interest to disclose.
Footnotes
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2014.07.110.
Appendix A. Supplementary data
The following are the supplementary data to this article:
References
- 1.Aaby P., Whittle H., Stabell Benn C. Vaccine programmes must consider their effect on general resistance. BMJ. 2012;344:e3769. doi: 10.1136/bmj.e3769. [10.1136/bmj.e3769] [DOI] [PubMed] [Google Scholar]
- 2.Flanagan K.L., van Crevel R., Curtis N., Shann F., Levy O., Optimmunize N. Heterologous (“nonspecific”) and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms. Clin Infect Dis. 2013;57:283–289. doi: 10.1093/cid/cit209. [10.1093/cid/cit209] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Benn C.S., Netea M.G., Selin L.K., Aaby P. A small jab—a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 2013;34:431–439. doi: 10.1016/j.it.2013.04.004. [10.1016/j.it.2013.04.004] [DOI] [PubMed] [Google Scholar]
- 4.Aaby P., Samb B., Simondon F., Seck A.M., Knudsen K., Whittle H. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. BMJ. 1995;311:481–485. doi: 10.1136/bmj.311.7003.481. [10.1136/bmj.311.7003.481] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Aaby P., Martins C.L., Garly M.L., Bale C., Andersen A., Rodrigues A. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ. 2010;341:c6495. doi: 10.1136/bmj.c6495. [10.1136/Bmj.C6495] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Aaby P., Roth A., Ravn H., Napirna B.M., Rodrigues A., Lisse I.M. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis. 2011;204:245–252. doi: 10.1093/infdis/jir240. [10.1093/infdis/jir240] [DOI] [PubMed] [Google Scholar]
- 7.Biering-Sorensen S., Aaby P., Napirna B.M., Roth A., Ravn H., Rodrigues A. Small randomized trial among low-birth-weight children receiving bacillus Calmette–Guerin vaccination at first health center contact. Pediatr Infect Dis J. 2012;31:306–308. doi: 10.1097/INF.0b013e3182458289. [10.1097/INF.0b013e3182458289] [DOI] [PubMed] [Google Scholar]
- 8.Shann F. The non-specific effects of vaccines. Arch Dis Child. 2010;95:662–667. doi: 10.1136/adc.2009.157537. [10.1136/adc.2009.157537] [DOI] [PubMed] [Google Scholar]
- 9.Aaby P., Jensen H., Gomes J., Fernandes M., Lisse I.M. The introduction of diphtheria–tetanus–pertussis vaccine and child mortality in rural Guinea-Bissau: an observational study. Int J Epidemiol. 2004;33:374–380. doi: 10.1093/ije/dyh005. [10.1093/ije/dyh005] [DOI] [PubMed] [Google Scholar]
- 10.Aaby P., Benn C.S., Nielsen J., Lisse I.M., Rodrigues A., Ravn H. Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ Open. 2012;2:e000707. doi: 10.1136/bmjopen-2011-000707. [10.1136/bmjopen-2011-000707] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Aaby P., Ravn H., Roth A., Rodrigues A., Lisse I.M., Diness B.R. Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial. Arch Dis Child. 2012;97:685–691. doi: 10.1136/archdischild-2011-300646. [10.1136/archdischild-2011-300646] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Aaby P., Benn C.S. Non-specific and sex-differential effects of routine vaccines: what evidence is needed to take these effects into consideration in low-income countries? Hum Vaccin. 2011;7:120–124. doi: 10.4161/hv.7.1.13848. [10.4161/hv.7.1.13848] [DOI] [PubMed] [Google Scholar]
- 13.Veirum J.E., Sodemann M., Biai S., Jakobsen M., Garly M.L., Hedegaard K. Routine vaccinations associated with divergent effects on female and male mortality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine. 2005;23:1197–1204. doi: 10.1016/j.vaccine.2004.02.053. [10.1016/j.vaccine.2004.02.053] [DOI] [PubMed] [Google Scholar]
- 14.Valentiner-Branth P., Perch M., Nielsen J., Steinsland H., Garly M.L., Fischer T.K. Community cohort study of Cryptosporidium parvum infections: sex-differential incidences associated with BCG and diphtheria-tetanus-pertussis vaccinations. Vaccine. 2007;25:2733–2741. doi: 10.1016/j.vaccine.2006.01.035. [10.1016/j.vaccine.2006.01.035] [DOI] [PubMed] [Google Scholar]
- 15.Rodrigues A., Fischer T.K., Valentiner-Branth P., Nielsen J., Steinsland H., Perch M. Community cohort study of rotavirus and other enteropathogens: are routine vaccinations associated with sex-differential incidence rates? Vaccine. 2006;24:4737–4746. doi: 10.1016/j.vaccine.2006.03.033. [10.1016/j.vaccine.2006.03.033] [DOI] [PubMed] [Google Scholar]
- 16.Stensballe L.G., Nante E., Jensen I.P., Kofoed P.E., Poulsen A., Jensen H. Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls community based case-control study. Vaccine. 2005;23:1251–1257. doi: 10.1016/j.vaccine.2004.09.006. [10.1016/j.vaccine.2004.09.006] [DOI] [PubMed] [Google Scholar]
- 17.Martins C.L., Benn C.S., Andersen A., Bale C., Schaltz-Buchholzer F., Do V.A. A randomized trial of a standard dose of Edmonston–Zagreb measles vaccine given at 4.5 months of age: effect on total hospital admissions. J Infect Dis. 2014;209:1731–1738. doi: 10.1093/infdis/jit804. [10.1093/infdis/jit804] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Sorup S., Villumsen M., Ravn H., Benn C.S., Sorensen T.I., Aaby P. Smallpox vaccination and all-cause infectious disease hospitalization: a Danish register-based cohort study. Int J Epidemiol. 2011;40:955–963. doi: 10.1093/ije/dyr063. [10.1093/ije/dyr063] [DOI] [PubMed] [Google Scholar]
- 19.Sorup S., Benn C.S., Poulsen A., Krause T.G., Aaby P., Ravn H. Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. JAMA. 2014;311:826–835. doi: 10.1001/jama.2014.470. [10.1001/jama.2014.470] [DOI] [PubMed] [Google Scholar]
- 20.Garcia-Garcia M.L., Calvo C., Pozo F., Villadangos P.A., Perez-Brena P., Casas I. Spectrum of respiratory viruses in children with community-acquired pneumonia. Pediatr Infect Dis J. 2012;31:808–813. doi: 10.1097/INF.0b013e3182568c67. [10.1097/INF.0b013e3182568c67] [DOI] [PubMed] [Google Scholar]
- 21.Nair H., Nokes D.J., Gessner B.D., Dherani M., Madhi S.A., Singleton R.J. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet. 2010;375:1545–1555. doi: 10.1016/S0140-6736(10)60206-1. [10.1016/S0140-6736(10)60206-1] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Law B.J., Carbonell-Estrany X., Simoes E.A. An update on respiratory syncytial virus epidemiology: a developed country perspective. Respir Med. 2002;96(Suppl B):S1–S7. [10.1053/rmed.2002.1294] [PubMed] [Google Scholar]
- 23.Pedersen C.B. The Danish Civil Registration System. Scand J Public Health. 2011;39:22–25. doi: 10.1177/1403494810387965. [10.1177/1403494810387965] [DOI] [PubMed] [Google Scholar]
- 24.Andersen J.S., Olivarius N.D.F., Krasnik A. The Danish National Health Service Register. Scand J Public Health. 2011;39:34–37. doi: 10.1177/1403494810394718. [10.1177/1403494810394718] [DOI] [PubMed] [Google Scholar]
- 25.Pedersen P.A., Hollnagel H., Olivarius N.F., Reusch S., Sorensen M., Thorsen H. Individual registration of children in the national health service. New possibilities for epidemiological research in primary health care. Ugeskr Laeger. 1999;161:6351–6354. [PubMed] [Google Scholar]
- 26.Stensballe L.G., Kristensen K., Nielsen J., Aaby P. Diagnosis coding in The Danish National Patient Registry for respiratory syncytial virus infections. Scand J Infect Dis. 2005;37:747–752. doi: 10.1080/00365540510012107. [10.1080/00365540510012107] [DOI] [PubMed] [Google Scholar]
- 27.Knudsen L.B., Olsen J. The Danish Medical Birth Registry. Dan Med Bull. 1998;45:320–323. [PubMed] [Google Scholar]
- 28.Lynge E., Sandegaard J.L., Rebolj M. The Danish National Patient Register. Scand J Public Health. 2011;39:30–33. doi: 10.1177/1403494811401482. [10.1177/1403494811401482] [DOI] [PubMed] [Google Scholar]
- 29.Baadsgaard M., Quitzau J. Danish registers on personal income and transfer payments. Scand J Public Health. 2011;39:103–105. doi: 10.1177/1403494811405098. [10.1177/1403494811405098] [DOI] [PubMed] [Google Scholar]
- 30.Jensen V.M., Rasmussen A.W. Danish Education Registers. Scand J Public Health. 2011;39:91–94. doi: 10.1177/1403494810394715. [10.1177/1403494810394715] [DOI] [PubMed] [Google Scholar]
- 31.Barros A.J., Hirakata V.N. Alternatives for logistic regression in cross-sectional studies: an empirical comparison of models that directly estimate the prevalence ratio. BMC Med Res Methodol. 2003;3:21. doi: 10.1186/1471-2288-3-21. [10.1186/1471-2288-3-21] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Okiro E.A., White L.J., Ngama M., Cane P.A., Medley G.F., Nokes D.J. Duration of shedding of respiratory syncytial virus in a community study of Kenyan children. BMC Infect Dis. 2010;10:15. doi: 10.1186/1471-2334-10-15. [10.1186/1471-2334-10-15] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Kristensen K., Hjuler T., Ravn H., Simoes E.A., Stensballe L.G. Chronic diseases, chromosomal abnormalities, and congenital malformations as risk factors for respiratory syncytial virus hospitalization: a population-based cohort study. Clin Infect Dis. 2012;54:810–817. doi: 10.1093/cid/cir928. [10.1093/cid/cir928] [DOI] [PubMed] [Google Scholar]
- 34.Wojcik O.P., Simonsen J., Molbak K., Valentiner-Branth P. Validation of the 5-year tetanus, diphtheria, pertussis and polio booster vaccination in the Danish childhood vaccination database. Vaccine. 2013;31:955–959. doi: 10.1016/j.vaccine.2012.11.100. [10.1016/j.vaccine.2012.11.100] [DOI] [PubMed] [Google Scholar]
- 35.Henrickson K.J., Hall C.B. Diagnostic assays for respiratory syncytial virus disease. Pediatr Infect Dis J. 2007;26:S36–S40. doi: 10.1097/INF.0b013e318157da6f. [10.1097/INF.0b013e318157da6f] [DOI] [PubMed] [Google Scholar]
- 36.Stowe J., Andrews N., Taylor B., Miller E. No evidence of an increase of bacterial and viral infections following measles, mumps and rubella vaccine. Vaccine. 2009;27:1422–1425. doi: 10.1016/j.vaccine.2008.12.038. [10.1016/j.vaccine.2008.12.038] [DOI] [PubMed] [Google Scholar]
- 37.Mullooly J.P., Schuler R., Mesa J., Drew L., DeStefano F., team V.S.D. Wheezing lower respiratory disease and vaccination of premature infants. Vaccine. 2011;29:7611–7617. doi: 10.1016/j.vaccine.2011.08.022. [10.1016/j.vaccine.2011.08.022] [DOI] [PubMed] [Google Scholar]
- 38.Aaby P., Garly M.L., Bale C., Martins C., Jensen H., Lisse I. Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study. Pediatr Infect Dis J. 2003;22:798–805. doi: 10.1097/01.inf.0000083821.33187.b5. [10.1097/01.inf.0000083821.33187.b5] [DOI] [PubMed] [Google Scholar]
- 39.Desgrees du L.A., Pison G., Aaby P. Role of immunizations in the recent decline in childhood mortality and the changes in the female/male mortality ratio in rural Senegal. Am J Epidemiol. 1995;142:643–652. doi: 10.1093/oxfordjournals.aje.a117688. [DOI] [PubMed] [Google Scholar]
- 40.Sommer C., Resch B., Simoes E.A. Risk factors for severe respiratory syncytial virus lower respiratory tract infection. Open Microbiol J. 2011;5:144–154. doi: 10.2174/1874285801105010144. [10.2174/1874285801105010144] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Stensballe L.G., Kristensen K., Simoes E.A., Jensen H., Nielsen J., Benn C.S. Atopic disposition, wheezing, and subsequent respiratory syncytial virus hospitalization in Danish children younger than 18 months: a nested case-control study. Pediatrics. 2006;118:e1360–e1368. doi: 10.1542/peds.2006-0907. [10.1542/peds.2006-0907] [DOI] [PubMed] [Google Scholar]
- 42.Kleinnijenhuis J., Quintin J., Preijers F., Joosten L.A., Ifrim D.C., Saeed S. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci USA. 2012;109:17537–17542. doi: 10.1073/pnas.1202870109. [10.1073/pnas.1202870109] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Welsh R.M., Che J.W., Brehm M.A., Selin L.K. Heterologous immunity between viruses. Immunol Rev. 2010;235:244–266. doi: 10.1111/j.0105-2896.2010.00897.x. [10.1111/j.0105-2896.2010.00897.x] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Ziola B., Smith R.H. T cell cross-reactivity among viruses of the paramyxoviridae. Viral Immunol. 1987;1:111–119. doi: 10.1089/vim.1987.1.111. [DOI] [PubMed] [Google Scholar]
- 45.Ziola B., Karvonen B., Stewart J. Prior infection by respiratory syncytial virus or parainfluenza viruses augments virus-specific IgG responses induced by the measles/mumps/rubella vaccine. Viral Immunol. 1994;7:205–214. doi: 10.1089/vim.1994.7.205. [DOI] [PubMed] [Google Scholar]
- 46.Meeting of the Strategic Advisory Group of Experts on immunization, April 2014—conclusions and recommendations. Wkly Epidemiol Rec 2014;89:221–36. [PubMed]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.