Signe Sørup

Live Vaccine Against Measles, Mumps, and Rubella and the Risk of Hospital Admissions for Nontargeted Infections

IMPORTANCE 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. OBJECTIVE 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. RESULTS 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.

Risk of lymphoma and leukaemia after bacille Calmette-Guérin and smallpox vaccination: A Danish case-cohort study

Vaccines may have non-specific effects as suggested mainly in mortality studies from low-income countries. The objective was to examine the effects of BCG and smallpox vaccinations on subsequent risk of lymphoma and leukaemia in a Danish population experiencing rapid out-phasing of these vaccines. In a background cohort (N=47,622) from the Copenhagen School Health Records Register, cases of leukaemia (N=20) and lymphoma (N=51) were identified through the Danish Cancer Registry. The vaccination status of the cases was compared with the vaccination status of a 5% random sample (N=2073) of the background cohort and analysed in a case-cohort design. BCG vaccination reduced the risk of lymphomas (HR=0.49 (95% CI: 0.26-0.93)), whereas smallpox vaccination did not (HR=1.32 (0.56-3.08)). With the small number of leukaemia cases, the analysis of leukaemia had limited power (BCG vaccination HR=0.81 (0.31-2.16); smallpox vaccination HR=1.32 (0.49-3.53)). The present study with very reliable vaccine history information indicates a beneficial effect of BCG vaccination on the risk of lymphomas.

BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial

Background The BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic diseases. The present randomised trial tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting. Methods Pregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age. Randomisation was stratified by prematurity. The primary study outcome was number of all-cause hospitalisations analysed as repeated events. Hospitalisations were identified using The Danish National Patient Register. Data were analysed by Cox proportional hazards models in intention-to-treat and per-protocol analyses. Results 4184 pregnant women were randomised and their 4262 children allocated to BCG or no intervention. There was no difference in risk of hospitalisation up to 15 months of age; 2129 children randomised to BCG experienced 1047 hospitalisations with a mean of 0.49 hospitalisation per child compared with 1003 hospitalisations among 2133 control children (mean 0.47), resulting in a HR comparing BCG versus no BCG of 1.05 (95% CI 0.93 to 1.18) (intention-to-treat analysis). The effect of BCG was the same in children born at term (1.05 (0.92 to 1.18)) and prematurely (1.07 (0.63 to 1.81), p=0.94). The effect was also similar in the two sexes and across study sites. The results were essentially identical in the per-protocol analysis and after adjustment for baseline characteristics. Conclusions BCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15 months of age in this Danish study population. Trial registration number NCT01694108, results.

Oral Polio Vaccination and Hospital Admissions With Non-Polio Infections in Denmark: Nationwide Retrospective Cohort Study

In a nationwide Danish register-based cohort study, the live oral polio vaccine was associated with fewer admissions for lower respiratory infections compared with the inactivated DTaP-IPV-Hib vaccine. There was no difference between oral polio vaccine and measles-mumps-rubella vaccine.

Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971–2010

Abstract Background: When vaccinations with vaccinia against smallpox and Bacillus Calmette-Guérin (BCG) against tuberculosis were phased out in some high-income countries around 1980, the impact on overall mortality was not examined. Recent studies from low-income countries have suggested that these vaccines are associated with mortality reductions, not explained by specific disease protection. We examined whether vaccinia and BCG administered in childhood were associated with long-term mortality reductions in a high-income population. Methods: In this case-cohort study, we followed 47 622 schoolchildren from Copenhagen, Denmark, born 1965 to 1976, from their first health examination to 2010. This cohort experienced the phase-out of vaccinia and BCG vaccination programmes. Results: A sub-cohort of 5 316 individuals (699 excluded) was followed for 164 450 person-years (0.2% were lost to follow-up), and 401 deaths due to natural causes (841 deaths in total) occurred in the full cohort. Compared with individuals who had not received vaccinia or BCG, those who had received both vaccinia and BCG had an adjusted hazard ratio (aHR) of 0.54 [95% confidence interval (CI): 0.36–0.81] for mortality due to natural causes of death; those who only received BCG had an aHR of 0.58 (95% CI: 0.39–0.85). Vaccinia and BCG were not associated with any protection against deaths by accidents, suicide or murder, the combined aHR being 0.94 (95% CI: 0.62–1.42). Conclusions: Vaccinia and BCG vaccinations were associated with better long-term survival, which was not explained by specific protection. Vaccines with beneficial non-specific effects may reduce overall mortality even after the target diseases are eradicated.

Measles–mumps–rubella vaccination and respiratory syncytial virus-associated hospital contact

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.

Risk of Inflammatory Bowel Disease following Bacille Calmette-Guérin and Smallpox Vaccination: A Population-based Danish Case-Cohort Study.

Background: Childhood immunology has been suggested to play a role in development of inflammatory bowel disease (IBD) based on the studies of childhood vaccinations, infections, and treatment with antibiotics. Bacille Calmette–Guérin (BCG) and smallpox vaccinations were gradually phased-out in Denmark for children born between 1965 and 1976, hence allowing the study of subsequent risk of Crohn’s disease and ulcerative colitis in a unique prospective design. Methods: The Copenhagen School Health Records Register contains detailed documentation of vaccination. Among the background cohort of individuals born between 1965 and 1976 (N = 47,622), cases with Crohn’s disease (n = 218) and ulcerative colitis (n = 256) were identified through linkage to the Danish National Patient Registry. The vaccination status of the cases was compared with that of a subcohort (n = 5741) of the background cohort and analyzed in a case–cohort design. Results: No difference in risk of IBD was observed between individuals vaccinated and unvaccinated with BCG (hazard ratio = 0.95; 95% confidence interval, 0.75–1.19) or smallpox vaccine (hazard ratio = 1.01; 95% confidence interval, 0.77–1.32). This was also the case for Crohn’s disease and ulcerative colitis separately. However, BCG given before 4 months of age may decrease the risk of IBD (hazard ratio = 0.43; 95% confidence interval, 0.20–0.93). Conclusions: This prospective long-term case–cohort study shows that BCG and smallpox vaccination do not cause IBD later in life. These findings are important for the etiological understanding of IBD and of clinical importance because BCG is still one of the most commonly used childhood vaccinations, smallpox vaccine has been reintroduced in the U.S. military, and both vaccines may be used as vectors in new vaccines.

Simultaneous vaccination with MMR and DTaP-IPV-Hib and rate of hospital admissions with any infections: A nationwide register based cohort study

Highlights • Nationwide retrospective cohort study of Danish children aged 15 months to 4 years.• Comparison of the live MMR + the inactivated DTaP-IPV-Hib vaccine vs MMR alone.• 27% higher rate of admissions for lower respiratory infections for MMR + DTaP-IPV-Hib.• No significant association with admissions for other types of infections.• Adjustment for a long range of potential confounders including exact age.

Commentary: BCG has no beneficial non-specific effects on Greenland. An answer to the wrong question?

Our group has spearheaded research into the ‘non-specific effects’ of vaccines in West Africa. Many observational studies and lately randomized trials have shown that BCG lowers all-cause mortality, particularly from septicaemia and respiratory infections. These beneficial non-specific effects are seen as long as BCG is the most recent vaccine. For this reason, a WHO-commissioned review of the nonspecific effects of vaccines specifically selected results for the shortest period of follow-up, and where possible with censoring for subsequent vaccines. In a meta-analysis of the included studies, BCG versus no BCG was associated with a 47% [95% confidence interval (CI) 1⁄4 28-60%] reduction in all-cause mortality. The other live vaccine under review, measles vaccine, was likewise associated with large reductions in mortality; in contrast, most studies suggested that the non-live diphtheria-tetanus-pertussis (DTP) vaccine was associated with increased all-cause mortality. In 2014, WHO recommended further research into the potential non-specific effects of vaccines. Haahr et al. used a transient or temporary discontinuation of neonatal BCG vaccination from 1991 to 1996 in Greenland to compare BCG-vaccinated and BCGunvaccinated birth cohorts with respect to infectious disease hospitalizations (the vast majority being due to respiratory infections) up to 3 years of age. They assumed that the only potential birth cohort effect was the possible BCG effect. This may not be correct; there were changes in the timing of subsequent non-live vaccines, which were also associated with birth cohort. Nonetheless, from 3 days to 3 months when BCG was the dominating vaccine, having received neonatal BCG was associated with a 28% (95% CI 1⁄4 -6-51%) reduction in the risk of infectious disease hospitalizations, corroborating the findings from the WHO review. Haahr et al. did however not emphasize this result; instead they focused on the period from 3 months to 3 years of age. What is studied in this age group is not the effect of neonatal BCG versus no BCG, but the effect of receiving first neonatal BCG and then non-live vaccines versus receiving non-live vaccines only. In this period, BCG was associated with a 7% (-4-20%) increased risk of infectious disease hospitalisation (test for similar BCG effect between 0-3 months and 3-35 months, P 1⁄4 0.05) (Table 1). The findings from Greenland are similar to the findings from a recent cohort study in Finland using hospital admission data from before and after neonatal BCG vaccination was stopped in 2006. The incidence rate ratio for hospital-treated pneumonia for BCG-vaccinated children was 0.73 (95% CI1⁄4 0.55-0.96) from birth and up to 3 months (before non-live vaccines were provided), versus 1.04 (0.89-1.20) from 3-12 months (test for interaction 0.03). The findings are also similar to the results of a recent randomized trial in Denmark where the incidence rate ratio for GP visits for suspected infection was 0.88 (95% CI1⁄4 0.79-0.98) from birth to 3 months (again emphasizing the period before non-live vaccines were given), versus 1.03 (0.97-1.09) from 3-13 months (test for interaction 0.01). The tendency for an age-differential effect of BCG was also seen for parental-reported infection, strongest for parent-reported fever [0.78 (0.52-1.03) before versus 1.05 (0.95-1.16) after 3 months] and pneumonia [0.50 (0.17-1.46) versus 1.26 (0.99-1.60)]. Thus, in the three studies from highincome settings, which have data on the effect of neonatal BCG on infectious diseases from birth to 3 months and from 3 months onwards, there are striking similarities: the effect of BCG was beneficial in the first months, but this effect disappeared after the children received non-live vaccines. International Journal of Epidemiology, 2016, Vol. 45, No. 6 2131

BCG Vaccination at Birth and Rate of Hospitalization for Infection Until 15 Months of Age in Danish Children: A Randomized Clinical Multicenter Trial

Background The bacillus Calmette-Guérin (BCG) vaccine against tuberculosis might reduce the non-tuberculosis-related child mortality rate in low-income settings. We tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalization for infection in Denmark, a high-income setting. Hospitalization for infection was a secondary outcome in a randomized trial with the primary aim to estimate the potential non-specific effects of BCG vaccination at birth on all-cause hospitalization. Methods A total of 4262 children included in the Danish Calmette Study were assigned randomly to either receive the BCG vaccine or not and were followed through the Danish National Patient Register. The outcome was number of hospitalizations for infection until the age of 15 months. Data were analyzed by Cox regression in intention-to-treat (ITT) and per-protocol (PP) analyses. Results In the ITT analysis, we observed 588 hospitalizations for infection (mean, 0.28 hospitalization per child) among the 2129 children allocated to receive the BCG vaccine and 595 hospitalizations for infection (mean, 0.28 hospitalization per child) among the 2133 children allocated to the control group (hazard ratio [HR], 0.99 [95% confidence interval (CI), 0.85-1.15]). The PP analysis yielded an HR of 1.00 (95% CI, 0.86-1.16). Predefined interaction ITT analyses showed that among 740 children with a BCG-vaccinated mother, the HR for BCG-vaccinated children was 0.65 (95% CI, 0.45-0.94); the HR for children who had a non-BCG-vaccinated mother was 1.10 (95% CI, 0.93-1.29) (P = .01, test of no interaction). Cesarean delivery modified the effect of BCG vaccination (HRs, 0.73 [95% CI, 0.54-0.99] in children born by cesarean section vs 1.10 [95% CI, 0.92-1.30] in other children; P = .02). When the outcome was defined as time to first hospitalization, the HR for premature children after BCG vaccination was 1.81 (95% CI, 0.95-3.43), whereas the HR was 0.94 (95% CI, 0.82-1.08) for children born at term (P = .05). Conclusion BCG vaccination did not affect the rate of hospitalization for infection up to the age of 15 months in Danish children. In future studies, the role of maternal BCG-vaccination, premature birth, and cesarean delivery needs further exploration.