Dorthe Lisbeth Jeppesen

Bacillus Calmette-Guérin immunisation at birth and morbidity among Danish children: A prospective, randomised, clinical trial

BACKGROUNDnStudies from low-income countries report positive non-specific effects of early Bacillus Calmette-Guérin (BCG) immunisation on childhood health and survival. Neonatal immunisation with BCG may prime the immune system and offer partial protection against other infectious and possibly allergic diseases. The potential clinical value of these non-specific effects has not yet been examined in a large randomised trial in high-income countries.nnnMETHODSnThe Danish Calmette Study is a multicentre randomised clinical trial conducted between October 2012 and November 2015. Within the first 7 days of life, infants were randomly assigned to intra-dermal vaccination with BCG or no intervention. At 3 and 13 months of age structured telephone interviews and clinical examinations of the children were conducted. In a subgroup of children blood samples were drawn and stool samples collected at age 4 days, 3 and 13 months. Thymus index was assessed by ultrasound in a subgroup at randomisation and at 3 months. The primary study outcome is hospitalisation within the first 15 months of life as assessed in Danish health registers. Secondary outcomes include infectious disease hospitalisations, wheezing, eczema, use of prescribed medication, growth, development, thymus index, T- and B-cell subpopulations assessed by flow cytometry, in vitro cytokine responses and specific antibody responses to other vaccines. Adverse reactions were registered.nnnDISCUSSIONnWith participation of 4184 families and more than 93% adherence to clinical follow-up at 3 and 13 months, this randomised clinical trial has the potential to create evidence regarding non-specific effects of BCG vaccination in a high-income setting.

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 7u2005days 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 15u2005months 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 15u2005months of age in this Danish study population. Trial registration number NCT01694108, results.

Changing oral vaccine to inactivated polio vaccine might increase mortality

We, the undersigned, write as physicians and scientists committed to optimising the benefi cial eff ects of vaccines to reduce infant mortality worldwide. In settings with high childhood mortality, live vaccines such as oral polio vaccine (OPV), BCG vaccine, and measles vaccine might have heterologous (non-specific) effects that reduce mortality from diseases other than poliomyelitis, tuberculosis, and measles, respectively, whereas inactivated vaccines might increase all-cause mortality. The importance of these eff ects is controversial. In 2014, the WHO Special Advisory Group of Experts (SAGE) reviewed the evidence regarding the non-specific effects of vaccines and concluded that further research is warranted. On average, about 75 cases of vaccine-associated paralytic poliomyelitis are reported each year worldwide, and WHO has suggested that OPV be gradually replaced by inactivated polio vaccine (IPV) to reduce the number of such cases. Results from a randomised trial in 2015 suggest that OPV might have benefi cial non-specific effects that reduce allcause mortality by 17%, possibly to a greater extent in boys than in girls, whereas previous evidence suggests that IPV increases all-cause mortality by 10%. Consequently, the proposed change from OPV to IPV might lead to increased all-cause mortality through loss of the beneficial non-specific eff ects of the live vaccine, and adverse non-specifi c eff ects of the inactivated vaccine. Replacement of OPV with IPV could translate to approximately 4000 deaths for each case of vaccineassociated paralytic poliomyelitis prevented, and might cause more than 300 000 additional deaths each year. In view of the possible effects on all-cause mortality, more data need week 6 of MBCT—so tapering and MBCT treatment obviously overlapped to some extent. Since evidence is accumulating that withdrawal symptoms after discontinuation of selective serotonin reuptake inhibitors (SSRIs) are more detrimental and prolonged than assumed (up to 1 year), we suggest that the discontinuation process might have interfered with the therapeutic effects of MBCT. In a systematic review, gradual tapering did not eliminate withdrawal reactions. We do not know what the predominant class of medication was in the study by Kuyken and colleagues, but it seems likely that SSRIs were involved to a large extent. Thus, we argue that, by consecutively undertaking medication tapering followed by a longer washout period before starting MBCT, even stronger eff ects of MBCT might be observed. In other studies, responders to cognitive behavioral therapy showed relapse rates of 39% in the 68 weeks after psychotherapy and 68% after discontinuation of medication; therefore, the discontinuation syndrome might explain the relatively high relapse rate of 44% in Kuyken and colleagues’ study of MBCT.

Factors associated with thymic size at birth among low and normal birth-weight infants

OBJECTIVEnTo study the effect of gestational and perinatal exposures on thymic size in 366 normal birth weight and 426 low birth weight (LBW) neonates in Guinea-Bissau in West Africa.nnnSTUDY DESIGNnIn a cross-sectional study, thymic size was measured at birth by the use of ultrasound. Information on possible determinants was collected from pregnancy cards, hospital records, and interviews with the mother. We used the log-transformed thymic index and thymus/weight index as outcome measures. Data were analyzed with adjusted linear regression models providing geometric mean ratios (GMRs) with 95% CI.nnnRESULTSnDeterminants of thymic size among normal birth weight infants were pathologic amniotic fluid (adjusted GMR for thymic index: 0.84 [0.74-0.96]) and male sex (GMR: 1.13 [1.06-1.22]). Among LBW infants, birth season (1.11 [1.01-1.22]), maternal body temperature (0.89 [0.79-0.98]), antibiotic treatment at the time of labor (0.84 [0.70-1.00]), number of pregnancy consultations (1.03 [1.00-1.05]), maternal age (0.91 [0.84-0.98]), Apgar score (1.06 [1.03-1.10]), and infant convulsions (0.44 [0.29-0.65]) were all independent determinants of thymic index but not all were determinants of thymus/weight index. Pathologic amniotic fluid and cesarean delivery were associated with thymus/weight index among LBW infants (0.85 [0.75-0.95] and 0.80 [0.67-0.96]) but were only borderline significant for thymic index.nnnCONCLUSIONnExposures mainly related to stress and infections were associated with a smaller thymus, mainly in LBW infants.

Bacille Calmette-Guerin (BCG) vaccination at birth and antibody responses to childhood vaccines. A randomised clinical trial

INTRODUCTIONnBCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guérin (BCG) vaccination at birth, The Danish Calmette Study, we investigated the effect of BCG at birth on the antibody response to the three routine vaccines against DiTeKiPol/Act-Hib and Prevenar 13 in a subgroup of participants.nnnMETHODSnWithin 7days after birth, children were randomised 1:1 to BCG vaccination or to the control group (no intervention). After three routine vaccinations given at age 3, 5 and 12months, antibodies against DiTeKiPol/Act-Hib and Prevenar 13 (Streptococcus pneumoniae serotype type 4, 6B, 9V, 14, 18C, 19F and 23F) were measured 4weeks after the third vaccine dose.nnnRESULTSnAmong the 300 included children (178 BCG; 122 controls), almost all children (>96%) had antibody responses above the protective levels. Overall BCG vaccination at birth did not affect the antibody level. When stratifying by age at randomisation we found a possible inducing effect of BCG on antibodies against B. pertussis and all pneumococcal serotypes, when BCG was given after the first day of life. Girls had significantly higher antibody levels for Haemophilus influenza type b and pneumococcus than boys.nnnCONCLUSIONS AND RELEVANCEnThree routine vaccinations with DiTeKiPol/Act-Hib and Prevenar 13 induced sero-protective levels in almost all children. No overall effect of neonatal BCG vaccination was observed.

Neonatal BCG vaccination has no effect on recurrent wheeze in the first year of life: A randomized clinical trial

Background: Recurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation. Objective: We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life. Methods: The Danish Calmette Study is a multicenter randomized trial conducted from 2012–2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no‐intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish‐speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician‐diagnosed and medically treated RW up to 13 months of age. Results: By 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89–1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW. Conclusion: Neonatal BCG had no effect on the development of RW before 13 months of age.

Adverse reactions to the Bacillus Calmette-Guérin (BCG) vaccine in new-born infants: an evaluation of the Danish strain 1331 SSI in a randomized clinical trial

OBJECTIVEnTo evaluate adverse reactions of the Bacillus Calmette-Guérin (BCG) Statens Serum Institut (SSI) (Danish strain 1331) used as intervention in a randomized clinical trial.nnnDESIGNnA randomized clinical multicenter trial, The Danish Calmette Study, randomizing newborns to BCG or no intervention. Follow-up until 13 months of age.nnnSETTINGnPediatric and maternity wards at three Danish university hospitals.nnnPARTICIPANTSnAll women planning to give birth at the three study sites (n=16,521) during the recruitment period were invited to participate in the study. Four thousand one hundred and eighty four families consented to participate and 4262 children, gestational age 32 weeks and above, were randomized: 2129 to BCG vaccine and 2133 to no vaccine. None of the participants withdrew because of adverse reactions.nnnMAIN OUTCOME AND MEASUREnTrial-registered adverse reactions after BCG vaccination at birth. Follow-up at 3 and 13 months by telephone interviews and clinical examinations.nnnRESULTSnAmong the 2118 BCG-vaccinated children we registered no cases of severe unexpected adverse reaction related to BCG vaccination and no cases of disseminated BCG disease. Two cases of regional lymphadenitis were hospitalized and thus classified as serious adverse reactions related to BCG. The most severe adverse reactions were 10 cases of suppurative lymphadenitis. This was nearly a fivefold increase compared to what was expected based on the summary of product characteristics of the vaccine. All cases were treated conservatively and recovered. Six of 10 (60%) families of children experiencing suppurative lymphadenitis compared to 117/2071 (6%) of those with no lymphadenitis indicated that the vaccine had more adverse effects than expected (p-value <0.001).nnnCONCLUSIONS AND RELEVANCEnBCG vaccination was associated with only mild morbidity and no mortality. A higher incidence of suppurative lymphadenitis than expected was observed. All children were treated conservatively without sequelae or complications.nnnTRIAL REGISTRATIONnTrial registration number NCT01694108 at www.clinicaltrials.gov.

Neonatal BCG has no effect on allergic sensitization and suspected food allergy until 13 months

Vaccination with Bacillus Calmette‐Guérin (BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non‐specific effects, reducing non‐tuberculosis mortality, morbidity, and atopic manifestations. In this study, we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age.

Bacillus Calmette-Guérin vaccination at birth and in vitro cytokine responses to non-specific stimulation. A randomized clinical trial

Several studies have shown increased in vitro cytokine responses to non-related pathogens after Bacillus Calmette-Guérin (BCG) vaccination. A total of 158 infants (80 BCG administered within 7xa0days of birth; 78 controls) were bled 4xa0days post-randomization, and at age 3 and 13xa0months. Geometric mean concentrations of IL-1β, TNF-α, IL-6 (24xa0h stimulation) and IFN-γ, IL-10, IL-17, IL-22 (96xa0h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG vaccination did not affect in vitro cytokine production, except IFN-γ and IL-22 response to BCG. Stratifying for ‘age at randomization’ we found a potentiating effect of BCG on cytokine production (TNF-α, IL-6, IL-10) in the 4xa0days post randomization stimulations, among children who were vaccinated at age 2–7xa0days versus age 0–1xa0days. BCG vaccination did not potentiate cytokine production to non-BCG antigens. At 4xa0days post randomization, BCG was associated with higher cytokine production in the later randomized children.

Does oral polio vaccine at birth affect the size of the thymus?: Observations within a randomized trial

BACKGROUNDnThere is increasing evidence that vaccines have an effect on general mortality which goes beyond specific disease protection. Oral polio vaccine (OPV) is widely used in low-income countries, but in observational studies in Guinea-Bissau we observed that not receiving OPV at birth was associated with reduced overall male infant mortality and enhanced immune response to BCG vaccine. We therefore initiated a randomized trial to test the overall effect of OPV at birth (OPV0).nnnOBJECTIVEnA small thymic gland is a predictor of mortality in high-mortality settings. Within the trial we aimed to test whether no-OPV0 was associated with increased thymic size.nnnMETHODSnIn 511 normal birth weight infants who were randomized to receive or not receive OPV0, thymic index and thymus/weight index were measured before randomization and after 2 weeks (N=49), 4 weeks (N=308) or 6 weeks (N=27). The association between OPV0 and the log transformed thymic size indicators were analyzed in ANCOVA models with thymic size at follow-up as the outcome and adjusting for thymic size at enrollment and age at follow-up. Estimates were reported as geometric mean ratios (GMR) with 95% confidence intervals, comparing no-OPV0 to OPV0.nnnRESULTSnNo-OPV0 was not associated with thymic index after 2 weeks (GMR: 1.14 (0.99-1.30)), after 4 weeks (GMR: 0.98 (0.93-1.05)) or after 6 weeks (GMR: 1.00 (0.81-1.23)). However, no-OPV0 was associated with increased thymus/weight index after 2 weeks (GMR: 1.22 (1.06-1.40)), but the effect was not seen after 4 weeks (GMR: 0.97 (0.92-1.03)) and 6 weeks (GMR: 0.99 (0.82-1.19)). There were no strong sex-differences.nnnDISCUSSIONnOverall there was no effect on thymic size of OPV0 when administered with BCG. The results could indicate that if an effect occurs, it is only within the first weeks after vaccination.