Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial

Kjærgaard, Jesper; Birk, Nina Marie; Nissen, Thomas Nørrelykke; Thøstesen, Lisbeth Marianne; Pihl, Gitte Thybo; Benn, Christine Stabell; Jeppesen, Dorthe Lisbeth; Pryds, Ole; Kofoed, Poul‐Erik; Aaby, Péter; Greisen, Gorm; Stensballe, Lone Graff

doi:10.1038/pr.2016.142

Cited by 47 publications

(51 citation statements)

References 25 publications

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“…The setting of such a study will need to be carefully considered as to date, the results of clinical trials have been mixed. Heterologous, BCG-induced protection against clinical outcomes related to infectious disease has been observed in a low-income setting in West Africa (15, 46) but was not recapitulated in another trial in a high income, European setting (47, 48). …”

Section: Discussionmentioning

confidence: 97%

Whole Blood Profiling of Bacillus Calmette–Guérin-Induced Trained Innate Immunity in Infants Identifies Epidermal Growth Factor, IL-6, Platelet-Derived Growth Factor-AB/BB, and Natural Killer Cell Activation

et al. 2017

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Vaccination of infants with bacillus Calmette–Guérin (BCG) activates both the innate and adaptive arms of the immune response. The antimycobacterial effects of these responses most likely account for the ability of BCG to protect against childhood forms of tuberculosis (TB). There is also evidence for a heterologous protective effect of BCG vaccination against TB-unrelated mortality in low birth weight infants. A possible mechanism of action of this effect, the induction of trained innate immunity, has been demonstrated when cells from BCG-vaccinated adults are restimulated in vitro with non-related microbial stimuli. Our aim was to examine an extensive panel of secreted immune biomarkers to characterize the profile of trained innate immunity in infants. Stimulation of whole blood for 48 h was performed 4 months after BCG vaccination, or in control unvaccinated infants. Stimulants were lipopolysaccharide; Pam3Cys (P3C); heat-killed Candida albicans, Staphylococcus aureus, Escherichia coli, and a lysate of Mycobacterium tuberculosis. Culture supernatants were tested for secreted cytokines and chemokines by 42-plex bead array and monocytes and natural killer (NK) cells assessed for expression of activation markers by flow cytometry. BCG-vaccinated infants displayed increases in 11 cytokines and chemokines in response to different non-specific innate immunity stimuli: epidermal growth factor (EGF); eotaxin; IL-6; IL-7; IL-8; IL-10; IL-12p40; monocyte chemotactic protein-3; macrophage inflammatory protein-1α; soluble CD40 ligand and platelet-derived growth factor (PDGF)-AB/BB. Although each stimulant induced a distinct response profile, three analytes, EGF, IL-6, and PDGF-AB/BB, were commonly higher after stimulation with Pam3Cys, C. albicans, and S. aureus. Conversely, certain cytokines such as interferon gamma-inducible protein-10, IL-2, IL-13, IL-17, GM-CSF, and GRO were suppressed in BCG-vaccinated infants, while no increases in TNFα or IL-1β production were detected. We did not observe a concomitant, BCG-associated change in monocyte surface activation markers in response to non-specific stimuli, but we detected a significant increase in CD69 expression on NK cells in response to Pam3Cys. Pam3Cys-induced NK cell activation correlated with the magnitude of IL-12p40 and IL-10 responses to the same stimulant. This study reveals a novel cytokine/chemokine biomarker signature of BCG-induced trained innate immunity in infants and the involvement of NK cells in these responses.

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Section: Discussionmentioning

confidence: 97%

Whole Blood Profiling of Bacillus Calmette–Guérin-Induced Trained Innate Immunity in Infants Identifies Epidermal Growth Factor, IL-6, Platelet-Derived Growth Factor-AB/BB, and Natural Killer Cell Activation

et al. 2017

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“…However, in a prespecified subgroup analysis, neonatal BCG vaccination may have reduced infections in the first 3 months of life in children whose mothers were vaccinated with BCG 13. Therefore, there remains uncertainty about the importance and applicability of the NSE of BCG in different populations today.…”

Section: Bacillus Calmette-guérinmentioning

confidence: 99%

Non-specific effects of vaccines: plausible and potentially important, but implications uncertain

Pollard¹,

2017

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Non-specific effects (NSE) or heterologous effects of vaccines are proposed to explain observations in some studies that certain vaccines have an impact beyond the direct protection against infection with the specific pathogen for which the vaccines were designed. The importance and implications of such effects remain controversial. There are several known immunological mechanisms which could lead to NSE, since it is widely recognised that the generation of specific immunity is initiated by non-specific innate immune mechanisms that may also have wider effects on adaptive immune function. However, there are no published studies that demonstrate a mechanistic link between such immunological phenomena and clinically relevant NSE in humans. While it is highly plausible that some vaccines do have NSE, their magnitude and duration, and thus importance, remain uncertain. Although the WHO recently concluded that current evidence does not justify changes to immunisation policy, further studies of sufficient size and quality are needed to assess the importance of NSE for all-cause mortality. This could provide insights into vaccine immunobiology with important implications for infant health and survival.

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“…21 A recently published randomised controlled study on BCG vaccination at birth in Denmark, however, did not find an effect on all cause hospital admissions 48 or childhood infections reported by parents. 49 Although we show that healthy vaccinee bias is probably present in our analysis, the impact of this bias is hard to quantify, and we cannot exclude that non-specific effects are still present in our study. If we assume that the lower rate of infection after the fourth versus the third DTaP-IPV-Hib+PCV vaccination is due to healthy vaccinee bias, the difference in hazard ratios between the MMR+MenC versus DTaP-IPV-Hib+PCV (hazard ratio of 0.62, 95% confidence interval 0.57 to 0.67) and the fourth versus the third DTaP-IPV-Hib+PCV (0.69, 0.63 to 0.76) could be ascribed to nonspecific effects.…”

Section: Discussionmentioning

confidence: 67%

Non-specific effects of measles, mumps, and rubella (MMR) vaccination in high income setting: population based cohort study in the Netherlands

Tielemans

Melker

Hahné

et al. 2017

BMJ

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OBJECTIVESTo investigate whether measles, mumps, and rubella (MMR) vaccine has positive non-specific effects in a high income setting and to compare rates of hospital admissions for infections between children aged ≤2 years who received live MMR vaccine and those who received an inactivated vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) as their most recent vaccination. DESIGNNationwide population based cohort study. SETTINGIn the Netherlands, DTaP-IPV-Hib+pneumococcal vaccination (PCV) is recommended at ages 2, 3, 4, and 11 months and MMR + meningococcal C (MenC) vaccination at age 14 months. Data from the national vaccine register were linked to hospital admission data. MAIN OUTCOME MEASURESHazard ratio for admission to hospital for infection in children with MMR+MenC compared with the fourth DTaP-IPV-Hib+PCV as their most recent vaccination. Cox regression was performed with most recent vaccination as time dependent variable, adjusted for potential confounders. Analyses were repeated with admission for injuries or poisoning as a negative control outcome. In addition, rate of admission for infection was compared between the fourth and third DTaP-IPV-Hib+PCVas most recent vaccination. RESULTS Having had CONCLUSIONSHealthy vaccinee bias could at least partly explain the observed lower rate of admission to hospital with infection after MMR vaccination. The lower rate is associated with receipt of any additional vaccine, not specifically MMR vaccine. This emphasises the caution required in the interpretation of findings from observational studies on non-specific effects of vaccination.

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Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial

Abstract: This study did not find a nonspecific public health benefit of BCG on parent-reported infections. BCG may have reduced the incidence of infections in children of BCG-vaccinated mothers during the first 3 mo.

Cited by 47 publications

References 25 publications

Whole Blood Profiling of Bacillus Calmette–Guérin-Induced Trained Innate Immunity in Infants Identifies Epidermal Growth Factor, IL-6, Platelet-Derived Growth Factor-AB/BB, and Natural Killer Cell Activation

Whole Blood Profiling of Bacillus Calmette–Guérin-Induced Trained Innate Immunity in Infants Identifies Epidermal Growth Factor, IL-6, Platelet-Derived Growth Factor-AB/BB, and Natural Killer Cell Activation

Non-specific effects of vaccines: plausible and potentially important, but implications uncertain

Non-specific effects of measles, mumps, and rubella (MMR) vaccination in high income setting: population based cohort study in the Netherlands

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