Non-specific effect of Bacille Calmette-Guérin vaccine on the immune response to routine immunisations

Ritz, Nicole; Mui, Milton; Balloch, Anne; Curtis, Nigel

doi:10.1016/j.vaccine.2013.03.059

Cited by 105 publications

(78 citation statements)

References 45 publications

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“…The production of adult-like levels of IL-12 p70 in neonates would promote the anti-mycobacterial CD4+ T-cell Th1 polarization that has been seen following neonatal BCG vaccination, and it could also contribute to beneficial heterologous Th1 immune effects of BCG vaccination [5, 9–11, 21]. Developing an effective Th1-inducing adjuvant for the neonatal period would be the first step towards the goal of improving vaccinations against toxins ( e .…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports have shown that BCG vaccination at birth results in neonatal IFN-γ production against mycobacterial antigens [1], and the levels of secreted IFN-γ are comparable to adult levels [2]. We and others have previously identified some of the heterologous immune effects of BCG vaccination, including Th1 polarization [5, 10, 11, 21]. IL-12 p70 is the prototypical Th1-polarizing cytokine [14].…”

Section: Introductionmentioning

confidence: 99%

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A Model to Explain How the Bacille Calmette Guérin (BCG) Vaccine Drives Interleukin-12 Production in Neonates

Kativhu

Libraty

2016

PLoS ONE

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The Bacille Calmette Guérin (BCG) vaccine is the only routine vaccination at birth that effectively induces neonatal T-helper 1 (Th1)-polarized immune responses. The primary cytokine that drives CD4+ T-cell Th1 differentiation is interleukin (IL)-12 p70, a heterodimeric cytokine composed of the IL-12 p35 and IL-12 p40 subunits. We therefore examined the mechanisms involved in BCG vaccine stimulation of IL-12 p35 and p40 production from human umbilical cord (neonatal) cells. We found that BCG bacilli did not upregulate IL-12 p35 mRNA production, but upregulated IL-12 p40 mRNA production in a Toll-like receptor (TLR)2-dependent manner, in human neonatal monocyte-derived dendritic cells (mdDCs). The combination of TLR2 signaling, Type I interferon (IFN), and Type II IFN induced maximal levels of IL-12 p35 and p40 mRNA production in human neonatal mdDCs. The cell-free supernatants of reconstituted BCG vaccine vials contained extracellular mycobacterial (BCG) DNA which could induce IFN-α (Type I IFN) production in human neonatal plasmacytoid dendritic cells (pDCs). BCG bacilli also stimulated human neonatal CD16lo natural killer (NK) cells to produce IFN-γ (Type II IFN) in a TLR2-dependent manner. We have therefore proposed a model where BCG vaccine could stimulate the combination of neonatal conventional DCs (cDCs), pDCs, and CD16lo NK cells to produce optimal neonatal IL-12 p35 and p40 (IL-12 p70) production and subsequent CD4+ T-cell Th1 polarization. An adjuvant that emulates the mechanism by which the BCG vaccine stimulates neonatal IL-12 p35 and p40 production could improve vaccine strategies at birth for protection against intracellular pathogens and toxins.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Model to Explain How the Bacille Calmette Guérin (BCG) Vaccine Drives Interleukin-12 Production in Neonates

Kativhu

Libraty

2016

PLoS ONE

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“…Overall child mortality was reduced by over 50% when low birth-weight children who received BCG earlier than currently recommended (166). It is important to note that though BCG vaccination may have beneficial non-specific effects, it can also modulate immune responses to subsequent vaccination (167). Non-specific effects of vaccines are not limited to BCG, but have also been reported for measles, and DTP (diphtheria, pertussis, and tetanus) vaccines; it has been suggested that optimization of immune scheduling in areas with high infectious disease burden could reduce child mortality by 30% (168).…”

Section: Variable Vaccine Responsementioning

confidence: 99%

The Role of Environmental Factors in Modulating Immune Responses in Early Life

2014

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The concept of immunological memory stipulates that past exposures shape present immune function. These exposures include not only specific antigens impacting adaptive immune memory but also conserved pathogen or danger associated molecular patterns that mold innate immune responses for prolonged periods of time. It should thus not come as a surprise that there is a vast range of external or environmental factors that impact immunity. The importance of environmental factors modulating immunity is most readily recognized in early life, a period of rapidly changing environments. We here summarize available data on the role of environment shaping immune development and from it derive an overarching hypothesis relating the underlying molecular mechanisms and evolutionary principles involved.

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“…Although it is widely believed that antibody is the correlate of protection against tetanus, for acellular pertussis, induction of cellular responses is important [29, 30]. We did not measure humoral responses to vaccination in this study, however previous studies of the effect of BCG on humoral responses to tetanus show mixed results [11, 12, 31]. The few studies that have examined the effect of BCG timing on humoral responses to pertussis showed no effect [32].…”

Section: Discussionmentioning

confidence: 99%

“…The effect of delaying BCG vaccination on HIV-exposed infants’ responses to the other routine vaccinations has been largely unexplored. In HIV-unexposed infants, BCG vaccination administered at birth improved humoral responses to pneumococcal, Haemophilus influenza type B (Hib) and tetanus toxoid antigens and increased cytokine responses to tetanus toxoid and polio antigens [10, 11]. Delaying BCG vaccination to 2 months of age increased cellular and humoral response to the hepatitis B vaccine, increased antibody response to polio, but had limited effect on cytokine response to tetanus toxoid, and no effect on antibody responses to tetanus and diphtheria toxoids [12].…”

Section: Introductionmentioning

confidence: 99%

Delayed BCG vaccination results in minimal alterations in T cell immunogenicity of acellular pertussis and tetanus immunizations in HIV-exposed infants

Blakney

Tchakoute

Hesseling

et al. 2015

Vaccine

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Background Bacille Calmette-Guerin (BCG) is effective in preventing disseminated tuberculosis (TB) in children but may also have non-specific benefits, and is thought to improve immunity to unrelated antigens through trained innate immunity. In HIV-infected infants, there is a risk of BCG-associated adverse events. We aimed to explore whether delaying BCG vaccination by 8 weeks, when in utero HIV is excluded, affected T-cell responses to B. pertussis (BP) and tetanus toxoid (TT), in HIV-exposed, uninfected infants. Methods Infants were randomized to receive BCG vaccination at birth or 8 weeks of age. At 8 and 14 weeks, T cell proliferation and intracellular cytokine (IL-2, IL-13, IL-17, and IFN-γ) expression was analyzed in response to BP, TT and Staphylococcal enterotoxin B (SEB) antigens. Results Delaying BCG vaccination did not alter T-cell proliferation to BP or TT antigens. Infants immunized with BCG at birth had higher CD4+ T cell proliferation to SEB at 14 weeks of age (p=0.018). Birth-vaccinated infants had increased CD8+ IL-2 expression in response to BP, but not TT or SEB, at 8 weeks. Infants vaccinated with BCG at 8 weeks had significantly lower IL-13 expression by BP-specific CD4+ and CD8+ T cells at 14 weeks (p=0.032 and p=0.0035 respectively). There were no observed differences in multifunctional cytokine response to TT, BP or SEB between infants vaccinated with BCG at birth versus 8 weeks of age. Conclusion Delaying BCG vaccination until 8 weeks of age results in robust T-cellular responses to BP and TT in HIV-exposed infants. Clinical Trial Registry NCT02062580

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Non-specific effect of Bacille Calmette-Guérin vaccine on the immune response to routine immunisations

Cited by 105 publications

References 45 publications

A Model to Explain How the Bacille Calmette Guérin (BCG) Vaccine Drives Interleukin-12 Production in Neonates

A Model to Explain How the Bacille Calmette Guérin (BCG) Vaccine Drives Interleukin-12 Production in Neonates

The Role of Environmental Factors in Modulating Immune Responses in Early Life

Delayed BCG vaccination results in minimal alterations in T cell immunogenicity of acellular pertussis and tetanus immunizations in HIV-exposed infants

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