Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-controlled Trial

Abstract

Background. Bacillus Calmette–Guérin (BCG) seems to have beneficial nonspecific effects; early BCG vaccination of low-birth-weight (LBW) newborns reduces neonatal mortality by >40% due to prevention of primarily septicemia and pneumonia.Methods. Within a randomized trial in LBW infants in Guinea-Bissau of early BCG vs the usual postponed BCG, a subgroup was bled 4 weeks after randomization. Levels of interleukin (IL)-1β, IL-5, IL-6, IL-10, IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured from whole-blood assays stimulated with innate agonists to Toll-like receptor (TLR)-2, -4 or -7/8, or purified protein derivative (PPD).Results. Among 467 infants, BCG significantly increased the in vitro cytokine responses to purified protein derivative of Mycobacterium tuberculosis (PPD), as expected. BCG was also associated with increased responses to heterologous innate stimulation, particularly of the cytokines IL-1β, IL-6, TNF-α, and IFN-γ.Conclusion. Four weeks after immunization, BCG-vaccinated infants have a significantly increased production of cytokines upon heterologous challenge, particularly T helper cell type 1 polarizing and typically monocyte-derived pro-inflammatory cytokines. BCG may accelerate the development of the neonatal immune system, mediating comprehensive protection against infections and mortality.

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

“…The data of the current study clearly demonstrated that our AMtb vaccines enhanced the functional responses of monocytes/macrophages and mDC and that these heightened responses persisted for at least 16 to 18 weeks after a single AMtb immunization at birth. These results are consistent with a recent study showing that African infants in Guinea-Bissau had greater responses to various TLR agonists at 4 weeks after BCG vaccination (58). Consistent with findings in BCG-vaccinated adults (16), we also observed vaccineinduced activation of CD4 ϩ and CD8 ϩ T cells and of B cells.…”

“…Consistent with findings in BCG-vaccinated adults (16), we also observed vaccineinduced activation of CD4 ϩ and CD8 ϩ T cells and of B cells. Our results in infant macaques, which mirrored results from the human pediatric study (58), imply that the phenomenon of mycobacterial-vaccine-induced trained immunity in adults (16) might also be applicable to infants. However, we have not specifically tested for the induction of heterologous immunity and limited cell numbers did not allow us to directly test whether our AMtb vaccines induced epigenetic modifications in myeloid cell populations similar to those observed in BCG-vaccinated adults (15).…”

In Vitro Experimental Model of Trained Innate Immunity in Human Primary Monocytes

“…Of course, we should be cautious in the extrapolation of all the details of the in vitro model to the in vivo situation: for example, vaccination trials performed both in infants and in adults showed increased proinflammatory cytokine responses after BCG vaccination, whereas no effects on anti-inflammatory cytokine responses were noted (8,24,26). Furthermore, in patients suffering from elevated levels of lipoprotein(a), which induces trained innate immunity in vitro, the anti-inflammatory cytokine response was even decreased (17).…”

Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

“…Such training effects were also seen in human monocytes following neonatal BCG vaccination. 37 Similar training effects were observed following stimulation of adult human monocytes in vitro with either C. albicans or β-glucan (a component of fungal cell walls) for 24 h. 38 Upon a second stimulation with C. albicans, bacteria or various PAMP/PRR ligands up to 2 weeks later, pre-stimulated monocytes showed significant increases (of up to 10-fold) in TNF-α and IL-6 production relative to naive monocytes. The magnitude of the training effects was dependent on the doses of both the primary and secondary stimulation.…”