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

Abstract

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

Adjuvant Effect of Bacille Calmette–Guérin on Hepatitis B Vaccine Immunogenicity in the Preterm and Term Newborn

“…BCG is the most commonly administered vaccine in world history with billions of doses given globally at or soon after birth to protect against disseminated TB during infancy ( 65 ). In addition to its protective effects against TB, for which there is no established correlate of protection, BCG administration may also enhance Ab responses to unrelated pathogens in human newborns and infants ( 20 , 27 , 28 ) and in newborn mice ( 26 ). Protective heterologous effects of certain live-attenuated vaccines including BCG have been demonstrated that reduce morbidity and mortality beyond what can be attributable to prevention of the target disease ( 23 , 25 ).…”

“…It is the only routinely administered neonatal vaccine that induces a Th1-polarized immune response ( 20 ). BCG administration may also, in an age-dependent manner, induce beneficial heterologous (“non-specific” or “trained”) immunity against unrelated pathogens and stimuli ( 21 – 25 ), impact responses to other vaccines ( 20 , 26 – 28 ), and immune-modulate in the context of allergic diseases as well ( 29 ).…”

Heterologous Effects of Infant BCG Vaccination: Potential Mechanisms of Immunity

“…Whole blood samples from BCG-immunized infants produced less IL-13 and IL-17 upon C. albicans stimulation at 4 months postimmunization than samples from unvaccinated controls [ 40 ]. Increased fraction of IL-2-producing, proliferating CD8 + Bordetella pertussis -specific T cells was found in BCG-vaccinated HIV-exposed uninfected South African infants compared with the control group [ 50 ]. This suggests that BCG may also regulate Th17, Th22 or cytotoxic T-lymphocyte subsets.…”

Current status of new tuberculosis vaccine in children

“…88 Concerns about this approach have been raised, however, as in some studies BCG has lowered all-cause mortality. 89 In addition to HIV-infected infants, a recent study by Kagina et al demonstrated that delaying BCG vaccination from birth to 10 weeks of age in HIV-unexposed infants resulted in higher frequencies of BCG-specific, polyfunctional CD4 T cells at 1 y of age. 90 In contrast, Burl and his colleagues found that delaying BCG vaccination from birth to 18 weeks of age led to decreased IFN-g and IL-17 production in the delayed vaccinated group.…”