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

Abstract

Immunization is key to protecting term and preterm infants from a heightened risk of infection. However, preterm immunity is distinct from that of the term, limiting its ability to effectively respond to vaccines routinely given at birth, such as hepatitis B vaccine (HBV). As part of the Expanded Program on Immunization, HBV is often given together with the live-attenuated vaccine Bacille Calmette–Guérin (BCG), known to activate multiple pattern-recognition receptors. Of note, some clinical studies suggest BCG can enhance efficacy of other vaccines in term newborns. However, little is known about whether BCG can shape Th-polarizing cytokine responses to HBV nor the age-dependency of such effects, including whether they may extend to the preterm. To characterize the effects of BCG on HBV immunogenicity, we studied individual and combined administration of these vaccines to cord newborn and adult human whole blood and mononuclear cells in vitro and to neonatal and adult mice in vivo. Compared to either BCG or HBV alone, (BCG + HBV) synergistically enhanced in vitro whole blood production of IL-1β, while (BCG + HBV) also promoted production of several cytokines/chemokines in all age groups, age-specific enhancement included IL-12p70 in the preterm and GM-CSF in the preterm and term. In human mononuclear cells, (BCG + HBV) enhanced mRNA expression of several genes including CSF2, which contributed to clustering of genes by vaccine treatment via principle component analysis. To assess the impact of BCG on HBV immunization, mice of three different age groups were immunized subcutaneously with, BCG, HBV, (BCG + HBV) into the same site; or BCG and HBV injected into separate sites. Whether injected into a separate site or at the same site, co-administration of BCG with HBV significantly enhanced anti-HBV IgG titers in mice immunized on day of life-0 or -7, respectively, but not in adult mice. In summary, our data demonstrate that innate and adaptive vaccine responses of preterm and term newborns are immunologically distinct. Furthermore, BCG or “BCG-like” adjuvants should be further studied as a promising adjuvantation approach to enhance immunogenicity of vaccines to protect these vulnerable populations.

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

“…When compared to subjects with classic latent Mtb infection, Mtb 'resisters' display enhanced Ab avidity and distinct Mtb-specific IgM and IgG Fc profiles (Lu et al, 2019). BCG may also enhance Ab responses and, in some cases, T cell responses to other early life vaccines, such as hepatitis B, pertussis, and pneumococcal vaccines (Ota et al, 2002;Ritz et al, 2013;Scheid et al, 2018). Overall, understanding formulation-specific BCG-induced responses may necessitate complimentary investigation of functional Ab responses to vaccination, which may prove to be as important as inducing T cell production of IFNγ and/or heterologous responses.…”

The sixth revolution in pediatric vaccinology: immunoengineering and delivery systems

“…Two foremost target populations are pregnant women and preterm infants. Notably, immunity of preterm infants is distinct from newborns (113), rendering them particularly susceptible to infection (114,115). Every year, ~15 million newborns are born preterm worldwide, which is ~11% of all live births (116).…”

“…Novel use of preexisting and clinical licensed vaccine formulatio ns may shed light on areas of optimization. Co-administration of BCG with HBV, for example, significantly enhanced anti-HBV IgG titers in mouse models of both term and preterm birth, equally, but not in adult mice (113).…”

Immunomodulation to Prevent or Treat Neonatal Sepsis: Past, Present, and Future

“…This heterologous innate immune protection may be due to “trained immunity,” the phenomenon whereby innate activation results in a heightened state of innate responses to a broad range of pathogens and thus broad protection, via innate memory as has been reviewed elsewhere ( 204 ). Of note, the combined administration of BCG plus the alum-adjuvanted hepatitis B vaccine (HBV) demonstrates age-dependent synergistic enhancement of IL-1ß, production potentially enhancing both innate and adaptive immune responses ( 205 ).…”