Bacillus subtilis spores: A novel microparticle adjuvant which can instruct a balanced Th1 and Th2 immune response to specific antigen

Abstract

There is a current need for safe, cheap, and effective vaccine adjuvants, to combine with sub-unit antigens to enhance their immunogenicity. In this study we have used probiotic Bacillus subtilis spores, known to be safe and fully tolerated by ingestion in man, and explored their ability to influence the magnitude and diversity of immune responses induced against two model antigens, tetanus toxoid fragment C (TT) and ovalbumin (OVA) in mice. The results show that B. subtilis spores not only increased antibody and T cell responses to a co-administered soluble antigen, but also broadened them, to include both antigen-specific CD4 + and CD8 + T cell responses as well as complement and non-complement fixing antibody isotypes. Furthermore, following intranasal immunization, spores augmented specific IgA to co-administered antigen both in the local respiratory and distal vaginal mucosa, as well as increased antigen-specific IgG antibody in draining LN and blood. Collectively, these data demonstrate that naturally occurring, non-pathogenic, non-commensal spores of B. subtilis both instruct and augment polyvalent immune responses and highlight their clinical potential in future vaccines to generate broad-based immunity.

Mucosal Vaccination against Tuberculosis Using Inert Bioparticles

“…Spores clearly enhance or augment immune responses, and these responses are consistent with those found in other studies showing that bacterial spores carry adjuvant properties (5,27). Presumably, spores facilitate entry of the M. tuberculosis antigens into the major histocompatibility complex class I and II presentation pathways, and their fate parallels the fate of other microparticulate carriers, such as immune-stimulating complexes (ISCOMs), virus-like particles (VLPs), and biodegradable microspheres (28)(29)(30)(31).…”

“…Thus, we showed that antigen-specific sIgA can be readily detected in the lung lavage fluid, and also, high IgG titers could be detected in the sera of immunized animals; moreover, the systemic immune response induced by mucosal vaccination with antigen-coated spores was evidenced by T cell proliferation, IFN-␥ secretion, and the recruitment of multifunctional T cells in the spleen. In contrast, intranasal delivery of either live (27) or killed (34) spores fails to generate a significant humoral or cellular response directed against the spore itself but generates a response only against the coadministered antigen. Regarding heat stability, extensive studies have shown that genetically modified spores of B. subtilis expressing a heterologous antigen can retain almost complete efficacy as vaccines for up to 12 months when stored at ambient temperature (35).…”

Selection of Adjuvants for Enhanced Vaccine Potency

“…Killed or inactivated spores appear equally effective as live spores in these studies. Intranasal administration of two model antigens, tetanus toxoid fragment C (TT) and ovalbumin (OVA), with Bacillus subtilis spores (safe and fully tolerated by ingestion in man) increased T cell response and specific IgA both in the local respiratory and distal vaginal mucosa, as well as increased antigen-specific IgG antibody in draining LN and blood in mice [409].…”

The PorB porin from commensal Neisseria lactamica induces Th1 and Th2 immune responses to ovalbumin in mice and is a potential immune adjuvant

“…Various TLR ligands have been shown to modulate the immune response [45][46][47] and act as vaccine adjuvants regardless of their pathogenic or non-pathogenic origin (i.e LPS, CpG DNA). Examples of non-pathogenic bacteria with adjuvant activity include Bacillus firmus [48], probiotic Bacillus subtilis spores [49] and some non-pathogenic intestinal gram-negative bacteria, including Bacteroides vulgatus or Veillonella parvula [50], which can induce both Th1-and Th2-type immune responses.…”