Abstract
The development of new effective vaccines strongly depends on adjuvants and formulations able to stimulate not only strong humoral responses against a certain pathogen but also effector as well as memory CD4+ and CD8+ T cells (Dubensky et al., 2013). However, the majority of vaccines licensed for human use or currently under clinical investigation fail to stimulate efficient cellular responses. For example, vaccines against hepatitis B virus (HBV), human papillomavirus (HPV), diphtheria, tetanus and influenza are usually administered by intramuscular (i.m.) injection and contain aluminum salts (alum) as adjuvant. Alum has been shown to stimulate Th2 immune cells resulting in increased production of antigen-specific antibodies but to be incapable of stimulating robust Th1 or cytotoxic responses. To overcome such limitations recent research has focused on the development of adjuvant combinations (e.g., MF59, AS03 or AS04) to not only further strengthen antigen-specific immune responses but to also allow their modulation. We have shown previously that bis-(3′,5′)-cyclic dimeric adenosine monophosphate (c-di-AMP) constitutes a promising adjuvant candidate stimulating both effective Th1/Th2 and cytotoxic immune responses when included in mucosal or parenteral vaccine formulations. In the present work we demonstrate that c-di-AMP can be also combined with other adjuvants like alum resulting in increases in not only humoral responses but more striking also in cellular immune responses. This leads to improved vaccine efficacy against intracellular pathogens.
Highlights
Today, infectious diseases represent the second leading cause of death worldwide (Global Health Observatory Data Repository, 2016)
An adjuvant system of alum/c-di-AMP could overcome the limitation of alum and further enhance the stimulated antigen-specific humoral response but at the same time promote the stimulation of T helper 1 (Th1) and cytotoxic T lymphocytes (CTLs) responses
The aim of this study was to investigate if c-di-AMP in combination with alum can further optimize the immune response against an antigen (β-Gal) when given by parenteral route
Summary
Infectious diseases represent the second leading cause of death worldwide (Global Health Observatory Data Repository, 2016). Adjuvants are used to enhance the stimulated antigen-specific immune responses and to tailor the immune responses according to the specific clinical needs In this regard, it is unlikely that a single adjuvant will be able to fulfill all the required properties to be implemented in all foreseeable vaccines. The cyclic di-nucleotide c-di-AMP, a second messenger in prokaryotes, exhibits strong immune modulatory properties stimulating antibody and mixed Th1/Th2 as well as cytotoxic responses when administered by either parenteral or mucosal routes (Ebensen et al, 2007a,b; Ebensen et al, 2017; Schulze et al, 2017a) This renders it very attractive for use in human vaccines, since most adjuvants supporting a Th1-dominated response lack the ability to induce humoral immunity (Libanova et al, 2010; Matos et al, 2017). An adjuvant system of alum/c-di-AMP could overcome the limitation of alum and further enhance the stimulated antigen-specific humoral response but at the same time promote the stimulation of Th1 and CTL responses
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