Mechanistic insight into the induction of cellular immune responses by encapsulated and admixed archaeosome-based vaccine formulations

Abstract

Archaeosomes are liposomes formulated using total polar lipids (TPLs) or semi-synthetic glycolipids derived from archaea. Conventional archaeosomes with entrapped antigen exhibit robust adjuvant activity as demonstrated by increased antigen-specific humoral and cell-mediated responses and enhanced protective immunity in various murine infection and cancer models. However, antigen entrapment efficiency can vary greatly resulting in antigen loss during formulation and variable antigen:lipid ratios. In order to circumvent this, we recently developed an admixed archaeosome formulation composed of a single semi-synthetic archaeal lipid (SLA, sulfated lactosylarchaeol) which can induce similarly robust adjuvant activity as an encapsulated formulation. Herein, we evaluate and compare the mechanisms involved in the induction of early innate and antigen-specific responses by both admixed (Adm) and encapsulated (Enc) SLA archaeosomes. We demonstrate that both archaeosome formulations result in increased immune cell infiltration, enhanced antigen retention at injection site and increased antigen uptake by antigen-presenting cells and other immune cell types, including neutrophils and monocytes following intramuscular injection to mice using ovalbumin as a model antigen. In vitro studies demonstrate SLA in either formulation is preferentially taken up by macrophages. Although the encapsulated formulation was better able to induce antigen-specific CD8 + T cell activation by dendritic cells in vitro, both encapsulated and admixed formulations gave equivalently enhanced protection from tumor challenge when tested in vivo using a B16-OVA melanoma model. Despite some differences in the immunostimulatory profile relative to the SLA (Enc) formulation, SLA (Adm) induces strong in vivo immunogenicity and efficacy, while offering an ease of formulation.

Sulfated Lactosyl Archaeol Archaeosomes Synergize with Poly(I:C) to Enhance the Immunogenicity and Efficacy of a Synthetic Long Peptide-Based Vaccine in a Melanoma Tumor Model

“…Hailemichael et al also demonstrated that shorter-lived vaccine formulations preferentially induced T cell localization to the tumor and increased anti-tumor activity. SLA archaeosomes mediate a short-term depot effect on antigen of <48 h [ 18 ] while still stimulating strong and long-lasting cellular responses to a variety of antigens in preclinical models [ 13 , 14 ]. These properties have the potential to make it a more ideal partner for adjuvant combination strategies including TLR agonists.…”

“…Head-to-head comparative preclinical studies demonstrated that SLA was superior to a number of adjuvant types, including TLR agonists, in inducing antigen-specific T cell responses [ 17 ]. In mice, SLA has been shown to increase 1) antigen retention at the injection site, 2) immune cell recruitment, 3) antigen uptake, and 4) cytokine/chemokine expression [ 17 , 18 , 19 ]. Finally, SLA-based vaccine formulations can induce efficacious antigen-specific anti-tumor responses in a mouse melanoma model [ 20 ].…”

The Synergistic Effects of Sulfated Lactosyl Archaeol Archaeosomes When Combined with Different Adjuvants in a Murine Model

“…Furthermore, using OVA or HBsAg as antigens, we also demonstrated that SLA archaeosomes induce equivalent or superior antigen-specific immune responses to those obtained with many other adjuvants, including TLR3/4/9 agonists, oil-in-water and water-in-oil emulsions and aluminum hydroxide [ 15 ]. Initial studies indicated that SLA archaeosomes enhance immune cell infiltration, antigen retention and antigen uptake at the injection site [ 22 ]. However, no studies to date have evaluated the use of SLA archaeosomes, or to the best of our knowledge any other type of archaeosome, in combination with a panel of other types of adjuvants.…”

“…Unlike most cationic liposomes used to deliver negatively charged nucleic acids, SLA archaeosomes are composed of a negatively charged lipid and hence are unlikely to bind to either CpG or Poly(I:C) directly. However, while it is unlikely that CpG or Poly(I:C) would interact with archaeosomes based on charge, it cannot be ruled out that the presence of archaeosomes could impact adjuvant distribution as has been shown previously for antigens [ 22 ].…”

“…While originally used as delivery vehicles for encapsulated antigen, a simplified SLA formulation where antigens were simply admixed with pre-formed empty SLA vesicles was shown to generate equivalent or superior humoral and cell-mediated immune responses to conventional antigen-entrapped archaeosome formulations [ 21 ]. Although the mechanism of action of the admixed SLA archaeosome formulation has not been fully elucidated, it does increase immune cell infiltration, antigen retention at injection site and antigen uptake by antigen-presenting cells and other immune cell types, including neutrophils and monocytes [ 22 , 23 ].…”