Abstract
Archaeosomes are liposomes traditionally comprised of total polar lipids (TPL) or semi-synthetic glycerolipids of ether-linked isoprenoid phytanyl cores with varied glyco- and amino-head groups. As adjuvants, they induce robust, long-lasting humoral and cell-mediated immune responses and enhance protection in murine models of infectious disease and cancer. Traditional total polar lipid (TPL) archaeosome formulations are relatively complex and first generation semi-synthetic archaeosomes involve many synthetic steps to arrive at the final desired glycolipid composition. We have developed a novel archaeosome formulation comprising a sulfated disaccharide group covalently linked to the free sn-1 hydroxyl backbone of an archaeal core lipid (sulfated S-lactosylarchaeol, SLA) that can be more readily synthesized yet retains strong immunostimulatory activity for induction of cell-mediated immunity following systemic immunization. Herein, we have evaluated the immunostimulatory effects of SLA archaeosomes when used as adjuvant with ovalbumin (OVA) and hepatitis B surface antigen (HBsAg) and compared this to various other adjuvants including TLR3/4/9 agonists, oil-in-water and water-in-oil emulsions and aluminum hydroxide. Overall, we found that semi-synthetic sulfated glycolipid archaeosomes induce strong Ag-specific IgG titers and CD8 T cells to both antigens. In addition, they induce the expression of a number of cytokines/chemokines including IL-6, G-CSF, KC & MIP-2. SLA archaeosome formulations demonstrated strong adjuvant activity, superior to many of the other tested adjuvants.
Highlights
Adjuvants are critical components of modern day vaccines, enabling protection against multiple pathogens through their ability to enhance immune responses to the inherently weak disease-associated antigens found in subunit vaccines that lack the immunostimulatory molecules present in live or attenuated vaccines
C57BL/6 mice were immunized on Days 0 and 21 with OVA alone or in combination with different adjuvants including two separate archaeosome based formulations (SLA and SLA/LA), aluminum hydroxide, the TLR agonists CpG (TLR9), Poly I:C (TLR3) and MPLA (TLR4), the water-in-oil emulsion Montanide 720 and the squalene-based oil-in-water emulsion Addavax
At day 20, highest anti-OVA IgG titers were induced with OVA plus SLA or Montanide 720 (p
Summary
Adjuvants are critical components of modern day vaccines, enabling protection against multiple pathogens through their ability to enhance immune responses to the inherently weak disease-associated antigens found in subunit vaccines that lack the immunostimulatory molecules present in live or attenuated vaccines. The inclusion of alum was based on the observation that it could induce higher antibody responses to vaccine antigens in vivo [1] Due to their clinical efficacy, acceptable safety profile and wide-spread use, alum salts were the only adjuvant approved for human vaccines for 70 years thereafter. All newly developed adjuvanted vaccines up till the 1990s included aluminum salts (e.g., vaccines against hepatitis A & B viruses, human papilloma virus, pneumococcus and meningococcus) [2] This was despite the lack of an in-depth understanding of its mechanism of action at the time, which is widely thought to be due a combination of an antigen depot effect and immunomodulatory activity through the NLRP3 inflammasome [3]
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