Homologous Prime-Boost Vaccination with OVA Entrapped in Self-Adjuvanting Archaeosomes Induces High Numbers of OVA-Specific CD8+ T Cells that Protect Against Subcutaneous B16-OVA Melanoma

Abstract

Homologous prime-boost vaccinations with live vectors typically fail to induce repeated strong CD8+ T cell responses due to the induction of anti-vector immunity, highlighting the need for alternative delivery vehicles. The unique ether lipids of archaea may be constituted into liposomes, archaeosomes, which do not induce anti-carrier responses, making them an ideal candidate for use in repeat vaccination systems. Herein, we evaluated in mice the maximum threshold of antigen-specific CD8+ T cell responses that may be induced by multiple homologous immunizations with ovalbumin (OVA) entrapped in archaeosomes derived from the ether glycerolipids of the archaeon Methanobrevibacter smithii (MS-OVA). Up to three immunizations with MS-OVA administered in optimized intervals (to allow for sufficient resting of the primed cells prior to boosting), induced a potent anti-OVA CD8+ T cell response of up to 45% of all circulating CD8+ T cells. Additional MS-OVA injections did not add any further benefit in increasing the memory of CD8+ T cell frequency. In contrast, OVA expressed by Listeria monocytogenes (LM-OVA), an intracellular bacterial vector failed to evoke a boosting effect after the second injection, resulting in significantly reduced antigen-specific CD8+ T cell frequencies. Furthermore, repeated vaccination with MS-OVA skewed the response increasingly towards an effector memory (CD62low) phenotype. Vaccinated animals were challenged with B16-OVA at late time points after vaccination (+7 months) and were afforded protection compared to control. Therefore, archaeosomes constituted a robust particulate delivery system to unravel the kinetics of CD8+ T cell response induction and memory maintenance and constitute an efficient vaccination regimen optimized for tumor protection.

Safety and biodistribution of sulfated archaeal glycolipid archaeosomes as vaccine adjuvants

“…injection and their safety profile was evaluated. Dose levels of archaeosomes used for vaccination studies in mice are typically between 0.3 -1.5 mg, 5,6,9 and therefore 1 mg was selected to represent a typical vaccine dose level, whereas 10 mg of SLA/LA allowed for the evaluation of safety parameters at lipid levels approximately 10-fold higher than normally administered in vivo. No significant differences were seen between male and female mice, and as such, data from female and male mice receiving similar treatments were combined for presentation purposes.…”

Simplified Admix Archaeal Glycolipid Adjuvanted Vaccine and Checkpoint Inhibitor Therapy Combination Enhances Protection from Murine Melanoma

“…Archaeal lipid adjuvants are a good potential candidate for use in combination with CPI's, as evidenced by their proven safety and efficacy in mice [19,44]. In multiple pre-clinical studies, they have been shown to activate antigen-specific CD8 + T cell responses [15,19,26,27] and generate protective immunity in tumor models, e.g., B16-OVA melanoma [7,13,19,23,26,27], and against multiple infectious diseases, e.g., H1N1 influenza [11], Listeria monocytogenes [7,12], Trypanosoma cruzi [13] and Mycobacterium tuberculosis [14]. When compared to commonly used commercial adjuvants, such as Poly(I:C) or Montanide, archaeal lipid vaccines were found to elicit equal or greater antigen specific CD8 + T cell-mediated cytotoxicity and IgG responses [10].…”

“…Tumor and spleen samples were collected at various time points during the study when the mice had reached their humane endpoint. Spleen and tumor samples were processed as described previously [15,27]. Briefly, spleen samples were mashed between two frosted glass slides to obtain a single-cell suspension.…”

“…MS-OVA archaeosomes have been previously used to deliver entrapped antigen and induce anti-tumor CD8 + T cell responses [10,15,16,27]. Using the solid B16-OVA melanoma tumor model, we have previously demonstrated a synergy between MS-OVA (enc) and CPI therapy (anti-PD-1, anti-programmed death-ligand 1 (anti-PD-L1) and anti-CTLA-4) in promoting long-term tumor-free survival in C57BL/6 mice [15].…”

Effect of Different Adjuvants on the Longevity and Strength of Humoral and Cellular Immune Responses to the HCV Envelope Glycoproteins

“…Traditional archaeosomal formulations consisted of liposomes formed from total polar lipids (TPL) derived from archaea such as the methanogen Methanobrevibacter smithii (MS). These archaeosomes were shown to effectively activate professional antigen-presenting cells [14][15][16] and generate robust cellular and humoral immune response to encapsulated antigen in both cancer and infectious disease models [11,12,17]. More recently, a novel simpler semi-synthetic archaeosome formulation composed of a sulfated disaccharide group covalently linked to the free sn-1 hydroxyl backbone of an archaeal core lipid (sulfated S-lactosylarchaeol, SLA), has been developed [18].…”