title: 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 archaeonMethanobrevibacter 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 byListeria 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.
authors.affiliation: Human Health Therapeutics, National Research Council of Canada, 1200 Montreal Rd., Ottawa, ON K1A 0R6, Canada. Felicity.Stark@nrc-cnrc.gc.ca.
authors.forename: Felicity C
authors.initials: FC
authors.lastname: Stark
authors.affiliation: Human Health Therapeutics, National Research Council of Canada, 1200 Montreal Rd., Ottawa, ON K1A 0R6, Canada. Michael.McCluskie@nrc-cnrc.gc.ca.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCluskie
authors.affiliation: Human Health Therapeutics, National Research Council of Canada, 1200 Montreal Rd., Ottawa, ON K1A 0R6, Canada. Lakshmi.Krishnan@nrc-cnrc.gc.ca.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Krishnan
keywords: B16; CD8 T cell response; archaeosome; central memory; effector memory; liposome; prime-boost; tumor vaccine