Combination of MIDGE-Th1 DNA vaccines with the cationic lipid SAINT-18: studies on formulation, biodistribution and vector clearance

Vaccine. 2014 Jun 5;32(27):3460-7. doi: 10.1016/j.vaccine.2014.03.048. Epub 2014 Mar 26.

Abstract

We have previously shown that the combination of MIDGE-Th1 DNA vectors with the cationic lipid SAINT-18 increases the immune response to the encoded antigen in mice. Here, we report on experiments to further optimize and characterize this approach. We evaluated different formulations of MIDGE-Th1 vectors with SAINT-18 by assessing their influence on the transfection efficiency in cell culture and on the immune response in mice. We found that high amounts of SAINT-18 in formulations with a w/w ratio MIDGE Th1/SAINT-18 of 1:4.8 are beneficial for cell transfection in vitro. In contrast, the formulation of HBsAg-encoding MIDGE-Th1 DNA vectors with the lowest amount of SAINT-18 (w/w ratio MIDGE Th1/SAINT-18 of 1:0.5) resulted in the highest serum IgG1 and IgG2a levels after intradermal immunization of mice. Consequently, latter formulation was selected for a comparative biodistribution study in rats. Following intradermal administration of both naked and formulated MIDGE-Th1 DNA, the vectors localized primarily at the site of injection. Vector DNA levels decreased substantially over the two months duration of the study. When administered in combination with SAINT-18, the vectors were found in significantly higher amounts in draining lymph nodes in comparison to administration of naked MIDGE-Th1 DNA. We propose that the high immune responses induced by MIDGE-Th1/SAINT-18 lipoplexes are mediated by enhanced transfection of cells in vivo, resulting in stronger antigen expression and presentation. Importantly, the combination of MIDGE-Th1 vectors with SAINT-18 was well tolerated in mice and rats and is expected to be safe in human clinical applications.

Keywords: Biodistribution; Cationic lipid; DNA vaccine; MIDGE-Th1; SAINT-18; Transfection reagent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Viral / blood
  • Cations
  • Female
  • Genetic Vectors / chemistry*
  • Genetic Vectors / pharmacokinetics
  • Hepatitis B Surface Antigens / immunology
  • Immunoglobulin G / blood
  • Lymph Nodes / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Pyridinium Compounds / chemistry*
  • Pyridinium Compounds / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Th1 Cells / immunology
  • Tissue Distribution
  • Transfection
  • Vaccines, DNA / immunology*
  • Vaccines, DNA / pharmacokinetics

Substances

  • 1-methyl-4-(9-dioleyl)methylpyridinium
  • Antibodies, Viral
  • Cations
  • Hepatitis B Surface Antigens
  • Immunoglobulin G
  • Pyridinium Compounds
  • Vaccines, DNA