Abstract
We prepared a series of cationic lipid vesicles comprising a cationic cholesterol derivative, DC-Chol with or without a neutral phospholipid, DOPC or DOPE. The vesicles were tested for their ability to bind and adjuvant split inactivated influenza vaccines. We found that DC-Chol-containing liposomes are capable to strongly bind influenza vaccine antigens upon simple mixing with the vaccine. The resulting formulations induced robust anti-influenza immune responses both after s.c. and i.n. administration in BALB/c mice while neutral Cholesterol/DOPC liposomes displayed virtually no stable antigen binding and no adjuvant effect. The parenteral adjuvant effect of DC-Chol on trivalent split influenza vaccines was then confirmed in outbred mice and monkeys. Among the most potent formulations tested, a simple mixture of the vaccine with a microfluidized dispersion of DC-Chol in an aqueous buffer is being considered for further development to produce an improved influenza vaccine.
MeSH terms
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Adjuvants, Immunologic*
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Administration, Intranasal
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Animals
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Animals, Outbred Strains
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Antibodies, Viral / immunology
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Cations / administration & dosage
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Cations / immunology
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Cations / metabolism
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Chemistry, Pharmaceutical
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Cholesterol / administration & dosage
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Cholesterol / analogs & derivatives
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Cholesterol / chemistry
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Cholesterol / immunology*
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Cholesterol / metabolism
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Drug Design*
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Drug Evaluation, Preclinical*
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Female
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Glycerophospholipids / administration & dosage
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Haplorhini / immunology
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Hemagglutination Inhibition Tests
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Hemagglutinin Glycoproteins, Influenza Virus / immunology
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Hemagglutinin Glycoproteins, Influenza Virus / metabolism
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Humans
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Immunity, Mucosal / immunology
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Influenza Vaccines / administration & dosage
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Influenza Vaccines / chemistry
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Influenza Vaccines / immunology*
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Influenza Vaccines / metabolism
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Injections, Subcutaneous
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Interferon-gamma / biosynthesis
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Liposomes / administration & dosage
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Liposomes / chemistry
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Liposomes / immunology
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Liposomes / metabolism
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Mice
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Mice, Inbred BALB C
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Particle Size
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Phosphatidylcholines / administration & dosage
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Phosphatidylethanolamines*
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Static Electricity
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T-Lymphocytes, Cytotoxic / immunology
Substances
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1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine
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Adjuvants, Immunologic
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Antibodies, Viral
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Cations
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Glycerophospholipids
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Hemagglutinin Glycoproteins, Influenza Virus
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Influenza Vaccines
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Liposomes
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Phosphatidylcholines
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Phosphatidylethanolamines
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3-(N-(N',N'-dimethylaminoethane)carbamoyl)cholesterol
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Interferon-gamma
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Cholesterol
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1,2-oleoylphosphatidylcholine