A new intranasal influenza vaccine based on a novel polycationic lipid-ceramide carbamoyl-spermine (CCS). II. Studies in mice and ferrets and mechanism of adjuvanticity.
We recently showed that lipid assemblies comprised of a novel polycationic sphingolipid (ceramide carbamoyl-spermine, CCS) are an effective adjuvant/carrier when complexed with cholesterol (CCS/C) for influenza and other vaccines administered parenterally and intranasally (i.n.) in mice. Here we expand these studies to ferrets, an established model of influenza infection. We also address the question of why the CCS/C-based liposomal vaccine (also known as VaxiSome™) in mice is superior to vaccines based on liposomes of other lipid compositions (neutral, anionic or cationic). Ferrets immunized i.n. with CCS/C-influenza vaccine produced significantly higher hemagglutination inhibition (HI) antibody titers compared to ferrets immunized intramuscularly with the unadjuvanted influenza vaccine, indicating that the CCS/C-based vaccine is very immunogenic. Furthermore, the i.n. adjuvanted vaccine was shown to significantly reduce the severity of influenza virus infection in ferrets following homologous viral challenge as determined by weight loss, temperature rise and viral titer. No adverse reactions were observed. Pharmacokinetic and biodistribution studies following i.n. administration in mice of CCS/C-based vaccine showed that both the lipids and antigens are retained in the nose and lung for at least 24h, and it appears that this retention correlates with the superior immunogenicity elicited by the adjuvanted vaccine formulation. The CCS lipid also increases production of cytokines (mainly IFN gamma, IL-2 and IL-12) and co-stimulatory molecules' expression, which might further explain the robust adjuvantation of this liposome-based vaccine.
Laboratory of Membrane and Liposome Research, IMRIC, The Hebrew University-Hadassah Medical School, P.O. Box 12272, Jerusalem 91120, Israel.
Orli
O
Even-Or
Aviva
A
Joseph
Noga
N
Itskovitz-Cooper
Sarit
S
Samira
Eli
E
Rochlin
Hagit
H
Eliyahu
Itzik
I
Goldwaser
Shobana
S
Balasingam
Alex J
AJ
Mann
Rob
R
Lambkin-Williams
Eli
E
Kedar
Yechezkel
Y
Barenholz
D000276:Adjuvants, Immunologic; D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001831:Body Temperature; D001835:Body Weight; D002518:Ceramides / Q000008:administration & dosage* / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005289:Ferrets; D006385:Hemagglutination Inhibition Tests; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D008055:Lipids / Q000008:administration & dosage* / Q000009:adverse effects; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000473:pathology / Q000517:prevention & control; D013096:Spermine / Q000008:administration & dosage* / Q000009:adverse effects; D019562:Viral Load
D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D002518:Ceramides; D016207:Cytokines; D007252:Influenza Vaccines; D008055:Lipids; D013096:Spermine; D009569:Nitric Oxide