A clinically applicable adjuvant for an atherosclerosis vaccine in mice

Abstract

Vaccination with MHC-II-restricted peptides from Apolipoprotein B (ApoB) with complete and incomplete Freund's adjuvant (CFA/IFA) is known to protect mice from atherosclerosis. This vaccination induces antigen-specific IgG1 and IgG2c antibody responses and a robust CD4 T cell response in lymph nodes. However, CFA/IFA cannot be used in humans. To find a clinically applicable adjuvant, we tested the effect of vaccinating Apoe-deficient mice with ApoB peptide P6 (TGAYSNASSTESASY). In a broad screening experiment, Addavax, a squalene-based oil-in-water adjuvant similar to MF59, was the only adjuvant that showed similar efficacy as CFA/IFA. This was confirmed in a confirmation experiment for both the aortic arch and whole aorta analyzed by en face analysis after atherosclerotic lesion staining. Mechanistically, restimulated peritoneal cells from mice immunized with P6 in Addavax released significant amounts of IL-10. Unlike P6 in CFA/IFA, vaccination with P6 in Addavax did not induce any detectable IgG1 or IgG2c antibodies to P6. These data suggest that squalene-based adjuvants such as MF59 are good candidate adjuvants for developing a clinically effective atherosclerosis vaccine.

Immunity and Inflammation in Atherosclerosis

“…It has been proposed that either T regs 42, 164-167 , IL-10 42,161,167,168 , or vaccination-induced IgG-antibodies may confer atheroprotection, depending on doses, routes, and adjuvants used 44 . Recent studies, however, suggest that atheroprotection does not require IgG-antibodies 169 and primarily proceeds by IL-10 + ApoB-specific T regs 42 .…”

“…Subcutaneous or intraperitoneal injections of both, CFA and IFA, were shown to elicit nonspecific inflammation 171,172 . This limitation was recently overcome by the discovery that a squalene oil, a class of adjuvants already used in clinical practice, can be used as an adjuvant for ApoB-peptides 169 . In addition, it remains unclear whether vaccination is effective in established atherosclerosis as most studies tested the prevention of de-novo atherosclerosis in rodents.…”

Atherosclerosis

“…This trial showed no evidence of efficacy of antibody treatment. In mouse models, it is known that vaccine-induced antibody responses are dispensable for atheroprotection 15 .…”

Immunität und Entzündung bei Arteriosklerose

“…Gegenwärtig werden hauptsächlich drei Wirkmechanismen diskutiert: Induktion von T regs (42,(164)(165)(166)(167), IL-10-Produktion (41,42,161,167) oder impfinduzierte IgG-Antikörper -abhängig von der Dosis, Administrationsroute und Adjuvantien (44). Neuere Studien legen nahe, dass IgG-Antikörper nicht notwendig sind (168), sodass die T reg und IL-10-Hypothesen wahrscheinlicher werden (42). Ob Arterioskleroseimpfungen für die klinische Anwendung entwickelt werden können, ist noch unklar.…”

“…Beide Adjuvanzien können nicht beim Menschen angewandt werden, da die subkutane oder intraperitoneale Injektion von CFA oder IFA starke unspezifische Entzündung induziert (170,171). Dieses Problem wurde in einer neueren Studie gelöst, in der gezeigt wurde, dass ein Squalenöl, ein Adjuvans das bereits in klinischen Impfstoffen benutzt wird, mit ApoB-Peptiden gegeben werden kann und effektiv vor Arteriosklerose schützt (168). Derzeit ist außerdem unbekannt, ob Impfung von Nagetieren mit bereits bestehender Arteriosklerose wirkt, da die meisten Studien nur die prophylaktische Verhütung von Arteriosklerose untersucht haben.…”