Abstract
Infection by Hepatitis C virus (HCV) can lead to liver cirrhosis/hepatocellular carcinoma and remains a major cause of serious disease morbidity and mortality worldwide. However, current treatment regimens remain inaccessible to most patients, particularly in developing countries, and, therefore, the development of a novel vaccine capable of protecting subjects from chronic infection by HCV could greatly reduce the rates of HCV infection, subsequent liver pathogenesis, and in some cases death. Herein, we evaluated two different semi-synthetic archaeosome formulations as an adjuvant to the E1/E2 HCV envelope protein in a murine model and compared antigen-specific humoral (levels of anti-E1/E2 IgG and HCV pseudoparticle neutralization) and cellular responses (numbers of antigen-specific cytokine-producing T cells) to those generated with adjuvant formulations composed of mimetics of commercial adjuvants including a squalene oil-in-water emulsion, aluminum hydroxide/monophosphoryl lipid A (MPLA) and liposome/MPLA/QS-21. In addition, we measured the longevity of these responses, tracking humoral, and cellular responses up to 6 months following vaccination. Overall, we show that the strength and longevity of anti-HCV responses can be influenced by adjuvant selection. In particular, a simple admixed sulfated S-lactosylarchaeol (SLA) archaeosome formulation generated strong levels of HCV neutralizing antibodies and polyfunctional antigen-specific CD4 T cells producing multiple cytokines such as IFN-γ, TNF-α, and IL-2. While liposome/MPLA/QS-21 as adjuvant generated superior cellular responses, the SLA E1/E2 admixed formulation was superior or equivalent to the other tested formulations in all immune parameters tested.
Highlights
Hepatitis C virus (HCV) is a highly pathogenic virus infecting over 70 million people globally [1].Chronic infection can lead to liver cirrhosis and hepatocellular carcinoma, causing approximately~400,000 deaths per year worldwide
Mice were immunized on days 0, 21, and 35 with E1/E2 antigen alone or in combination with different adjuvants including Addavax, Alum/Monophosphoryl lipid A (MPL) (AS04TM mimetic), Lipo/QS-21/MPL (AS01TM mimetic), and E1E2 either encapsulated within SLA archaeosomes, SLA
The administration of the low dose E1/E2 antigen on day 220 led to a significant rise in antibody titers in animals previously vaccinated with E1/E2 adjuvanted with SLA (Adm), Addavax or Lipo/QS-21/MPL with 2-fold (p < 0.01), 3-fold (p < 0.05) and 2-fold (p < 0.0001) increases in antibody geometric mean titers (GMT) seen between days 219 and 224, respectively
Summary
Hepatitis C virus (HCV) is a highly pathogenic virus infecting over 70 million people globally [1]. Archaeal lipid-based adjuvants have been previously shown to induce both antibody and cellular immune responses against multiple antigens, including ovalbumin and Hepatitis B surface antigen (HBsAg) in preclinical mouse models [10,11,12,13] They have not been tested clinically yet. Traditional archaeosomal formulations consisted of liposomes formed from total polar lipids (TPL) derived from archaea such as the methanogen Methanobrevibacter smithii (MS) These archaeosomes were shown to effectively activate professional antigen-presenting cells [14,15,16] and generate robust cellular and humoral immune response to encapsulated antigen in both cancer and infectious disease models [11,12,17]. MF59® mimetics, induce robust and long-lived immune responses detectable in mice up to 6 months following the last vaccination
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