Beck Zoltan, Matyas Gary R, Jalah Rashmi, Rao Mangala, Polonis Victoria R, Alving Carl R
U.S. Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Drive, Bethesda, MD 20817, USA; Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
Vaccine. 2015 Oct 13;33(42):5578-5587. doi: 10.1016/j.vaccine.2015.09.001. Epub 2015 Sep 13.
Liposomes have shown promise as constituents of adjuvant formulations in vaccines to parasitic and viral diseases. A particular type of liposomal construct, referred to as Army Liposome Formulation (ALF), containing neutral and anionic saturated phospholipids, cholesterol, and monophosphoryl lipid A (MPLA), has been used as an adjuvant for many years. Here we investigated the effects of physical and chemical changes of ALF liposomes on adjuvanted immune responses to CN54 gp140, a recombinant HIV-1 envelope protein. While holding the total amounts of liposomal MPLA and the gp140 antigen constant, different liposome sizes and liposomal MPLA:phospholipid molar ratios, and the effect of adding QS21 to the liposomes were compared for inducing immune responses to the gp140. For liposomes lacking QS21, higher titers of IgG binding antibodies to gp140 were induced by small unilamellar vesicle (SUV) rather than by large multilamellar vesicle (MLV) liposomes, and the highest titers were obtained with SUV having the MPLA:phospholipid ratio of 1:5.6. ALF plus QS21 (ALFQ) liposomes induced the same maximal binding antibody titers regardless of the MPLA:phospholipid ratio. ALF MLV liposomes induced mainly IgG1 and very low IgG2a antibodies, while ALF SUV liposomes induced IgG1≥IgG2a>IgG2b antibodies. Liposomes containing QS21 induced IgG1>IgG2a>IgG2b>IgG3 antibodies. ELISPOT analysis of splenocytes from immunized mice revealed that ALF liposomes induced low levels of IFN-γ, but ALFQ induced high levels. ALF and ALFQ liposomes each induced approximately equivalent high levels of IL-4. Based on antibody subtypes and cytokine secretion, we conclude that ALF liposomes predominantly stimulate Th2, while ALFQ strongly induces both Th1 and Th2 immunity. When CN54 gp140 was adjuvanted with either ALF or ALFQ liposomes, antibodies were induced that neutralized two HIV-1 tier 1 clade C strain pseudoviruses.
脂质体已显示出有望作为寄生虫病和病毒病疫苗佐剂配方的成分。一种特殊类型的脂质体构建体，称为陆军脂质体配方（ALF），含有中性和阴离子饱和磷脂、胆固醇和单磷酰脂质A（MPLA），多年来一直用作佐剂。在此，我们研究了ALF脂质体的物理和化学变化对佐剂化免疫反应针对重组HIV-1包膜蛋白CN54 gp140的影响。在脂质体MPLA和gp140抗原总量保持恒定的情况下，比较了不同的脂质体大小、脂质体MPLA与磷脂的摩尔比以及向脂质体中添加QS21的效果，以诱导针对gp140的免疫反应。对于不含QS21的脂质体，小单层囊泡（SUV）诱导的针对gp140的IgG结合抗体滴度高于大多层囊泡（MLV）脂质体，并且在MPLA与磷脂比例为1:5.6的SUV中获得了最高滴度。无论MPLA与磷脂的比例如何，ALF加QS21（ALFQ）脂质体诱导的最大结合抗体滴度相同。ALF MLV脂质体主要诱导IgG1和极低水平的IgG2a抗体，而ALF SUV脂质体诱导IgG1≥IgG2a>IgG2b抗体。含有QS21的脂质体诱导IgG1>IgG2a>IgG2b>IgG3抗体。对免疫小鼠脾细胞的ELISPOT分析显示，ALF脂质体诱导的IFN-γ水平较低，但ALFQ诱导的水平较高。ALF和ALFQ脂质体各自诱导的IL-4水平大致相当且较高。基于抗体亚型和细胞因子分泌，我们得出结论，ALF脂质体主要刺激Th2，而ALFQ强烈诱导Th1和Th2免疫。当CN54 gp140用ALF或ALFQ脂质体佐剂化时，诱导产生的抗体可中和两种HIV-1一级C亚型分支毒株假病毒。
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