Increased immunogenicity of HIV envelope subunit complexed with alpha2-macroglobulin when combined with monophosphoryl lipid A and GM-CSF.
Increased immunogenicity of HIV envelope subunit complexed with alpha2-macroglobulin when combined with monophosphoryl lipid A and GM-CSF.
复制标题
当与单磷酰脂质 A 和 GM-CSF 结合时，与 α2-巨球蛋白复合的 HIV 包膜亚基的免疫原性增加。
DOI：
10.1016/s0264-410x(02)00090-7
复制
发表时间：
2002
期刊：
影响因子：
5.5
通讯作者：
Haynes,BartonF
中科院分区：
文献类型：
--
作者：
Liao,HuaXin;Cianciolo,GeorgeJ;Staats,HermanF;Scearce,RichardM;Lapple,DanaM;Stauffer,StephenH;Thomasch,JamesR;Pizzo,SalvatoreV;Montefiori,DavidC;Hagen,Michael;Eldridge,John;Haynes,BartonF
HIV-1亚单位疫苗成功的关键是提高疫苗免疫原性的策略的发展。成功的佐剂必须不仅提高免疫原性高于目前的佐剂水平，而且还必须降低最佳免疫原性所需的免疫原剂量。我们评价了活化的α2-巨球蛋白（α 2 M β）和含有单磷酰脂质A（MPL-SE）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的角鲨烯稳定乳剂作为增强候选HIV免疫原的免疫原性的佐剂。在第0、14和28天，用100-0.1μg来自HIV IIIB（C4-V3 IIIB）或SHIV 89.6P（C4-V389.6P）的HIV-1包膜gp 120 C4-V3免疫原皮下免疫Balb/c小鼠。检测了与α 2 M β共价偶联、与MPL-SE/GM-CSF配制或两者组合的免疫原。使用CFA/IFA，仅50和100μg，而不是更低剂量的C4-V3 IIIB肽诱导抗体应答。相反，在用10μg偶联至α 2 M β的C4-V3肽（α 2 M β-肽）免疫的小鼠中检测到峰值抗体应答。与CFA/IFA类似，MPL-SE/GM-CSF在50和100μg C4-V3免疫原下诱导最佳抗体应答。然而，MPL-SE/GM-CSF与α 2 M β-C4-V3肽的组合将最佳应答所需的C4-V3剂量降低至C4-V3 IIIB为5μg，C4-V389.6P为0.1μg。总之，HIV包膜gp 120 C4-V3肽与α 2 M β共价复合，并与MPL-SE/GM-CSF一起配制，产生了一种亚单位HIV免疫原，其能够诱导抗HIV包膜抗体应答，其剂量比单独使用CFA/IFA或MPL-SE/GM-CSF所需的剂量低100倍。
Critical to the success of HIV-1 subunit vaccines is the development of strategies to augment vaccine immunogenicity. Successful adjuvants must not only improve immunogenicity above current adjuvant levels, but must also decrease the dose of immunogen required for optimal immunogenicity. We have evaluated activated α2-macroglobulin (α2M∗) and a squalene-based stable emulsion containing monophosphoryl lipid A (MPL-SE) with granulocyte-macrophage colony stimulating factor (GM-CSF) as adjuvants to enhance the immunogencity of candidate HIV immunogens. Balb/c mice were subcutaneously immunized on days 0, 14 and 28 with 100–0.1μg of HIV-1 envelope gp120 C4–V3 immunogens from either HIV IIIB (C4–V3IIIB) or SHIV 89.6P (C4–V389.6P). Immunogens were tested covalently coupled to α2M∗, formulated with MPL-SE/GM-CSF, or as a combination of both. Using CFA/IFA, only 50 and 100μg, but not lower doses of C4–V3IIIBpeptides, induced antibody responses. In contrast, peak antibody responses were detected in mice immunized with 10μg of C4–V3 peptide coupled to α2M∗(α2M∗-peptide). Similar to CFA/IFA, MPL-SE/GM-CSF induced optimal antibody responses at 50 and 100μg of C4–V3 immunogen. However, the combination of MPL-SE/GM-CSF with α2M∗-C4–V3 peptide decreased the dose of C4–V3 required for optimal response to 5μg for C4–V3IIIB, and to 0.1μg for C4–V389.6P. Taken together, HIV envelope gp120 C4–V3 peptides covalently complexed with α2M∗and formulated with MPL-SE/GM-CSF resulted in a subunit HIV immunogen capable of inducing anti-HIV envelope antibody responses at doses up to100-fold less than those needed with CFA/IFA or MPL-SE/GM-CSF alone.