Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells and promote germinal center induction
Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells and promote germinal center induction
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DOI：
10.1073/pnas.1112648109
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发表时间：
2012-01-24
影响因子：
11.1
通讯作者：
Irvine, Darrell J.
中科院分区：
文献类型：
--
作者：
Moon, James J.;Suh, Heikyung;Irvine, Darrell J.
对亚单位疫苗来说，佐剂在形成免疫记忆方面起着关键作用。抗原和/或分子危险信号的纳米颗粒(NP)递送系统是一种很有前途的佐剂，能够促进细胞和体液免疫反应，但在大多数情况下，这些材料的作用机制尚不清楚。在这里，我们研究了由携带重组间日疟原虫环子孢子抗原VMP001的多层“装订”脂泡组成的NPs所引发的免疫反应，这些NPs既被包裹在水核中，又被锚定在脂质双层表面。用这些颗粒和美国食品和药物管理局批准的Toll样受体-4免疫刺激激动剂单磷脂A(MPLA)免疫，可以促进针对VMP001的高滴度、高亲和力抗体应答，在小鼠中持续一年以上，剂量比传统佐剂低10倍。与可溶性VMP001与MPLA混合，VMP001-NPs促进更广泛的体液反应，靶向蛋白质的多个表位和来自抗原特异性T细胞的更平衡的Th1/Th2细胞因子谱。为了开始了解潜在的机制，我们检查了B细胞反应的组成部分，发现在低剂量的抗原下，NPs促进了强大的生发中心(GC)的形成，而可溶性蛋白免疫没有发生生发中心(GC)的诱导，并且随着时间的推移，GCs在NPs的储存库附近成核，NPs积累在引流淋巴结中。同时，与可溶性VMP001或明矾疫苗相比，NP疫苗促进了抗原特异性滤泡辅助T细胞(T-fh)的增殖。因此，NP疫苗可能是一种有希望的策略，通过增强B细胞反应的关键成分来增强体液免疫的持久性、广度和效力。
For subunit vaccines, adjuvants play a key role in shaping immunological memory. Nanoparticle (NP) delivery systems for antigens and/or molecular danger signals are promising adjuvants capable of promoting both cellular and humoral immune responses, but in most cases the mechanisms of action of these materials are poorly understood. Here, we studied the immune response elicited by NPs composed of multilamellar "stapled" lipid vesicles carrying a recombinant Plasmodium vivax circumsporozoite antigen, VMP001, both entrapped in the aqueous core and anchored to the lipid bilayer surfaces. Immunization with these particles and monophosphoryl lipid A (MPLA), a US Food and Drug Administration-approved immunostimulatory agonist for Toll-like receptor-4, promoted high-titer, high-avidity antibody responses against VMP001, lasting more than 1 y in mice at 10-fold lower doses than conventional adjuvants. Compared to soluble VMP001 mixed with MPLA, VMP001-NPs promoted broader humoral responses, targeting multiple epitopes of the protein and a more balanced Th1/Th2 cytokine profile from antigen-specific T cells. To begin to understand the underlying mechanisms, we examined components of the B-cell response and found that NPs promoted robust germinal center (GC) formation at low doses of antigen where no GC induction occurred with soluble protein immunization, and that GCs nucleated near depots of NPs accumulating in the draining lymph nodes over time. In parallel, NP vaccination enhanced the expansion of antigen-specific follicular helper T cells (T-fh), compared to vaccinations with soluble VMP001 or alum. Thus, NP vaccines may be a promising strategy to enhance the durability, breadth, and potency of humoral immunity by enhancing key elements of the B-cell response.