Plasmodium falciparum synthetic LbL microparticle vaccine elicits protective neutralizing antibody and parasite-specific cellular immune responses.
Plasmodium falciparum synthetic LbL microparticle vaccine elicits protective neutralizing antibody and parasite-specific cellular immune responses.
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DOI：
10.1016/j.vaccine.2013.02.027
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发表时间：
2013-04-08
期刊：
影响因子：
5.5
通讯作者：
Nardin E
中科院分区：
文献类型：
--
作者：
Powell TJ;Tang J;Derome ME;Mitchell RA;Jacobs A;Deng Y;Palath N;Cardenas E;Boyd JG;Nardin E
恶性疟原虫（Plasmodium falciparum）的环子孢子（circumsporozoite，CS）蛋白质的表位已被证明在实验动物和人类志愿者中引起保护性免疫。免疫机制包括寄生虫中和抗体，其可以抑制寄生虫在感染部位的皮肤中以及在转运至肝细胞宿主细胞期间在血流中的运动性，并且还阻断与肝细胞上的宿主细胞受体的相互作用。此外，特异性CD4+和CD8+细胞机制靶向细胞内肝形式，从而防止红细胞期寄生虫从受感染的肝细胞释放以及随后导致临床疾病的血液阶段循环。一种用于生产颗粒疫苗的创新方法，即在固体CaCO 3核上逐层（LbL）制造多肽膜，用于生产含有三表位CS肽T1 BT * 和两个T细胞表位（高度保守的T1表位和通用表位T*）的合成疟疾疫苗，所述三表位CS肽T1 BT * 包含CS重复区（B）的抗体表位。用载有T1BT* 肽的微粒免疫的小鼠产生寄生虫中和抗体和疟疾特异性T细胞应答，包括细胞毒性效应T细胞。用受感染蚊子的活子孢子攻击后对肝脏阶段感染的保护与中和抗体水平相关。尽管一些具有低或不可检测的中和抗体的免疫小鼠也受到保护，但在攻击前T细胞的消耗导致大多数小鼠对攻击保持抗性。此外，用仅携带T细胞表位的微粒免疫的小鼠不受保护，表明单独的细胞免疫不足以获得保护性免疫。尽管没有佐剂的微粒具有免疫原性和保护性，但用脂肽TLR2激动剂Pam3Cys进行简单修饰增加了LbL疫苗候选物的效力和功效。这项研究证明了LbL颗粒作为有希望的疟疾疫苗候选物的潜力，使用来自恶性疟原虫CS蛋白的T1BT* 表位。
Epitopes of the circumsporozoite (CS) protein of Plasmodium falciparum, the most pathogenic species of the malaria parasite, have been shown to elicit protective immunity in experimental animals and human volunteers. The mechanisms of immunity include parasite-neutralizing antibodies that can inhibit parasite motility in the skin at the site of infection and in the bloodstream during transit to the hepatocyte host cell and also block interaction with host cell receptors on hepatocytes. In addition, specific CD4+ and CD8+ cellular mechanisms target the intracellular hepatic forms, thus preventing release of erythrocytic stage parasites from the infected hepatocyte and the ensuing blood stage cycle responsible for clinical disease. An innovative method for producing particle vaccines, layer-by-layer (LbL) fabrication of polypeptide films on solid CaCO3 cores, was used to produce synthetic malaria vaccines containing a tri-epitope CS peptide T1BT* comprising the antibody epitope of the CS repeat region (B) and two T-cell epitopes, the highly conserved T1 epitope and the universal epitope T*. Mice immunized with microparticles loaded with T1BT* peptide developed parasite-neutralizing antibodies and malaria-specific T-cell responses including cytotoxic effector T-cells. Protection from liver stage infection following challenge with live sporozoites from infected mosquitoes correlated with neutralizing antibody levels. Although some immunized mice with low or undetectable neutralizing antibodies were also protected, depletion of T-cells prior to challenge resulted in the majority of mice remaining resistant to challenge. In addition, mice immunized with microparticles bearing only T-cell epitopes were not protected, demonstrating that cellular immunity alone was not sufficient for protective immunity. Although the microparticles without adjuvant were immunogenic and protective, a simple modification with the lipopeptide TLR2 agonist Pam3Cys increased the potency and efficacy of the LbL vaccine candidate. This study demonstrates the potential of LbL particles as promising malaria vaccine candidates using the T1BT* epitopes from the P. falciparum CS protein.
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DOI：
10.1073/pnas.1112648109
发表时间：
2012-01-24
影响因子：
11.1
作者：
Moon, James J.;Suh, Heikyung;Irvine, Darrell J.
通讯作者：
Irvine, Darrell J.
影响因子：
3.7
作者：
Makidon, Paul E.;Bielinska, Anna U.;Baker, James R., Jr.
通讯作者：
Baker, James R., Jr.
DOI：
10.1016/j.jconrel.2005.02.027
发表时间：
2005-07-20
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Kwon YJ;Standley SM;Goh SL;Fréchet JM
通讯作者：
Fréchet JM
影响因子：
5.5
作者：
Demento SL;Eisenbarth SC;Foellmer HG;Platt C;Caplan MJ;Mark Saltzman W;Mellman I;Ledizet M;Fikrig E;Flavell RA;Fahmy TM
通讯作者：
Fahmy TM
影响因子：
158.5
作者：
Mian-McCarthy, Sara;Agnandji, Selidji Todagbe;Vansadia, Preeti
通讯作者：
Vansadia, Preeti