P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections.
P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections.
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DOI：
10.1371/journal.pone.0124856
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Milich DR
中科院分区：
文献类型：
--
作者：
Whitacre DC;Espinosa DA;Peters CJ;Jones JE;Tucker AE;Peterson DL;Zavala FP;Milich DR
为了设计恶性疟原虫红细胞前疫苗候选物，产生在土拨鼠肝炎病毒核心抗原（WHcAg）VLP平台上展示的环子孢子（CS）T和B细胞表位的文库。为了测试WHcAg-CS VLP的保护效力，使用杂交CS伯氏疟原虫/恶性疟原虫（Pb/Pf）子孢子攻击免疫小鼠。携带1个或2个不同CS重复B细胞表位的VLP和携带不同CS非重复B细胞表位的3个VLP引起高水平的抗插入抗体（Ab）。然而，携带CS重复B细胞表位的VLP赋予肝脏针对10，000 Pb/Pf子孢子攻击的98%保护，携带CS非重复B细胞表位的VLP是最低限度至非保护性的。一至三个CS特异性CD 4/CD 8 T细胞位点也与VLP融合，其引发CS特异性以及WHcAg特异性T细胞。然而，仅携带3个T细胞结构域的VLP未能保护免受子孢子攻击，表明需要抗CS重复抗体。在明矾佐剂中携带2个CS重复B细胞表位和3个CS T细胞位点的VLP引发高滴度抗CS Ab（终点稀释滴度> 1x 106），并提供80-100%针对血液期疟疾的保护。使用类似的策略，构建携带间日疟原虫CS重复B细胞表位（WHc-Pv-78）的VLP，其引发高水平的抗CS Ab，并赋予肝脏99%的保护以抵抗10，000 Pb/Pv子孢子攻击，并引发对血液阶段感染的无菌免疫。这些结果表明，用携带来自恶性疟原虫和间日疟原虫CS蛋白的选择的B和T细胞表位的表位聚焦VLP免疫可引发针对血液期疟疾的无菌免疫。杂交WHcAg-CS VLP可为恶性疟原虫/间日疟原虫疟疾双价疫苗提供基础。
In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf) sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs). Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg-specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer >1x106) and provided 80–100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc-Pv-78), which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P. falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine.
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影响因子：
5.5
作者：
Billaud, Jean-Noel;Peterson, Darrell;Milich, David
通讯作者：
Milich, David
DOI：
10.1073/pnas.85.4.1199
发表时间：
1988-02-01
影响因子：
11.1
作者：
GOOD, MF;POMBO, D;MILLER, LH
通讯作者：
MILLER, LH
影响因子：
6.4
作者：
GORDON, DM;MCGOVERN, TW;BALLOU, WR
通讯作者：
BALLOU, WR
DOI：
10.4049/jimmunol.0803683
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lee BO;Tucker A;Frelin L;Sallberg M;Jones J;Peters C;Hughes J;Whitacre D;Darsow B;Peterson DL;Milich DR
通讯作者：
Milich DR
影响因子：
168.9
作者：
Aponte, John J.;Aide, Pedro;Alonso, Pedro L.
通讯作者：
Alonso, Pedro L.