Preclinical development of a dengue tetravalent recombinant subunit vaccine: Immunogenicity and protective efficacy in nonhuman primates
Preclinical development of a dengue tetravalent recombinant subunit vaccine: Immunogenicity and protective efficacy in nonhuman primates
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DOI：
10.1016/j.vaccine.2015.06.067
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发表时间：
2015-08-07
期刊：
影响因子：
5.5
通讯作者：
Bett, Andrew J.
中科院分区：
文献类型：
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作者：
Govindarajan, Dhanasekaran;Meschino, Steven;Bett, Andrew J.
我们在这里描述了一种登革热疫苗的临床前开发，该疫苗由四种登革热血清型中每一种的重组亚单位羧基截短包膜（E）蛋白（DEN-80 E）组成。在恒河猴中进行免疫原性和保护效力研究以评价用ISCOMATRIX（TM）佐剂配制的单价和四价DEN-80 E疫苗。在这些研究中评价了三种不同剂量和两种给药方案（0、1、2个月和0、1、2和6个月）。我们首先评估了DEN 4 - 80 E的单体（DEN 4 - 80 E）和二聚体（DEN 4 - 80 EZip）形式，后者是为了改善免疫原性而产生的。以6、20和100 μ g/剂量与ISCOMATRIX（TM）佐剂配制的两种抗原进行评价，它们具有相同的免疫原性。用20 μ g DEN 4 - 80 E和Alhydrogel（TM）免疫的组诱导弱得多的应答。当用野生型登革4型病毒攻击时，6和20 μ g组中的所有动物以及DEN 4 - 80 EZip 100 μ g组中除一只外的所有动物都被保护免于病毒血症。在Alhydrogel（TM）组中，三只猴子中有两只出现了突破性病毒血症。进行类似的研究以评价低剂量（分别为3、3、3、6 μ g DEN 1 - 80 E、DEN 2 - 80 E、DEN 3 - 80 E和DEN 4 - 80 E）、中剂量（10、10、10、20 μ g）和高剂量（50、50、50、100 μ g）的四价制剂。所有剂量均具有低免疫原性，并诱导针对所有四种DENV的高滴度、平衡的中和抗体。在用四种野生型DENV攻击后，低剂量组和中剂量组中的所有动物都受到保护而免于病毒血症，而高剂量组中的两只动物表现出突破性病毒血症。我们的研究还表明，在持久性方面，0、1、2和6个月的疫苗接种方案上级优于0、1和2个月方案。总体而言，证明亚单位疫苗诱导强中和滴度，导致即使在最后一次疫苗给药后8-12个月攻毒后也能预防病毒血症。(C)2015爱思唯尔有限公司版权所有。
We describe here the preclinical development of a dengue vaccine composed of recombinant subunit carboxy-truncated envelope (E) proteins (DEN-80E) for each of the four dengue serotypes. Immunogenicity and protective efficacy studies in Rhesus monkeys were conducted to evaluate monovalent and tetravalent DEN-80E vaccines formulated with ISCOMATRIX (TM) adjuvant. Three different doses and two dosing regimens (0, 1, 2 months and 0, 1, 2, and 6 months) were evaluated in these studies. We first evaluated monomeric (DEN4-80E) and dimeric (DEN4-80EZip) versions of DEN4-80E, the latter generated in an attempt to improve immunogenicity. The two antigens, evaluated at 6,20 and 100 mu g/dose formulated with ISCOMATRIX (TM) adjuvant, were equally immunogenic. A group immunized with 20 mu g DEN4-80E and Alhydrogel (TM) induced much weaker responses. When challenged with wild-type dengue type 4 virus, all animals in the 6 and 20 mu g groups and all but one in the DEN4-80EZip 100 mu g group were protected from viremia. Two out of three monkeys in the Alhydrogel (TM) group had breakthrough viremia. A similar study was conducted to evaluate tetravalent formulations at low (3, 3, 3, 6 mu g of DEN1-80E, DEN2-80E, DEN3-80E and DEN4-80E respectively), medium (10, 10, 10, 20 mu g) and high (50, 50, 50, 100 mu g) doses. All doses were comparably immunogenic and induced high titer, balanced neutralizing antibodies against all four DENV. Upon challenge with the four wild-type DENV, all animals in the low and medium dose groups were protected against viremia while two animals in the high-dose group exhibited breakthrough viremia. Our studies also indicated that a 0, 1, 2 and 6 month vaccination schedule is superior to the 0, 1, and 2 month schedule in terms of durability. Overall, the subunit vaccine was demonstrated to induce strong neutralization titers resulting in protection against viremia following challenge even 8-12 months after the last vaccine dose. (C) 2015 Elsevier Ltd. All rights reserved.