In vitro studies with recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1):: Production and activity of an AMA1 vaccine and generation of a multiallelic response
In vitro studies with recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1):: Production and activity of an AMA1 vaccine and generation of a multiallelic response
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DOI：
10.1128/iai.70.12.6948-6960.2002
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发表时间：
2002-12-01
影响因子：
3.1
通讯作者：
Stowers, AW
中科院分区：
文献类型：
--
作者：
Kennedy, MC;Wang, J;Stowers, AW
顶膜抗原1（AMA1）被认为是一种领先的疟疾血液阶段疫苗候选者。虽然AMA1的整体结构在疟原虫属中是保守的，已经描述了恶性疟原虫的许多AMA1等位基因变体。AMA1等位基因多样性对重组AMA1疫苗保护人类免受不同恶性疟原虫株感染的能力的影响尚不清楚。我们表征了两种等位基因形式的AMA1，这两种等位基因形式都是在巴斯德毕赤酵母中以足够的规模经济生产的，可用于临床疫苗研究。这两种蛋白单独和组合用于免疫兔，以评估其免疫原性和引发的抗体阻断不同恶性疟原虫克隆生长的能力。这两种抗原，单独使用时，引起高同源抗AMA1滴度，减少应变交叉反应性。同样，用单一抗原免疫的兔血清能够阻断同源寄生虫株的生长，理论上足以清除寄生虫感染。然而，异源抑制显著减少，提供了实验证据，AMA1等位基因多样性是免疫压力的结果。令人鼓舞的是，用这两种抗原的组合免疫的兔表现出与单抗原免疫的兔对每个同源寄生虫系一样好的寄生虫抑制的滴度和水平，因此表现出等位基因多样性覆盖范围的扩大。
Apical membrane antigen 1 (AMA1) is regarded as a leading malaria blood-stage vaccine candidate. While the overall structure of AMA1 is conserved in Plasmodium spp., numerous AMA1 allelic variants of P. falciparum have been described. The effect of AMA1 allelic diversity on the ability of a recombinant AMA1 vaccine to protect against human infection by different P. falciparum strains is unknown. We characterize two allelic forms of AMA1 that were both produced in Pichia pastoris at a sufficient economy of scale to be usable for clinical vaccine studies. Both proteins were used to immunize rabbits, singly and in combination, in order to evaluate their immunogenicity and the ability of elicited antibodies to block the growth of different P. falciparum clones. Both antigens, when used alone, elicited high homologous anti-AMA1 titers, with reduced strain cross-reactivity. Similarly, sera from rabbits immunized with a single antigen were capable of blocking the growth of homologous parasite strains at levels theoretically sufficient to clear parasite infections. However, heterologous inhibition was significantly reduced, providing experimental evidence that AMA1 allelic diversity is a result of immune pressure. Encouragingly, rabbits immunized with a combination of both antigens exhibited titers and levels of parasite inhibition as good as those of the single-antigen-immunized rabbits for each of the homologous parasite lines, and consequently exhibited a broadening of allelic diversity coverage.