多等位基因 PfAMA1 疫苗诱导体液免疫应答;佐剂和成分等位基因数量对反应广度的影响。

Generation of humoral immune responses to multi-allele PfAMA1 vaccines; effect of adjuvant and number of component alleles on the breadth of response.

机构信息

Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

出版信息

PLoS One. 2010 Nov 3;5(11):e15391. doi: 10.1371/journal.pone.0015391.

Abstract

There is increasing interest in multi-allele vaccines to overcome strain-specificity against polymorphic vaccine targets such as Apical Membrane Antigen 1 (AMA1). These have been shown to induce broad inhibitory antibodies in vitro and formed the basis for the design of three Diversity-Covering (DiCo) proteins with similar immunological effects. The antibodies produced are to epitopes that are shared between vaccine alleles and theoretically, increasing the number of component AMA1 alleles is expected to broaden the antibody response. A plateau effect could however impose a limit on the number of alleles needed to achieve the broadest specificity. Moreover, production cost and the vaccine formulation process would limit the number of component alleles. In this paper, we compare rabbit antibody responses elicited with multi-allele vaccines incorporating seven (three DiCos and four natural AMA1 alleles) and three (DiCo mix) antigens for gains in broadened specificity. We also investigate the effect of three adjuvant platforms on antigen specificity and antibody functionality. Our data confirms a broadened response after immunisation with DiCo mix in all three adjuvants. Higher antibody titres were elicited with either CoVaccine HT™ or Montanide ISA 51, resulting in similar in vitro inhibition (65-82%) of five out of six culture-adapted P. falciparum strains. The antigen binding specificities of elicited antibodies were also similar and independent of the adjuvant used or the number of vaccine component alleles. Thus neither the four extra antigens nor adjuvant had any observable benefits with respect to specificity broadening, although adjuvant choice influenced the absolute antibody levels and thus the extent of parasite inhibition. Our data confirms the feasibility and potential of multi-allele PfAMA1 formulations, and highlights the need for adjuvants with improved antibody potentiation properties for AMA1-based vaccines.

摘要

人们越来越关注多等位基因疫苗,以克服针对多态性疫苗靶标(如顶端膜抗原 1(AMA1))的菌株特异性。这些疫苗已被证明在体外诱导广泛的抑制性抗体,并为设计具有类似免疫效果的三种多样性覆盖(DiCo)蛋白奠定了基础。所产生的抗体针对的是疫苗等位基因之间共享的表位,理论上,增加 AMA1 等位基因的数量有望扩大抗体反应。然而,平台效应可能会限制达到最广泛特异性所需的等位基因数量。此外,生产成本和疫苗配方过程将限制成分等位基因的数量。在本文中,我们比较了用包含七个(三个 DiCo 和四个天然 AMA1 等位基因)和三个(DiCo 混合物)抗原的多等位基因疫苗引发的兔抗体反应,以获得更广泛的特异性增益。我们还研究了三种佐剂平台对抗原特异性和抗体功能的影响。我们的数据证实,在用 DiCo 混合物免疫的所有三种佐剂中,反应都得到了拓宽。CoVaccine HT™或 Montanide ISA 51 产生了更高的抗体滴度,导致对五种适应培养的疟原虫株中的五种产生了类似的体外抑制(65-82%)。所引发抗体的抗原结合特异性也相似,与佐剂的使用或疫苗成分等位基因的数量无关。因此,与特异性拓宽相比,无论是四种额外的抗原还是佐剂都没有任何明显的益处,尽管佐剂的选择会影响绝对抗体水平,从而影响寄生虫抑制的程度。我们的数据证实了 PfAMA1 多等位基因配方的可行性和潜力,并强调了需要具有改进的抗体增强特性的佐剂来开发基于 AMA1 的疫苗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0d2a/2972715/d052aa58a91c/pone.0015391.g001.jpg

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