Diversity Covering AMA1-MSP119 Fusion Proteins as Malaria Vaccines
Diversity Covering AMA1-MSP119 Fusion Proteins as Malaria Vaccines
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DOI：
10.1128/iai.01267-12
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发表时间：
2013-05-01
影响因子：
3.1
通讯作者：
Kocken, Clemens H. M.
中科院分区：
文献类型：
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作者：
Faber, Bart W.;Younis, Sumera;Kocken, Clemens H. M.
为了克服疟疾疫苗候选恶性疟原虫顶膜抗原1(PfAMA1)基因的多态性，构建了由3个多样性覆盖(DICO)PfAMA1分子(D1、D2和D3)和裂殖子表面蛋白1(MSP1(19))C末端19 kDa区(MSP1(19))(变异体M1和M2)组成的融合蛋白嵌合体。在一组兔的免疫学研究中，将融合蛋白(D1M1/D2M2D3)和D1M1D2M2D3融合蛋白与单单位混合物(D1/D2/D3/M1)进行了比较。免疫后，针对4个自然产生的PfAMA1等位基因的抗体效价(Abs)和针对两个抗原性不同的实验室寄生虫株的生长抑制试验(GIA)水平都很高。AMA1与MSP1(19)的融合不能抑制针对AMA1组分的抗体水平。此外，抗体反应的广度没有受到影响。抗AMA1抗体是寄生虫生长抑制的主要原因，通过加入竞争的AMA1抗原进行的逆转抑制实验表明。对于所有的组，将MSP1(19)抗原滴定到GIA中只导致寄生虫抑制的轻微下降，尽管融合蛋白免疫组的MSP1(19)抗体滴度增加了15倍。与亲和纯化的抗MSP1(19)抗体的GIA显示，对于所有受试动物，抗MSP1(19)抗体制剂的50%抑制浓度是相同的数量级，从而得出结论，将MSP1(19)与PfAMA1融合导致功能抗体水平小幅但显著增加。这项研究表明，多个候选疫苗在融合蛋白中的结合可能会导致疫苗特性的改善。
To overcome polymorphism in the malaria vaccine candidate Plasmodium falciparum apical membrane antigen 1 (PfAMA1), fusion protein chimeras comprised of three diversity-covering (DiCo) PfAMA1 molecules (D1, D2, and D3) and two allelic variants of the C-terminal 19-kDa region of merozoite surface protein 1 (MSP1(19)) (variants M1 and M2) were generated. A mixture of fusion proteins (D1M1/D2M2D3) and the D1M1D2M2D3 fusion were compared to a single-unit mixture (D1/D2/D3/M1) in an immunological study in groups of rabbits. Following immunization, titers of antibodies (Abs) against four naturally occurring PfAMA1 alleles were high for all groups, as were growth inhibition assay (GIA) levels against two antigenically distinct laboratory parasite strains. Fusion of AMA1 to MSP1(19) did not suppress levels of antibodies against the AMA1 component. In addition, the breadth of antibody responses was unaffected. Anti-AMA1 antibodies were largely responsible for parasite growth inhibition, as shown in reversal-of-inhibition experiments by adding competing AMA1 antigen. For all groups, titration of the MSP1(19) antigen into the GIA led to only a small decrease in parasite inhibition, although titers of antibodies against MSP1(19) were increased 15-fold for the groups immunized with fusion proteins. GIA with affinity-purified anti-MSP1(19) antibodies showed that the 50% inhibitory concentrations of the anti-MSP1(19) antibody preparations were in the same order of magnitude for all animals tested, leading to the conclusion that fusing MSP1(19) to PfAMA1 leads to a small but significant increase in functional antibody levels. This study shows that combination of multiple vaccine candidates in fusion proteins may lead to improved characteristics of the vaccine.