PDF(Pubmed)
Abstract：
The Duffy-binding protein (DBP) is a promising antigen for a malaria vaccine that would protect against clinical symptoms caused by Plasmodium vivax infection. Region II of DBP (DBP-II) contains the receptor-binding domain that engages host red blood cells, but DBP-II vaccines elicit many non-neutralizing antibodies that bind distal to the receptor-binding surface. Here, we engineered a truncated DBP-II immunogen that focuses the immune response to the receptor-binding surface. This immunogen contains the receptor-binding subdomain S1S2 and lacks the immunodominant subdomain S3. Structure-based computational design of S1S2 identified combinatorial amino acid changes that stabilized the isolated S1S2 without perturbing neutralizing epitopes. This immunogen elicited DBP-II-specific antibodies in immunized mice that were significantly enriched for blocking activity compared to the native DBP-II antigen. This generalizable design process successfully stabilized an integral core fragment of a protein and focused the immune response to desired epitopes to create a promising new antigen for malaria vaccine development.
摘要：
Duffy结合蛋白（DBP）是疟疾疫苗的一种有前途的抗原，可以预防由间日疟原虫感染引起的临床症状。DBP的II区（DBP-II）含有参与宿主红细胞的受体结合域，但DBP-II疫苗会引发许多与受体结合表面远端结合的非中和抗体.这里,我们设计了一种截短的DBP-II免疫原,该免疫原将免疫应答集中在受体结合表面.该免疫原含有受体结合亚结构域S1S2并且缺乏免疫显性亚结构域S3。S1S2的基于结构的计算设计鉴定了组合氨基酸变化,其稳定了分离的S1S2而不干扰中和表位。该免疫原在免疫小鼠中引发DBP-II特异性抗体,其与天然DBP-II抗原相比显著富集阻断活性。这种可推广的设计过程成功地稳定了蛋白质的完整核心片段，并将免疫应答集中在所需表位上，从而为疟疾疫苗的开发创造了有希望的新抗原。
