Design of Broadly Cross-Reactive M Protein-Based Group A Streptococcal Vaccines.
Design of Broadly Cross-Reactive M Protein-Based Group A Streptococcal Vaccines.
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DOI：
10.4049/jimmunol.2100286
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发表时间：
2021-08-15
期刊：
影响因子：
--
通讯作者：
Smith JC
中科院分区：
文献类型：
--
作者：
Aranha MP;Penfound TA;Salehi S;Botteaux A;Smeesters P;Dale JB;Smith JC
A组链球菌感染是全球发病率和死亡率的重要原因。一个主要的疫苗候选者是表面M蛋白，一个主要的毒力决定因素和保护性抗原。开发基于M蛋白的疫苗的一个障碍是由含有保护性表位的N-末端序列定义的>200种不同的M类型。尽管序列变异性，M蛋白共享卷曲螺旋结构基序，结合宿主蛋白所需的毒力。在这里，我们利用这种潜在的“阿喀琉斯之踵”的保守结构来预测交叉反应的M肽，可以作为广泛的保护性疫苗抗原。将序列与结构预测相结合，预测序列相关簇中的六种异源M肽与簇中剩余的五种非疫苗M类型引发交叉反应性抗体。六价疫苗在兔中引发与簇中的所有11种M肽反应的抗体，以及针对簇中的疫苗和非疫苗M型的功能性调理素抗体。接下来，我们用四种序列无关的M肽免疫小鼠，预测其含有不同的卷曲螺旋倾向，并测试抗血清对41种异源M肽的交叉反应性。基于这些结果，我们开发了一种改进的算法，使用卷曲螺旋长度和倾向的附加参数来选择交叉反应性肽对。修订后的算法准确预测交叉反应性抗体结合，将马修斯相关系数从0.42提高到0.74。这些结果构成了选择最少数量的N-末端M肽以包括在可能广泛有效的多价疫苗中的基础，所述多价疫苗可能影响A组链球菌疾病的总体全球负担。
Group A streptococcal infections are a significant cause of global morbidity and mortality. A leading vaccine candidate is the surface M protein, a major virulence determinant and protective antigen. One obstacle to the development of M protein-based vaccines is the >200 different M types defined by the N-terminal sequences that contain protective epitopes. Despite sequence variability, M proteins share coiled-coil structural motifs that bind host proteins required for virulence. Here, we exploit this potential “Achilles heel” of conserved structure to predict cross-reactive M peptides that could serve as broadly protective vaccine antigens. Combining sequences with structural predictions, six heterologous M peptides in a sequence-related cluster were predicted to elicit cross-reactive antibodies with the remaining five non-vaccine M types in the cluster. The six-valent vaccine elicited antibodies in rabbits that reacted with all eleven M peptides in the cluster and functional opsonic antibodies against vaccine and non-vaccine M types in the cluster. We next immunized mice with four sequence-unrelated M peptides predicted to contain different coiled-coil propensities and tested the antisera for cross-reactivity against 41 heterologous M peptides. Based on these results, we developed an improved algorithm to select cross-reactive peptide pairs using additional parameters of coiled-coil length and propensity. The revised algorithm accurately predicted cross-reactive antibody binding, improving the Matthews correlation coefficient from 0.42 to 0.74. These results form the basis for selecting the minimum number of N-terminal M peptides to include in potentially broadly efficacious multivalent vaccines that could impact the overall global burden of group A streptococcal diseases.
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DOI：
10.1093/cid/cix599
发表时间：
2017-10-16
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Frost HR;Laho D;Sanderson-Smith ML;Licciardi P;Donath S;Curtis N;Kado J;Dale JB;Steer AC;Smeesters PR
通讯作者：
Smeesters PR
影响因子：
5.8
作者：
Delorenzi, M;Speed, T
通讯作者：
Speed, T
影响因子：
3
作者：
Abraham, Tintu;Sistla, Sujatha
通讯作者：
Sistla, Sujatha
影响因子：
1.5
作者：
Leow, Chiuan Yee;Willis, Charlene;Jones, Malcolm
通讯作者：
Jones, Malcolm
恶性疟原虫和疟原虫直系同源卷曲圈候选物，用于潜在的交叉保护疫苗。
影响因子：
7.3
作者：
Ayadi I;Balam S;Audran R;Bikorimana JP;Nebie I;Diakité M;Felger I;Tanner M;Spertini F;Corradin G;Arevalo M;Herrera S;Agnolon V
通讯作者：
Agnolon V