Preclinical efficacy of a cell division protein candidate gonococcal vaccine identified by artificial intelligence.
Preclinical efficacy of a cell division protein candidate gonococcal vaccine identified by artificial intelligence.
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迫切需要一种安全有效的疫苗来对抗多重耐药（MDR）淋病奈瑟菌的全球威胁。我们筛选了由人工智能驱动的平台发现的26种淋球菌蛋白质，该平台名为有效性判别教育网络（EDEN），该网络经过训练，可识别针对病原菌的新型保护性疫苗抗原，以在淋病的小鼠阴道定殖模型中获得有效性。用GLA-SE佐剂化的两种至三种抗原的组合（诱导TH 1应答）产生了11组用于接种小鼠。11组抗血清的补体依赖性杀菌活性与淋球菌定植负荷呈负相关。NGO 1549（FtsN;细胞分裂体蛋白）和NGO 0265（预测的细胞分裂蛋白）的组合最显著地降低了MDR菌株WHO X的定殖负担。每组抗原的EDEN预测评分与总体细菌负荷的减少呈正相关，为其预测潜力提供了证据。单独、联合或作为嵌合蛋白给予FtsN和NGO 0265显著减弱了所有三种测试菌株的淋球菌阴道定殖。来自用嵌合NGO 0265-FtsN蛋白免疫的小鼠的抗血清中的IgG支持对所有50种（100%）测试的淋球菌分离株的补体依赖性杀伤。嵌合NGO 0265-FtsN疫苗的效力需要补体的膜攻击复合物（C5 b-9），这通过在补体C9−/−小鼠中丧失效力来证明。总之，包含用具有广泛抗淋球菌杀菌活性的GLA-SE eliminant IgG佐剂化的NGO 0265和FtsN的嵌合分子以补体依赖性方式减弱淋球菌定殖，并且代表有希望的淋球菌疫苗候选物。迫切需要疫苗来遏制耐多药淋病的全球传播。在此，通过人工智能驱动的平台（功效判别教育网络[EDEN]）鉴定的26种候选疫苗在小鼠阴道定殖模型中筛选功效。补体依赖性杀菌活性的抗血清和EDEN保护分数都与整体细菌定植负担的减少呈正相关。NGO 1549（FtsN）和NGO 0265都参与细胞分裂，显示出最好的活性，并被选择用于进一步开发。两种抗原，当融合创建一个嵌合蛋白，引起杀菌抗体对广泛的淋球菌分离株和显着减弱的持续时间和负荷淋球菌定植小鼠阴道。在缺乏补体C9（膜攻击复合孔形成的最后一步）的小鼠中，保护被废除，表明补体依赖性杀菌活性是疫苗保护的机制相关性。FtsN和NGO 0265代表了有希望的淋病候选疫苗。
A safe and effective vaccine is urgently needed to combat the global threat of multidrug-resistant (MDR) Neisseria gonorrhoeae. We screened 26 gonococcal proteins discovered by an artificial intelligence-driven platform called Efficacy Discriminative Educated Network (EDEN) trained to identify novel, protective vaccine antigens against pathogenic bacteria for efficacy in the mouse vaginal colonization model of gonorrhea. Combinations of two to three antigens adjuvanted with GLA-SE (induces TH1 responses) yielded 11 groups that were used to vaccinate mice. An inverse correlation was noted between the complement-dependent bactericidal activity of antisera from each of the 11 groups and the burden of gonococcal colonization. The combination of NGO1549 (FtsN; cell divisome protein) and NGO0265 (predicted cell division protein) most substantially reduced the burden of colonization by MDR strain WHO X. The EDEN prediction score for each group of antigens correlated positively with reductions in overall bacterial burden, providing evidence for its predictive potential. FtsN and NGO0265 administered either individually, in combination, or as a chimeric protein significantly attenuated gonococcal vaginal colonization by all three test strains. IgG in antisera from mice immunized with the chimeric NGO0265-FtsN protein supported the complement-dependent killing of all 50 (100%) gonococcal isolates tested. The efficacy of the chimeric NGO0265-FtsN vaccine required the membrane attack complex (C5b-9) of complement, evidenced by loss of efficacy in complement C9−/− mice. In conclusion, a chimeric molecule comprising NGO0265 and FtsN adjuvanted with GLA-SE elicits IgG with broad anti-gonococcal bactericidal activity, attenuates gonococcal colonization in a complement-dependent manner, and represents a promising gonococcal vaccine candidate. Vaccines to curb the global spread of multidrug-resistant gonorrhea are urgently needed. Here, 26 vaccine candidates identified by an artificial intelligence-driven platform (Efficacy Discriminative Educated Network[EDEN]) were screened for efficacy in the mouse vaginal colonization model. Complement-dependent bactericidal activity of antisera and the EDEN protective scores both correlated positively with the reduction in overall bacterial colonization burden. NGO1549 (FtsN) and NGO0265, both involved in cell division, displayed the best activity and were selected for further development. Both antigens, when fused to create a chimeric protein, elicited bactericidal antibodies against a wide array of gonococcal isolates and significantly attenuated the duration and burden of gonococcal colonization of mouse vaginas. Protection was abrogated in mice that lacked complement C9, the last step in the formation of the membrane attack complex pore, suggesting complement-dependent bactericidal activity as a mechanistic correlate of protection of the vaccine. FtsN and NGO0265 represent promising vaccine candidates against gonorrhea.
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DOI：
10.1038/nrmicro2713
发表时间：
2012-01-31
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
56.3
作者：
Abara, Winston E.;Bernstein, Kyle T.;Lewis, Felicia M. T.;Schillinger, Julia A.;Feemster, Kristen;Pathela, Preeti;Hariri, Susan;Islam, Aras;Eberhart, Michael;Cheng, Iris;Ternier, Alexandra;Slutsker, Jennifer Sanderson;Mbaeyi, Sarah;Madera, Robbie;Kirkcaldy, Robert D.
通讯作者：
Kirkcaldy, Robert D.
影响因子：
16.6
作者：
Muir A;Gurung I;Cehovin A;Bazin A;Vallenet D;Pelicic V
通讯作者：
Pelicic V
影响因子：
6.4
作者：
Gulati, Sunita;Pennington, Michael W.;Rice, Peter A.
通讯作者：
Rice, Peter A.
DOI：
10.4049/jimmunol.1003623
发表时间：
2011-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ray TD;Lewis LA;Gulati S;Rice PA;Ram S
通讯作者：
Ram S