Synergistic malaria vaccine combinations identified by systematic antigen screening.
Synergistic malaria vaccine combinations identified by systematic antigen screening.
复制标题
DOI：
10.1073/pnas.1702944114
复制
发表时间：
2017-11-07
影响因子：
11.1
通讯作者：
Rayner JC
中科院分区：
文献类型：
--
作者：
Bustamante LY;Powell GT;Lin YC;Macklin MD;Cross N;Kemp A;Cawkill P;Sanderson T;Crosnier C;Muller-Sienerth N;Doumbo OK;Traore B;Crompton PD;Cicuta P;Tran TM;Wright GJ;Rayner JC
每年仍有数十万儿童死于疟疾。疟疾疫苗的开发因寄生虫的高度遗传多样性而变得复杂，这使得单一靶疫苗容易受到变异特异性免疫的影响。为了克服这一障碍，我们系统地筛选了一组来自最致命的人类疟疾寄生虫恶性疟原虫的29种血液阶段抗原。我们确定了几个目标，能够抑制红细胞侵袭两个遗传多样性菌株。对这些靶点进行组合测试，发现了几对组合比单独更有效地阻止入侵的靶点。视频显微镜和对患者对疟疾的自然免疫反应的研究表明，针对入侵的多个步骤更有可能产生协同疫苗反应。一种高效的疫苗将是消灭疟疾的宝贵武器。目前还没有这样的疫苗，寄生虫基因组中数百种潜在候选疫苗中只有少数得到了评估。在这项研究中，我们系统地评估了29个抗原可能参与红细胞入侵，一个重要的发展阶段，在此期间，疟疾寄生虫是容易受到抗体介导的抑制。单独和组合测试抗原确定了几种在体外具有协同组合效应的菌株超越靶标，而在流行人群中的研究表明，相同抗原的组合与保护免受发热性疟疾有关。视频显微镜确定，最有效的组合针对多个离散阶段的入侵，提出了协同作用的机制解释。总的来说，这项研究既确定了高优先级临床试验的特定抗原组合，又建立了一种更有可能产生有效疫苗的可推广方法。
Malaria still kills hundreds of thousands of children each year. Malaria vaccine development is complicated by high levels of parasite genetic diversity, which makes single target vaccines vulnerable to the development of variant-specific immunity. To overcome this hurdle, we systematically screened a panel of 29 blood-stage antigens from the most deadly human malaria parasite, Plasmodium falciparum. We identified several targets that were able to inhibit erythrocyte invasion in two genetically diverse strains. Testing these targets in combination identified several pairs that blocked invasion more effectively in combination than in isolation. Video microscopy and studies of natural immune responses to malaria in patients suggest that targeting multiple steps in invasion is more likely to produce a synergistic vaccine response. A highly effective vaccine would be a valuable weapon in the drive toward malaria elimination. No such vaccine currently exists, and only a handful of the hundreds of potential candidates in the parasite genome have been evaluated. In this study, we systematically evaluated 29 antigens likely to be involved in erythrocyte invasion, an essential developmental stage during which the malaria parasite is vulnerable to antibody-mediated inhibition. Testing antigens alone and in combination identified several strain-transcending targets that had synergistic combinatorial effects in vitro, while studies in an endemic population revealed that combinations of the same antigens were associated with protection from febrile malaria. Video microscopy established that the most effective combinations targeted multiple discrete stages of invasion, suggesting a mechanistic explanation for synergy. Overall, this study both identifies specific antigen combinations for high-priority clinical testing and establishes a generalizable approach that is more likely to produce effective vaccines.
登录
查看更多内容
影响因子：
3.7
作者：
Ogutu BR;Apollo OJ;McKinney D;Okoth W;Siangla J;Dubovsky F;Tucker K;Waitumbi JN;Diggs C;Wittes J;Malkin E;Leach A;Soisson LA;Milman JB;Otieno L;Holland CA;Polhemus M;Remich SA;Ockenhouse CF;Cohen J;Ballou WR;Martin SK;Angov E;Stewart VA;Lyon JA;Heppner DG;Withers MR;MSP-1 Malaria Vaccine Working Group
通讯作者：
MSP-1 Malaria Vaccine Working Group
影响因子：
17.1
作者：
Osier FH;Mackinnon MJ;Crosnier C;Fegan G;Kamuyu G;Wanaguru M;Ogada E;McDade B;Rayner JC;Wright GJ;Marsh K
通讯作者：
Marsh K
影响因子：
4.6
作者：
Hjerrild KA;Jin J;Wright KE;Brown RE;Marshall JM;Labbé GM;Silk SE;Cherry CJ;Clemmensen SB;Jørgensen T;Illingworth JJ;Alanine DG;Milne KH;Ashfield R;de Jongh WA;Douglas AD;Higgins MK;Draper SJ
通讯作者：
Draper SJ
影响因子：
4.8
作者：
Miller, SK;Good, RT;Crabb, BS
通讯作者：
Crabb, BS
影响因子：
3.4
作者：
Crick, Alex J.;Tiffert, Teresa;Cicuta, Pietro
通讯作者：
Cicuta, Pietro