Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens
Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens
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最佳免疫鸡尾酒可以促进诱导针对高度变异病原体的广泛中和抗体
DOI：
10.1073/pnas.1614940113
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
A. Chakraborty
中科院分区：
文献类型：
--
作者：
J. Shaffer;P. Moore;P. Moore;P. Moore;M. Kardar;A. Chakraborty
重要意义疫苗接种战略的设计将对全球健康产生重大影响，该战略可产生针对艾滋病毒和疟疾等高度变异病原体的不同菌株的有效抗体。这种抗体被称为广谱中和抗体(BNAbs)。ABS是由达尔文式的称为亲和力成熟的进化过程产生的。诱导bNAbs可能需要用不同的突变抗原接种。在多种不同抗原存在的情况下，亲和力如何成熟还不是很清楚，因此阻碍了免疫策略的合理设计。我们利用计算机模拟和统计力学理论来研究这一问题。我们的结果为合理设计最优疫苗接种策略提供了指导，并揭示了处于免疫学和进化生物学十字路口的机制原理。诱导能够中和高度变异病原体的不同菌株的抗体的策略很可能导致一种有效的疫苗。从患者身上分离出了抗HIV的广谱中和抗体(BNAbs)，证明人类免疫系统可以进化它们。利用计算机模拟和理论，我们研究了不同的变种抗原(AGS)混合免疫。我们的结果表明，对于变异AGS的数量和它们之间的突变距离的特定选择，最大限度地增加了诱导bNAbs的可能性。变异的AGS代表了潜在的相互冲突的选择力量，这可能会阻碍达尔文的亲和力成熟的进化过程。中等程度的挫折最大限度地增加了进化bNAbs的机会。一个简单的模型生动地解释了这一最佳挫折原则的由来。结合过去的研究，我们的结果表明，通过优化设计的混合物(使用我们描述的原理)进行适当的免疫排列，以及使用以相对较大的突变距离分隔的变异AGs进行连续免疫，可能会最好地促进bNAbs的进化。
Significance The design of vaccination strategies that generate potent Abs directed against diverse strains of highly mutable pathogens, like HIV and malaria, will significantly impact global health. Such Abs are called broadly neutralizing Abs (bnAbs). Abs are produced by a Darwinian evolutionary process called affinity maturation. Induction of bnAbs will likely require vaccination with diverse mutant antigens. How affinity maturation occurs in the presence of multiple diverse antigens is not well-understood, thus hindering rational design of immunization strategies. We study this issue using computer simulations and statistical mechanical theory. Our results provide guides for the rational design of optimal vaccination strategies, and they reveal mechanistic principles at a crossroad of immunology and evolutionary biology. Strategies to elicit Abs that can neutralize diverse strains of a highly mutable pathogen are likely to result in a potent vaccine. Broadly neutralizing Abs (bnAbs) against HIV have been isolated from patients, proving that the human immune system can evolve them. Using computer simulations and theory, we study immunization with diverse mixtures of variant antigens (Ags). Our results show that particular choices for the number of variant Ags and the mutational distances separating them maximize the probability of inducing bnAbs. The variant Ags represent potentially conflicting selection forces that can frustrate the Darwinian evolutionary process of affinity maturation. An intermediate level of frustration maximizes the chance of evolving bnAbs. A simple model makes vivid the origin of this principle of optimal frustration. Our results, combined with past studies, suggest that an appropriately chosen permutation of immunization with an optimally designed mixture (using the principles that we describe) and sequential immunization with variant Ags that are separated by relatively large mutational distances may best promote the evolution of bnAbs.
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影响因子：
30.3
作者：
Burton DR;Ahmed R;Barouch DH;Butera ST;Crotty S;Godzik A;Kaufmann DE;McElrath MJ;Nussenzweig MC;Pulendran B;Scanlan CN;Schief WR;Silvestri G;Streeck H;Walker BD;Walker LM;Ward AB;Wilson IA;Wyatt R
通讯作者：
Wyatt R
协调库转移与亲和力成熟：有害突变的作用。
DOI：
--
发表时间：
1999
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Shannon,M;Mehr,R
通讯作者：
Mehr,R
影响因子：
29.7
作者：
Burton DR;Hangartner L
通讯作者：
Hangartner L
影响因子：
32.4
作者：
Andrabi R;Voss JE;Liang CH;Briney B;McCoy LE;Wu CY;Wong CH;Poignard P;Burton DR
通讯作者：
Burton DR
影响因子：
32.4
作者：
MacLeod, Daniel T.;Choi, Nancy M.;Briney, Bryan;Garces, Fernando;Ver, Lorena S.;Landais, Elise;Murrell, Ben;Wrin, Terri;Kilembe, William;Liang, Chi-Hui;Ramos, Alejandra;Bian, Chaoran B.;Wickramasinghe, Lalinda;Kong, Leopold;Eren, Kemal;Wu, Chung-Yi;Wong, Chi-Huey;Pond, Sergei L. Kosakovsky;Wilson, Ian A.;Burton, Dennis R.;Poignard, Pascal
通讯作者：
Poignard, Pascal