Immune subdominant antigens as vaccine candidates against Mycobacterium tuberculosis.
Immune subdominant antigens as vaccine candidates against Mycobacterium tuberculosis.
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DOI：
10.4049/jimmunol.1401103
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发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
Reed SG
中科院分区：
文献类型：
--
作者：
Orr MT;Ireton GC;Beebe EA;Huang PW;Reese VA;Argilla D;Coler RN;Reed SG
与大多数病原体不同，结核分枝杆菌 (Mtb) 的许多免疫显性表位都处于纯化选择之下。这一惊人的发现表明，结核分枝杆菌可能通过将人类免疫反应集中于选定的蛋白质而获得进化优势。尽管这对疫苗开发的影响尚不完全清楚，但有人建议，针对在自然感染过程中仅微弱识别的抗原诱导强烈的 TH1 反应可能会绕过这种逃避策略并提高疫苗功效。为了检验亚优势和/或弱 Mtb 抗原是可行的候选疫苗的假设，并避免由于人类和实验动物中不同的免疫优势等级而引起的并发症，我们在实验感染的小鼠中定义了 84 种重组 Mtb 蛋白的免疫优势等级。然后，我们将这些显性或次显性抗原的子集与 TH1 增强佐剂 GLA-SE 组合，以评估它们在未接触 Mtb 的动物中的免疫原性，以及通过预防性接种疫苗后受感染动物肺部 Mtb 负担的减少来衡量的保护效果。我们观察到原发性结核分枝杆菌感染期间的免疫优势与疫苗功效之间几乎没有相关性，证实了次优势和弱抗原性结核分枝杆菌蛋白是可行的候选疫苗的假设。最后我们开发了两种基于强保护性亚优势融合蛋白的融合蛋白。当与 GLA-SE 佐剂配对时，这些融合蛋白在单次免疫感染后至少六周内引发强烈的 TH1 反应并限制肺部 Mtb。这些发现扩大了可被视为候选疫苗抗原的结核分枝杆菌蛋白的潜在库。
Unlike most pathogens many of the immunodominant epitopes from Mycobacterium tuberculosis (Mtb) are under purifying selection. This startling finding suggests that Mtb may gain an evolutionary advantage by focusing the human immune response against selected proteins. Although the implications of this to vaccine development are incompletely understood, it has been suggested that inducing strong TH1 responses against antigens that are only weakly recognized during natural infection may circumvent this evasion strategy and increase vaccine efficacy. To test the hypothesis that subdominant and/or weak Mtb antigens are viable vaccine candidates and to avoid complications due to differential immunodominance hierarchies in humans and experimental animals we defined the immunodominance hierarchy of 84 recombinant Mtb proteins in experimentally infected mice. We then combined a subset of these dominant or subdominant antigens with a TH1 augmenting adjuvant, GLA-SE to assess their immunogenicity in Mtb-naïve animals and protective efficacy as measured by a reduction in lung Mtb burden of infected animals following prophylactic vaccination. We observed little correlation between immunodominance during primary Mtb infection and vaccine efficacy, confirming the hypothesis that subdominant and weakly antigenic Mtb proteins are viable vaccine candidates. Finally we developed two fusion proteins based on strongly protective subdominant fusion proteins. When paired with the GLA-SE adjuvant these fusion proteins elicited robust TH1 responses and limited pulmonary Mtb for at least six weeks after infection with a single immunization. These finding expand the potential pool of Mtb proteins that can be considered as vaccine antigen candidates.
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影响因子：
4.4
作者：
Dietrich, Jes;Billeskov, Rolf;Andersen, Peter
通讯作者：
Andersen, Peter
影响因子：
3.7
作者：
Aagaard C;Hoang TT;Izzo A;Billeskov R;Troudt J;Arnett K;Keyser A;Elvang T;Andersen P;Dietrich J
通讯作者：
Dietrich J
DOI：
10.1093/infdis/jit647
发表时间：
2014-04-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Harris SA;Meyer J;Satti I;Marsay L;Poulton ID;Tanner R;Minassian AM;Fletcher HA;McShane H
通讯作者：
McShane H
影响因子：
5.4
作者：
Caccamo, Nadia;Guggino, Giuliana;Dieli, Francesco
通讯作者：
Dieli, Francesco
DOI：
10.1073/pnas.1219985110
发表时间：
2013-04-16
影响因子：
11.1
作者：
Heuts, Frank;Gavier-Widen, Dolores;Rottenberg, Martin E.
通讯作者：
Rottenberg, Martin E.