One Dose of Staphylococcus aureus 4C-Staph Vaccine Formulated with a Novel TLR7-Dependent Adjuvant Rapidly Protects Mice through Antibodies, Effector CD4+ T Cells, and IL-17A.
One Dose of Staphylococcus aureus 4C-Staph Vaccine Formulated with a Novel TLR7-Dependent Adjuvant Rapidly Protects Mice through Antibodies, Effector CD4+ T Cells, and IL-17A.
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DOI：
10.1371/journal.pone.0147767
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Bertholet S
中科院分区：
文献类型：
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作者：
Mancini F;Monaci E;Lofano G;Torre A;Bacconi M;Tavarini S;Sammicheli C;Arcidiacono L;Galletti B;Laera D;Pallaoro M;Tuscano G;Fontana MR;Bensi G;Grandi G;Rossi-Paccani S;Nuti S;Rappuoli R;De Gregorio E;Bagnoli F;Soldaini E;Bertholet S
对于计划接受大手术或重症监护病房的患者来说，一种快速有效的金黄色葡萄球菌单剂疫苗将非常有益。在这里，我们展示了多组分金黄色葡萄球菌候选疫苗4C-Staph与新型TLR7依赖佐剂T7-明矾配制的一次免疫，在肾脓肿和腹膜炎模型中很容易保护小鼠免于死亡和细菌传播，效果优于明矾配方疫苗。更高的疫苗特异性和α溶血素中和抗体效价以及Th1型/Th17型细胞反应与这种增强的疗效是平行的。抗体发挥了关键的保护作用，4C-Staph/T7-明矾疫苗在B细胞缺陷小鼠中缺乏保护作用，血清转移实验也表明了这一点。在4C-Staph/T7-明矾免疫的小鼠中，去除效应的CD4+T细胞不仅降低了小鼠的存活率，而且增加了金黄色葡萄球菌的载量。体内中和实验表明，IL-17A对4C-Staph/T7-明矾免疫小鼠的细菌传播有抑制作用。我们认为，单剂4C-Staph/T7-明矾疫苗通过抗体、CD4+效应T细胞和IL-17A的联合作用，迅速有效地保护小鼠免受金黄色葡萄球菌感染。这些数据表明，加入一种不仅能诱导快速抗体反应，还能诱导产生IL-17的细胞介导的效应反应的佐剂，可以有效地保护预定接受大手术或重症监护病房的患者。
A rapidly acting, single dose vaccine against Staphylococcus aureus would be highly beneficial for patients scheduled for major surgeries or in intensive care units. Here we show that one immunization with a multicomponent S. aureus candidate vaccine, 4C-Staph, formulated with a novel TLR7-dependent adjuvant, T7-alum, readily protected mice from death and from bacterial dissemination, both in kidney abscess and peritonitis models, outperforming alum-formulated vaccine. This increased efficacy was paralleled by higher vaccine-specific and α-hemolysin-neutralizing antibody titers and Th1/Th17 cell responses. Antibodies played a crucial protective role, as shown by the lack of protection of 4C-Staph/T7-alum vaccine in B-cell-deficient mice and by serum transfer experiments. Depletion of effector CD4+ T cells not only reduced survival but also increased S. aureus load in kidneys of mice immunized with 4C-Staph/T7-alum. The role of IL-17A in the control of bacterial dissemination in 4C-Staph/T7-alum vaccinated mice was indicated by in vivo neutralization experiments. We conclude that single dose 4C-Staph/T7-alum vaccine promptly and efficiently protected mice against S. aureus through the combined actions of antibodies, CD4+ effector T cells, and IL-17A. These data suggest that inclusion of an adjuvant that induces not only fast antibody responses but also IL-17-producing cell-mediated effector responses could efficaciously protect patients scheduled for major surgeries or in intensive care units.