Evaluation of Adenylate Cyclase Toxoid Antigen in Acellular Pertussis Vaccines by Using a Bordetella pertussis Challenge Model in Mice
Evaluation of Adenylate Cyclase Toxoid Antigen in Acellular Pertussis Vaccines by Using a Bordetella pertussis Challenge Model in Mice
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DOI：
10.1128/iai.00857-17
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发表时间：
2018-10-01
影响因子：
3.1
通讯作者：
Damron, F. Heath
中科院分区：
文献类型：
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作者：
Boehm, Dylan T.;Hall, Jesse M.;Damron, F. Heath
百日咳博德特氏菌是百日咳（百日咳）的主要病原体，百日咳是一种呼吸道感染，会导致剧烈咳嗽，对婴儿可能致命。由于自全细胞百日咳疫苗（wP）转为无细胞百日咳疫苗（aP；白喉-破伤风-无细胞-百日咳疫苗/破伤风-白喉-百日咳疫苗）以来，美国百日咳病例再次出现，因此需要开发更有效的疫苗。腺苷酸环化酶毒素 (ACT) 是百日咳博德特氏菌的主要毒力因子，它是 (i) 建立感染所需的，(ii) 有效的免疫原，以及 (iii) 保护性抗原。 ACT 的 C 端重复毒素结构域 (RTX) 足以诱导毒素中和抗体的产生。在这项研究中，我们表征了含有 RTX 抗原的疫苗对抗实验性小鼠百日咳博德特氏菌感染的有效性。 RTX 作为单抗原疫苗对百日咳博德特氏菌攻击没有保护作用，并且将 RTX 添加到 1/5 人类剂量的 aP 中并不能增强保护作用。由于小鼠研究中使用的 aP 剂量与小鼠/人体质量不成比例，因此我们将 aP 从人体剂量的 1/20 滴定到 1/160。接受 1/80 人 aP 剂量的小鼠的细菌负荷与未接受实验的对照组相当。将 RTX 抗原添加到 1/80 aP 碱基中可增强细菌清除率。 RTX的加入诱导了识别RTX的抗体的产生，增强了抗百日咳毒素的产生，减少了促炎细胞因子（例如白细胞介素6）的分泌，并减少了肺中总巨噬细胞的募集。这项研究表明，将 RTX 抗原添加到适当剂量的 aP 中可以增强小鼠对 8. 百日咳攻击的保护。
Bordetella pertussis is the primary causative agent of pertussis (whooping cough), which is a respiratory infection that leads to a violent cough and can be fatal in infants. There is a need to develop more effective vaccines because of the resurgence of cases of pertussis in the United States since the switch from the whole-cell pertussis vaccines (wP) to the acellular pertussis vaccines (aP; diphtheria-tetanus-acellular-pertussis vaccine/tetanus-diphtheria-pertussis vaccine). Adenylate cyclase toxin (ACT) is a major virulence factor of B. pertussis that is (i) required for establishment of infection, (ii) an effective immunogen, and (iii) a protective antigen. The C-terminal repeats-in-toxin domain (RTX) of ACT is sufficient to induce production of toxin-neutralizing antibodies. In this study, we characterized the effectiveness of vaccines containing the RTX antigen against experimental murine infection with B. pertussis. RTX was not protective as a single-antigen vaccine against B. pertussis challenge, and adding RTX to 1/5 human dose of aP did not enhance protection. Since the doses of aP used in murine studies are not proportionate to mouse/human body masses, we titrated the aP from 1/20 to 1/160 of the human dose. Mice receiving 1/80 human aP dose had bacterial burden comparable to those of naive controls. Adding RTX antigen to the 1/80 aP base resulted in enhanced bacterial clearance. Inclusion of RTX induced production of antibodies recognizing RTX, enhanced production of anti-pertussis toxin, decreased secretion of proinflammatory cytokines, such as interleukin-6, and decreased recruitment of total macrophages in the lung. This study shows that adding RTX antigen to an appropriate dose of aP can enhance protection against 8. pertussis challenge in mice.