GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis.
GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis.
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DOI：
10.1016/j.vaccine.2010.09.031
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发表时间：
2010-11-03
期刊：
影响因子：
5.5
通讯作者：
Malley, Richard
中科院分区：
文献类型：
--
作者：
Lu, Ying-Jie;Leite, Luciana;Goncalves, Viviane Maimoni;Dias, Waldely de Oliveira;Liberman, Celia;Fratelli, Fernando;Alderson, Mark;Tate, Andrea;Maisonneuve, Jean-Francois;Robertson, George;Graca, Rita;Sayeed, Sabina;Thompson, Claudette M.;Anderson, Porter;Malley, Richard
用灭活的全细胞肺炎球菌疫苗与肠毒素相关佐剂一起给予的粘液素免疫接种已被证明可在小鼠中赋予针对鼻咽和中耳定殖的多血清型保护。然而，由于新的粘膜免疫策略可能难以实施，在这里我们评估了皮下注射。菌株RM 200被工程化为荚膜阴性、自溶素阴性，并表达无毒突变体肺炎球菌。升规模和60-L良好生产规范（GMP）培养物在不含牛的大豆基培养基中生长，用氯仿或β-丙内酯杀死，并注射到不含或含有铝佐剂的C57 B1/6小鼠中。佐剂Al（OH）3强烈增加反应，特别是如果用磷酸盐预处理。在几种测试的模型感染中发现了保护作用：血清型6 B菌株的鼻定植以及血清型3和5菌株的致命吸入性败血症。针对定殖的保护机制依赖于攻击时CD 4 + T细胞的存在;相反，在3型抽吸-脓毒症模型中，攻击时不需要CD 4 + T细胞进行保护，这表明在该模型中单独的抗体足以保护免于死亡。在初步毒性研究中接受连续肌内注射的家兔在注射部位显示局部反应原性，但无临床体征。由此产生的兔抗血清在体外吞噬细胞杀伤测定中是活性的，并且在3型抽吸-脓毒症模型中被动保护小鼠。目前正在寻求批准对这种疫苗进行人体试验。
Mucosal immunization with a killed whole-cell pneumococcal vaccine, given with enterotoxin-related adjuvants, has been shown to confer multi-serotype protection against colonization of the nasopharynx and middle ear in mice. However, because novel mucosal immunization strategies may be difficult to implement, here we evaluated subcutaneous injection. Strain RM200 was engineered to be capsule-negative, autolysin-negative, and to express a non-toxic mutant pneumolysoid. Liter-scale and 60-L Good Manufacturing Practice (GMP) cultures were grown in bovine-free soy-based medium, killed with chloroform or beta-propiolactone, and injected into C57Bl/6 mice without or with aluminum adjuvant. The adjuvant Al(OH)3 strongly increased responses, particularly if pre-treated with phosphate. Protection was found in several tested model infections: nasal colonization with a serotype 6B strain and fatal aspiration-sepsis with strains of serotype 3 and 5. Protection against colonization was mechanistically dependent on the presence of CD4+ T cells at the time of challenge; in contrast, in the type 3 aspiration-sepsis model, CD4+ T cells were not required for protection at the time of challenge, suggesting that antibody alone was sufficient to protect against death in this model. Rabbits receiving sequential intramuscular injections in a pilot toxicity study displayed local reactogenicity at injection sites but no clinical signs. The rabbit antiserum thus produced was active in an in vitro phagocytic killing assay and passively protected mice in the type 3 aspiration-sepsis model. Approval is being sought for human trials of this vaccine.
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影响因子：
158.5
作者：
Klugman, KP;Madhi, SA;Pierce, N
通讯作者：
Pierce, N
白介素17a介导获得的对肺炎球菌定殖的免疫力。
影响因子：
6.7
作者：
Lu, Ying-Jie;Gross, Jane;Bogaert, Debby;Finn, Adam;Bagrade, Linda;Zhang, Qibo;Kolls, Jay K.;Srivastava, Amit;Lundgren, Anna;Forte, Sophie;Thompson, Claudette M.;Harney, Kathleen F.;Anderson, Porter W.;Lipsitch, Marc;Malley, Richard
通讯作者：
Malley, Richard
DOI：
10.1073/pnas.0501254102
发表时间：
2005-03-29
影响因子：
11.1
作者：
Malley, R;Trzcinski, K;Lipsitch, M
通讯作者：
Lipsitch, M
影响因子：
168.9
作者：
Cutts, FT;Zaman, SMA;Adegbola, RA
通讯作者：
Adegbola, RA
影响因子：
3.1
作者：
Malley, R;Srivastava, A;Anderson, PW
通讯作者：
Anderson, PW