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Improving the immunogenicity of a trivalent Neisseria meningitidis native outer membrane vesicle vaccine by genetic modification

机译：通过基因修饰提高三价脑膜炎奈瑟氏球菌天然外膜囊泡疫苗的免疫原性

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Trivalent native outer membrane vesicles (nOMVs) derived from three genetically modified Neisseria meningitidis serogroup B strains have been previously evaluated immunologically in mice and rabbits. This nOMV vaccine elicited serum bactericidal activity (SBA) against multiple N. meningitidis serogroup B strains as well as strains from serogroups C, Y, W, and X. In this study, we used trivalent nOMVs isolated from the same vaccine strains and evaluated their immunogenicity in an infant Rhesus macaque (IRM) model whose immune responses to the vaccine are likely to be more predictive of the responses in human infants. IRMs were immunized with trivalent nOMV vaccines and sera were evaluated for exogenous human serum complement-dependent SBA (hSBA). Antibody responses to selected hSBA generating antigens contained within the trivalent nOMVs were also measured and we found that antibody titers against factor H binding protein variant 2 (fHbpv2) were very low in the sera from animals immunized with these original nOMV vaccines. To increase the fHbp content in the nOMVs, the vaccine strains were further genetically altered by addition of another fHbp gene copy into the porB locus. Trivalent nOMVs from the three new vaccine strains had higher fHbp antigen levels and generated higher anti-fHbp antibody responses in immunized mice and IRMs. As expected, fHbp insertion into the porB locus resulted in no PorB expression. Interestingly, higher expression of PorA, an hSBA generating antigen, was observed for all three modified vaccine strains. Compared to the trivalent nOMVs from the original strains, higher PorA levels in the improved nOMVs resulted in higher anti-PorA antibody responses in mice and IRMs. In addition, hSBA titers against other strains with PorA as the only hSBA antigen in common with the vaccine strains also increased. (C) 2016 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ. Published by Elsevier Ltd.
机译：先前已在小鼠和兔子中通过免疫学评估了衍生自三种基因改造的脑膜炎奈瑟氏球菌血清B株的三价天然外膜囊泡（nOMV）。这种nOMV疫苗引起针对多种脑膜炎奈瑟氏球菌B血清群以及C，Y，W和X血清群的菌株的血清杀菌活性（SBA）。在这项研究中，我们使用了从同一疫苗株中分离的三价nOMV，并对其进行了评估婴儿猕猴（IRM）模型的免疫原性，其对疫苗的免疫反应可能更能预测人类婴儿的反应。用三价nOMV疫苗免疫IRM，并评估血清中外源性人类血清补体依赖性SBA（hSBA）。还测量了对包含在三价nOMV中的选定hSBA产生抗原的抗体反应，我们发现在用这些原始nOMV疫苗免疫的动物血清中，针对因子H结合蛋白变体2（fHbpv2）的抗体效价非常低。为了增加nOMV中的fHbp含量，通过向porB基因座中添加另一个fHbp基因拷贝来进一步改变疫苗株的遗传。来自三种新疫苗株的三价nOMV在免疫小鼠和IRM中具有较高的fHbp抗原水平，并产生较高的抗fHbp抗体反应。如预期的那样，将fHbp插入porB基因座中不会导致PorB表达。有趣的是，对于所有三种修饰的疫苗株，都观察到了porA（一种产生hSBA的抗原）的更高表达。与原始菌株的三价nOMV相比，改良的nOMV中较高的PorA水平导致小鼠和IRM中较高的抗PorA抗体反应。另外，hSBA针对其他菌株的滴度也增加了，其中PorA是与疫苗菌株共有的唯一hSBA抗原。 （C）2016年，默克·夏普（Merck Sharp＆Dohme Corp.），是位于新泽西州Kenilworth的默克公司（Merck＆Co.，Inc.）的子公司。由Elsevier Ltd.发布

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