Safety and immunogenicity of nasal inoculation with recombinant Neisseria lactamica expressing Factor H binding protein and Neisseria Adhesin A.

表达 H 因子结合蛋白和奈瑟氏球菌粘附素 A 的重组乳酰胺奈瑟氏球菌经鼻接种的安全性和免疫原性。

• 批准号: MR/X019284/1
• 负责人: Jay Laver
• 金额: $ 318.5万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX019284%2F1
• 关键词: Safety; immunogenicity; nasal; inoculation; recombinant

The purpose of this study is to determine whether deliberate infection of human volunteers with a mixture of four different strains of a genetically modified, harmless bacterium can produce antibodies that kill the bacteria responsible for causing meningococcal disease. Simultaneously, the study will show whether becoming colonised with the mixture of harmless bacteria can prevent volunteers from becoming colonised with the same mixture a second time. If the mixture of bacteria can produce antibodies that kill the meningococcal disease-causing bacteria, it is likely useful for preventing this disease. It might be used as a future 'bacterial medicine' in populations susceptible to meningococcal disease. If becoming colonised with this mixture of bacteria prevents the same bacteria from colonising a second time, then we will have shown this model of controlled human infection (CHI) is useful for identifying what elements of the immune system are responsible for this phenomenon. This knowledge is important to guide the development of new vaccines that prevent people from carrying disease-causing organisms. Without disease-causing organisms, it is impossible for disease to occur. Moreover, if disease-causing organisms are not passed between people, then everyone's risk of developing disease is also eliminated. Referred to as 'herd protection', this powerful effect could lead to vaccines that not only protect the vaccine recipient from disease, but also protect other people who have not themselves received the vaccine. The protective effect against disease using this new type of vaccine would be greater, with significant benefits to public health.In the proposed research, we will create four genetically modified strains of the harmless bacterium Neisseria lactamica (Nlac), each of which will make two foreign proteins normally made by its close cousin, the meningococcal disease-causing bacterium, Neisseria meningitidis (Nmen). Both proteins are components of existing vaccines designed to prevent meningococcal disease, which means they are known to be targeted by antibodies capable of killing Nmen. We have previously used CHI to infect volunteers with one strain of genetically modified Nlac (GM-Nlac), which makes only one of these proteins, called Neisseria Adhesin A (NadA). We showed that in the blood of half of the volunteers colonised by this strain, the ability to kill Nmen that make NadA developed over time. By adding the Nmen protein, Factor H-binding protein (FHbp) into our GM-Nlac strains, which is present on almost all strains of circulating Nmen, we predict that two things will happen: (i) more people will develop the ability to kill Nmen in their blood, (ii) the blood of these volunteers will be able to kill a wider variety of Nmen strains. Note that we need four strains because there are differences between variants of FHbp, and we want to give each volunteer's immune system examples of this variety, so they can become more broadly immunised.Importantly, whilst the current protein-based vaccines against meningococcal disease are good at protecting against illness, they have shown no ability to prevent vaccinated people from carrying the disease-causing organism. On the other hand, we have shown in previous uses of CHI that people carrying Nlac in their nose and throat are far less likely to also carry Nmen. In addition, people we know have previously carried Nmen at some point in their lives (i.e. those who have memory cells that make antibodies against the proteins of Nmen), are less hospitable to Nlac when we try to deliberately infect them. This latter point suggests there could be a role for the natural processes of infection, and our body's responses to it, in preventing bacterial colonisation and excluding these sorts of organisms from carriage. Therefore, this study could lead to the development of an entirely new way of protecting against infectious diseases, one that harnesses natural mechanisms.

这项研究的目的是确定人类志愿者故意感染四种不同的转基因无害细菌菌株的混合物是否能产生抗体，杀死导致脑膜炎球菌病的细菌。同时，这项研究将表明，被无害细菌的混合物定植是否可以防止志愿者第二次被相同的混合物定植。如果这种细菌混合物能产生抗体，杀死脑膜炎球菌致病细菌，那么它很可能对预防这种疾病有用。它可能被用作未来对脑膜炎球菌病易感人群的“细菌药物”。如果被这种细菌的混合物定植可以防止相同的细菌第二次定植，那么我们将证明这种控制人类感染（CHI）模型对于确定免疫系统的哪些元素负责这种现象是有用的。这一知识对于指导开发防止人们携带致病生物体的新疫苗非常重要。没有致病微生物，就不可能发生疾病。此外，如果致病微生物不会在人与人之间传播，那么每个人患病的风险也就被消除了。这种强大的效应被称为“群体保护”，可能导致疫苗不仅保护疫苗接种者免受疾病侵害，而且还保护自己没有接种疫苗的其他人。使用这种新型疫苗对疾病的保护作用将更大，对公共卫生有重大好处。在拟议的研究中，我们将培育出四种无害的内酰胺奈瑟菌（Neisseria lactamica, Nlac）的转基因菌株，每一株都将产生两种通常由其近亲——脑膜炎球菌致病细菌脑膜炎奈瑟菌（Neisseria meningitidis, Nmen）产生的外来蛋白质。这两种蛋白质都是现有预防脑膜炎球菌病疫苗的成分，这意味着已知它们是能够杀死Nmen的抗体的目标。我们之前使用CHI让志愿者感染了一种转基因Nlac （GM-Nlac）菌株，这种菌株只产生一种叫做奈瑟菌粘连素A （NadA）的蛋白质。我们发现，在被这种菌株感染的一半志愿者的血液中，随着时间的推移，杀死产生NadA的Nmen的能力逐渐增强。通过将Nmen蛋白，因子h结合蛋白（FHbp）添加到我们的GM-Nlac菌株中，该菌株几乎存在于所有循环的Nmen菌株中，我们预测会发生两件事：(i)更多的人将发展出杀死血液中的Nmen的能力，（ii）这些志愿者的血液将能够杀死更多种类的Nmen菌株。请注意，我们需要四种菌株，因为FHbp的变体之间存在差异，我们想给每个志愿者的免疫系统提供这种变体的例子，这样他们就可以获得更广泛的免疫。重要的是，虽然目前针对脑膜炎球菌病的基于蛋白质的疫苗在预防疾病方面很好，但它们没有显示出阻止接种疫苗的人携带致病生物体的能力。另一方面，我们在之前的CHI使用中已经表明，在鼻子和喉咙中携带Nlac的人同时携带Nmen的可能性要小得多。此外，当我们试图故意感染Nlac时，我们所知道的在生命中的某个时刻曾携带过Nmen的人（即那些拥有能够产生针对Nmen蛋白质抗体的记忆细胞的人）对Nlac不那么友好。后一点表明，感染的自然过程，以及我们身体对它的反应，可能在阻止细菌定植和排除这些生物的运输中发挥作用。因此，这项研究可能会导致开发一种全新的预防传染病的方法，一种利用自然机制的方法。