Developmental Clinical Studies - Depletion of serum amyloid P component to enhance the immune response to DNA vaccination

我们设想一种新的疫苗接种办法，将适用于目前还没有有效疫苗的所有人类疾病，包括艾滋病毒-艾滋病、疟疾、结核病和癌症。这里提出的HIV-1疫苗临床试验的成功将建立一个关键的概念证明，为我们的新方法的普遍应用开辟道路。疫苗接种是医学最重要的成就之一。注射经过修饰的细菌或由它们产生的物质，可诱导对它们引起的感染产生保护性免疫。天花已经从地球上根除，小儿麻痹症也几乎消失。白喉、破伤风和百日咳已经从发达国家基本消灭，如果不是因为虚假的反对MMR疫苗的运动，麻疹也可能大大减少。成功的免疫诱导对目标细菌的特定成分（即所谓的免疫原）产生保护性免疫反应。对于一些疾病，免疫原是未知的，而对于另一些疾病，免疫原的生产、运输和管理既困难又昂贵，例如流感疫苗必须用数百万个鸡蛋生产。一个非常有吸引力的潜在解决方案是注射编码免疫原的DNA基因，而不是免疫原本身。在这个被称为DNA疫苗接种的过程中，DNA进入细胞，主要是在注射部位，并使它们在体内局部产生免疫原。DNA疫苗接种效果很好，能在老鼠、马、狗、兔子和猪身上激发极好的保护性免疫，抵御各种不同的感染，甚至某些癌症。但在人类和其他灵长类动物，以及牛羊中，对DNA疫苗的免疫反应非常微弱。尽管学术界和制药行业做出了巨大的努力，但这种失败的原因仍未被理解或克服。我们之前在MRC资助的工作中发现，人类血液中的一种蛋白质，即血清淀粉样蛋白P成分（SAP），是唯一一种与DNA紧密结合的正常血液蛋白。我们现在已经发现，在每一种DNA疫苗有效的动物物种中，这种蛋白质要么不存在，要么即使存在，它与DNA的结合也很弱。相比之下，非人类灵长类动物、牛和羊与人类一样，存在与DNA紧密结合的SAP蛋白。我们认为，SAP与DNA的结合可能会阻断DNA诱导的免疫反应，而去除SAP可能会克服这种抑制作用。SAP与淀粉样变性和阿尔茨海默病等重要的人类疾病有关，在MRC资助的治疗这些疾病的工作中，我们之前开发了一种药物CPHPC，它可以安全地从人类血液中去除几乎所有的SAP。另一个实验室最近报告说，人类SAP的存在会抑制小鼠的DNA疫苗接种，而我们的药物CPHPC可以逆转这种效应。这些观察证实了我们的假设。我们现在建议在SAP耗尽后进行DNA疫苗接种的首次人类临床研究。我们将测量正常成年男性对HIV-1的免疫反应，比较在接种DNA疫苗时SAP完全耗尽的一组和未接种SAP耗尽的对照组。我们预测在接种疫苗时SAP的消耗将增强免疫反应。要测试的DNA疫苗是一种很有前途的抗艾滋病毒-艾滋病的新疫苗，是利用以前的MRC奖开发和制造的。如果结果是积极的，与增强对艾滋病毒-1的保护性免疫相一致，那将是非常令人鼓舞的。此外，SAP耗竭可以增强人类对DNA疫苗接种的免疫反应这一概念的证明，将为许多其他尚未存在有效疫苗接种的疾病开辟这种方法，在这些疾病中，它可以有治疗和预防的应用。因此，潜在的全球健康和经济效益非常大。

We envisage a new approach to vaccination which will be applicable to all human diseases for which effective vaccines do not yet exist, including HIV-AIDS, malaria, tuberculosis and cancer. Success in the clinical trial proposed here with an HIV-1 vaccine will establish a critical proof of concept, opening the way to general application of our new approach. Vaccination is one of the most important achievements of medicine. Injection of modified germs, or materials from them, induces protective immunity against the infections which they cause. Smallpox has been eradicated from the planet, polio is almost gone. Diphtheria, tetanus and pertussis have been essentially eliminated from developed countries and, had it not been for the mendacious campaign against MMR vaccine, measles could also have been greatly reduced. Successful immunisation induces a protective immune response against particular component(s) of the target germ, the so-called immunogen(s). For some diseases the immunogens are not known and for others they are difficult and expensive to produce, transport and administer, for example influenza vaccine must be produced in millions of chicken eggs. A very attractive potential solution is to inject the DNA gene encoding the immunogen rather than the immunogen itself. In this process, known as DNA vaccination, the DNA enters cells, predominantly at the site of injection, and causes them to produce the immunogen locally within the body. DNA vaccination works well and stimulates excellent protective immunity against a variety of different infections, and even some cancers, in mice, horses, dogs, rabbits and pigs. But in humans and other primates, and in cows and sheep, the immune response to DNA vaccination is very feeble. Despite enormous academic and pharmaceutical industry efforts, the reasons for this failure have not been understood or overcome. We previously discovered, in work funded by the MRC, that a protein in human blood, known as serum amyloid P component (SAP), is the only normal blood protein which binds strongly to DNA. We have now found that, in each of the animal species in which DNA vaccination is effective, this protein is either absent or, if it is present, it binds only weakly to DNA. In contrast, non-human primates, cows and sheep share with humans the presence of SAP proteins which strongly bind to DNA. We believe that binding of DNA by SAP may be responsible for blocking induction of immune responses by DNA and that removal of SAP may overcome this inhibition. SAP contributes to important human diseases, amyloidosis and Alzheimer's disease, and, in MRC funded work towards treatment for these conditions, we have previously developed a drug, CPHPC, which safely removes almost all SAP from the blood in humans. Another laboratory has recently reported that the presence of human SAP inhibits DNA vaccination in mice and that this effect is reversed by our drug, CPHPC. These observations confirm our hypothesis. We now propose to undertake the first human clinical study of DNA vaccination after SAP depletion. We will measure the immune responses to HIV-1 in normal adult men, comparing a group in whom SAP has been completely depleted at the time of DNA vaccination and a control group vaccinated without SAP depletion. We predict that SAP depletion at the time of vaccination will enhance the immune response. The DNA vaccine to be tested is a promising new vaccine against HIV-AIDS, developed and manufactured with previous MRC awards. A positive result, consistent with improved protective immunity against HIV-1, will be very encouraging. Furthermore, proof of the concept that SAP depletion can enhance immune responses to DNA vaccination in humans will open up this approach for the many other diseases for which effective vaccination does not yet exist and in which it could have therapeutic as well as prophylactic applications. The potential worldwide health and economic benefits are therefore very great.