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

我们设想采取一种新的疫苗接种办法，适用于目前尚不存在有效疫苗的所有人类疾病，包括艾滋病毒/艾滋病、疟疾、肺结核和癌症。在这里提出的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从细菌中提取的物质，可以诱导对它们引起的感染的保护性免疫。天花已经从地球上根除，小儿麻痹症几乎消失。白喉、破伤风和百日咳在发达国家已基本消灭，如果不是因为针对MMR疫苗的虚假宣传，麻疹也可能大大减少。成功的免疫诱导针对目标细菌的特定组分（所谓的免疫原）的保护性免疫应答。对于一些疾病，免疫原是未知的，而对于其他疾病，它们的生产、运输和施用是困难和昂贵的，例如流感疫苗必须在数百万个鸡蛋中生产。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主要在注射部位进入细胞，并使它们在体内局部产生免疫原。DNA疫苗在小鼠、马、狗、兔和猪中效果良好，并激发了针对各种不同感染甚至某些癌症的良好保护性免疫力。但在人类和其他灵长类动物中，以及牛和羊中，DNA疫苗的免疫反应非常微弱。尽管学术界和制药业做出了巨大的努力，但这种失败的原因尚未被理解或克服。我们先前在MRC资助的工作中发现，人类血液中的一种蛋白质，称为血清淀粉样蛋白P组分（SAP），是唯一与DNA强烈结合的正常血液蛋白质。我们现在已经发现，在DNA疫苗接种有效的每一种动物中，这种蛋白质要么不存在，要么即使存在，它也只与DNA弱结合。相比之下，非人类灵长类动物，牛和羊与人类共享SAP蛋白的存在，该蛋白与DNA强烈结合。我们认为SAP与DNA的结合可能是阻断DNA诱导免疫应答的原因，而去除SAP可能会克服这种抑制作用。SAP导致重要的人类疾病，淀粉样变性和阿尔茨海默病，并且在MRC资助的治疗这些疾病的工作中，我们以前开发了一种药物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SAP的存在抑制了小鼠的DNA疫苗接种，这种作用被我们的药物CPHPC逆转。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的免疫应答，比较在DNA疫苗接种时SAP已完全耗尽的一组和未耗尽SAP的对照组。我们预测在接种疫苗时SAP消耗将增强免疫应答。将要测试的DNA疫苗是一种很有前途的艾滋病毒/艾滋病新疫苗，是由MRC以前的奖项开发和生产的。阳性结果与针对HIV-1的保护性免疫力的提高一致，这将是非常令人鼓舞的。此外，证明SAP耗竭可以增强人类对DNA疫苗接种的免疫应答的概念将为许多其他疾病开辟这种方法，对于这些疾病，有效的疫苗接种还不存在，并且它可以具有治疗性和预防性应用。因此，潜在的全球健康和经济利益非常巨大。

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.