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

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.

Parenteral injection of naked DNA encoding immunogenic epitopes is a highly desirable approach to vaccination but, for reasons which have not hitherto been understood, it is not efficacious in some species, including humans. Serum amyloid P component (SAP) is the single normal human plasma protein which binds avidly to DNA under physiological conditions. We have lately discovered that, among species tested so far, there is complete concordance between the efficacy of DNA vaccination and the absence of circulating SAP which binds strongly to DNA. Mice respond well to DNA vaccination and their SAP binds DNA very weakly. It has lately been reported that human SAP potently blocks murine immune responses to DNA vaccination and that this inhibition is completely abrogated by CPHPC, the SAP depleting drug developed by Pepys. We now propose to conduct the first human clinical trial of DNA vaccination in subjects undergoing SAP depletion by CPHPC. Medicinal CPHPC and a suitable GMP DNA vaccine against HIV-1 are available, together with extensive expertise in conduct of HIV vaccine trials and monitoring of SAP and CPHPC. Forty healthy adult male volunteers will receive three priming doses of DNA vaccine, followed by a protein antigen boost. Half the subjects will be randomly allocated to receive a CPHPC infusion to provide maximal SAP depletion at the time of each DNA injection; controls will receive saline alone. Comprehensive assessment of the T cell immune response to each priming dose and to boosting, including viral suppression assays, will establish whether the immune response is significantly enhanced by SAP depletion and achieves a clinically useful level. A positive result will open the way in humans to use of prophylactic and therapeutic DNA vaccination against major infections including HIV, malaria and tuberculosis, and also cancer, with enormous potential health and economic benefits.

Convincing evidence that SAP depletion enhances immune responses to DNA vaccination to an extent consistent with practical clinical benefit, will reignite the interest of the pharmaceutical and vaccine industry, and trigger further academic and commercial research. Despite its great theoretical and practical advantages as a strategy for prophylactic and therapeutic immunisation in a very wide range of diseases, DNA vaccination has been abandoned by almost all major pharmaceutical companies and vaccine manufacturers, because of its poor efficacy in humans. Elucidation of the reasons for this failure and provision of a solution will enable development of effective vaccines and make them much more widely available. Major beneficiaries will be the individuals and populations who can be protected from infections which are currently widespread and poorly treatable, as well as the vaccine and pharmaceutical sectors of industry. The capacity to arrest the spread of HIV-AIDS would obviously have a major impact on health and wealth, especially in Africa and other developing countries, but also in the developed world. Reduction of the enormous burden of malaria, tuberculosis and other infections for which no prophylactic immunisation is yet available, would also provide massive international benefits. Conduct in the UK of the world's first proof of concept demonstration in humans, and the presence here of the leading expertise related to this innovation, will be highly beneficial to UK industry, government and society generally.