Immunodominance in vaccinia virus and recombinant vaccinia vaccines

当面对入侵的微生物时，人类免疫系统无法识别其整体形状。相反，微生物被切成微小的片段，称为肽，这些片段可以被免疫系统中称为T细胞的特殊细胞识别，从而协调反应。我们对这个切割过程有很好的理解，可以预测许多这样的肽，但这只是故事的一部分。并非所有的肽都能被T细胞识别。此外，通过我们不太了解的过程，仅识别许多肽中的少数肽的T细胞将主导整个免疫反应。因此，免疫反应集中在这样一种方式，它们只识别入侵微生物的一小部分。免疫反应的集中也发生在疫苗免疫期间。一些新的基因工程疫苗使用一种无害的微生物来携带更危险的病原体的一小部分。选择的部分本身不会引起任何疾病，因此整个疫苗是安全的。以这种方式制造的疫苗正在进行艾滋病和疟疾等疾病的临床试验，但效果并不像人们希望的那样好。这些新疫苗主要由载体组成，我们希望免疫的微生物部分（例如艾滋病病毒的一部分）只是整个疫苗的一小部分。理想情况下，我们希望免疫系统专注于我们选择的这一小部分，但少数研究表明情况并非如此。在这个项目中，我们将研究使用一种名为牛痘病毒的载体的疫苗。我们将测试免疫反应在多大程度上被不适当地集中。然后，我们将从基因上改变病毒，并使用新的免疫策略来尝试转移免疫反应的重点，使其靶向疫苗的正确部分。最终目标是改进疫苗，但在这个过程中，我们可能会更多地了解免疫系统如何选择其目标。

When confronted with an invading microbe, the human immune system does not recognise its overall shape. Instead, the microbe is chopped up into tiny fragments, called peptides, and these can be recognised by special cells of the immune system called T cells which orchestrate a response. We have a good understanding of this chopping process and can predict many of these peptides, but this is only part of the story. Not all peptides will be recognized by a T cell. Further, through processes we do not understand well, T cells that recognize only a few out of the many peptides will dominate an entire immune response. As a result, immune responses are focused in such a way that they recognize only a tiny portion of an invading microbe. Focusing of immune responses also occurs during immunization with vaccines. Some new, genetically engineered vaccines use a harmless microbe to carry small parts of more dangerous pathogens. The parts chosen will not cause any disease by themselves, so the whole vaccine is safe. Vaccines built in this way are in clinical trials for diseases such as AIDS and malaria, but do not work as well as was hoped. These new vaccines are largely made up of the carrier and the parts of the microbe we wish to immunize against (e.g. a part of the AIDS virus) will be only a small fraction of the whole vaccine. Ideally we would like the immune system to focus on this small part of our choosing, but the few studies done suggest that this is not the case. In this project we will study vaccines that use a carrier called vaccinia virus. We will test to what extent immune responses are focused inappropriately. We will then genetically alter the virus and use new immunisation strategies to try and shift the focus of the immune response so that it targets the right parts of the vaccine. The ultimate aim is to improve vaccines, but in the process we may learn more about how the immune system chooses its targets.