A mutable vaccine for biodefense

描述（申请人提供）：疫苗接种在预防传染病方面发挥着重要作用，因此是生物战的一种可能解决方案。传统疫苗的固定性质是其成功的主要限制。一些病原体，如艾滋病毒、SARS、流感和丙型肝炎会自然变异，而其他病原体可能会为了军事用途而故意变异。由于免疫反应通常比新变种发展得慢得多，突变的病原体可以逃脱疫苗接种的控制，并迅速产生流行病。目前的战略要求对每一种新发现的病原体进行免疫。然而，由于无法预测哪些变种将被故意产生用于生物战，重复接种疫苗无法主动预防“新”病原体。拟议的研究将测试一种新型疫苗，该疫苗将触发针对抗原变异的免疫反应，以应对病原体的多样化，即可变疫苗。变异疫苗是一种DNA疫苗，其中编码抗原的基因的变异频率是典型基因的一百万倍，与变异病毒的变异率相当。因为突变抗原的出现将预示着变异的出现，所以突变病原体不太可能逃避免疫应答。总体目标是证明可变疫苗的原理。为此，流感被用作模型。将生产编码突变流感血凝素（HA）基因的载体，并检测产生HA抗原变体的能力。然后将测试疫苗促进针对流感抗原变体的免疫应答的能力。

DESCRIPTION (provided by applicant): Vaccination plays an important role in preventing infectious diseases and is therefore a possible solution for biological warfare. The fixed nature of the traditional vaccine is a major limitation to its success. Some pathogens, such as HIV, SARS, influenza, and hepatitis C naturally mutate and others may be deliberately mutated for military uses. Because immune responses typically develop much more slowly than new variants, mutated pathogens can escape control by vaccination and rapidly generate epidemics. The current strategy calls for immunizing against every newly identified pathogen. However, since it is not possible to predict which variants will be deliberately generated for biological warfare, repeated vaccination cannot proactively protect against "new" pathogens. The proposed research will test a novel type of vaccine that will trigger immune responses directed against antigenic variants in anticipation of pathogen diversification, the mutable vaccine. A mutable vaccine is a DNA vaccine in which the gene coding for the antigen is caused to mutate a million times more frequently than a typical gene, at a rate comparable to that of a mutable virus. Because the appearance of mutant antigens will anticipate the appearance of variants, a mutant pathogen is less likely to evade the immune response. The overall goal is to demonstrate the proof of principle for the mutable vaccine. For this end influenza is used as a model. A vector encoding a mutable influenza hemagglutinin (HA) gene will be produced and ability to generate HA antigenic variants will be tested. The vaccine will then be tested for ability to promote an immune response against antigenic variants of influenza.