Synthetic Peptide Consensus Sequence Vaccine Development

描述（由申请人提供）：医院获得性感染，如铜绿假单胞菌（PA）影响高达10%的急性护理医院入院患者，在北美每年超过1000万住院日。PA感染导致显著的患者发病率和死亡率（北美每年约有80,000例重症监护病房（ICU）患者因PA呼吸机相关肺炎死亡）。被认为有PA感染风险的患者是那些免疫系统因事故、疾病或其他原因而减弱的患者。PA感染常见于癌症、囊性纤维化、艾滋病、烧伤创面或有长期住院史的患者。虽然在治疗中使用抗生素治疗，但往往不能解决感染。这种缺乏有效性的部分原因是细菌对抗生素的耐药性，难以建立准确的诊断，以及自相矛盾的是，抗生素的使用选择了耐药细菌。需要以预防为基础的新方法来控制感染。这里所描述的研究就是这样一种方法。我们的实验室在过去的10年里研究了PA感染，并证明了通过使用主动疫苗接种或被动使用抗体治疗的新方法来预防PA感染的可行性。这两种方法都在感染的初始阶段即细菌附着在宿主细胞表面时进行攻击。然而，存在的问题是，PA细菌有多种菌株，有效的疫苗或抗体治疗必须考虑到该病原体的所有现有菌株。在这个建议中，我们正在开发1)一种新的共识序列疫苗方法，用于覆盖所有的PA菌株；2)一种免疫原的限制性肽拟物，当用作活性肽疫苗时，可以增强免疫原性，以阻断细菌附着；3)单克隆抗体（制备为选定的肽免疫原），具有广泛的交叉反应性，具有最大的亲和力，可作为抗体治疗。

DESCRIPTION (provided by applicant): Hospital acquired infections such as Pseudomonas aeruginosa (PA) affect up to 10% of patients admitted to acute care hospitals, representing upwards of 10 million hospital days annually in North America. PA infection results in significant patient morbidity and mortality (ca. 80,000 deaths in North America per year due to PA ventilator-associated pneumonia in intensive care unit (ICU) patients). Patients considered being at risk of PA infections are those whose immune systems have been weakened because of accident, disease or other causes. PA infections are commonly found in patients with cancer, cystic fibrosis, AIDS, burn wounds or who have a long history of hospitalization. Although antibiotic therapy is employed in treatment it is often incapable of resolving the infection. This lack of effectiveness is due in part to antibiotic resistance of the bacteria, difficulty in establishing an exact diagnosis, and, paradoxically, antibiotic use which selects resistant bacteria. New approaches are needed to control infection which are based on prevention. The research described here is such an approach. Our laboratory has investigated PA infection for the last 10 years and has demonstrated the feasibility of preventing PA infection by using novel approaches to both active vaccination or by passive use of antibody therapeutics. Both these methods attack the infection process at its initial stage: attachment of the bacterium to the host's cell surfaces. However, the problem exists that there are multiple strains of PA bacteria and an efficacious vaccine or antibody therapeutic must account for all existing strains of this pathogen. In this proposal we are developing 1) a novel consensus sequence vaccine approach forcoverage against all strains of PA, 2) a constrained peptidomimetic of the immunogen to enhance immunogenicity when used as an active peptide vaccine to block bacteria attachment and 3) monoclonal antibodies (prepared to selected peptide immunogens) that are broadly cross-reactive with maximal affinity for use as an antibody therapeutic.