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Development of Novel Adjuvants LTA and LTA1

新型佐剂LTA和LTA1的开发

基本信息

批准号：
8910934
负责人：
Elizabeth B Norton
金额：
$ 18.81万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8910934
关键词：
Adjuvant Adjuvanticity Adverse effects Alzheimer&apos s Disease Animals Antibodies Antigens Bell Palsy Binding Brain Cell Maturation Cell surface Cholera Cholera Toxin Clinical Clinical Trials Communicable Diseases Cyclic AMP Data Degenerative Disorder Dendritic Cells Dendritic cell activation Development Disease Dose Drug Formulations Effectiveness Elderly Elements Enterotoxins Erythema Escherichia coli Excipients Facial paralysis Family Fluzone Future Gangliosides Heating Human Immune response Immunity Immunization Immunocompromised Host In Vitro Induration Infectious Diseases Research Inflammatory Response Influenza Influenza vaccination Injection of therapeutic agent Investigation Laboratories Life Link Malignant Neoplasms Mediating Memory Methods Modeling Mucosal Immunity Nature Neurons Parents Population Preparation Procedures Property Proteins Publishing Reaction Recombinants Reporting Risk Safety Signal Transduction Site Skin Stretching Surface Testing Toxin Vaccination Vaccines Viral base biophysical properties cancer therapy cost effective design high risk holotoxins immunogenicity improved in vivo influenza virus vaccine influenzavirus intradermal injection irritation liquid formulation mutant next generation novel novel vaccines olfactory bulb pandemic disease pandemic influenza pathogen prevent protective efficacy public health relevance receptor binding response vaccine development vaccine efficacy vaccine trial

项目摘要

DESCRIPTION (provided by applicant): Vaccines are the established and proven method to prevent diseases. As a technological platform they are also expanding into nontraditional applications such as cancer and Alzheimer's therapy, but continue to be relevant in infectious diseases research, including strategies for controlling pandemic Influenza virus. Proper selection and use of adjuvant formulations can overcome barriers to vaccine efficacy by promoting long-lasting protective immunity, overcoming poor immunity in high-risk populations (i.e., young, elderly, immunocompromised), and/or simply augmenting the existing antigen supply to reach a greater number of people (dose-sparing). The objective of this proposal is to develop next generation adjuvants based on the A-subunit of the heat-labile enterotoxin from Escherichia coli (LT), including LTA and LTA1. The enterotoxin family of adjuvants are powerful mucosal adjuvants, but have been hindered by major safety concerns in past clinical trials, particularly for intranasal delivery. Our preliminary studies indicate LTA and LTA1 proteins are safe and effective mucosal adjuvants because they can achieve broad mucosal and systemic immunity without the potential safety risks of the parent proteins and high levels of immunogenicity (i.e., anti-LT antibodies). In this proposal, we will critically evaluate LTA and LTA1 as adjuvants in combination with inactivated, pandemic influenza antigen. In our studies, we will determine how these adjuvants (1) improve correlates of protective immunity and responses to viral challenge by intranasal or intradermal influenza vaccination, (2) provide a new, safe and stable alternative to their parent protein or related B-subunit containing derivatives, (3) improve vaccination efficacy through cAMP-mediated dendritic cell activation and Th17 induction. Upon completion of this investigation, we expect to generate clear safety and efficacy data using a candidate influenza antigen for intranasal and intradermal immunization, specifically valuable for future human use in a pandemic disease setting or for use in high-risk populations. Based on the nature of the information generated by this proposal, we will also provide clear rational for novel LTA and LTA1 adjuvant inclusion in other unique vaccine formulations targeting bacterial and viral pathogens or degenerative disease like cancer.