Enhancing the immune response to antigens delivered by the bacterial vector, Stre

描述（由申请人提供）：本提案的重点是开发一种安全、有效的亚单位疫苗递送系统。为了实现这一目标，我们将利用我们的细菌共生载体（BCV）技术。BCV利用革兰氏阳性共生菌戈多链球菌在其外表面表达感兴趣的异源抗原。I期人体临床试验表明，这种戈多氏链球菌在人体中是安全且耐受性良好的。用表达痘苗病毒（VV）蛋白的戈多氏链球菌对小鼠进行粘膜免疫，可诱导小鼠唾液和血清中痘苗病毒特异性抗体显著增加。此外，从免疫小鼠获得的血清中含有抗牛痘病毒的中和抗体。然而，用BCV:VV构建体对小鼠进行免疫，只能对致命的牛痘攻击产生部分保护。我们假设通过BCV系统共表达免疫调节分子将增强对编码抗原的体液或细胞反应，从而提供一种安全、有效和廉价的亚单位疫苗递送系统，适用于许多病毒或细菌病原体。为了进一步发展BCV系统，提出了以下具体目标：1)通过与模型抗原共表达细胞因子来增强重组链球菌的免疫原性。2)观察小鼠经鼻注射戈氏链球菌双重组体后对模型抗原的体液和细胞免疫应答。

DESCRIPTION (provided by applicant): The focus of this proposal is to develop a safe, effective subunit vaccine delivery system. To accomplish this, we will utilize our bacterial commensal vector (BCV) technology. BCV uses the Gram-positive commensal bacteria, Streptococcus gordonii, to express heterologous antigens of interest on its external surface. Phase I human clinical trials indicate that this S. gordonii strain is safe and well-tolerated in humans. Mucosal immunization of mice with S. gordonii expressing vaccinia virus (VV) proteins induced significantly increased vaccinia virus specific antibodies in saliva and serum compared to control animals. Furthermore, serum obtained from immunized mice contained neutralizing antibodies against vaccinia virus. However, immunization of mice with the BCV:VV constructs elicited only partial protection against lethal vaccinia challenge. We hypothesize that co-expression of immunomodulatory molecules by the BCV system will enhance humoral or cellular responses to the encoded antigens, thus providing a safe, effective, and inexpensive subunit vaccine delivery system suitable for use against many viral or bacterial pathogens. To further develop the BCV system the following specific aims are proposed: 1) To enhance the immunogenicity of S. gordonii recombinants by co-expressing cytokines with a model antigen. 2) To evaluate humoral and cellular immune responses to the model antigen after intranasal vaccination of mice with the S. gordonii double recombinants.