VACCINE SAFETY AND IMMUNOGENICITY

迫切需要开发针对HIV-1的粘膜疫苗。出于这个原因，在过去的十年中，我们的小组一直在寻求减毒伤寒沙门氏菌作为HIV-1抗原的粘膜递送系统。这项工作导致了在细菌外周质中表达截断的gp120蛋白（tgp120）的减毒伤寒沙门氏菌的第一个I期临床试验。以该研究为背景，我们现在可以评估减毒伤寒沙门氏菌在口服接种人类志愿者后传递表达HIV-1Ba-l分离物gp120的DNA疫苗（gp120Ba-l）的能力。因此，本项目的主要目标是获得由减毒伤寒沙门氏菌递送的gp120Ba- L DNA疫苗在人类志愿者中的安全性数据。目前还迫切需要比gp120更广泛和更有效的免疫原，以便将其放入任何用于HIV-1疫苗的运载工具中。为此，项目1和项目2的临床前研究探索了一种新的免疫原的安全性和免疫原性，即使用HIV-1Ba-L分离物（scgp Ba-L-CD4）的gp120的单链scgp120Ba-L-CD4嵌合体。如果这些项目的临床前数据得到保证，该免疫原预计会引发广泛中和的抗HIV-1抗体，项目3还将在人类志愿者中获得scgp120 Ba- L-CD4作为减毒伤寒沙门氏菌DNA疫苗和作为可溶性亚基蛋白肌肉注射的安全性数据。有三个具体目的：1)确定由减毒伤寒沙门氏菌递送的gp120Ba-L DNA疫苗在人类志愿者中的安全性（研究1）。据我们所知，这将是第一个在志愿者中进行的第一阶段研究，通过细菌载体来传递DNA疫苗。因此，它将提供在第二阶段或第三阶段进一步探索这种疫苗战略所需的初步安全性数据，其中一个将根据项目1和项目2获得的临床前数据进行；2)确定scgp120 Ba- L-CD4嵌合体在人类志愿者中的安全性（研究2）。如果临床前数据得到保证（项目1和项目2），将在正常健康志愿者中评估由减毒伤寒沙门氏菌传递的scgp120Ba-L-CD4 DNA疫苗和纯化的scgp120Ba-L-CD4亚基蛋白的安全性（研究2）。本研究的长期目标是开发在初始促进策略中使用scgp120Ba-L-CD4的组件；3)确定经减毒伤寒沙门氏菌多次接种的gp120Ba-L DNA疫苗在人体志愿者中的安全性（研究3）。如果项目1和项目20的临床前研究不支持开展上述目标2，则将使用减毒伤寒沙门氏菌进行扩展的I期研究，以提供目标1中使用的gp120Ba- L DNA疫苗。本研究（研究3）将确定多次接种该疫苗对gp120Ba- L免疫的安全性。

There is a pressing need for the development of mucosal vaccines against HIV-1. For this reason, over the last decade, our group has pursued attenuated Salmonella typhi as a mucosal delivery system for HIV-1 antigens. This work has led to the first Phase I clinical trial of attenuated Salmonella typhi expressing a truncated gp120 protein (tgp120) in the bacterial periplasm. Using that work as a backdrop, we are now positioned to evaluate the ability of attenuated Salmonella typhi to deliver a DNA vaccine expressing gp120 of the HIV-1Ba-l isolate (gp120Ba-l) in human volunteers after oral inoculation . Accordingly, the principal goal of this project is to obtain safety data in human volunteers for a gp120Ba- L DNA vaccine delivered by attenuated Salmonella typhi. There is also a pressing need for broader and more effective immunogens than gp120 to be put in any delivery vehicle used as a vaccine against HIV-1. To this end, preclinical studies in Projects 1 and 2 explore the safety and immunogenicity of a new immunogen, a single chain scgp120Ba-L-CD4 chimera that uses gp120 of the HIV-1Ba-L isolate (scgp Ba-L-CD4). This immunogen is predicted to elicit broadly neutralizing antibodies against HIV-1 If warranted by the preclinical data from those projects, Project 3 is also designed to obtain safety data in human volunteers on scgp120 Ba- L-CD4 delivered as a DNA vaccine by attenuated Salmonella typhi and as a soluble subunit protein given intramuscularly. There are 3 specific aims: 1) to determine the safety of a gp120Ba-L DNA vaccine delivered by attenuated Salmonella typhi in human volunteers (Study 1). To our knowledge, this will be the first Phase I study in volunteers to a bacterial vector to deliver a DNA vaccine. A such, it will provide the initial safety data required for further exploration of this vaccine strategy in Aim 2 or Aim 3, one of which will be carried out depending on the preclinical data obtained in Projects 1 and 2; 2) to determine the safety of a scgp120 Ba- L-CD4 chimera in human volunteers (Study 2). If warranted by preclinical data (Projects 1 and 2), both a scgp120Ba-L-CD4 DNA vaccine delivered by attenuated Salmonella typhi and a purified scgp120Ba-L-CD4 subunit protein will be evaluated for safety in normal healthy volunteers (Study 2). The long-term goal of this study is to develop the components to use scgp120Ba-L-CD4 in a prime-boost strategy; 3) to determine the safety of a gp120Ba-L DNA vaccine delivered by attenuated Salmonella typhi using multiple inoculations in human volunteers (Study 3). If the preclinical studies from Projects 1 and 2o do not support carrying out Aim 2 above, an expanded Phase I study will be carried using attenuated Salmonella typhi to deliver the gp120Ba- L DNA vaccines used in Aim 1. This study (Study 3) will determine the safety of multiple inoculations of this vaccine on immunity to gp120Ba- L.