VACCINE SAFETY AND IMMUNOGENICITY

迫切需要开发针对HIV-1的粘膜疫苗。由于这个原因，在过去的十年中，我们小组一直在研究减毒伤寒沙门氏菌作为HIV-1抗原的粘膜递送系统。这项工作导致了减毒伤寒沙门氏菌在细菌周质中表达截短的gp 120蛋白（tgp 120）的第一个I期临床试验。利用这项工作作为背景，我们现在定位于评估减毒伤寒沙门氏菌在口服接种后在人类志愿者中递送表达HIV-1Ba-l分离株（gp 120 Ba-l）的gp 120的DNA疫苗的能力。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gp 120 Ba-L DNA疫苗在人类志愿者中的安全性数据。此外，还迫切需要比gp 120更广泛和更有效的免疫原，用于任何用作HIV-1疫苗的运载工具。为此，项目1和2中的临床前研究探索了一种新免疫原的安全性和免疫原性，这种免疫原是一种单链scgp 120 Ba-L-CD 4嵌合体，它使用HIV-1Ba-L分离株的gp 120（scgp Ba-L-CD 4）。预计该免疫原可引发针对HIV-1的广泛中和抗体。如果根据这些项目的临床前数据，项目3还旨在获得人类志愿者中scgp 120 Ba-L-CD 4的安全性数据，scgp 120 Ba-L-CD 4作为减毒伤寒沙门氏菌DNA疫苗和可溶性亚单位蛋白肌内给药。有三个具体目标：1）确定由减毒伤寒沙门氏菌递送的gp 120 Ba-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细菌载体递送DNA疫苗的I期研究。因此，它将提供在目标2或目标3中进一步探索该疫苗策略所需的初始安全性数据，其中之一将根据项目1和2中获得的临床前数据进行; 2）确定scgp 120 Ba-L-CD 4嵌合体在人类志愿者中的安全性（研究2）。如果临床前数据（项目1和2）有保证，将在正常健康志愿者中评价减毒伤寒沙门氏菌递送的scgp 120 Ba-L-CD 4 DNA疫苗和纯化的scgp 120 Ba-L-CD 4亚单位蛋白的安全性（研究2）。本研究的长期目标是开发在初免-加强免疫策略中使用scgp 120 Ba-L-CD 4的组分; 3）在人类志愿者中使用多次接种确定由减毒伤寒沙门氏菌递送的gp 120 Ba-L DNA疫苗的安全性（研究3）。如果项目1和2 o的临床前研究不支持实施上述目标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gp 120 Ba-L DNA疫苗。本研究（研究3）将确定该疫苗多次接种对gp 120 Ba-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.