Addendum to HIV Active and Passive Clinical Material Manufacturing

项目摘要 VRC的首要任务仍然是开发一种疫苗或其他免疫调节剂来防止艾滋病毒感染。这项任务的总体目标包括为被动预防试验生产艾滋病毒候选疫苗或广泛中和抗体的活动，以及开发新的产品开发技术，以使艾滋病毒候选疫苗临床试验的时间更短。 目标1：开发艾滋病毒疫苗 背景 目前还没有疫苗可以预防艾滋病毒感染。在一次疫苗效力试验中提供的适度保护与诱导针对HIV包膜V1V2区域的抗体有关。稳定的可溶性HIV env三聚体在抗原性上优于目前未切割的三聚体，并应作为一种改进的免疫原来刺激主要中和表位的抗体，包括V1V2抗体。因此，制造稳定的三聚体的能力将通过加速对目前因缺乏适当的艾滋病毒环境免疫原而停滞不前的多种疫苗策略的临床测试，推动单独使用或与现有疫苗平台结合使用的艾滋病毒疫苗的开发。 项目要求 尽管HIV env gp140可溶性三聚体(BGSOS SOSIP664)已经开发和结构确定，但在可制造性和稳定性方面的困难阻碍了它的临床开发。使用来自新的原子级晶体结构的数据，VRC已经确定了一种方法来创建具有更好的稳定性和可制造性的gp140三聚体。这种三聚体可以结合所有类别的广谱中和抗体，但不能结合非中和抗体。此外，我们还确定了可能诱发VlV2抗体的最佳序列特征。 1/VRC请求cGMP制造和技术转让*支持VRC用于推进临床试验的重组稳定gp140三聚体疫苗候选。 目标2：HIV MPER bNAbs用于预防、治疗或治愈背景 针对多个中和表位的长半衰期bNAbs的生产和临床测试将提高bNAbs的覆盖率和在预防、治疗和治疗策略方面的可能成功。这一领域的进展将广泛影响以下战略：1)预防艾滋病毒-1感染母亲向新生儿和母乳喂养婴儿的传播；2)通过性传播预防艾滋病毒感染；以及3)艾滋病毒-1感染者的治疗应用(包括消除潜伏的宿主)。 项目要求 1/VRC请求为VRC的第一代MPER bNAb候选者提供cGMP制造和技术转让支持，以推进临床试验。 2/VRC要求cGMP制造和技术转让*支持第二代MPER bNAb候选者，以及额外的新的广泛中和候选者，可能包括双特异性或其他抗体方法，以使VRC进入临床试验 *所有流程开发活动将由VRC独立承担。但是，一般技术转让活动，包括可能向“蒙特利尔议定书”缔约方会议转让的工艺，已列入支助请求。

PROJECT ABSTRACT The VRC's highest priority remains development of a vaccine or other immune modulator that prevents HIV acquisition. The overarching objectives of this task include activities to produce HIV candidate vaccines or broadly neutralizing antibodies for passive prevention trials and to develop novel product development technologies to enable faster timelines to clinical trial for HIV vaccine candidates. OBJECTIVE 1: HIV VACCINE DEVELOPMENT BACKGROUND No vaccine is currently available to prevent HIV infection. The moderate protection afforded in one vaccine efficacy trial was associated with the induction of antibodies to the V1V2 region of HIV envelope. A stabilized soluble HIV env trimer is antigenically preferable to current un­cleaved trimers and should serve as an improved immunogen to stimulate antibodies to the major neutralization epitopes, including V1V2 antibodies. Thus, the ability to manufacture a stabilized trimer will advance the development of HIV vaccines, used alone or in combination with existing vaccine platforms, by accelerating clinical testing of multiple vaccine strategies that are currently stalled for lack of an appropriate HIV env immunogen. PROJECT REQUIREMENTS Despite the development and structural determination of a soluble trimer of HIV Env gp140 (BGSOS SOSIP664) difficulties in manufacturability and stability hamper its clinical development. Using data from new atomic level crystal structures, the VRC has determined a method for creating a gp140 trimer with improved stability and manufacturability. This trimer binds all classes of broadly neutralizing antibodies, but not non-neutralizing antibodies. In addition, we have determined optimal sequence characteristics for the potential to elicit VlV2 antibodies. 1/ The VRC requests cGMP manufacturing and technology transfer* support for a recombinant stabilized gp140 trimer vaccine candidate for the VRC to advance to clinical trials. OBJECTIVE 2: HIV MPER BNABS FOR PREVENTION, THERAPY, OR CURE BACKGROUND Production and clinical testing of long half-life bNAbs targeting multiple neutralizing epitopes will improve the coverage and likely success of bNAbs for prophylaxis, therapy, and cure strategies. Advances in this area will broadly impact strategies for: 1) prevention of transmission from HIV-1 infected mothers to newborn and breastfeeding infants; 2) prevention of HIV infection by sexual transmission; and 3) therapeutic application in HIV-1 infected individuals (including elimination of the latent reservoir). PROJECT REQUIREMENTS 1/ The VRC requests cGMP manufacturing and technology transfer support for 1st generation MPER bNAb candidates for the VRC to advance to clinical trials. 2/ The VRC requests cGMP manufacturing and technology transfer* support for 2nd generation MPER bNAb candidates, and for additional novel broadly neutralizing candidates, potentially including bi-specific or other antibody approaches, for the VRC to advance to clinical trials *All process development activity will be independently undertaken by the VRC. However, general technology transfer activities, involving potential process transfer to the VCMP, are included in the request for support.