Self-amplifying mRNA-based vaccines to elicit VRC01-class bnAbs

摘要总体 我们IPCAVD计划拨款的主要目标是评估人类自我扩增的mRNAs (SARNA)疫苗，表达两种HIV-1包膜衍生蛋白免疫原，分别激活和 启动VRC01类B细胞受体(BCR)的成熟。第一种免疫原， 426C.Mo.Core，被专门设计为与未突变的(生殖系， 这些BCR在幼稚B细胞表面表达时的形式。第二 免疫基因，HxB2.WT.Core，虽然不能结合胚系VRC01类BCR，但可以结合 VRC01级BCR，由426c.Mo.Core激活，并已积累了一些 体细胞突变。因此，HxB2.WT.Core的增强免疫进一步促进了 426c.Mo.Core诱导的VRC01类抗体的成熟这些观察结果 用这两种免疫原的佐剂重组(Rec)形式制成。作为mRNA- 基于疫苗的疫苗成本更低，更容易由GMP制造，可以记录蛋白质，我们 相信他们将加快HIV-1 Env来源的临床前和临床评估 免疫原。在这里，我们建议首先在临床前比较VRC01B细胞和抗体 这两种Env免疫原经SARNA疫苗免疫后产生的免疫应答 由相应的佐剂REC蛋白诱导。然后，如果结果是有希望的， 表达这两种免疫原的SARNA疫苗将被GMP生产用于临床 评估。作为426c.Mo.核心佐剂的rec蛋白将在#年进行临床评估(I期) 2022年春季(HVTN301)和HxB2.WT.core rec蛋白目前正在进行GMP 为2023年的后续I期临床评估而生产，我们将处于独特的地位 比较它们免疫人的VRC01B细胞和抗体反应 两种HIV-1 Env来源的免疫原作为佐剂REC蛋白和AS 由Sarna疫苗表达。为了实现我们在IPCAVD赠款中的目标，我们将接受 利用我们在免疫原设计和检测、B细胞分析方面的专业知识 以及接种疫苗和感染期间引发的抗体反应，我们迅速 利用高通量的PUT技术测序BCR基因，获得合适的动物 模型，我们在萨那疫苗技术方面的专业知识，我们在临床上的独特专业知识 艾滋病毒-1疫苗测试、参与小组之间现有的合作以及 记录学员成功管理复杂项目的专业知识。

ABSTRACT OVERALL The main goal of our IPCAVD Program grant is to evaluate in humans self-amplifying mRNA (saRNA) vaccines that express two HIV-1 Env-derived protein immunogens that activate and initiate the maturation of VRC01-class B cell receptors (BCRs). The first immunogen, 426c.Mod.Core, was specifically designed to bind with high affinity to the unmutated (germline, gl) forms of those BCRs as they are expressed on the surface of naïve B cells. The second immunogen, HxB2.WT.Core, although unable to bind germline VRC01-class BCRs, binds the VRC01-class BCRs that became activated by 426c.Mod.Core and have accumulated some somatic mutations. As a result, the boost immunization with HxB2.WT.Core furthers the maturation of the VRC01-class antibodies elicited by the 426c.Mod.Core. These observations were made with the adjuvanted recombinant (rec) forms of these two immunogens. As mRNA- based vaccines are less costly and more easily GMP-manufactured that rec proteins, we believe that they will accelerate the preclinical and clinical evaluation of HIV-1 Env-derived immunogens. Here, we propose to first compare preclinically the VRC01 B cell and antibody responses elicited by these two Env immunogens when delivered by saRNA vaccines to those elicited by the corresponding adjuvanted rec proteins. And then, if the results are promising, the saRNA vaccines expressing the two immunogens will be GMP-manufactured for clinical evaluation. As the 426c.Mod.Core adjuvanted rec protein will be evaluated clinically (phase I) in the spring of 2022 (HVTN301) and the HxB2.WT.Core rec protein is currently being GMP manufactured for a follow-up phase I clinical evaluation in 2023, we will be in a unique position to compare the VRC01 B cell and antibody responses elicited by humans immunized with these two HIV-1 Env-derived immunogens when delivered as adjuvanted rec proteins and as expressed by saRNA vaccines. To accomplish our goals in this IPCAVD grant we will take advantage of our expertise in immunogen-design and testing, expertise in the analysis of B cell and antibody responses elicited by vaccination and during infection, our ability to rapidly sequence BCR genes using high through put technologies, the availability of appropriate animal models, our expertise in saRNA vaccine technology, our unique expertise in conducting clinical testing of HIV-1 vaccines, the existing collaboration among the participating groups and the documented expertise of the participants to successfully manage complex Programs.