Agrawal Parul, Khechaduri Arineh, Salladay Kelsey R, MacCamy Anna, Ralph Duncan K, Riker Andrew, Stuart Andrew B, Siddaramaiah Latha Kallur, Shen Xiaoying, Matsen Frederick A, Montefiori David, Stamatatos Leonidas
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, WA, USA.
bioRxiv. 2025 Mar 14:2025.03.13.642975. doi: 10.1101/2025.03.13.642975.
Antibodies belonging to the VRC01-class display broad and potent neutralizing activities and have been isolated from several people living with HIV (PLWH). A member of that class, monoclonal antibody VRC01, was shown to reduce HIV-acquisition in two phase 2b efficacy trials. VRC01-class antibodies are therefore expected to be a key component of an effective HIV-1 vaccine. In contrast to the VRC01-class antibodies that are highly mutated, their unmutated forms do not engage HIV-1 envelope (Env) and do not display neutralizing activities. Hence, specifically modified Env-derived proteins have been designed to engage the unmutated forms of VRC01-class antibodies, and to activate the corresponding naïve B cells. Selected heterologous Env must then be used as boost immunogens to guide the proper maturation of these elicited VRC01-class antibodies. Here we examined whether and how the valency of the prime and boost immunogens influences VRC01-class antibody-maturation. Our findings indicate that, indeed the valency of the immunogen affects the maturation of elicited antibody responses by preferentially selecting VRC01-class antibodies that have accumulated somatic mutations present in broadly neutralizing VRC01-class antibodies isolated from PLWH. As a result, antibodies isolated from animals immunized with the higher valency immunogens display broader Env cross-binding properties and improved neutralizing potentials than those isolated from animals immunized with the lower valency immunogens. Our results are relevant to current and upcoming phase 1 clinical trials that evaluate the ability of novel immunogens aiming to elicit cross-reactive VRC01-class antibody responses.
属于VRC01类的抗体具有广泛而有效的中和活性，并且已从数名感染HIV的人（PLWH）中分离出来。该类别的一个成员，单克隆抗体VRC01，在两项2b期疗效试验中显示出可降低HIV感染率。因此，VRC01类抗体有望成为有效的HIV-1疫苗的关键组成部分。与高度突变的VRC01类抗体形成对比的是，它们未突变的形式不与HIV-1包膜（Env）结合，也不显示中和活性。因此，已经设计了经过特殊修饰的Env衍生蛋白，以与VRC01类抗体的未突变形式结合，并激活相应的初始B细胞。然后必须使用选定的异源Env作为加强免疫原，以引导这些引发的VRC01类抗体的正确成熟。在这里，我们研究了初始免疫原和加强免疫原的价态是否以及如何影响VRC01类抗体的成熟。我们的研究结果表明，免疫原的价态确实会影响引发的抗体反应的成熟，通过优先选择积累了从PLWH中分离出的广泛中和性VRC01类抗体中存在的体细胞突变的VRC01类抗体。结果，与用低价态免疫原免疫的动物相比，用高价态免疫原免疫的动物分离出的抗体显示出更广泛的Env交叉结合特性和更高的中和潜力。我们的结果与当前和即将进行的1期临床试验相关，这些试验评估旨在引发交叉反应性VRC01类抗体反应的新型免疫原的能力。
