Department of Medicine, University of California Irvine, School of Medicine, Irvine, California, USA.
Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
J Virol. 2019 Sep 30;93(20). doi: 10.1128/JVI.01188-19. Print 2019 Oct 15.
Immune complex (IC) vaccines have been successfully used to increase immune responses against various pathogens, including HIV-1. Additionally, IC vaccines can induce qualitatively different antibody responses, with distinct antigenic specificities compared to the same antigens used alone. Here we measured the HIV-1-specific antibody responses in female New Zealand White rabbits after immunization with ICs made from BG505 SOSIP.664 trimers (BG505 trimers) and three rabbit monoclonal antibodies (MAbs) with different neutralization profiles. Two of the MAbs were specific for a hole in the glycan shield of the BG505 trimer, while the third, which bound less avidly, was specific for determinants at the gp41-gp120 interface. We found that immunization with one of the glycan-hole-specific ICs resulted in lower levels of trimer-binding antibodies compared to vaccination with the uncomplexed trimer, and that ICs made using either of the glycan-hole-specific MAbs resulted in lower rates of anti-trimer antibody decay. We concluded that ICs based on MAbs that bound to the immunodominant glycan hole epitope likely diverted antibody responses, to some extent, away from this site and to other regions of the trimer. However, this outcome was not accompanied by a widening of the breadth or an increase in the potency of neutralizing antibody responses compared with uncomplexed trimers. Immunodominant epitopes may suppress immune responses to more desirable determinants, such as those that elicit potentially protective neutralizing antibody responses. To overcome this problem, we attempted to mask immunodominant glycan holes by immunizing rabbits with ICs consisting of the BG505 SOSIP.664 gp140 trimer and MAbs that targeted the glycan holes. We found that IC vaccination likely diverted antibody responses, to some extent, away from the glycan holes and toward other regions of the trimer. IC vaccination resulted in slower decay of HIV-1-specific antibodies than did immunization with uncomplexed trimer. We did not observe a widening of the breadth or an increase in the potency of neutralizing antibody responses compared to uncomplexed trimers. Our results suggest that selective epitope dampening of BG505 trimers by ICs is rather ineffective. However, IC vaccination may represent a novel means of increasing the duration of vaccine-induced antibody responses.
免疫复合物 (IC) 疫苗已成功用于提高针对各种病原体（包括 HIV-1）的免疫反应。此外，IC 疫苗可以诱导与单独使用相同抗原相比具有不同抗原特异性的定性不同的抗体反应。在这里，我们测量了新西兰白兔在接种 BG505 SOSIP.664 三聚体（BG505 三聚体）和三种具有不同中和谱的兔单克隆抗体（mAb）制成的 IC 后的 HIV-1 特异性抗体反应。两种 mAb 特异性针对 BG505 三聚体糖罩中的一个孔，而第三种结合亲和力较低的 mAb 特异性针对 gp41-gp120 界面上的决定簇。我们发现，与接种未复合三聚体相比，接种一种糖孔特异性 IC 会导致三聚体结合抗体水平降低，并且使用任何一种糖孔特异性 mAb 制成的 IC 都会导致抗三聚体抗体衰减率降低。我们得出结论，基于与免疫优势糖孔表位结合的 mAb 的 IC 可能在某种程度上将抗体反应从该部位转移到三聚体的其他区域。然而，与未复合三聚体相比，这一结果并没有伴随着中和抗体反应的广度或效力的扩大。免疫显性表位可能会抑制对更理想决定簇的免疫反应，例如那些引发潜在保护性中和抗体反应的决定簇。为了克服这个问题，我们试图通过用包含 BG505 SOSIP.664 gp140 三聚体和针对糖孔的 mAb 的 IC 免疫兔子来掩盖免疫显性糖孔。我们发现，IC 疫苗接种可能在某种程度上将抗体反应从糖孔转移到三聚体的其他区域。IC 疫苗接种导致 HIV-1 特异性抗体的衰减速度比接种未复合三聚体慢。与未复合三聚体相比，我们没有观察到中和抗体反应的广度或效力的扩大。我们的结果表明，通过 IC 对 BG505 三聚体进行选择性表位抑制的效果相当差。然而，IC 疫苗接种可能代表一种增加疫苗诱导的抗体反应持续时间的新方法。
