Shen Xiaoying, Basu Rahul, Sawant Sheetal, Beaumont David, Kwa Sue Fen, LaBranche Celia, Seaton Kelly E, Yates Nicole L, Montefiori David C, Ferrari Guido, Wyatt Linda S, Moss Bernard, Alam S Munir, Haynes Barton F, Tomaras Georgia D, Robinson Harriet L
Duke Human Vaccine Institute, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
GeoVax, Inc., Smyrna, Georgia, USA.
J Virol. 2017 Nov 30;91(24). doi: 10.1128/JVI.01077-17. Print 2017 Dec 15.
An important goal of human immunodeficiency virus (HIV) vaccine design is identification of strategies that elicit effective antiviral humoral immunity. One novel approach comprises priming with DNA and boosting with modified vaccinia virus Ankara (MVA) expressing HIV-1 Env on virus-like particles. In this study, we evaluated whether the addition of a gp120 protein in alum or MVA-expressed secreted gp140 (MVAgp140) could improve immunogenicity of a DNA prime-MVA boost vaccine. Five rhesus macaques per group received two DNA primes at weeks 0 and 8 followed by three MVA boosts (with or without additional protein or MVAgp140) at weeks 18, 26, and 40. Both boost immunogens enhanced the breadth of HIV-1 gp120 and V1V2 responses, antibody-dependent cellular cytotoxicity (ADCC), and low-titer tier 1B and tier 2 neutralizing antibody responses. However, there were differences in antibody kinetics, linear epitope specificity, and CD4 T cell responses between the groups. The gp120 protein boost elicited earlier and higher peak responses, whereas the MVAgp140 boost resulted in improved antibody durability and comparable peak responses after the final immunization. Linear V3 specific IgG responses were particularly enhanced by the gp120 boost, whereas the MVAgp140 boost also enhanced responses to linear C5 and C2.2 epitopes. Interestingly, gp120, but not the MVAgp140 boost, increased peak CD4 T cell responses. Thus, both gp120 and MVAgp140 can augment potential protection of a DNA/MVA vaccine by enhancing gp120 and V1/V2 antibody responses, whereas potential protection by gp120, but not MVAgp140 boosts, may be further impacted by increased CD4 T cell responses. Prior immune correlate analyses with humans and nonhuman primates revealed the importance of antibody responses in preventing HIV-1 infection. A DNA prime-modified vaccinia virus Ankara (MVA) boost vaccine has proven to be potent in eliciting antibody responses. Here we explore the ability of boosts with recombinant gp120 protein or MVA-expressed gp140 to enhance antibody responses elicited by the GOVX-B11 DNA prime-MVA boost vaccine. We found that both types of immunogen boosts enhanced potentially protective antibody responses, whereas the gp120 protein boosts also increased CD4 T cell responses. Our data provide important information for HIV vaccine designs that aim for effective and balanced humoral and T cell responses.
人类免疫缺陷病毒（HIV）疫苗设计的一个重要目标是确定能引发有效抗病毒体液免疫的策略。一种新方法包括先用DNA进行初免，然后用在病毒样颗粒上表达HIV-1 Env的改良安卡拉痘苗病毒（MVA）进行加强免疫。在本研究中，我们评估了在明矾中添加gp120蛋白或MVA表达的分泌型gp140（MVAgp140）是否能提高DNA初免-MVA加强疫苗的免疫原性。每组五只恒河猴在第0周和第8周接受两次DNA初免，随后在第18、26和40周接受三次MVA加强免疫（有或无额外蛋白或MVAgp140）。两种加强免疫原均增强了HIV-1 gp120和V1V2反应的广度、抗体依赖性细胞毒性（ADCC）以及低滴度1B级和2级中和抗体反应。然而，各组之间在抗体动力学、线性表位特异性和CD4 T细胞反应方面存在差异。gp120蛋白加强免疫引发了更早且更高的峰值反应，而MVAgp140加强免疫导致抗体持久性提高，且在末次免疫后峰值反应相当。gp120加强免疫特别增强了线性V3特异性IgG反应，而MVAgp140加强免疫也增强了对线性C5和C2.2表位的反应。有趣的是，gp120加强免疫增加了峰值CD4 T细胞反应，而MVAgp140加强免疫则没有。因此，gp120和MVAgp140均可通过增强gp120和V1/V2抗体反应来增强DNA/MVA疫苗的潜在保护作用，而gp120加强免疫而非MVAgp140加强免疫的潜在保护作用可能会因CD4 T细胞反应增加而受到进一步影响。此前对人类和非人灵长类动物的免疫相关分析揭示了抗体反应在预防HIV-1感染中的重要性。一种DNA初免-改良安卡拉痘苗病毒（MVA）加强疫苗已被证明在引发抗体反应方面有效。在此，我们探讨用重组gp120蛋白或MVA表达的gp140进行加强免疫以增强GOVX-B11 DNA初免-MVA加强疫苗引发的抗体反应的能力。我们发现两种类型的免疫原加强免疫均增强了潜在的保护性抗体反应，而gp120蛋白加强免疫还增加了CD4 T细胞反应。我们的数据为旨在实现有效且平衡的体液和T细胞反应的HIV疫苗设计提供了重要信息。
