Asbach Benedikt, Kliche Alexander, Köstler Josef, Perdiguero Beatriz, Esteban Mariano, Jacobs Bertram L, Montefiori David C, LaBranche Celia C, Yates Nicole L, Tomaras Georgia D, Ferrari Guido, Foulds Kathryn E, Roederer Mario, Landucci Gary, Forthal Donald N, Seaman Michael S, Hawkins Natalie, Self Steven G, Sato Alicia, Gottardo Raphael, Phogat Sanjay, Tartaglia James, Barnett Susan W, Burke Brian, Cristillo Anthony D, Weiss Deborah E, Francis Jesse, Galmin Lindsey, Ding Song, Heeney Jonathan L, Pantaleo Giuseppe, Wagner Ralf
Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
Institute of Clinical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
J Virol. 2016 Mar 28;90(8):4133-4149. doi: 10.1128/JVI.03135-15. Print 2016 Apr.
UNLABELLED: In a follow-up to the modest efficacy observed in the RV144 trial, researchers in the HIV vaccine field seek to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc trials 01 to 03) evaluated the immunogenicity of HIV-1 clade C GagPolNef and gp120 antigens delivered via the poxviral vector NYVAC. These showed that a vaccination regimen including DNA-C priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses compared to those with NYVAC-C alone. Moreover, responses were improved by using three as opposed to two DNA-C primes. In the present study, we assessed in nonhuman primates whether such vaccination regimens can be streamlined further by using fewer and accelerated immunizations and employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C+ protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well-balanced CD8(+)and CD4(+)T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial antibody-dependent cellular cytotoxicity (ADCC), and modest antibody-dependent cell-mediated virus inhibition (ADCVI), but very low neutralization activity, were measured after the final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth, and quality than those of earlier EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified by using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination, especially in resource-constrained settings. IMPORTANCE: Within the EuroVacc clinical trials, we previously assessed the immunogenicity of HIV clade C antigens delivered in a DNA prime/NYVAC boost regimen. The trials showed that the DNA prime crucially improved the responses, and three DNA primes with a NYVAC boost appeared to be optimal. Nevertheless, T cell responses were primarily directed toward Env, and humoral responses were modest. The aim of this study was to assess improved antigens for the capacity to elicit more potent and balanced responses in rhesus macaques, even with various simpler immunization regimens. Our results showed that the novel antigens in fact elicited larger numbers of T cells with a polyfunctional profile and a good Env-GagPolNef balance, as well as high-titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols.
未标注：在RV144试验中观察到适度疗效之后，HIV疫苗领域的研究人员试图通过评估其他痘病毒载体以及与DNA和蛋白质疫苗的组合来证实并扩展该结果。早期临床试验（欧洲疫苗试验01至03）评估了通过痘病毒载体NYVAC递送的HIV-1 C亚型GagPolNef和gp120抗原的免疫原性。这些试验表明，与单独使用NYVAC-C相比，在NYVAC-C加强免疫之前进行DNA-C初免的疫苗接种方案可显著增强疫苗引发的免疫反应。此外，使用三次而非两次DNA-C初免可改善反应。在本研究中，我们在非人类灵长类动物中评估了是否可以通过减少免疫次数并加速免疫接种，以及采用新一代经过改进的、设计用于实现更高表达水平和更平衡免疫反应的DNA-C和NYVAC-C候选疫苗，来进一步简化此类疫苗接种方案。在恒河猴中测试了三种不同的DNA-C初免/NYVAC-C加蛋白质加强免疫的疫苗接种方案。所有方案均引发了强烈且平衡的CD8(+)和CD4(+) T细胞反应，这些反应广泛且具有多功能性。在最后一次免疫后，检测到非常高的IgG结合滴度、显著的抗体依赖性细胞毒性（ADCC）和适度的抗体依赖性细胞介导的病毒抑制（ADCVI），但中和活性非常低。总体而言，所有三组引发的免疫反应非常相似，且在强度、广度和质量上均优于早期欧洲疫苗。总之，这些发现表明，通过使用改进的抗原和方案可以简化疫苗接种计划。这可能提供一种更实用且经济实惠的方法，在接种疫苗时引发潜在的保护性免疫反应，尤其是在资源有限的环境中。 重要性：在欧洲疫苗临床试验中，我们之前评估了DNA初免/NYVAC加强免疫方案中递送的HIV C亚型抗原的免疫原性。试验表明，DNA初免对反应有至关重要的改善作用，三次DNA初免加NYVAC加强免疫似乎是最佳方案。然而，T细胞反应主要针对Env，体液反应适度。本研究的目的是评估改进的抗原在恒河猴中引发更强且平衡反应的能力，即使采用各种更简单的免疫方案。我们的结果表明，新型抗原实际上引发了更多具有多功能特征且Env-GagPolNef平衡良好的T细胞，以及高滴度和具有Fc功能的抗体反应。最后，不同方案的比较表明，仅两次DNA初免和一次NYVAC加强免疫并结合蛋白质的更简单方案可能非常有效，因此表明新型抗原允许采用更简便的免疫方案。
Vaccines (Basel). 2019-6-13
Stat Biopharm Res. 2012-1-1
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