Definition and induction of broadly protective responses against HIV-1

针对 HIV-1 的广泛保护性反应的定义和归纳

• 批准号: MR/N023668/1
• 负责人: Tomas Hanke
• 金额: $ 157.3万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN023668%2F1
• 关键词: Definition; induction; broadly; protective; responses

Despite remarkable progress achieved in decreasing HIV transmission and AIDS-related deaths in the last decade due to development of over 30 antiretroviral drugs, HIV continues to spread in a virtually uncontrolled manner. An effective HIV vaccine remains one of the priorities of HIV/AIDS research and will always be the best solution and likely key to any strategy for halting the AIDS epidemic. The biggest challenge in developing such a vaccine is the enormous HIV variability, which dwarfs that of any other virus except hepatitis C virus. However, all parts of HIV cannot easily change; to remain alive, HIV has to keep some smaller regions of its proteins more or less constant to maintain function. Our vaccine strategy takes advantage of this and focuses the body defenses on these conserved parts of HIV, its Achilles heel. Because conserved regions are common to most of the global HIV variants, the vaccine, if successful, could be used in Africa, Asia, Europe, America and Australia: it would be universal. The 1st generation conserved-region vaccine was very safe and induced strong immune responses in adult volunteers in the UK and Africa. In 2014, the pharmaceutical company GSK acquired a small biotech company, which developed one of the benign viruses we used for vaccine delivery, and unilaterally decided that we could no longer use the jointly owned vaccine in high risk people. Thus we needed to switch to an alternative vaccine virus and this provided an opportunity to also substantially improve the 1st generation vaccine. These modifications are based on our experience from human vaccine testing and other developments in the HIV vaccine field over the last 10 years since its original design. Thus, the 2nd generation vaccine was born, using a new vaccine virus (ChAdOx1) owned by Oxford University and combining conserved regions with computer-designed proteins (mosaics), which significantly increase the vaccine match to global HIV variants. (Note that even the highly conserved regions are still somewhat variable.) Vaccines should match circulating HIVs as much as possible to stop them efficiently. The 2nd generation vaccines have been constructed, shown to induce strong immune responses in animal models and are now bound for testing in human volunteers. The requested funds will allow to us see how well the 2nd generation vaccine works in trying to get rid of HIV from already infected individuals and for larger scale testing in HIV-1 negative healthy volunteers in Africa. The latter study will aim first evidence that the vaccine can stop HIV from infecting healthy people. The funding will also allow clinical testing of the vaccine enabling further improvements including some new aimed at keeping ahead of HIV.

尽管在过去的十年中，由于30多种抗逆转录病毒药物的发展，在过去十年中降低HIV传播和与AIDS相关的死亡方面取得了显着进展，但HIV仍以几乎不受控制的方式继续传播。有效的艾滋病毒疫苗仍然是艾滋病毒/艾滋病研究的优先事项之一，将永远是阻止艾滋病流行病的任何策略的最佳解决方案和关键。开发这种疫苗的最大挑战是巨大的艾滋病毒变异性，除乙型肝炎病毒外，其他任何病毒都相形见war。但是，艾滋病毒的所有部位都无法轻易改变。为了保持生命，艾滋病毒必须或多或少地保持其蛋白质的一些较小区域以保持功能。我们的疫苗策略利用了这一点，并将身体防御力集中在艾滋病毒的这些保守部分，其致命弱点。由于保守的地区对于大多数全球艾滋病毒变种都是常见的，因此，如果成功的话，可以在非洲，亚洲，欧洲，美国和澳大利亚使用疫苗：这将是普遍的。在英国和非洲的成年志愿者中，第一代保守区域疫苗非常安全，并且诱发了强烈的免疫反应。 2014年，制药公司GSK收购了一家小型生物技术公司，该公司开发了一种我们用于疫苗输送的良性病毒之一，并单方面决定我们无法再使用高风险人员的共同拥有的疫苗。因此，我们需要切换到替代疫苗病毒，这为也实质上改善了第一代疫苗的机会提供了机会。这些修改基于我们从原始设计以来的过去10年中人类疫苗测试和其他艾滋病毒疫苗领域的其他发展的经验。因此，第二代疫苗是使用牛津大学拥有的新疫苗病毒（Chadox1）诞生的，并将保守区域与计算机设计的蛋白质（马赛克）相结合，该蛋白质（Mosaics）显着增加了与全球HIV变种的疫苗匹配。 （请注意，即使是高度保守的区域仍然有些变化。）疫苗应尽可能与循环的艾滋病毒相匹配，以便有效地阻止它们。已经构建了第二代疫苗，证明可以在动物模型中诱导强烈的免疫反应，现在被绑定在人类志愿者中。要求的资金将使我们看到第二代疫苗试图从已经受感染的人那里摆脱艾滋病毒以及在非洲HIV-1负面健康志愿者中进行大规模测试方面的效果。后一项研究将首先证明疫苗可以阻止艾滋病毒感染健康的人。资金还将允许对疫苗进行临床测试，以进一步改善，包括一些旨在保持艾滋病毒的新疫苗。

项目成果

Gut microbiome signatures linked to HIV-1 reservoir size and viremia control.

• DOI: 10.1186/s40168-022-01247-6
• 发表时间: 2022-04-11
• 期刊: MICROBIOME
• 影响因子: 15.5
• 作者: Borgognone, Alessandra;Noguera-Julian, Marc;Oriol, Bruna;Noel-Romas, Laura;Ruiz-Riol, Marta;Guillen, Yolanda;Parera, Mariona;Casadella, Maria;Duran, Clara;Puertas, Maria C.;Catala-Moll, Francesc;De Leon, Marlon;Knodel, Samantha;Birse, Kenzie;Manzardo, Christian;Miro, Jose M.;Clotet, Bonaventura;Martinez-Picado, Javier;Molto, Jose;Mothe, Beatriz;Burgener, Adam;Brander, Christian;Paredes, Roger
• 通讯作者: Paredes, Roger

Novel Nested Peptide Epitopes Recognized by CD4+ T Cells Induced by HIV-1 Conserved-Region Vaccines

• DOI: 10.3390/vaccines8010028
• 发表时间: 2020-03-01
• 期刊: VACCINES
• 影响因子: 7.8
• 作者: Borthwick, Nicola;Silva-Arrieta, Sandra;Hanke, Tomas
• 通讯作者: Hanke, Tomas

Combined intranasal and intramuscular parainfluenza 5-, simian adenovirus ChAdOx1- and poxvirus MVA-vectored vaccines induce synergistically HIV-1-specific T cells in the mucosa.

• DOI: 10.3389/fimmu.2023.1186478
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3

No evidence of neuronal damage as measured by neurofilament light chain in a HIV cure study utilising a kick-and-kill approach.

• DOI: 10.1016/j.jve.2021.100056
• 发表时间: 2021-09
• 期刊: Journal of virus eradication
• 影响因子: 5.5
• 作者: Alagaratnam J;Stöhr W;Toombs J;Heslegrave A;Zetterberg H;Gisslén M;Pett S;Nelson M;Clarke A;Nwokolo N;Johnson MA;Khan M;Hanke T;Kopycinski J;Dorrell L;Fox J;Kinloch S;Underwood J;Pace M;Frater J;Winston A;Fidler S;RIVER trial study group
• 通讯作者: RIVER trial study group

Correction: HIV-1-neutralizing antibody induced by simian adenovirus- and poxvirus MVA-vectored BG505 native-like envelope trimers.

• DOI: 10.1371/journal.pone.0293148
• 发表时间: 2023
• 期刊: PloS one
• 影响因子: 3.7