HIV vaccine vCP2438(Sanofi Pasteur)

//   DNA/蛋白质联合疫苗1期临床试验HVTN 124中，序贯接种的受试者的抗体滴度达到上万级，诱导产生的功能抗体对HIV亚型和重组形式的覆盖率预测高达95%以上。“所有突破性的结果都出现在一款设计疫苗的试验中，这是此前从未有过的。”卢山表示。 吉利德公布了HIV预防药物lenacapavir 100%有效性的惊人数据。相比之下，全球HIV疫苗30多年研发之路可谓坎坷，于是业界有观点认为艾滋疫苗的研发已无必要。 在美国麻省大学医学院终身名誉教授卢山看来，“用药物预防感染性疾病是很新的尝试”，但“和疫苗相比价格不菲，需要终身用药才能有实际意义，每6个月就要注射一次，对于一个非洲年轻人来说，需要使用50年以上。这会带来另一个问题，就是社区对此种药物使用的依从性。” “世界上艾滋感染高发人群大多数都是在贫穷落后偏远的地区，缺医少药，如何能让这种高大上的药在世界上最需要的人群得到使用，不是一件简单的工作。”他提到，目前非洲等地对已感染人群的治疗性用药，基本上是靠美国等国家的捐助买药。最近美国国会已经在讨论是否还愿意继续这种昂贵的援助。 而相比之下，疫苗可及性更优秀。“只要打3~4针，就可以终身保护免于感染，总价格可能不超过一次药物的费用，而且很容易得到国际社会的支持，也较容易在贫穷地区落实。”他表示，“从这点来说，lenacapavir的成功更加激励我们努力尽快把有效的疫苗做出来。” 卢山教授 卢山教授是DNA疫苗技术主要发明人之一，曾任国际疫苗学会主席及理事会主席，中国国家感染病医学中心的高级顾问。他于2018年在美国创立了伍斯特艾滋疫苗公司（WHV），公司的唯一使命就是开发出艾滋疫苗。 前所未有的突破 今年5月，卢山团队在Lancet HIV上发表文章，公布其DNA/蛋白质联合疫苗1期人体试验HVTN 124取得的新进展。研究结果显示，HVTN 124中序贯接种的受试者全部出现抗体反应，抗体滴度达到上万级；另外，他们团队在几乎同时发表的另一篇文章中报道从疫苗志愿者体内分离一株单克隆抗体，能中和多种HIV亚型，这是既往疫苗未能取得的突破。 “HVTN 124对于全世界艾滋病毒16种主要亚型和重组形式的覆盖率预测可以达到95％以上。”卢山说。 来源 | Lancet HIV HVTN 124还诱导出了具有ADCC（抗体依赖的细胞介导的细胞毒作用）活性的功能性抗体。早在2008年美国军方和赛诺菲开展的3期临床试验RV144已证实，HIV疫苗的保护效力与疫苗诱导的ADCC活性功能性抗体相关。 此外，HVTN 124所有受试者体内都产生了高水平的CD4+T细胞免疫反应。美国HVTN实验网络发现，高特异性CD4+T细胞加上特异抗体与降低HIV-1感染具有显著相关性。卢山团队此前发表的工作成果表明，他们的疫苗还具有持久特异性B细胞反应。 来源|卢山提供 卢山团队另一项重要相关研究结果也于今年5月在Nature Communications发表。研究者从接受DNA/蛋白质联合疫苗的志愿者身上，分离出一株能针对HIV受体CD4位点的中和单克隆抗体。学术界公认对抗HIV的最佳单克隆抗体VRC01也是对准这个位点。过去几十年，科学家们的一个重要目标就是通过疫苗诱导这一类型的抗体，这次卢山团队完成0到1的突破，第一次在世界上实现这个目标。 据卢山介绍，这是第一次实现一款HIV疫苗可同时诱导多种功能性抗体免疫和细胞免疫反应，且接种后未出现迟发型超敏反应、血管炎或任何严重的临床不良事件，安全性和耐受性良好。 法国国家生命研究院前院长Yves Levy在同期Lancet HIV上发布了对这项研究结果的评论。他认为，目前全球还没有新的具有潜力的候选艾滋疫苗进入大型 2b/3 期试验，HVTN 124的设计对未来艾滋疫苗的开发提供了重要洞见。 两大关键挑战 “开发HIV疫苗的最大挑战，是需要克服HIV病毒包膜蛋白免疫原性低和病毒突变率高的两个关键问题。”卢山说。 不同于流感和新冠病毒，HIV作为一种逆转录病毒，如果在感染后没能被及时消灭，则会插入人基因组与患者终身相伴。HIV的包膜蛋白免疫原性低，导致接种传统形式的各种疫苗后很难短期内在人体内诱导出较高的抗体水平，其复制快和反转录酶错配率高的特点导致高突变率和新病毒株不断产生。 “这就要求在疫苗接种后，除了要快速升高抗体滴度，要求抗体具有广谱性，同时还要有足够多的可产生抗体的免疫细胞长期在体内‘巡航’，才有可能实现有效保护。”他说。 为了满足这些要求，HVTN 124采用的疫苗设计是全新的5价DNA+4价蛋白疫苗。 其作用原理是首先利用编码HIV包膜蛋白抗原的DNA疫苗激活抗原特异性B细胞反应，DNA初免可以保持病毒抗原的原始结构，从而诱导出高质量的保护抗体。然后用对应的重组HIV包膜蛋白刺激放大这些B细胞的作用，从而产生大量HIV包膜蛋白特异性抗体。这种免疫方式可以维护长期的高滴度抗体水平，同时，多价HIV包膜蛋白抗原组分诱导广谱性反应。 将序贯免疫理论进行到底 此前全球已进行过数十次临床试验，从早期的经典疫苗策略到后来的重组病毒疫苗都没能成功。直到2008年曙光才出现。前面提到的3期临床试验RV144，使用的就是序贯免疫方法。当时用的是金丝雀痘病毒载体初免，加上重组gp120蛋白做加强免疫。 不过， RV144临床试验的有效保护在完成全部疫苗接种后仅持续了6个月，且总体保护效果只有31.2％。后来，由美国和南非政府、盖茨基金会支持的HVTN 702、705和706研究陆续，希望延续RV144的思路取得进一步的突破。但随着2023年HVTN 706研究宣告失败，让该领域再度陷入悲观之中。 这些试验之所以失败，卢山分析认为，原因包括病毒载体本身有多种缺陷、病毒里的抗原竞争、病毒载体接种过后再次使用的不确定性等。“同时，他们未对抗原进行优化选择。”卢山表示，既往做到2b/3期的HIV疫苗研究，或是对HIV表面的原始抗原做各种修饰而没有利用病毒原始抗原，或仅靠T细胞免疫，或是选用表面拼凑的抗原（modified/mosaic）。 “HVTN 124选择的是经过筛选的广谱且可以交叉反应的抗原，没有进行任何抗原基因的改变，且和初免疫苗的DNA相对应。这样设计的原因是初免和加强疫苗的抗原要很对路子，否则初免疫苗将免疫系统激活，加强的蛋白抗原不能配套，效果就会不理想。”他说。 “即往的这些研究证明，经典疫苗策略诱导的抗体质量不能取得对人群的免疫保护。而单纯的T细胞免疫不足以提供有效的免疫保护，反而可能有害。”卢山说。 HVTN 124的设计是基于卢山在2009年提出的疫苗的异型序贯联合免疫理论（prime+boost ），简单来说，就是先后接种两种不同的疫苗，结果比同样任何一种疫苗单独接种多次的效果更好。 他坦言，建立自己的实验室后提出序贯免疫理论时曾受到很多质疑，一个疫苗使用两种产品的复杂方案被只当作是科学家的奇思妙想。为了证明自己，他选择挑战最难做的HIV疫苗。“这个决定是经过深思熟虑的，对于艾滋病毒这样狡猾又棘手的病原体，该方案是天然的克星。”他说。 在RV144试验结果发布的稍晚点，卢山团队也公开了他们第一代疫苗的1期临床试验结果，论证了DNA/蛋白质序贯疫苗的可行性。HVTN 124使用的是卢山进一步优化的第二代艾滋疫苗产品。 在理论提出前，卢山已经研究DNA疫苗多年。他在美国读博期间主攻免疫学，曾获得Howard Hughes 博后研究基金。随后又成为注册专业医师，同时一直继续新型疫苗的科研工作，曾获多项美国NIH的科研经费支持。 卢山博后所在的Harriet Robinson实验室是全球早期3个主要研究核酸疫苗的实验室之一。在这个领域的拓荒期，实验室最艰难时只有卢山和导师两人，由于卢山是相关研究的主要也是唯一执行者，后被业界认为是DNA疫苗的创始人之一。 不止HIV 随着试验成果发表，卢山创立的伍斯特艾滋疫苗公司再次进入人们视野。该公司曾与美国麻省大学医学院签署独家许可协议获得了卢山团队HIV疫苗相关原始专利的授权。卢山还邀请了被誉为国际疫苗教父的Stanley Plotkin教授和赛诺菲前疫苗部全球总裁Michel De Wilde等权威专家担任WHV的科学顾问。 “伍斯特是我们医学院所在的城市，以此纪念所有支持过我们研究的同事和朋友，公司的唯一使命就是开发出艾滋疫苗。”卢山告诉研发客。 目前，WHV已备齐下一轮人体试验的疫苗产品，2a期临床将于南非和美国启动。卢山也希望能在中国开展一项快速跟进的1/2期研究，然后在2b/3期临床时中外开发路线融合，以期同步上市。 除了HIV，卢山的实验室曾做过很多其他病原微生物感染的基础研究，接下来也还会继续开发针对其他疾病的疫苗，DNA疫苗将始终是他最趁手的武器。他认为，相比mRNA疫苗，DNA/蛋白质联合疫苗在稳定性、持久性和安全性等方面更具优势，未来发展潜力会很大。 “过去几年，mRNA技术被镀上了太多光环，从科学的角度讲，宣称一种技术可以解决很多疾病往往是不现实的，疫苗的开发思路更不是这样。不同的疫苗，需要设计不同的抗原组分，单是疫苗技术本身并不是万能钥匙。”他最后表示。 编辑 | 姚嘉  陈小娟 yao.jia@PharmaDJ.com  xiaojuan.chen@PharmaDJ.com 总第2148期 访问研发客网站可浏览更多文章 www.PharmaDJ.com

Image Credit: Getty Images / Javier Zayas Photography Only a few weeks into the new year, the prospect of getting a successful advanced HIV vaccine shrank after the discontinuation of yet another late-stage trial. On January 18, Janssen , a Johnson & Johnson (J&J) subsidiary, stated that its vaccine was not effective in preventing HIV infections . This marks the second time one of Janssen’s HIV vaccines failed after another showed disappointing results in the Phase IIb Imbokodo trial in August 2021. The failure of several late-stage trials highlights the challenging nature of HIV vaccine development . Since HIV integrates with the DNA, eliminating the virus from the body is very difficult, explains David Montefiori, PhD, director of the Laboratory for AIDS Vaccine Research and Development at Duke University in Durham, North Carolina. Once a patient is infected with HIV, they are infected for life, except for a few rare cases, he says. While vaccines like those against Covid-19 are designed to prevent serious illness and death, HIV vaccines are meant to prevent infection. “Right away, that sets the bar high, because that means that we need a vaccine that will prevent the acquisition of infection altogether,” says Montefiori. Now, the HIV research community is setting its sights on vaccines that are in earlier stages of development, based on new approaches like messenger RNA (mRNA) -based vaccines or those using human cytomegalovirus (HCMV) vectors. Additionally, advances in the study of broadly neutralising antibodies (bNAbs) have led to new candidates being studied in early trials. A partial change in perspectives The RV144 trial that took place between 2003 and 2006 in Thailand r eported modest efficacy results , which generated enthusiasm for vaccines that induce responses from non-neutralising antibodies, says Montefiori. The study was done in collaboration with the United States Army Medical Research and Development Command (USAMRDC), the Thai Ministry of Health, and others. The trial tested a regimen featuring Sanofi’s recombinant canarypox vector vaccine ALVAC-HIV and two booster injections of the recombinant glycoprotein 120 subunit vaccine AIDSVAX produced by VaxGen . Starting in 2016, the South African Uhambo HVTN 702 study, studied the ALVAC vaccine followed by a different booster , but the trial was unsuccessful. The Janssen vaccines studied in the Imbokodo and Mosaico studies were based on the mosaic concept, where they were intentionally designed to include a broader immunogen that could be used everywhere, says Dr. Mary Marovich, director of the Vaccine Research Program at National Institute of Allergy and Infectious Diseases (NIAID). Both studies featured a vaccine that was delivered using the adenovirus serotype 26 vector (Ad26), which was also a part of the J&J Covid-19 vaccine. Mosaico was a collaboration between the NIAID, Janssen, USAMRDC, and others. Imbokodo was also sponsored by the Bill & Melinda Gates Foundation. Mosaico’s failure is a reminder of how complex HIV is as a virus, says Dr. Kundai Chinyenze, director of the International AIDS Vaccine Initiative’s (IAVI) Africa team. While the trials did not report significant efficacy, they still indicated signals that mandated further study, in the view of some researchers. In Imbokodo, two parts of the immune response seemed to correlate with protection, one of which is the activity of antibodies to the V1 and V2 regions of the envelope protein, says Susan Zolla-Pazner, PhD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York City. This response was also seen in the RV 144 trial, she notes. But others in the research space are now testing out other concepts that have been largely theoretical. A move toward bNAbs There are several promising approaches being studied in the early stages of development, and those focusing on generating bNAbs are particularly interesting, says Chinyenze. While prior vaccines largely focused on T cell development to kill infected cells, these do not necessarily work well at preventing initial transmission, says Dr. Steven Deeks, professor of medicine at the University of California, San Francisco. To truly prevent transmission from the first day the virus appears in the tissue, there needs to be something that can block any cell from being infected, and bNAbs could achieve this, says Deeks. Even though the immune system makes antibodies in response to a virus, HIV mutates too quickly, and the created antibodies cannot target the virus, explains Dr. Salim Abdool Karim, director of the Centre for the AIDS Program of Research in South Africa (CAPRISA). However, in rare cases, some individuals can make bNAbs that target multiple strains of HIV, he explains. While the production of bNAbs is a complicated process, vaccines could be designed to prompt the body to induce bNAbs, says Karim. The IAVI is studying vaccines that use a bNAb-focused approach in several trials. The first among these, IAVI G001, had positive Phase I results published in Science in December 2022. Conducted in collaboration with Scripps Research and other institutions, the study investigated the effect of the eOD-GT8 60mer immunogen, and found that it induced a targeted response in 97% of vaccinated subjects. Additionally, the Phase I results added weight to germline targeting, a concept where bNAb precursor B cells are stimulated to eventually develop bNAbs, says Marovich. This could mean that multiple jabs are needed for the vaccine to successfully work, says Deeks. “We believe we’re going to need multiple different vaccines that will gently coax the immune system to make these bNAbs,” he says. The question now is how to design additional immunogens to create bNAbs from these precursor cells, says Montefiori. At the same time, this approach can be challenging, as it requires further additional vaccinations for necessary maturation, says Peter Kwong, PhD, chief of the Structural Biology Section at the NIAID. IAVI now aims to complete the IAVI G002 and IAVI G003 trials, which are testing the delivery of these immunogens through an mRNA platform by July, confirms Chinyenze. The trials will test distinct immunogens in different population and are being done in collaboration with Scripps Research, the Bill & Melinda Gates Foundation, and other partners. These newer vaccine approaches aim to induce different kinds of antibodies, and the mRNA delivery platform offers the advantage of faster vaccine manufacturing and increases the field’s capacity to study different immunogens or vaccine strategies simultaneously, says Chinyenze. mRNA vaccines can be made and modified quickly compared to protein subunit vaccines, says Montefiore. Other ongoing HIV vaccine trials While mRNA vaccines continue to stay in the limelight, other approaches are also being investigated for HIV. Vir Biotechnology is developing a HCMV-based vaccine, which is currently in a Phase I trial. While data from the first two cohorts did not show any HIV insert-specific T cell response , a third cohort readout is expected in H1 2023. Since this is a first-in-human study, the vaccine’s safety profile still needs to be understood, which explains why the first two cohorts received low doses, says Deeks. The third cohort features the highest studied dose. At even earlier stages of development, Kwong aims to push an epitope-based vaccine approach into the clinic at the NIAID next year. “The cutting edge of vaccinology has always been with HIV,” says Deeks. “Even though we do not necessarily make great progress with HIV, we make great progress for everything else. It is hard to predict the future, [but] right now, people are on the cutting edge of science.”