编者按:在HIV疫苗研发领域,美国宾夕法尼亚大学医学院Ian Frank教授正引领一场先锋性试验。Frank教授及其团队通过创新的多价疫苗设计,旨在应对HIV的高度变异性,为全球HIV预防工作带来新希望。他们采用先接种多价DNA疫苗、后接种多价蛋白疫苗的策略,确保疫苗序列的一致性,从而优化免疫系统的响应。这一策略不仅展示了广泛的适用性,还可能在诱导长期免疫记忆方面表现出色。随着研究的深入,Frank教授团队正努力筹集资金,以支持更大规模、更多样化人群的研究,为全球HIV预防战略贡献重要力量。
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《感染医线》:在您的研究中,匹配Env免疫原作为初次接种-加强接种方案(prime-boost regimen)或联合给药时,对疫苗诱导的免疫反应有何不同影响?哪种方案看起来更有效?
Frank教授:这是我们的研究中一个非常基本且核心的问题,它直接关系到疫苗设计的有效性和免疫系统的响应机制。在我们的疫苗研究中,我们采取了一种全新的策略,即先给患者接种多价DNA疫苗,随后再接种多价蛋白疫苗。这一过程中的关键在于,蛋白疫苗中的蛋白质与DNA疫苗诱导的序列是完全一致的,这确保了疫苗的各个组成部分在免疫过程中能够协同作用,达到最佳效果。
这一策略与以往疫苗的研究方法有着显著的不同。在过去,很多疫苗研究采用的是不匹配的序列,无论是相对于蛋白质、DNA还是病毒疫苗启动,这种不匹配往往会导致免疫系统响应的复杂性和不确定性。而我们的方法则力求从源头上避免这种问题,通过确保序列的一致性,来优化免疫系统的响应。
我们认为,研究所看到的免疫结果充分验证了这种多价方法的有效性。通过给患者接种包含多种不同序列的疫苗,我们不仅使他们接触到了更广泛的病原体信息,还允许免疫系统从接触疫苗之初就开始发展出一种多价的抗体反应。这种反应更加全面、更加灵活,能够更好地应对实际生活中复杂多变的病原体挑战。
此外,我们的研究还显示受试者中没有重大的安全问题,仅在免疫接种部位出现了反应性反应、一些疼痛和一些肿胀,但没有明显的全身影响。
IIDF: How did the use of matched Env immunogens as a prime-boost regimen or co-administered impact the vaccine-induced immune responses in your study? Which approach appeared more effective?
Dr Frank: This is one of the very fundamental issues involving our study. What we did in our vaccine study is that we started by giving patients a polyvalent DNA vaccine followed by a polyvalent protein vaccine in which the proteins were identically matched to the sequences elicited by the DNA. That differs from the approaches that have been taken previously with vaccines, where they used mismatched sequences (with respect to the protein or the DNA or the viral vaccine priming). We think the immunization results that we saw validate this polyvalent approach, because we are giving people exposure to diverse sequences, and we are allowing the immune system to develop a polyvalent antibody response from the very beginning of exposure.
We had no significant safety issues. We saw patients develop reactogenicity responses, some pain, and some swelling at the site of the immunization, but no significant general effects.
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《感染医线》:针对HIV的高度变异性,您的多价疫苗设计是如何确保对多种HIV亚型的有效覆盖的?这是否意味着该疫苗具有更广泛的适用性?
Frank教授:传统的疫苗设计往往针对单一的病原体或病原体的一部分,而多价疫苗则通过包含多种不同的抗原,能够刺激免疫系统产生针对多种病原体的免疫反应。在HIV疫苗的研发中,这一点尤为重要,因为HIV具有极高的变异性,其包膜序列在全球范围内存在着广泛的多样性。
我们所研发的正是这种多价疫苗,正式让免疫系统接触到HIV的高度变异性,而不是仅仅局限于有限的暴露。这意味着,我们的疫苗包含了来自不同HIV亚型的包膜序列,能够模拟真实世界中的病毒多样性。通过这种方式,我们希望能够训练免疫系统,使其在面对真实的HIV感染时,能够更有效地识别和清除病毒。
此外,我们还发现,多价疫苗策略在诱导长期免疫记忆方面也表现出色。这意味着,即使接种疫苗后一段时间,免疫系统仍然能够保持对HIV的包膜序列的记忆,并在再次遇到病毒时迅速作出反应。这对于开发有效且持久的HIV疫苗至关重要。
IIDF: Given the high variability of HIV, how did your polyvalent vaccine design ensure effective coverage against multiple HIV subtypes? Does this imply a broader applicability of the vaccine?
Dr Frank: It is the polyvalent nature of the vaccine that leads to the generation of a multiclade immune response. So again, we are allowing the immune system to be exposed to the diversity of HIV envelope sequences that exist globally, rather than starting out with limited exposure. We think we are priming the immune response to react to very diverse envelope sequences, again, right from the very beginning.
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《感染医线》:在您的研究中,疫苗诱导的免疫反应持续时间是多久?这对于开发HIV预防性疫苗来说有何重要意义?
Frank教授:不幸的是,我们目前还没有这个问题的答案,即疫苗能够提供的保护时长有多久。显然,疫苗的持久性是评估其有效性和实用性的一个至关重要因素。为了解答这个问题,我们目前已经开始观察参与者在最后一次免疫原性时间点六个月后的情况。尽管我们目前还没有最终的数据,但我们对研究的进展感到鼓舞。我们已经看到了一些初步的迹象,表明疫苗可能在接种后的一段时间内持续提供保护。然而,为了得出更确切的结论,我们需要更多的数据,特别是长期跟踪的数据。
IIDF: What was the duration of the immune responses induced by the vaccine in your study? How significant is this for the development of an HIV preventive vaccine?
Dr Frank: We don’t have an answer to that question yet unfortunately. Obviously, the durability of a vaccine is going to be essential, and we are just now starting to look at participants six months after their last immunogenicity time point. We hope to have that data soon, but we don’t have it right now. Obviously, a very important question.
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《感染医线》:未来,您计划如何进一步推进这项研究?是否有计划进行更大规模的临床试验,或者探索与其他疗法(如暴露前预防药物)的联合使用?
Frank教授:为了更深入地了解疫苗的有效性和安全性,以及其在不同人群中的适用性,目前我们正努力筹集资金,以支持在更多不同人群中开展更大规模的研究。我们希望能够在南非进行更大规模的研究,因为该地区HIV感染率较高,且人群多样性丰富,这对于评估疫苗的广泛适用性至关重要。同时,我们也希望能在美国或在南美洲进行另一项研究,以进一步验证疫苗在不同地域和人群中的效果。
需要强调的是,疫苗和暴露前预防用药(PrEP)是两种完全不同的预防HIV感染的策略。它们并非相互排斥、非此即彼的关系,而是可以相互补充的,二者共同构成更全面的HIV预防策略。PrEP作为一种医疗护理手段,已经显示出极高的保护效果,但面临着各种挑战,如经济、社会或心理因素等。而疫苗则作为一种更为传统的预防策略,具有潜在的长期保护优势。当然,我们也不能忽视疫苗研发面临的挑战。也许疫苗的效果在某些方面不如生物制剂PrEP,但人们在生活的不同阶段,对预防策略的接受度和可行性也会有所不同。因此,我们认为疫苗是对PrEP的重要补充,两者共同构成了更全面的预防HIV感染的策略。
众所周知,目前的PrEP在临床试验中几乎能达到100%的保护效果,为HIV预防提供了前所未有的希望。然而,在现实世界中,尽管美国有足够的资源为所有人提供PrEP,但据估计,在应该服用PrEP的高风险人群中,只有不到40%的人实际在服用。这凸显了我们需要更多样化的预防策略的重要性。
因此,我们认为疫苗是全球预防HIV战略的重要组成部分。疫苗具有潜在的广泛适用性、长期保护效果和相对较低的成本,使其成为预防HIV感染的有力工具。我们正在积极推进疫苗的研发和试验工作,希望在未来能够为全球HIV预防工作做出重要贡献。同时,我们也呼吁更多的资源和关注投入到这一领域,共同推动HIV预防工作的进展。
IIDF: How do you plan to further advance this research in the future? Are there plans for larger-scale clinical trials, or exploring combination use with other therapies (such as pre-exposure prophylaxis drugs)?
Dr Frank: We are trying to get some funding to support a larger study in more diverse populations. We hope to do a study in South Africa. We also hope to do another study in the United States, or possibly, South America. It is important for folks to understand that a vaccine and PrEP are two totally different strategies to prevent HIV acquisition. They are not mutually exclusive. It is not one or the other. Many people who are at risk for acquiring HIV infection are not yet ready to seek medical care. PrEP is medical care. A vaccine is a more traditional preventative strategy, and hopefully, if an immune response is long-lasting, people don’t need to seek regular healthcare as they will be protected by the vaccine. Maybe a vaccine will not be as effective as biologic PrEP, but people at different times in their lives are better able to access different types of strategies. So we think that a vaccine is complementary to PrEP, but PrEP will not protect everybody. We know that PrEP right now is virtually 100% protective. What we have now is almost 100% protective, but in the United States, where the resources are available to provide PrEP to everybody, the estimates are that <40% of people who should be on PrEP are on PrEP. We need other interventions, and I think a vaccine is an important part of the strategy to prevent HIV globally.