HIV Immunovirology Laboratory, St Vincent's Centre for Applied Medical Research, Sydney, New South Wales, Australia.
Drugs. 2011 Mar 5;71(4):387-414. doi: 10.2165/11585400-000000000-00000.
The quest for an effective and safe HIV-1 vaccine has been and still is the aspiration of many scientists and clinicians worldwide. Until recently, the hopes for an effective vaccine were thwarted by the disappointing results and early termination in September 2007 of the STEP study, which saw a subgroup of male vaccine recipients at an increased risk of HIV-1 infection, and the failure of earlier trials of vaccines based on recombinant envelope proteins to provide any level of protection. The results of the STEP study raised important questions in the field of HIV vaccines, including the use of recombinant adenovirus vectors as immunogens, the rationale for the development of T-cell-based vaccines and the development pathway for these vaccines, in terms of assessment of immunogenicity and the challenge models used. The study of neutralizing antibodies has demonstrated that the induction of high-titre, broadly neutralizing antibodies in the majority of recipients is likely to be highly problematic. However, the results of the RV144 Thai trial released in September 2009 have brought new optimism to the field. This study employed envelope-based immunogens delivered as a priming vaccination with a recombinant poxvirus vector and boosting with recombinant proteins. This regimen provided modest protection to HIV-1 infection in a low-risk population. Although the correlates of protection are currently unknown, extensive studies are underway to try to determine these. Neutralizing antibodies were not induced in the RV144 study; however, considerable titres of binding antibodies to HIV-1 viral envelope (Env) were. It is speculated that these antibodies may have provided a means of protection by a mechanism such as antibody-dependent cell-mediated cytotoxicity. In addition, no CD8+ T-cell responses were induced, but robust CD4+ T-cell responses were, and correlates of protection are being sought by analysing the quality of this aspect of the vaccine-induced immune response. The current paradigm for an optimal HIV-1 vaccine is to design immunogens and vaccination protocols that allow the induction of both broadly neutralizing humoral and broadly reactive and effective cell-mediated immunity, to act at sites of possible infection and post-infection, respectively. However, this is challenged by the results of the RV144 trial as neither of these responses were induced but modest protection was observed. Understanding the biology and immunopathology of HIV-1 early following infection, its modes of transmission and the human immune system's response to the virus should aid in the rational design of vaccines of increased efficacy.
寻找一种有效且安全的 HIV-1 疫苗一直是全球许多科学家和临床医生的愿望。直到最近，由于 STEP 研究令人失望的结果以及该研究于 2007 年 9 月提前终止，人们对有效疫苗的希望破灭了，该研究发现，亚组男性疫苗接种者感染 HIV-1 的风险增加，并且以前基于重组包膜蛋白的疫苗试验未能提供任何保护水平。STEP 研究的结果在 HIV 疫苗领域提出了一些重要问题，包括使用重组腺病毒载体作为免疫原、基于 T 细胞疫苗的合理性以及这些疫苗的开发途径，包括免疫原性评估和使用的挑战模型。中和抗体的研究表明，诱导大多数受者产生高滴度、广泛中和抗体可能会非常困难。然而，2009 年 9 月发布的泰国 RV144 试验结果为该领域带来了新的乐观情绪。该研究采用基于包膜的免疫原，作为重组痘苗病毒载体的初免疫苗接种，并使用重组蛋白进行加强免疫。这种方案为低风险人群中的 HIV-1 感染提供了适度的保护。尽管目前尚不清楚保护相关因素，但正在进行广泛的研究以试图确定这些因素。在 RV144 研究中没有诱导中和抗体，但是对 HIV-1 病毒包膜（Env）有相当数量的结合抗体。有人推测，这些抗体可能通过抗体依赖性细胞介导的细胞毒性等机制提供了一种保护手段。此外，没有诱导 CD8+ T 细胞反应，但诱导了强烈的 CD4+ T 细胞反应，并且正在通过分析疫苗诱导的免疫反应中这一方面的质量来寻找保护相关因素。目前 HIV-1 疫苗的最佳范例是设计免疫原和接种方案，以诱导广泛中和的体液免疫和广泛反应性且有效的细胞介导免疫，分别在可能感染和感染后的部位发挥作用。然而，这一目标受到 RV144 试验结果的挑战，因为这两种反应都没有诱导，但观察到适度的保护。了解 HIV-1 感染后早期的生物学和免疫病理学、其传播模式以及人类免疫系统对病毒的反应，应有助于合理设计更有效的疫苗。
