HIV疫苗研究进展

自从1983年发现人类免疫缺陷病毒(Human immunodeficiency virus,HIV)以来,HIV一直以惊人的速度在全球蔓延,感染HIV的人数也日益增多。到目前为止,因患艾滋病死亡的人数已达到2500万,到2010年这一数字可能会突破8000万,因此研究预防和治疗艾滋病的药物也正日益迫切地摆在人们面     

HIV-1中和抗体疫苗研究进展

由于HIV具有与其它微生物极为不同的生物学特点,HIV疫苗的研究面临着前所未有的困难和挑战。20多年来,艾滋病疫苗研究主要采用了诱发中和抗体为主或细胞免疫为主两种策略,然而至今尚无实质性突破。诱发有效中和抗体一直是传统疫苗研发的重要策略,但HIV的高变异、多亚型等特点,使该策略在HIV疫苗研发中的应用成效甚微。近年来,一些具有广谱中和活性的HIV单抗的发现及其相应抗原表位的阐明,给HIV中和抗体疫苗的研究带来了新的希望。综合分析与评述这些进展,对于重新思考艾滋病疫苗和采用更好的策略进行艾滋病疫苗研究会衣纸帮助。     

HIV疫苗研究进展

自从1983年发现人类免疫缺陷病毒(Human immunodeficiency virus,HIV)以来,HIV一直以惊人的速度在全球蔓延,感染HIV的人数也日益增多.到目前为止,因患艾滋病死亡的人数已达到2500万,到2010年这一数字可能会突破8000万,因此研究预防和治疗艾滋病的药物也正日益迫切地摆在人们面前.     

艾滋病核酸疫苗研究进展与前景

艾滋病肆虐全球,已成为世界上危害人类健康和生命最严重的病毒性疾病之一。疫苗在预防和控制艾滋病中具有重要意义,理想的HIV疫苗必须能够产生广泛的交叉反应性中和抗体、有效的抗病毒细胞毒性T细胞(CTL)反应。近年来,核酸疫苗的研究已经取得了可喜的进展,科学家正不断努力研制更有效、更强大、更广谱的新型疫苗。综述了艾滋病核酸疫苗的载体改造、抗原选择、免疫策略等方面的研究进展,并对其今后的研究发展方向进行了阐述。     

HIV-1中和抗体和基于抗体的疫苗设计

研制一种安全有效并能广泛使用的HIV疫苗对于预防和控制HIV的流行具有重要的意义。尽管人类在HIV-1病原学和免疫学方面的认识不断取得新的进步,对于HIV-1而言,普遍认为诱导保护性中和抗体的科学障碍很难逾越。在抗击HIV-1的感染中传统的疫苗策略不能提供保护。然而,近来的研究揭示在小部分HIV-1感染病人的血清中存在的某些抗体能够中和大多数的HIV-1毒株,对这些血清抗体的深入分析有助于人们揭示抗体识别的病毒表位,这些研究表明自然产生的能够中和HIV-1的中和抗体的发现可能引导未来疫苗设计的思路。高分辨率的结构信息将揭示Env 和中和抗体(Nab)结合区原子水平的结构,这些信息能够帮助设计更好的免疫原。     

抗HIV-1中和抗体的研究进展

自1982年美国疾病预防与控制中心(CDC)对那些与免疫缺陷和卡氏肺囊虫肺炎等症状有关的病例命名为获得性免疫缺陷综合征(AIDS)以来,研究者们对预防和治疗性AIDS疫苗的研究进行了不懈的努力,实验中的疫苗包括env亚单位疫苗、减毒活疫苗、灭活疫苗、DNA疫苗等等,但至今尚没有一种疫苗能获得理想的免疫效果。最近研究者们对中和抗体(Neutralizationantibody,nAb.)在HIV1感染中的作用的研究结果让人们看到一些新的曙光。尽管对nAb是否在预防HIV1感染过程中具有保护作用存在争议,但是仍然有不少的研究者在nAb方面展开了大量的工作,以期…     

日本企业积极开发抗HIV药剂对新一代抗体和疫苗寄予希望

设在日内瓦的联合国艾滋病规划署(UNAIDS) 发布了"GLOBALREPORT UNAIDS Report on the globalAIDS epidemic 2010",2010 年世界艾滋病流行情况报告总结了因感染人免疫缺陷病毒(HIV)而引发的获得性免疫缺陷综合征(艾滋病)的流行现状和人类面临的课题.     

丙型肝炎病毒疫苗的研究进展

丙型肝炎是由丙型肝炎病毒(HCV)感染引起的重要传染病,有效的治疗性和预防性疫苗目前均尚未研制成功.HCV的高变异性及多种免疫逃避途径是疫苗研制的主要障碍.目前,已有多种类型的HCV候选疫苗进入临床试验或临床前期试验阶段,但其有效性、安全性等还不能令人满意.随着对HCV相关免疫应答机制的深入了解,有望研制出相应的治疗性和预防性疫苗.     

High level serum neutralizing antibody against HIV-1 in Chinese long-term non-progressors

NAb have been considered to be an important component of a protective immune response to HIV-1, yet the relationship between the capacity of HIV-1 NAb, the conserved neutralization epitopes and disease progression has been unclear. To gain a better understanding of the protective roles that NAb and conserved neutralization epitopes could play in LTNP, twenty-eight HIV-1-infected subjects were investigated by evaluation of the concentrations of HIV-1 NAb and conserved neutralization epitopes, using single-round PBMC neutralization assay and sequencing. Our study revealed that the concentration of NAb in LTNP was significantly higher than that in subjects with asymptomatic HIV (P < 0.05) and AIDS (P < 0.01). No amino acids substitutions were found in the conserved epitopes of the HIV-1 gp120 region in LTNP, whereas the viruses circulating both in persons with asymptomatic HIV and those with AIDS had amino acid substitutions in their conserved neutralization epitopes. This study suggests that high levels of NAb and stable epitopes in gp120 could play a crucial role in protection against disease progression.     

呼吸道合胞病毒疫苗及其抗体制剂的研究进展

呼吸道合胞病毒(respiratory syncytial virus,RSV)感染是一个全球性的健康问题,目前临床上仍缺乏特异的治疗手段。接种疫苗主动免疫预防或使用抗体制剂被动免疫预防是避免重症感染和减少死亡的重要措施。针对不同的人群,须研制不同类型的RSV疫苗：减毒活疫苗对婴儿来说,可能是最佳选择;亚单位疫苗有引起增强型呼吸道疾病的风险,不适合RSV血清学阴性的婴幼儿接种,主要适用于老年人和孕妇。研发安全且有效的RSV疫苗难度大,虽然已有30余种RSV疫苗进入临床研究阶段,并显示出应用潜力,其中F纳米颗粒疫苗已率先进入III期临床试验,但在老年人和孕妇中未达预期效果。在RSV流行季节前,使用特异性抗体制剂也是预防高危人群严重RSV感染性疾病的有效手段。长效单克隆抗体MEDI8897比帕利珠单抗更具成本效益,已进入III期临床试验,且获得优先研发资格。多克隆免疫球蛋白RI-002已在免疫缺陷人群中显示出较好的预防效果,具有进一步研发的现实意义。本综述针对近年来RSV疫苗及其抗体的研究进展进行阐述,期望为RSV的预防提供参考。     

Structure and design of broadly-neutralizing antibodies against HIV

Since the discovery more than 30 years ago of human immunodeficiency virus (HIV) as the causative agent of the deadly disease, acquired immune deficiency disease (AIDS), there have been no efficient vaccines against the virus. For the infection of the virus, the HIV surface glycoprotein gp120 first recognizes the CD4 receptor on the target helper T-cell, which initiates HIV fusion with the target cell and, if unchecked, leads to destruction of the patient's immune system. Despite the difficulty of developing appropriate immune responses in HIV-infected individuals, patient sera often contain antibodies that have broad neutralization activity, indicating the possibility of immunological treatment and prevention. Recently, through extensive structural studies of neutralizing antibodies of HIV in complex with gp120, the critical mechanisms of broad neutralization against HIV have been elucidated. Based on these discoveries, the structure-aided designs of antibodies and novel scaffolds were performed to create extremely potent neutralizing antibodies against HIV. These new discoveries and advances shed light on the road to development of efficient immunological therapies against AIDS.     

10E8-like neutralizing antibodies against HIV-1 induced using a precisely designed conformational peptide as a vaccine prime

Recent studies have demonstrated that the membrane-proximal external region(MPER)of human immunodeficiency virus 1(HIV-1)glycoprotein 41 contains a series of epitopes for human monoclonal antibodies,including 2F5,Z13e1,4E10,and10E8,which were isolated from HIV-1-infected individuals and show broad neutralizing activities.This suggests that MPER is a good target for the development of effective HIV-1 vaccines.However,many studies have shown that it is difficult to induce antibodies with similar broad neutralizing activities using MPER-based peptide antigens.Here,we report that 10E8-like neutralizing antibodies with effective anti-HIV-1 activity were readily induced using a precisely designed conformational immunogenic peptide containing the 10E8-specific epitope.This immunogenic peptide(designated T10HE)contains a 15-mer MPER-derived 10E8-specific epitope fused to T-helper-cell epitopes from tetanus toxin(tt),which showed a significantly stabilized-helix structure after a series of modifications,including substitution with an(S)--(2-pentenyl)alanine containing an olefin-bearing tether and ruthenium-catalyzed olefin metathesis,compared with the unmodified T10E peptide.The stabilized-helix structure of T10HE did not affect its capacity to bind the 10E8 antibody,as evaluated with an enzyme linked immunosorbent assay(ELISA)and surface plasmon resonance binding assay(SPR assay).The efficacies of the T10HE and T10E epitope vaccines were evaluated after a standard vaccination procedure in which the experimental mice were primed with either the T10HE or T10E immunogen and boosted with HIV-1 JRFL pseudoviruses.Higher titers of 10E8-like antibodies were induced by T10HE than that by T10E.More importantly,the antibodies induced by T10HE showed enhanced antiviral potency against HIV-1 strains with both X4 and R5 tropism and a greater degree of broad neutralizing activity than the antibodies induced by T10E.These results indicate that a 10E8-epitope-based structure-specific peptide immunogen can elicit neutralizing antibodies when used as a vaccine prime.     

Duration of neutralizing antibody titer after Japanese encephalitis vaccination

In paired serum samples collected from 17 children, we measured neutralizing antibody (NTAb) titers after the second series of routine Japanese encephalitis (JE) vaccination in Japan to estimate the duration of NTAb titer when children did not receive the third series of routine vaccination by applying a random coefficient model. We also measured NTAb titers in adult serum samples to confirm the duration of NTAb titer estimated in the analysis of pediatric serum samples. In the absence of the third series of routine vaccination, 18% (3/17), 47% (8/17), 82% (14/17) and 100% (17/17) of children were estimated to become NTAb negative at 5, 10, 15, and 20 years after the second series of routine vaccination, respectively. Of 38 adults, 39.5% (15/38) became NTAb negative; the percentage was somewhat lower than that of antibody-negative children. The results suggested that JE vaccination schedule should be reevaluated in the future.     

Induction of neutralizing antibody against human cytomegalovirus (HCMV) with DNA-mediated immunization of HCMV glycoprotein B in mice.

Immunization was accomplished by inoculating pcGB containing human cytomegalovirus (HCMV) glycoprotein B (gB) gene into BALB/c mice intramuscularly. IgM antibody was detected in all the immunized group. IgG antibody was also found in all the tested mice with a mean peak antibody titer of 1:262 in three-times immunized groups. IgG antibody appeared at 2 weeks postinoculation, raised peak levels at 7 weeks postinoculation and persisted over 6 months. Neutralizing antibody was developed, and the percent reduction of input infectivity in 1:100 diluted sera was 74.5 % in three-times immunized groups. This study suggested that DNA vaccine using the gene encoding HCMV gB is a candidate method for developing immunity to HCMV.     

Structural mimicry of CD4 by a cross-reactive HIV-1 neutralizing antibody with CDR-H2 and H3 containing unique motifs

Human immunodeficiency virus (HIV) entry into cells is initiated by the binding of its envelope glycoprotein (Env) gp120 to receptor CD4. Antibodies that bind to epitopes overlapping the CD4-binding site (CD4bs) on gp120 can prevent HIV entry by competing with cell-associated CD4; their ability to outcompete CD4 is a major determinant of their neutralizing potency and is proportional to their avidity. The breadth of neutralization and the likelihood of the emergence of antibody-resistant virus are critically dependent on the structure of their epitopes. Because CD4bs is highly conserved, it is reasonable to hypothesize that antibodies closely mimicking CD4 could exhibit relatively broad cross-reactivity and a high probability of preventing the emergence of resistant viruses. Previously, in a search for antibodies that mimic CD4 or the co-receptor, we identified and characterized a broadly cross-reactive HIV-neutralizing CD4bs human monoclonal antibody (hmAb), m18. Here, we describe the crystal structure of Fab m18 at 2.03 A resolution, which reveals unique conformations of heavy chain complementarity-determining regions (CDRs) 2 and 3 (H2 and H3). H2 is highly bulged and lacks cross-linking interstrand hydrogen bonds observed in all four canonical structures. H3 is 17.5 A long and rigid, forming an extended beta-sheet decorated with an alpha-turn motif bearing a phenylalanine-isoleucine fork at the apex. It shows striking similarity to the Ig CDR2-like C'C' region of the CD4 first domain D1 that dominates the binding of CD4 to gp120. Docking simulations suggest significant similarity between the m18 epitope and the CD4bs on gp120. Fab m18 does not enhance binding of CD4-induced (CD4i) antibodies, nor does it induce CD4-independent fusion mediated by the HIV Env. Thus, vaccine immunogens based on the m18 epitope structure are unlikely to elicit antibodies that could enhance infection. The structure can also serve as a basis for the design of novel, highly efficient inhibitors of HIV entry.     

Vaccine elicitation and structural basis for antibody protection against alphaviruses

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