研究人员成功地对两个有可能最终通过联合使用来抵御艾滋病感染的候选疫苗进行了测试。他们的这个研究成果已经发表在12月15日的《传染病杂志》上，目前还不能在线查阅。
来自马里兰州国家IH健康疫苗研究中心、位于西雅图Fred Hutchinson癌症研究中心以及GenVec的Barney S. Graham博士和他的同事们合作检测了两种可能的HIV疫苗，希望这两种疫苗能在健康人体中产生免疫应答。其中一种是表达三种优势HIV亚型基于质粒DNA的疫苗，另一种是使用重组腺病毒血清型5（rAd5）作为载体来表达相似的HIV菌株。
“两种方法都是由基因表达产生常规情况下由宿主细胞产生的启动免疫应答的疫苗抗体。DNA简单又不会产生抗载体免疫力的问题。但是，DNA可能比基于载体的基因表达效果要差一些。复制有缺陷的rAd5具有其作为靶点的优势，有效的基因表达以及高效价，但是可能在抗载体免疫方面存在疑问，”Graham说。
两种疫苗都已经在健康成人志愿者身上进行了试验。DNA疫苗表现出了良好的安全性和耐受性。进行免疫12周后，有97.5%的免疫者产生了CD4 T细胞阳性应答，40%产生了CD8 T细胞的应答。
两种疫苗联合使用同样表现出了很好的耐受性，但是更高的剂量导致了一些诸如疼痛和发热等不良反应的发生。进行免疫4周后，93.3%的免疫者产生了CD4 T细胞阳性应答，60%产生了CD8 T细胞的应答。
“HIV特异性CD8细胞应答可以清除病毒感染的细胞。 CD8细胞会在急性感染后病毒血症下降的时候产生，”Graham解释说，“HIV特异性CD4应答在感染的初期达到峰值，但是这种应答会在血清学转换后很快减小。保持有效的HIV特异性CD4细胞应答与长时间非进行性HIV有关。”
Emory大学的Harriet L. Robinson博士以及杜克大学的Kent J. Weinhold博士评论这项成果的影响时说：“他们首先证明了DNA疫苗可以在免疫者身上成功的引发免疫应答，DNA研究对于这种基于DNA的疫苗起到了里程碑的作用，”他们说，“重组Ad5 HIV疫苗与DNA疫苗相比具有更高的应答率以及更高的免疫应答反应。”
Graham表示下一步将是“评价联合使用DNA引发以及rAd5提高作用。联合使用这些基因表达疫苗的方法具有与单独使用不同的、引导更高水平Ｔ细胞应答的潜力。”
Robinson和Weinhold补充说，联合用药的想法是基于“疫苗应用DNA来引发免疫应答以及产生有缺陷的重组腺病毒血清型５载体来提高应答反应。”
Source: Infectious Diseases Society of America
Date: November 14, 2006
Progress Made In HIV Vaccine Development
Researchers have successfully tested two candidate vaccines that may eventually be used together to confer immunity against HIV infection. Their findings are published in the December 15 issue of The Journal of Infectious Diseases, now available online.
Barney S. Graham, MD, PhD, and colleagues from the National Institutes of Health IH Vaccine Research Center in Maryland, the Fred Hutchinson Cancer Research Center in Seattle, and GenVec Incorporated tested two possible HIV vaccines with the hope of producing an immune response in healthy, uninfected adults. One was a plasmid DNA-based vaccine expressing genes from three dominant HIV subtypes, and the second used recombinant adenovirus serotype 5 (rAd5) as a vector to deliver similar HIV strains.
"Both approaches operate by gene delivery of customized vaccine antigens that are produced by host cells to initiate an immune response. DNA is simple and does not have the problem of anti-vector immunity. However, DNA may be less potent than vector-based gene delivery strategies. Replication-defective rAd5 has the advantage of targeted, efficient gene delivery and high potency, but may be susceptible to anti-vector immunity," said Graham.
Both vaccines were tested in healthy uninfected adult volunteers. The DNA vaccine was found safe and well-tolerated. By week 12 following immunization, 97.5% of vaccinees experienced positive CD4 T cell responses and 40% experienced positive CD8 T cell responses.
The recombinant vector vaccine was also well-tolerated, but higher doses led to some adverse events such as pain and fever. By week 4 following immunization, 93.3% of vaccinees experienced positive CD4 T cell responses, and 60% experienced positive CD8 T cell responses.
"HIV-specific CD8 cell responses clear virus infected cells, and appear during the declining viremia following acute infection," explained Graham. "HIV-specific CD4 responses also peak early in infection; however this response diminishes soon after seroconversion. Maintenance of a functional HIV-specific CD4 T cell response correlates with long term non-progression of HIV disease."
Harriet L. Robinson, PhD, from Emory University and Kent J. Weinhold, PhD, from Duke University commented on the impact of these results in their accompanying editorial. "The DNA studies are a landmark for DNA-based vaccines in that they are the first to demonstrate a DNA vaccine successfully eliciting immune responses in essentially all vaccinated volunteers," they said. "The Ad5 recombinant HIV vaccine had both a higher percentage of responders and, overall, a higher magnitude of responses than the DNA vaccine."
The next step, according to Graham, is "to evaluate the combination of DNA priming and rAd5 boosting. Combining these distinct gene-delivery vaccination approaches has the potential to induce higher levels of T cell responses and a different quality of response than either approach by itself."
As Robinson and Weinhold add, the idea behind combining strategies is that "the vaccine uses DNA to prime the immune response and a replication defective recombinant adenovirus serotype 5 vector to boost responses."
http://www.sciencedaily.com/releases/2006/11/061112094540.htm
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