Weaver Eric A, Nehete Pramod N, Buchl Stephanie S, Senac Julien S, Palmer Donna, Ng Philip, Sastry K Jagannadha, Barry Michael A
Department of Internal Medicine, Division of Infectious Diseases, Translational Immunovirology Program, Mayo Clinic, Rochester, MN, USA.
PLoS One. 2009;4(3):e5059. doi: 10.1371/journal.pone.0005059. Epub 2009 Mar 31.
All studies using human serotype 5 Adenovirus (Ad) vectors must address two major obstacles: safety and the presence of pre-existing neutralizing antibodies. Helper-Dependent (HD) Ads have been proposed as alternative vectors for gene therapy and vaccine development because they have an improved safety profile. To evaluate the potential of HD-Ad vaccines, we compared replication-competent (RC), first-generation (FG) and HD vectors for their ability to induce immune responses in mice. We show that RC-Ad5 and HD-Ad5 vectors generate stronger immune responses than FG-Ad5 vectors. HD-Ad5 vectors gave lower side effects than RC or FG-Ad, producing lower levels of tissue damage and anti-Ad T cell responses. Also, HD vectors have the benefit of being packaged by all subgroup C serotype helper viruses. We found that HD serotypes 1, 2, 5, and 6 induce anti-HIV responses equivalently. By using these HD serotypes in heterologous succession we showed that HD vectors can be used to significantly boost anti-HIV immune responses in mice and in FG-Ad5-immune macaques. Since HD vectors have been show to have an increased safety profile, do not possess any Ad genes, can be packaged by multiple serotype helper viruses, and elicit strong anti-HIV immune responses, they warrant further investigation as alternatives to FG vectors as gene-based vaccines.
所有使用人5型腺病毒（Ad）载体的研究都必须克服两个主要障碍：安全性和预先存在的中和抗体。依赖辅助病毒的（HD）腺病毒已被提议作为基因治疗和疫苗开发的替代载体，因为它们具有更好的安全性。为了评估HD腺病毒疫苗的潜力，我们比较了具有复制能力的（RC）、第一代（FG）和HD载体在小鼠体内诱导免疫反应的能力。我们发现，RC-Ad5和HD-Ad5载体比FG-Ad5载体产生更强的免疫反应。HD-Ad5载体的副作用比RC或FG-Ad低，产生的组织损伤和抗Ad T细胞反应水平更低。此外，HD载体的优势在于可由所有C亚组血清型辅助病毒包装。我们发现HD血清型1、2、5和6诱导抗HIV反应的效果相当。通过在异源序贯中使用这些HD血清型，我们表明HD载体可用于显著增强小鼠和FG-Ad5免疫猕猴体内的抗HIV免疫反应。由于HD载体已被证明具有更高的安全性，不含有任何Ad基因，可由多种血清型辅助病毒包装，并能引发强烈的抗HIV免疫反应，因此作为基于基因的疫苗，它们作为FG载体的替代品值得进一步研究。
