Buge S L, Murty L, Arora K, Kalyanaraman V S, Markham P D, Richardson E S, Aldrich K, Patterson L J, Miller C J, Cheng S M, Robert-Guroff M
Basic Research Laboratory, National Cancer Institute, Bethesda, Maryland 20892, USA.
J Virol. 1999 Sep;73(9):7430-40. doi: 10.1128/JVI.73.9.7430-7440.1999.
Rhesus macaques were immunized with a combination vaccine regimen consisting of adenovirus type 5 host range mutant-simian immunodeficiency virus envelope (Ad5hr-SIVenv) recombinant priming and boosting with native SIV gp120. Upon intravaginal challenge with SIVmac251, both persistently and transiently viremic animals were observed (S. L. Buge, E. Richardson, S. Alipanah, P. Markham, S. Cheng, N. Kalyan, C. J. Miller, M. Lubeck, S. Udem, J. Eldridge, and M. Robert-Guroff, J. Virol. 71:8531-8541, 1997). Long-term follow-up of the persistently viremic immunized macaques, which displayed significantly reduced viral burdens during the first 18 weeks postchallenge compared to controls, has now shown that one of four became a slow progressor, clearing virus from plasma and remaining asymptomatic with stable CD4 counts for 134 weeks postchallenge. Reboosting of the transiently viremic macaques did not reactivate latent virus. Rechallenge with two sequential SIVmac251 intravaginal exposures again resulted in partial protection of one of two immunized macaques, manifested by viral clearance and stable CD4 counts. No single immune parameter was associated with partial protection. Development of a strong antibody response capable of neutralizing a primary SIVmac251 isolate together with SIV-specific cytotoxic T lymphocytes were implicated, while CD8(+) T-cell antiviral activity and mucosal immune responses were not associated with delayed disease progression. Our data show that even a third immunization with the same Ad5hr-SIVenv recombinant can elicit significant immune responses to the inserted gene product, suggesting that preexisting Ad antibodies may not preclude effective immunization. Further, the partial protection against a virulent, pathogenic SIV challenge observed in two of six macaques immunized with a vaccine regimen based solely on the viral envelope indicates that this vectored-vaccine approach has promise and that multicomponent vaccines based in the same system merit further investigation.
恒河猴用由5型腺病毒宿主范围突变体-猿猴免疫缺陷病毒包膜（Ad5hr-SIVenv）重组体进行初次免疫，并以天然SIV gp120进行加强免疫的联合疫苗方案进行免疫。在用SIVmac251进行阴道攻击后，观察到了持续和短暂病毒血症的动物（S.L.布格、E.理查森、S.阿里帕纳、P.马克姆、S.程、N.卡利安、C.J.米勒、M.卢贝克、S.乌德姆、J.埃尔德里奇和M.罗伯特-古罗夫，《病毒学杂志》71:8531-8541，1997年）。对持续病毒血症的免疫猕猴进行长期随访，与对照组相比，这些猕猴在攻击后前18周的病毒载量显著降低，现在已经表明，四只中有一只成为缓慢进展者，在攻击后134周从血浆中清除病毒并保持无症状，CD4计数稳定。对短暂病毒血症的猕猴进行再次加强免疫并没有重新激活潜伏病毒。用两次连续的SIVmac251阴道暴露进行再次攻击，再次导致两只免疫猕猴中的一只获得部分保护，表现为病毒清除和CD4计数稳定。没有单一的免疫参数与部分保护相关。涉及到产生能够中和原发性SIVmac251分离株的强烈抗体反应以及SIV特异性细胞毒性T淋巴细胞，而CD8(+) T细胞抗病毒活性和黏膜免疫反应与疾病进展延迟无关。我们的数据表明，即使使用相同Ad5hr-SIVenv重组体进行第三次免疫也能引发对插入基因产物的显著免疫反应，这表明预先存在的Ad抗体可能并不排除有效的免疫接种。此外，在用仅基于病毒包膜的疫苗方案免疫的六只猕猴中的两只中观察到对强毒、致病性SIV攻击的部分保护，这表明这种载体疫苗方法有前景，并且基于同一系统的多组分疫苗值得进一步研究。
