Crotty S, Miller C J, Lohman B L, Neagu M R, Compton L, Lu D, Lü F X, Fritts L, Lifson J D, Andino R
Department of Microbiology and Immunology, University of California, San Francisco, California 94143-0414, USA.
J Virol. 2001 Aug;75(16):7435-52. doi: 10.1128/JVI.75.16.7435-7452.2001.
Here we provide the first report of protection against a vaginal challenge with a highly virulent simian immunodeficiency virus (SIV) by using a vaccine vector. New poliovirus vectors based on Sabin 1 and 2 vaccine strain viruses were constructed, and these vectors were used to generate a series of new viruses containing SIV gag, pol, env, nef, and tat in overlapping fragments. Two cocktails of 20 transgenic polioviruses (SabRV1-SIV and SabRV2-SIV) were inoculated into seven cynomolgus macaques. All monkeys produced substantial anti-SIV serum and mucosal antibody responses. SIV-specific cytotoxic T-lymphocyte responses were detected in three of seven monkeys after vaccination. All 7 vaccinated macaques, as well as 12 control macaques, were challenged vaginally with pathogenic SIVmac251. Strikingly, four of the seven vaccinated animals exhibited substantial protection against the vaginal SIV challenge. All 12 control monkeys became SIV positive. In two of the seven SabRV-SIV-vaccinated monkeys we found no virological evidence of infection following challenge, indicating that these two monkeys were completely protected. Two additional SabRV-SIV-vaccinated monkeys exhibited a pronounced reduction in postacute viremia to <10(3) copies/ml, suggesting that the vaccine elicited an effective cellular immune response. Three of six control animals developed clinical AIDS by 48 weeks postchallenge. In contrast, all seven vaccinated monkeys remained healthy as judged by all clinical parameters. These results demonstrate the efficacy of SabRV as a potential human vaccine vector, and they show that the use of a vaccine vector cocktail expressing an array of defined antigenic sequences can be an effective vaccination strategy in an outbred population.
在此，我们首次报告了使用疫苗载体预防高致病性猿猴免疫缺陷病毒（SIV）阴道攻击的情况。构建了基于萨宾1型和2型疫苗株病毒的新型脊髓灰质炎病毒载体，这些载体用于产生一系列包含SIV gag、pol、env、nef和tat重叠片段的新病毒。将两种由20种转基因脊髓灰质炎病毒组成的混合物（SabRV1-SIV和SabRV2-SIV）接种到7只食蟹猴体内。所有猴子均产生了大量抗SIV血清和黏膜抗体反应。接种疫苗后，在7只猴子中的3只检测到了SIV特异性细胞毒性T淋巴细胞反应。所有7只接种疫苗的猕猴以及12只对照猕猴均经阴道接种致病性SIVmac251。令人惊讶的是，7只接种疫苗的动物中有4只对阴道SIV攻击表现出显著的保护作用。所有12只对照猴子均感染SIV呈阳性。在7只接种SabRV-SIV的猴子中有2只，在攻击后未发现病毒感染的病毒学证据，表明这两只猴子得到了完全保护。另外2只接种SabRV-SIV的猴子在急性感染后病毒血症明显降低至<10³拷贝/毫升，表明该疫苗引发了有效的细胞免疫反应。6只对照动物中有3只在攻击后48周出现临床艾滋病。相比之下，根据所有临床参数判断，所有7只接种疫苗的猴子均保持健康。这些结果证明了SabRV作为一种潜在的人类疫苗载体的有效性，并且表明使用表达一系列确定抗原序列的疫苗载体混合物在远交群体中可以是一种有效的疫苗接种策略。
