A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge
A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge
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DOI：
10.1126/scitranslmed.aaw2607
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发表时间：
2019-07-17
影响因子：
17.1
通讯作者：
Picker, Louis J.
中科院分区：
文献类型：
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作者：
Hansen, Scott G.;Marshall, Emily E.;Picker, Louis J.
先前的研究已经证实，68-1衍生的恒河巨细胞病毒（RhCMV）载体表达猴免疫缺陷病毒（SIV）蛋白（RhCMV/SIV）能够引发和维持细胞免疫反应，从而保护恒河猴（RMs）免受高致病性SIV的粘膜攻击。然而，这些有效的RhCMV/SIV载体具有复制和传播能力，因此有可能在免疫功能低下的受试者中引起疾病。为了开发一种更安全的cmv疫苗用于临床，我们通过删除编码pp71被膜蛋白（Delta Rh110）的Rh110基因来减毒68-1 RhCMV/SIV载体，从而抑制裂解基因的表达。Delta Rh110 RhCMV/SIV载体在体内高度传播缺陷（与亲本载体相比，类似于1000倍），但仍然能够重叠感染RhCMV+ rmm并产生高频效应记忆偏向T细胞反应。在这里，我们证明表达同源或异源SIV抗原的Delta Rh110 68-1 RhCMV/SIV对阴道内（IVag） SIVmac239攻击非常有效，在59%的接种过SIV的rm中提供控制和逐步清除SIV感染。此外，在12个接种Delta Rh110 RhCMV/SIV疫苗的RMs中，控制并逐步清除了最初的SIV攻击，9个能够在最后一次接种后3年内严格控制第二次SIV攻击，表明该疫苗的持久性。因此，Delta Rh110 RhCMV/SIV载体具有安全性和有效性，值得适应和临床评估相应的HCMV载体作为预防性HIV/AIDS疫苗。
Previous studies have established that strain 68-1-derived rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) proteins (RhCMV/SIV) are able to elicit and maintain cellular immune responses that provide protection against mucosal challenge of highly pathogenic SIV in rhesus monkeys (RMs). However, these efficacious RhCMV/SIV vectors were replication and spread competent and therefore have the potential to cause disease in immunocompromised subjects. To develop a safer CMV-based vaccine for clinical use, we attenuated 68-1 RhCMV/SIV vectors by deletion of the Rh110 gene encoding the pp71 tegument protein (Delta Rh110), allowing for suppression of lytic gene expression. Delta Rh110 RhCMV/SIV vectors are highly spread deficient in vivo (similar to 1000-fold compared to the parent vector) yet are still able to superinfect RhCMV+ RMs and generate high-frequency effector-memory-biased T cell responses. Here, we demonstrate that Delta Rh110 68-1 RhCMV/SIV-expressing homologous or heterologous SIV antigens are highly efficacious against intravaginal (IVag) SIVmac239 challenge, providing control and progressive clearance of SIV infection in 59% of vaccinated RMs. Moreover, among 12 Delta Rh110 RhCMV/SIV-vaccinated RMs that controlled and progressively cleared an initial SIV challenge, 9 were able to stringently control a second SIV challenge similar to 3 years after last vaccination, demonstrating the durability of this vaccine. Thus, Delta Rh110 RhCMV/SIV vectors have a safety and efficacy profile that warrants adaptation and clinical evaluation of corresponding HCMV vectors as a prophylactic HIV/AIDS vaccine.