标题: A live-attenuated RhCMV/SIV vaccine [打印本页] 作者: wwwkkk83 时间: 2019-7-18 08:01 标题: A live-attenuated RhCMV/SIV vaccine A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge
Scott G. Hansen1, Emily E. Marshall1,*, Daniel Malouli1, Abigail B. Ventura1, Colette M. Hughes1, Emily Ainslie1, Julia C. Ford1, David Morrow1, Roxanne M. Gilbride1, Jin Y. Bae1, Alfred W. Legasse1, Kelli Oswald2, Rebecca Shoemaker2, Brian Berkemeier2, William J. Bosche2, Michael Hull2, Jennie Womack1, Jason Shao3, Paul T. Edlefsen3, Jason S. Reed1, Ben J. Burwitz1, Jonah B. Sacha1, Michael K. Axthelm1, Klaus Früh1, Jeffrey D. Lifson2 and Louis J. Picker1,†
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Building a safer CMV vector
Vaccine vectors based on cytomegalovirus (CMV) show strong T cell induction and protection against a multitude of pathogens. However, CMV can be harmful to people who are immunodeficient or immunosuppressed. Marshall et al. genetically modified rhesus CMV to allow engagement of host intrinsic immunity. The modified ΔRh110 vector did not spread once administered to nonhuman primates but still induced robust T cell immunity. Hansen et al. showed in a simian immunodeficiency virus (SIV) challenge model that the ΔRh110 vector provided equivalent protection to the parental vector, enabling control and progressive clearance of virus from more than half of the vaccinated primates. Most protected animals that were rechallenged 3 years later were able to control the second challenge, demonstrating the durability of this vaccine. Mutations in the human CMV vector should lead to a potent but restrained CMV that could be used widely in people.
Abstract
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 (ΔRh110), allowing for suppression of lytic gene expression. ΔRh110 RhCMV/SIV vectors are highly spread deficient in vivo (~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 ΔRh110 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 ΔRh110 RhCMV/SIV–vaccinated RMs that controlled and progressively cleared an initial SIV challenge, 9 were able to stringently control a second SIV challenge ~3 years after last vaccination, demonstrating the durability of this vaccine. Thus, ΔRh110 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.