A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge

Scott G. Hansen, Emily E. Marshall, Daniel Malouli, Abigail B. Ventura, Colette M. Hughes, Emily Ainslie, Julia C. Ford, David Morrow, Roxanne M. Gilbride, Jin Y. Bae, Alfred W. Legasse, Kelli Oswald, Rebecca Shoemaker, Brian Berkemeier, William J. Bosche, Michael Hull, Jennie Womack, Jason Shao, Paul T. Edlefsen, Jason S. ReedBen J. Burwitz, Jonah B. Sacha, Michael K. Axthelm, Klaus Früh, Jeffrey D. Lifson, Louis J. Picker

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Article numbereaaw2607
JournalScience translational medicine
Volume11
Issue number501
DOIs
StatePublished - Jul 17 2019

ASJC Scopus subject areas

  • Medicine(all)

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