Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 11, Issue 501, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaw2607
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Funding
- Bill AMP
- Melinda Gates Foundation-supported Collaboration for AIDS Vaccine Discovery [OPP1033121]
- National Institute of Allergy and Infectious Diseases (NIAID) [P01 AI094417, R37 AI054292, R01 AI059457]
- NIH Office of the Director [P51 OD011092]
- National Cancer Institute [HHSN261200800001E]
- Bill and Melinda Gates Foundation [OPP1033121] Funding Source: Bill and Melinda Gates Foundation
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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.
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