Increases in NKG2C Expression on T Cells and Higher Levels of Circulating CD8⁺B Cells Are Associated with Sterilizing Immunity Provided by a Live Attenuated SIV Vaccine

Abstract

Vaccines based on live attenuated viruses are highly effective immunogens in the simian immunodeficiency virus (SIV)/rhesus macaque animal model and offer the possibility of studying correlates of protection against infection with virulent virus. We utilized a tether system for studying, in naive macaques and animals vaccinated with a live-attenuated vaccine, the acute events after challenge with pathogenic SIV. This approach allowed for the frequent sampling of small blood volumes without sedation or restraining of the animals, thus reducing the confounding effect of sampling stress. Before challenge, vaccinated animals presented significantly higher levels of proliferating and activated B cells than naive macaques, which were manifested by high expression of CD8 on B cells. After SIV challenge, the only changes observed in protected vaccinated macaques were significant increases in expression of the NK marker NKG2C on CD4 and CD8 T cells. We also identified that infection of naive macaques with SIV resulted in a transient peak of expression of CD20 on CD8 T cells and a constant rise in the number of B cells expressing CD8. Finally, analysis of a larger cohort of vaccinated animals identified that, even when circulating levels of vaccine virus are below the limit of detection, live attenuated vaccines induce systemic increases of IP-10 and perforin. These studies indicate that components of both the innate and adaptive immune systems of animals inoculated with a live-attenuated SIV vaccine respond to and control infection with virulent virus. Persistence of the vaccine virus in tissues may explain the elevated cytokine and B-cell activation levels. In addition, our report underpins the utility of the tether system for the intensive study of acute immune responses to viral infections.

Responsiveness to Influenza Vaccination Correlates with NKG2C-Expression on NK Cells

“…These findings might suggest that the observed increase in NKG2C-expressing NK cells upon pandemic influenza vaccination is due to adjuvantation with AS03. However, the immunization of macaques with a live attenuated SIV vaccine and a subsequent challenge was found to result in elevated frequencies of NKG2C-expressing circulating T cells in vaccinated but not unvaccinated animals [ 38 ]. Another study with SIV-infected rhesus macaques demonstrated the NK cell-mediated killing of antigen-pulsed DCs in a NKG2C-dependent manner [ 39 ].…”

Humanized Mice for Live-Attenuated Vaccine Research: From Unmet Potential to New Promises

“…Therefore, many LAV strategies have been evaluated in NHPs using live-attenuated simian immunodeficiency virus (SIV) [204][205][206][207][208][209], the simian version of HIV-1 that only replicates in NHP species. Additional strategies employing HIV-1 related viruses [210,211] or engineered viruses harboring HIV-1 or SIV antigens [212,213] have also been tested in NHPs. NHPs have also been employed to investigate and/or evaluate the immunogenicity of many other LAVs, such as viral vectors harboring Ebola virus glycoproteins [214][215][216][217][218], LAIV [195], OPV [189,190], MV-LAV [150,185,197,[219][220][221], BCG [156], live-attenuated Venezuelan equine encephalitis virus [222], YFV-17D [151] or live-attenuated Zika virus [43].…”