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Abstract
Rhesus cytomegalovirus (RhCMV) strain 68-1-vectored simian immunodeficiency virus (RhCMV/SIV) vaccines are associated with complete clearance of pathogenic SIV challenge virus, non-canonical major histocompatibility complex restriction, and absent antibody responses in recipients previously infected with wild-type RhCMV. This report presents the first investigation of RhCMV/SIV vaccines in RhCMV-seronegative macaques lacking anti-vector immunity. Fifty percent of rhesus macaques (RM) vaccinated with a combined RhCMV-Gag, -Env, and -Retanef (RTN) vaccine controlled pathogenic SIV challenge despite high peak viremia. However, kinetics of viral load control by vaccinated RM were considerably delayed compared to previous reports. Impact of a TLR5 agonist (flagellin; FliC) on vaccine efficacy and immunogenicity was also examined. An altered vaccine regimen containing an SIV Gag-FliC fusion antigen instead of Gag was significantly less immunogenic and resulted in reduced protection. Notably, RhCMV-Gag and RhCMV-Env vaccines elicited anti-Gag and anti-Env antibodies in RhCMV-seronegative RM, an unexpected contrast to vaccination of RhCMV-seropositive RM. These findings confirm that RhCMV-vectored SIV vaccines significantly protect against SIV pathogenesis. However, pre-existing vector immunity and a pro-inflammatory vaccine adjuvant may influence RhCMV/SIV vaccine immunogenicity and efficacy. Future investigation of the impact of pre-existing anti-vector immune responses on protective immunity conferred by this vaccine platform is warranted.
Highlights
Rhesus cytomegalovirus (RhCMV) strain 68-1-vectored simian immunodeficiency virus (RhCMV/SIV) vaccines are associated with complete clearance of pathogenic SIV challenge virus, non-canonical major histocompatibility complex restriction, and absent antibody responses in recipients previously infected with wild-type RhCMV
Remarkable rates of 50–59% efficacy have been reported for the RhCMV68-1-vectored SIV vaccine and an attenuated version vectored by ΔRH110 RhCMV
Our current study found that four of eight viremic rhesus macaques (RM) (50%) vaccinated with the RhCMV68-1-vectored SIV vaccine demonstrated superior control of virus loads after challenge, as defined by a significant decline in plasma viral loads (Fig. 4b), a parallel decline in anti-Gag antibody responses (Fig. 5a), and sparing of CD4 T cells in blood and tissues (Supp Fig. S5) at later time points
Summary
Rhesus cytomegalovirus (RhCMV) strain 68-1-vectored simian immunodeficiency virus (RhCMV/SIV) vaccines are associated with complete clearance of pathogenic SIV challenge virus, non-canonical major histocompatibility complex restriction, and absent antibody responses in recipients previously infected with wild-type RhCMV. The only HIV-1 vaccine showing efficacy in human clinical trials remains the RV144 ALVAC-HIV (vCP1521) and AIDSVAX® B/E regimen, which is based on a recombinant canarypox vector boosted by a recombinant glycoprotein gp[120] s ubunit[1] This vaccine was associated with 31.2% protection against HIV acquisition, with envelope (Env)-binding antibodies capable of antibody-dependent cytotoxicity implicated as an immune correlate of protection[1,2]. These encouraging results propelled further development of antibody-based approaches using the nonhuman primate (NHP) simian immunodeficiency virus (SIV) model with the goal of further optimizing protection through generation of antibodies with broadly neutralizing and/or Fc-receptor-mediated effector activity. Studies described will compare immunogenicity and efficacy of regimens including RhCMV-Gag versus RhCMV-Gag-FliC when administered to previously RhCMV-seronegative recipients
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