Enhancing safety of cytomegalovirus-based vaccine vectors by engaging host intrinsic immunity

Marshall, Emily E.; Malouli, Daniel; Hansen, Scott G.; Gilbride, Roxanne M.; Hughes, Colette M.; Ventura, Abigail B.; Ainslie, Emily; Selseth, Andrea N.; Ford, Julia C.; Burke, David; Kreklywich, Craig N.; Womack, Jennie; Legasse, Alfred W.; Axthelm, Michael K.; Kahl, Christoph; Streblow, Daniel N.; Edlefsen, Paul T.; Picker, Louis J.; Früh, Klaus

doi:10.1126/scitranslmed.aaw2603

Cited by 29 publications

(62 citation statements)

References 81 publications

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“…In a companion report (20), we describe a CMV attenuation strategy based on deletion of the Rh110 gene (RhCMV ortholog to HCMV UL82), which encodes pp71, a tegument phospho-protein which functions to disperse and/or degrade the host intrinsic immunity protein death-domain associated protein (DAXX). DAXX functions in nuclear ND10 bodies to repress transcription of viral immediate early (IE) genes, which are critical for early and late CMV gene expression, and thus, viral genome replication, assembly and egress (21)(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

“…In the absence of viral pp71, DAXX represses lytic CMV replication, and the infection becomes and remains latent. Although DAXX can be overcome at high multiplicities of infection in vitro, ΔRh110 (Δpp71) RhCMV is highly spread-deficient in vivo, with infection largely restricted to the inoculating dose at the site of inoculation and draining lymph nodes (20). In contrast to parental 68-1 RhCMV, ΔRh110 68-1 RhCMV was not shed in urine, nor transferred to new hosts by close contact or adoptive cell transfer, and this attenuation was stable over time with no signs of reversion in vivo.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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 (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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Although detected, responses were inconsistent and of lower magnitude (Fig. 2b www.nature.com/scientificreports/ than expected based on previous reports with this vaccine 17,19,20,26 . Furthermore, both CD4 and CD8 T-cell responses were detected for this supertope and MHC-E restriction could not be confirmed for RM within this study due to inconsistent blocking activity by the MHC-E-binding peptide, VL9.…”

Section: Discussionmentioning

confidence: 62%

RhCMV serostatus and vaccine adjuvant impact immunogenicity of RhCMV/SIV vaccines

Chang

Deere

Kieu

et al. 2020

Sci Rep

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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 preexisting anti-vector immune responses on protective immunity conferred by this vaccine platform is warranted. Development of an efficacious human immunodeficiency virus (HIV-1) vaccine remains a high-priority goal. 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 gp120 subunit 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. These approaches, based on a wide assortment of viral and DNA vectors and recombinant protein immunogens, have shown modest protection against acquisition of challenge virus 3-6. However, a news release by NIH/ NIAD (2020) revealed that the HVTN 702 human clinical trial testing a vaccine approach based on the RV144 regimen, adapted to the subtype Clade C, and conducted in southern Africa, did not recapitulate the efficacy

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“…∆Rh110 RhCMV/SIV set [23,24] Attenuated RhCMV strain 68-1 7/13 showed long-lasting absence of SIV viremia RhCMV/EBOV-GP [25] RhCMV strain IgG responses correlated to protection with no neutralizing antibodies.…”

Section: Plasmodium Knowlesi Sporozoite Challengementioning

confidence: 99%

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

2019

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Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.Vaccines 2019, 7, 152 2 of 28 CMV-based vaccines, the large pool of functional antigen-specific T cells in the periphery and the possibility to modify CMV genomes due to improvements in viral genetics [11] draw a strong interest to CMV as a vaccine vector [12,13] (Table 1). The inflationary response appears linked to immune protection [14,15] and has been proposed as a target for immunization induction [16]. Vaccines 2019, 7, 152 3 of 28 Full-length HPV16 E6 and E7 Antigen fused to the C-terminus of ie2 Transient limitation of tumour cell growth MCMV IE2E7 [14] MHC-I restricted HPV16 E7 49-57 epitope Epitope fused to the C-terminus of ie2 No tumour cell growth upon challenge MCMV-M79-FKBP-E7 [36] MCMV Smith Strain with FKBP-mediated destabilization of the essential M79 gene Vaccines 2019, 7, 152 5 of 28Besides the exceptional induction of adaptive immune response in humans [2,37], CMV possesses assets that conveniently address weaknesses common to other vector candidates. The cloning of CMV genomes as bacterial artificial chromosomes in Escherichia coli [38] has allowed genetic engineering approaches to effectively express multiple exogenous immunogens or modify large genome portions [39,40]. Furthermore, CMV is known to superinfect hosts with a history of prior exposure to the virus [41] due to its immune evasive properties that protect the virus from recognition by primed T-cells [42] and CMV vectors induce protective immunity in experimentally vaccinated animals with documented prior exposure to 36]. Therefore, CMV vector candidates would avoid immune interference as described for AdV. CMV is a pathogenic organism in immunodeficient populations [43] or in congenitally infected children. Therefore, it is imperative for any HCMV vaccine vector to be attenuated. The generation of replication deficient CMVs that maintain their immunogenicity [36,44] and the modification of genome portions that contain evasions genes [45], as well as the insertion of activating ligands to increase immune control of CMV [46][47][48] are strategies that will be described in this review. Inter...

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Enhancing safety of cytomegalovirus-based vaccine vectors by engaging host intrinsic immunity

Cited by 29 publications

References 81 publications

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

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

RhCMV serostatus and vaccine adjuvant impact immunogenicity of RhCMV/SIV vaccines

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

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