A Phase 1/2 Study of a Multiclade HIV‐1 DNA Plasmid Prime and Recombinant Adenovirus Serotype 5 Boost Vaccine in HIV‐Uninfected East Africans (RV 172)

179

154

Replication-defective adenovirus (rAd) vectors are powerful inducers of cellular immune responses and have therefore come to serve as useful vectors for gene-based vaccines, particularly for lentiviruses and filoviruses, as well as other nonviral pathogens (14,34,39,40,43,44,46). Adenovirus-based vaccines have several advantages as human vaccines-they can be produced to high titers under good manufacturing practice (GMP) conditions and have proven to be safe and immunogenic in humans (2,6,12,16,18). While most of the initial vaccine work was conducted using rAd serotype 5 (rAd5) due to its significant potency in eliciting broad antibody and CD8 ϩ T-cell responses, preexisting immunity to rAd5 in humans may limit efficacy (5-7, 29). This property might restrict the use of rAd5 vectors in clinical applications for many vaccines that are currently in development, including those for Ebolavirus (EBOV) and Marburg virus (MARV).To circumvent the issue of preexisting immunity to rAd5, several alternative vectors are currently under investigation. These include adenoviral vectors derived from rare human serotypes and vectors derived from other animals, such as chimpanzees (1,39,49). Research on the use of animal-derived adenoviral vectors is relatively nascent, while human adenoviruses possess the advantages of having well-characterized biology and tropism on human cells, as well as documented manufacturability (48). Immunogenicity of these vectors and their potential as vaccines has been demonstrated with animal models, primarily as prime-boost combinations with heterologous vectors (1, 41).Adenovirus seroprevalence frequencies are cohort dependent (28), but among the large group of 51 human adenoviruses tested, Ad35 and Ad11 were the most rarely neutralized by sera from six geographic locations (49). rAd35 vector vaccines have been shown to be immunogenic in mice, nonhuman primates (NHPs), and humans and are able to circumvent Ad5 immunity (4,30,31,36,47). rAd35 vectors grow to high titers in cell lines suitable for production of clinical-grade vaccines (13) and have been formulated for injection as well as stable inhalable powder (15). These vectors show efficient transduction of human dendritic cells (8,26) and thus have the capability to mediate high-level antigen delivery and presentation.Prime-boost regimens based on vectors derived from closely related adenovirus serotypes, such as Ad11 and Ad35, both from subgroup B, are less immunogenic than combinations of more genetically and immunologically distinct adenoviral vec-* Corresponding author. Mailing address:

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Recombinant Adenovirus Serotype 26 (Ad26) and Ad35 Vaccine Vectors Bypass Immunity to Ad5 and Protect Nonhuman Primates against Ebolavirus Challenge

Geisbert

Bailey

Hensley

et al. 2011

179

154

“…A regimen of priming with recombinant DNA and boosting with a viral vector has been shown to elicit strong T-cell immune responses (1)(2)(3); thus, it is becoming one of the most prevalent vaccine strategies (4). Several regimens have been widely adopted, including the DNA prime-vaccinia vector vaccine boost and the DNA prime-adenoviral vector vaccine boost (5).…”

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confidence: 99%

Boosting Functional Avidity of CD8 ⁺ T Cells by Vaccinia Virus Vaccination Depends on Intrinsic T-Cell MyD88 Expression but Not the Inflammatory Milieu

Wang

Wan

et al. 2014

T-cell functional avidity is a crucial determinant for efficient pathogen clearance. Although recombinant DNA priming coupled with a vaccinia-vectored vaccine (VACV) boost has been widely used to mount robust CD8 ؉ T-cell responses, how VACV boost shapes the properties of memory CD8 ؉ T cells remains poorly defined. Here, we characterize the memory CD8 ؉ T cells boosted by VACV and demonstrate that the intrinsic expression of MyD88 is critical for their high functional avidity. Independent of selection of clones with high-affinity T-cell receptor (TCR) or of enhanced proximal TCR signaling, the VACV boost significantly increased T-cell functional avidity through a decrease in the activation threshold. VACV-induced inflammatory milieu is not sufficient for this improvement, as simultaneous administration of the DNA vaccine and mock VACV had no effects on the functional avidity of memory CD8 ؉ T cells. Furthermore, reciprocal adoptive transfer models revealed that the intrinsic MyD88 pathway is required for instructing the functional avidity of CD8 ؉ T cells boosted by VACV. Taking these results together, the intrinsic MyD88 pathway is required for the high functional avidity of VACV-boosted CD8 ؉ T cells independent of TCR selection or the VACV infection-induced MyD88-mediated inflammatory milieu. IMPORTANCEFunctional avidity is one of the crucial determinants of T-cell functionality. Interestingly, although it has been demonstrated that a DNA prime-VACV boost regimen elicits high levels of T-cell functional avidity, how VACV changes the low avidity of CD8 ؉ T cells primed by DNA into higher ones in vivo is less defined. Here, we proved that the enhancement of CD8 ؉ T cell avidity induced by VACV boost is mediated by the intrinsic MyD88 pathway but not the MyD88-mediated inflammatory milieu, which might provide prompts in vaccine design.

“…We found that a multiclade DNA prime/recombinant adenovirus type 5 (rAd5) boost vaccine (14) elicited CD8 ϩ T cells with antiviral activity that was best associated with expression of CD107a and MIP-1␤. Elicitation of this antiviral activity did not require maturation to the late stages of differentiation, suggesting that vaccination in the absence of chronic antigen stimulation is sufficient for eliciting CD8 ϩ T-cell-mediated virus inhibition.…”

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confidence: 99%

Phenotypic and Functional Profile of HIV-Inhibitory CD8 T Cells Elicited by Natural Infection and Heterologous Prime/Boost Vaccination

Freel

Lamoreaux²,

Chattopadhyay

et al. 2010

117

149

Control of HIV-1 replication following nonsterilizing HIV-1 vaccination could be achieved by vaccine-elicited CD8؉ T-cell-mediated antiviral activity. To date, neither the functional nor the phenotypic profiles of CD8 ؉ T cells capable of this activity are clearly understood; consequently, little is known regarding the ability of vaccine strategies to elicit them. We used multiparameter flow cytometry and viable cell sorts from phenotypically defined CD8؉ T-cell subsets in combination with a highly standardized virus inhibition assay to evaluate CD8 ؉ T-cell-mediated inhibition of viral replication. Here we show that vaccination against HIV-1 Env and Gag-Pol by DNA priming followed by recombinant adenovirus type 5 (rAd5) boosting elicited CD8 ؉ T-cell-mediated antiviral activity against several viruses with either lab-adapted or transmitted virus envelopes. As it did for chronically infected virus controllers, this activity correlated with HIV-1-specific CD107a or macrophage inflammatory protein 1␤ (MIP-1␤) expression from HIV-1-specific T cells. Moreover, for vaccinees or virus controllers, purified memory CD8؉ T cells from a wide range of differentiation stages were capable of significantly inhibiting virus replication. Our data define attributes of an antiviral CD8 ؉ T-cell response that may be optimized in the search for an efficacious HIV-1 vaccine.