Immunogenicity of Seven New Recombinant Yellow Fever Viruses 17D Expressing Fragments of SIVmac239 Gag, Nef, and Vif in Indian Rhesus Macaques

Abstract

An effective vaccine remains the best solution to stop the spread of human immunodeficiency virus (HIV). Cellular immune responses have been repeatedly associated with control of viral replication and thus may be an important element of the immune response that must be evoked by an efficacious vaccine. Recombinant viral vectors can induce potent T-cell responses. Although several viral vectors have been developed to deliver HIV genes, only a few have been advanced for clinical trials. The live-attenuated yellow fever vaccine virus 17D (YF17D) has many properties that make it an attractive vector for AIDS vaccine regimens. YF17D is well tolerated in humans and vaccination induces robust T-cell responses that persist for years. Additionally, methods to manipulate the YF17D genome have been established, enabling the generation of recombinant (r)YF17D vectors carrying genes from unrelated pathogens. Here, we report the generation of seven new rYF17D viruses expressing fragments of simian immunodeficiency virus (SIV)mac239 Gag, Nef, and Vif. Studies in Indian rhesus macaques demonstrated that these live-attenuated vectors replicated in vivo, but only elicited low levels of SIV-specific cellular responses. Boosting with recombinant Adenovirus type-5 (rAd5) vectors resulted in robust expansion of SIV-specific CD8+ T-cell responses, particularly those targeting Vif. Priming with rYF17D also increased the frequency of CD4+ cellular responses in rYF17D/rAd5-immunized macaques compared to animals that received rAd5 only. The effect of the rYF17D prime on the breadth of SIV-specific T-cell responses was limited and we also found evidence that some rYF17D vectors were more effective than others at priming SIV-specific T-cell responses. Together, our data suggest that YF17D – a clinically relevant vaccine vector – can be used to prime AIDS virus-specific T-cell responses in heterologous prime boost regimens. However, it will be important to optimize rYF17D-based vaccine regimens to ensure maximum delivery of all immunogens in a multivalent vaccine.

Vaccine-Induced Simian Immunodeficiency Virus-Specific CD8 + T-Cell Responses Focused on a Single Nef Epitope Select for Escape Variants Shortly after Infection

“…Indeed, rh2099's rYF17D viremia reached 3.4 ϫ 10 5 vRNA copies/ml of plasma on day 6 post-rYF17D vaccination, the largest plasma concentration of rYF17D detected in Ͼ25 rYF17D-immunized animals examined in previous studies conducted by our laboratory (see Fig. S1A in the supplemental material) (27,32,33). Subsequent ICS assays demonstrated that these high-frequency CD8 ϩ T-cell responses were directed against a single epitope within aa 170 to 179 (TFGWLWKLVP) (see Fig.…”

“…Viral RNA was reverse transcribed and amplified using the TaqMan Fast Virus 1-Step master mix (Applied Biosystems) in an Applied Biosystems 7500 Fast instrument. Each reaction mixture contained 7.5 l of 4ϫ TaqMan Fast Virus 1-Step master mix, 400 nM forward primer, 900 nM reverse primer, 250 nM probe (5= FAM [6-carboxyfluorescein]/ZEN/ 3= IBFQ [Iowa Black FQ quencher]), and 20 l of RNA sample in a final volume of 30 l. The sequences of the primers and probe have been described previously (27). The reverse transcription was performed at 50°C for 5 min.…”

The yellow fever 17D virus as a platform for new live attenuated vaccines

“…. [71][72][73] In one of these experiments, animals expressing the Mamu-B*08 allele, a rhesus model for an HLA-B*27 mediated elite controller, controlled the replication of SIV after vaccination with a heterologous immunization regimen with recombinant YF17D viruses as a prime dose and recombinant Adenoviruses 5 as a booster dose, both expressing fragments of Vif and Nef. These animals exhibited a high frequency of CD8 + T cells detected in blood, lymph nodes, and colon that were specific to 3 different Mamu-B*08 restricted epitopes.…”

“…In order to better evaluate the efficacy of replicative-competent recombinant YF vectors, 7 YF17D viruses expressing fragments of the SIVmac239 Gag, Nef, and Vif proteins were utilized to vaccinate rhesus monkeys with different MHC haplotypes. 72 Despite the detection of replication of YF viruses in rhesus monkeys after vaccination, in general, they only elicited low levels of SIV-specific cellular immune responses, which considerably improved only after a recombinant Adenovirus type-5 vector booster. However, an increase of CD4 + T cellular responses was only observed after heterologous YF17D/rAd5 immunization, but not after Ad5 vaccination only, advocating a role of recombinant YF17D viruses to prime virus-specific T-cell responses in heterologous primeboost immunizations.…”

Immune activation alters cellular and humoral responses to yellow fever 17D vaccine

“…Defining vaccine efficacy in African populations is of paramount importance, as these populations are targeted by most of the currently tested vaccines for HIV, tuberculosis, malaria, and dengue virus (DENV) (19). Of note, several vaccine candidates use the YF-17D backbone as a vector for presentation of antigens from DENV, Japanese encephalitis virus, West Nile virus, and HIV (20)(21)(22).…”