Understanding the Role of Innate Immunity in the Mechanism of Action of the Live Attenuated Yellow Fever Vaccine 17D

Querec, Troy D.; Pulendran, Bali

doi:10.1007/978-0-387-34814-8_3

Cited by 33 publications

(19 citation statements)

References 68 publications

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“…These VREPs, based on Semliki Forest virus (SFV), induce strong antibody and cellular responses in animals [5-10]. SFV, being a RNA virus, may target several innate signalling pathways [11,12] including toll-like receptor (TLR) 3 and 7, as well as cytoplasmic receptors of the RIG-I-like receptor (RLR) family [13]. We have shown that replication of VREP generates double-stranded (ds) RNA intermediates, and that immunization of mice with VREP infected Vero cells activates the TLR3 pathway leading to enhanced cross-priming [3].…”

Section: Introductionmentioning

confidence: 99%

Role of innate signalling pathways in the immunogenicity of alphaviral replicon-based vaccines

Näslund

Kostic

Nordström

et al. 2011

Virol J

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BackgroundAlphaviral replicon-based vectors induce potent immune responses both when given as viral particles (VREP) or as DNA (DREP). It has been suggested that the strong immune stimulatory effect induced by these types of vectors is mediated by induction of danger signals and activation of innate signalling pathways due to the replicase activity. To investigate the innate signalling pathways involved, mice deficient in either toll-like receptors or downstream innate signalling molecules were immunized with DREP or VREP.ResultsWe show that the induction of a CD8+ T cell response did not require functional TLR3 or MyD88 signalling. However, IRF3, converging several innate signalling pathways and important for generation of pro-inflammatory cytokines and type I IFNs, was needed for obtaining a robust primary immune response. Interestingly, type I interferon (IFN), induced by most innate signalling pathways, had a suppressing effect on both the primary and memory T cell responses after DREP and VREP immunization.ConclusionsWe show that alphaviral replicon-based vectors activate multiple innate signalling pathways, which both activate and restrict the induced immune response. These results further show that there is a delicate balance in the strength of innate signalling and induction of adaptive immune responses that should be taken into consideration when innate signalling molecules, such as type I IFNs, are used as vaccine adjuvant.

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Section: Introductionmentioning

confidence: 99%

Role of innate signalling pathways in the immunogenicity of alphaviral replicon-based vaccines

Näslund

Kostic

Nordström

et al. 2011

Virol J

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“…These activated dendritic cells most likely migrate to regional lymph nodes and stimulate both cell-mediated and humoral adaptive immune responses ( Iwasaki and Medzhitov, 2004 ;Kawai and Akira, 2006 ;Palmer et al, 2007 ;Querec and Pulendran, 2007 ). Viral interaction with alternate TLRs modifies the Th1 and Th2 cytokine balance produced by the activated immune cells, and it is possible that nonviral vaccine components could also influence this balance ( Querec et al, 2006 ;Querec and Pulendran, 2007 ). The interferon-induced peripheral lymphocyte response from vaccinees may be mediated in part through the action of 2Ј-5Ј oligoadenylate synthetase.…”

Section: Innate Immune Responsementioning

confidence: 96%

“…The 17D vaccine strain replicates minimally (perhaps abortively) in dendritic cells without causing substantial apoptotic cell death Palmer et al, 2007 ) and stimulates TLR 2, 7, 8, and 9 ( Querec et al, 2006 ), which results in the production of type I interferon and other inflammatory cytokines ( Wheelock and Sibley, 1965 ) and dendritic cell activation and maturation. These activated dendritic cells most likely migrate to regional lymph nodes and stimulate both cell-mediated and humoral adaptive immune responses ( Iwasaki and Medzhitov, 2004 ;Kawai and Akira, 2006 ;Palmer et al, 2007 ;Querec and Pulendran, 2007 ). Viral interaction with alternate TLRs modifies the Th1 and Th2 cytokine balance produced by the activated immune cells, and it is possible that nonviral vaccine components could also influence this balance ( Querec et al, 2006 ;Querec and Pulendran, 2007 ).…”

Section: Innate Immune Responsementioning

confidence: 97%

Yellow Fever

Galbraith

Barrett

2009

Vaccines for Biodefense and Emerging and Neglected Diseases

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“…More than 400 million people have been vaccinated since its development in the 1930s, with only rare adverse events [19], [26]–[28]. Perhaps because it can replicate in humans, YF17D triggers several innate immune pathways, which likely contributes to its high immunogenicity [29], [30]. Indeed, vaccination results in polyvalent adaptive immune responses consisting of effector CD8 + T-cells and a mixed T H 1/T H 2 CD4 + T-cell profile [28].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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.

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Understanding the Role of Innate Immunity in the Mechanism of Action of the Live Attenuated Yellow Fever Vaccine 17D

Cited by 33 publications

References 68 publications

Role of innate signalling pathways in the immunogenicity of alphaviral replicon-based vaccines

Role of innate signalling pathways in the immunogenicity of alphaviral replicon-based vaccines

Yellow Fever

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

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