A vaccine inducing solely cytotoxic T lymphocytes fully prevents Zika virus infection and fetal damage

Gambino, Frank; Tai, Wanbo; Voronin, Denis; Zhang, Yi; Zhang, Xiujuan; Shi, Juan; Wang, Xinyi; Wang, Ning; Du, Lanying; Qiao, Liang

doi:10.1016/j.celrep.2021.109107

Cited by 20 publications

(24 citation statements)

References 101 publications

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“…ZIKV NS5 protein cannot target murine STAT2 to evade IFN signaling, which hinders the use of WT mice in studying ZIKV-induced diseases 61 – 63 . Therefore, Ifnar1 −/− mice have been commonly used to study the pathogenesis of ZIKV and to test antiviral vaccines in vivo 3 , 5 , 43 , 64 . To characterize the infectivity profile of Z7 in vivo, we infected Ifnar1 −/− mice with Z7 (G10 or G11) or Z1 as a control.…”

Section: Discussionmentioning

confidence: 99%

An effective live-attenuated Zika vaccine candidate with a modified 5′ untranslated region

et al. 2023

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Zika virus (ZIKV) is a mosquito-transmitted flavivirus that has caused devastating congenital Zika syndrome (CZS), including microcephaly, congenital malformation, and fetal demise in human newborns in recent epidemics. ZIKV infection can also cause Guillain-Barré syndrome (GBS) and meningoencephalitis in adults. Despite intensive research in recent years, there are no approved vaccines or antiviral therapeutics against CZS and adult Zika diseases. In this report, we developed a novel live-attenuated ZIKV strain (named Z7) by inserting 50 RNA nucleotides (nt) into the 5′ untranslated region (UTR) of a pre-epidemic ZIKV Cambodian strain, FSS13025. We used this particular ZIKV strain as it is attenuated in neurovirulence, immune antagonism, and mosquito infectivity compared with the American epidemic isolates. Our data demonstrate that Z7 replicates efficiently and produces high titers without causing apparent cytopathic effects (CPE) in Vero cells or losing the insert sequence, even after ten passages. Significantly, Z7 induces robust humoral and cellular immune responses that completely prevent viremia after a challenge with a high dose of an American epidemic ZIKV strain PRVABC59 infection in type I interferon (IFN) receptor A deficient (Ifnar1−/−) mice. Moreover, adoptive transfer of plasma collected from Z7 immunized mice protects Ifnar1−/− mice from ZIKV (strain PRVABC59) infection. These results suggest that modifying the ZIKV 5′ UTR is a novel strategy to develop live-attenuated vaccine candidates for ZIKV and potentially for other flaviviruses.

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Section: Discussionmentioning

confidence: 99%

An effective live-attenuated Zika vaccine candidate with a modified 5′ untranslated region

et al. 2023

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“…17 Early efforts to facilitate processing include incorporation of protease cleavage sites by cathepsin and furin proteases, 18 but these enzymes also mediate endosomal processing which favors class II presentation. 19 Recent efforts to facilitate cytosolic processing include the incorporation of ubiquitin fusion proteins 20,21 and proteolysis-targeting chimeras (PROTACs). 22 Although these efforts enhance immunogenicity, the rules to predict processing and presentation for a given epitope remain to be uncovered.…”

Section: ■ Introductionmentioning

confidence: 99%

Design of Cytotoxic T Cell Epitopes by Machine Learning of Human Degrons

Truex,

Mohapatra,

Melo

et al. 2024

ACS Cent. Sci.

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Antigen processing is critical for therapeutic vaccines to generate epitopes for priming cytotoxic T cell responses against cancer and pathogens, but insufficient processing often limits the quantity of epitopes released. We address this challenge using machine learning to ascribe a proteasomal degradation score to epitope sequences. Epitopes with varying scores were translocated into cells using nontoxic anthrax proteins. Epitopes with a low score show pronounced immunogenicity due to antigen processing, but epitopes with a high score show limited immunogenicity. This work sheds light on the sequence–activity relationships between proteasomal degradation and epitope immunogenicity. We anticipate that future efforts to incorporate proteasomal degradation signals into vaccine designs will lead to enhanced cytotoxic T cell priming by these vaccines in clinical settings.

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“…Generating reliable and rapid data on peptide-MHC binding is beneficial for understanding the underlying biology of adaptive immunity and for clinical applications, including for optimized T cell epitopes in vaccine design ( Dai et al, 2021 ; Keskin et al, 2019 ; Liu et al, 2020 ; Liu et al, 2021b ; Moise et al, 2015 ; Ott et al, 2017 ; Patronov and Doytchinova, 2013 ; Rosati et al, 2021 ). In fact, therapeutics to generate antigen-specific T cell responses have shown great promise in cancer ( Keskin et al, 2019 ; Ott et al, 2017 ) and infectious disease ( Gambino et al, 2021 ). Since understanding peptide-MHC binding is critical for identifying and engineering T cell epitopes, there have been sustained efforts to produce high-quality experimental data and predictive algorithms.…”

Section: Introductionmentioning

confidence: 99%

A high-throughput yeast display approach to profile pathogen proteomes for MHC-II binding

Huisman

Dai

Gifford

et al. 2022

eLife

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T cells play a critical role in the adaptive immune response, recognizing peptide antigens presented on the cell surface by Major Histocompatibility Complex (MHC) proteins. While assessing peptides for MHC binding is an important component of probing these interactions, traditional assays for testing peptides of interest for MHC binding are limited in throughput. Here we present a yeast display-based platform for assessing the binding of tens of thousands of user-defined peptides in a high throughput manner. We apply this approach to assess a tiled library covering the SARS-CoV-2 proteome and four dengue virus serotypes for binding to human class II MHCs, including HLA-DR401, -DR402, and -DR404. While the peptide datasets show broad agreement with previously described MHC-binding motifs, they additionally reveal experimentally validated computational false positives and false negatives. We therefore present this approach as able to complement current experimental datasets and computational predictions. Further, our yeast display approach underlines design considerations for epitope identification experiments and serves as a framework for examining relationships between viral conservation and MHC binding, which can be used to identify potentially high-interest peptide binders from viral proteins. These results demonstrate the utility of our approach to determine peptide-MHC binding interactions in a manner that can supplement and potentially enhance current algorithm-based approaches.

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A vaccine inducing solely cytotoxic T lymphocytes fully prevents Zika virus infection and fetal damage

Cited by 20 publications

References 101 publications

An effective live-attenuated Zika vaccine candidate with a modified 5′ untranslated region

An effective live-attenuated Zika vaccine candidate with a modified 5′ untranslated region

Design of Cytotoxic T Cell Epitopes by Machine Learning of Human Degrons

A high-throughput yeast display approach to profile pathogen proteomes for MHC-II binding

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