Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry

Miles, John J.; Tan, Mai Ping; Dolton, Garry; Edwards, Emily S.J.; Galloway, Sarah A. E.; Laugel, Bruno; Clement, Mathew; Makinde, Julia; Ladell, Kristin; Matthews, Katherine; Watkins, Thomas S.; Tungatt, Katie; Wong, Yide; Lee, Han Siean; Clark, Richard J.; Pentier, Johanne; Attaf, Meriem; Lissina, Anna; Ager, Ann; Gallimore, Awen; Rizkallah, P.J.; Gras, Stéphanie; Rossjohn, Jamie; Burrows, Scott R.; Cole, David K.; Price, David A.; Sewell, Andrew K.

doi:10.1172/jci91512

Cited by 26 publications

(30 citation statements)

References 59 publications

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“…Further work will be required to reveal if any of the potential infection-derived peptides found by our work are genuinely presented to T-cells in vivo. Moreover, this combined computational-experimental approach also has the potential to be used to discover potent peptide agonists of any T-cell clone for use in TCR-optimised peptide skewing of the repertoire of T-cells (TOPSORT) (66) and to rank the agonist potential of D-amino acid peptides (67). The GPU-accelerated strategy has not only surpassed the previous framework (17) in terms of speed, cost-, and power-efficiency, but it has also demonstrated its robustness by addressing the theoretical peptide ranking problem.…”

Section: Discussionmentioning

confidence: 99%

GPU-Accelerated Discovery of Pathogen-Derived Molecular Mimics of a T-Cell Insulin Epitope

et al. 2020

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The strong links between (Human Leukocyte Antigen) HLA, infection and autoimmunity combine to implicate T-cells as primary triggers of autoimmune disease (AD). T-cell crossreactivity between microbially-derived peptides and self-peptides has been shown to break tolerance and trigger AD in experimental animal models. Detailed examination of the potential for T-cell crossreactivity to trigger human AD will require means of predicting which peptides might be recognised by autoimmune T-cell receptors (TCRs). Recent developments in high throughput sequencing and bioinformatics mean that it is now possible to link individual TCRs to specific pathologies for the first time. Deconvolution of TCR function requires knowledge of TCR specificity. Positional Scanning Combinatorial Peptide Libraries (PS-CPLs) can be used to predict HLA-restriction and define antigenic peptides derived from self and pathogen proteins. In silico search of the known terrestrial proteome with a prediction algorithm that ranks potential antigens in order of recognition likelihood requires complex, large-scale computations over several days that are infeasible on a personal computer. We decreased the time required for peptide searching to under 30 min using multiple blocks on graphics processing units (GPUs). This time-efficient, cost-effective hardware accelerator was used to screen bacterial and fungal human pathogens for peptide sequences predicted to activate a T-cell clone, InsB4, that was isolated from a patient with type 1 diabetes and recognised the insulin B-derived epitope HLVEALYLV in the context of disease-risk allele HLA A * 0201. InsB4 was shown to kill HLA A * 0201 + human insulin producing β-cells demonstrating that T-cells with this specificity might contribute to disease. The GPU-accelerated algorithm and multispecies pathogen proteomic databases were validated to discover pathogen-derived peptide sequences that acted as super-agonists for the InsB4 T-cell clone. Peptide-MHC tetramer binding and surface plasmon resonance were used to confirm that the InsB4 TCR bound to the highest-ranked peptide agonists derived from infectious bacteria and fungi. Adoption of GPU-accelerated prediction of T-cell agonists has the capacity to revolutionise our understanding of AD by identifying potential targets for autoimmune T-cells. This approach has further potential for dissecting T-cell responses to infectious disease and cancer.

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Section: Discussionmentioning

confidence: 99%

GPU-Accelerated Discovery of Pathogen-Derived Molecular Mimics of a T-Cell Insulin Epitope

et al. 2020

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“…The neoantigen KRAS G12D in complex with HLA-C*08:02 is a typical case of a human driver mutation derived neoantigen-MHC structure which has been linked to clinical benefits. With these structures, further research could be undertaken to heighten the immunogenicity and stability of KRAS G12D-C*08:02 neoepitope, by taking modification of agonist peptides or by screening non-natural synthetic epitopes [72,73]. Alternatively, our structures could be used to design artificial receptors that bind mutant KRAS peptides based on synthetic biology means.…”

Section: Discussionmentioning

confidence: 99%

Immune-based mutation classification enables neoantigen prioritization and immune feature discovery in cancer immunotherapy

Bai

Zhou

et al. 2019

Preprint

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21Cancer mutations lead to the production of mutated proteins from which can be processed and 22 presented to CD8 + T cells as neoantigens. Despite the promise of immunotherapy targeting 23 neoantigens, which mutant peptides are likely to induce immune responses remain elusive. Here, we 24 determined two sets of MHC-I bound neoantigen structures and performed bioinformatics investigation 25 based on neoantigen data. Structural and bioinformatic analyses reveal that some types of mutations in 26 immunogenic neoantigens are preferentially selected. We also developed a strategy to expand the usage 27 of a known neoantigen by scanning potential MHC alleles. Overall, our results will extend the ability to 28 discover neoantigens that may be useful for cancer immunotherapy. 30Introduction 31The immune system can sometimes recognize and destroy cancer cells(1). CD8 + T cells have been 32 demonstrated to be a major component in this process by both recognizing and destroying the target 33 cells(2-5). For T cells to react with tumor cells two components are required, major histocompatibility 34 complex class I and possibly class II proteins (MHC-I, MHC-II) on the tumor cells and peptides which 35 processed by the tumors bound to these MHC proteins. CD8 + T cells can then recognize the 36 combination of MHCI and tumor derived peptides on the cancer cells. Thus, it is crucial to identify 37 effective tumor antigenic peptides with their relevant MHCs. 38During the last 25 years, great efforts have been made to identify tumor antigens(6). These tumor 39 antigens can be classified into two broad categories, self-antigens which are seldom expressed in 40 normal tissue or expressed at much higher levels on the cancer cell versus normal tissues (like NY- 41ESO-1, MART-1) and non-self-antigens called neoantigens which are derived from somatic mutations 42 in the tumor(7). The neoantigens are not presented by normal tissues, hence the immune system is not 43 tolerant to them and views them, correctly, as foreign antigens and responds appropriately (8, 9). 44Recently, next-generation sequencing (NGS) provide formidable identification of tumor-specific non-45 synonymous mutations, frameshift mutations, and gene rearrangements, which have driven clinical 46 immunotherapeutic methods such as vaccination, adoptive cell transfer (ACT) and blockade of the 47 proteins that inhibit T cell activation, have demonstrated that immunotherapy targeting tumor 48 neoantigens can induce objective clinical responses in many patients with metastatic cancers (10)(11)(12)(13). It 49 appears that T cell targeting of tumor neoantigens might represent the "final common pathway" to treat 50 cancer(14). However, neoantigen discovery and validation remains a daunting problem. Classical 51 cDNA expressing screening methods to identify tumor neoantigens without knowledge of the 52 properties needed for a mutated peptide to be a successful immunotherapeutic is not efficient(15). To 53 solve this problem, recently, a study identified mouse neoantigens by combinat...

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“…Collectively, this work augments the establishment of pigs as an important model of human influenza infection and further the use of pigs as models for other clinically-relevant human diseases. Indeed, we are currently exploring the potential use of non-biologic T-cell ligands for IAV vaccination [ 67 ] in the Babraham model.…”

Section: Discussionmentioning

confidence: 99%

Induction of influenza-specific local CD8 T-cells in the respiratory tract after aerosol delivery of vaccine antigen or virus in the Babraham inbred pig

et al. 2018

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There is increasing evidence that induction of local immune responses is a key component of effective vaccines. For respiratory pathogens, for example tuberculosis and influenza, aerosol delivery is being actively explored as a method to administer vaccine antigens. Current animal models used to study respiratory pathogens suffer from anatomical disparity with humans. The pig is a natural and important host of influenza viruses and is physiologically more comparable to humans than other animal models in terms of size, respiratory tract biology and volume. It may also be an important vector in the birds to human infection cycle. A major drawback of the current pig model is the inability to analyze antigen-specific CD8+ T-cell responses, which are critical to respiratory immunity. Here we address this knowledge gap using an established in-bred pig model with a high degree of genetic identity between individuals, including the MHC (Swine Leukocyte Antigen (SLA)) locus. We developed a toolset that included long-term in vitro pig T-cell culture and cloning and identification of novel immunodominant influenza-derived T-cell epitopes. We also generated structures of the two SLA class I molecules found in these animals presenting the immunodominant epitopes. These structures allowed definition of the primary anchor points for epitopes in the SLA binding groove and established SLA binding motifs that were used to successfully predict other influenza-derived peptide sequences capable of stimulating T-cells. Peptide-SLA tetramers were constructed and used to track influenza-specific T-cells ex vivo in blood, the lungs and draining lymph nodes. Aerosol immunization with attenuated single cycle influenza viruses (S-FLU) induced large numbers of CD8+ T-cells specific for conserved NP peptides in the respiratory tract. Collectively, these data substantially increase the utility of pigs as an effective model for studying protective local cellular immunity against respiratory pathogens.

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Peptide mimic for influenza vaccination using nonnatural combinatorial chemistry

Cited by 26 publications

References 59 publications

GPU-Accelerated Discovery of Pathogen-Derived Molecular Mimics of a T-Cell Insulin Epitope

GPU-Accelerated Discovery of Pathogen-Derived Molecular Mimics of a T-Cell Insulin Epitope

Immune-based mutation classification enables neoantigen prioritization and immune feature discovery in cancer immunotherapy

Induction of influenza-specific local CD8 T-cells in the respiratory tract after aerosol delivery of vaccine antigen or virus in the Babraham inbred pig

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