Peptide Vaccine Design Research Articles

Peptide Vaccines for Leishmaniasis.

Due to an increase in the incidence of leishmaniases worldwide, the development of new strategies such as prophylactic vaccines to prevent infection and decrease the disease have become a high priority. Classic vaccines against leishmaniases were based on live or attenuated parasites or their subunits. Nevertheless, the use of whole parasite or their subunits for vaccine production has numerous disadvantages. Therefore, the use of Leishmania peptides to design more specific vaccines against leishmaniases seems promising. Moreover, peptides have several benefits in comparison with other kinds of antigens, for instance, good stability, absence of potentially damaging materials, antigen low complexity, and low-cost to scale up. By contrast, peptides are poor immunogenic alone, and they need to be delivered correctly. In this context, several approaches described in this review are useful to solve these drawbacks. Approaches, such as, peptides in combination with potent adjuvants, cellular vaccinations, adenovirus, polyepitopes, or DNA vaccines have been used to develop peptide-based vaccines. Recent advancements in peptide vaccine design, chimeric, or polypeptide vaccines and nanovaccines based on particles attached or formulated with antigenic components or peptides have been increasingly employed to drive a specific immune response. In this review, we briefly summarize the old, current, and future stands on peptide-based vaccines, describing the disadvantages and benefits associated with them. We also propose possible approaches to overcome the related weaknesses of synthetic vaccines and suggest future guidelines for their development.

Preclinical development of peptide vaccination combined with oncolytic MG1-E6E7 for HPV-associated cancer

Human papilloma virus (HPV)-associated cancer is a significant global health burden and despite the presence of viral transforming antigens within neoplastic cells, therapeutic vaccinations are ineffective for advanced disease. HPV positive TC1 cells are susceptible to viral oncolysis by MG1-E6E7, a custom designed oncolytic Maraba virus. Epitope mapping of mice vaccinated with MG1-E6E7 enabled the rational design of synthetic long peptide (SLP) vaccines against HPV16 and HPV18 antigens. SLPs were able to induce specific CD8+ immune responses and the magnitude of these responses significantly increased when boosted by MG1-E6E7. Logically designed vaccination induced multi-functional CD8+ T cells and provided complete sterilising immunity of mice challenged with TC1 cells. In mice bearing large HPV-positive tumours, SLP vaccination combined with MG1-E6E7 was able to clear tumours in 60% of mice and these mice were completely protected against a long term aggressive re-challenge with the TC1 tumour model. Combining conventional SLPs with the multi-functional oncolytic MG1-E6E7 represents a promising approach against advanced HPV positive neoplasia.

T Cell Immunity To Enterovirus 71 Infection In Humans And Implications For Vaccine Development.

Enterovirus 71 (EV-A71) is one of the major pathogens causing hand, foot and mouth disease (HFMD). Some strains can lead to neurological disease and fatality in children. Up to date, there is no FDA-approved vaccine to prevent severe HFMD and mortality. Although the inactivated vaccine has advanced to production in China, lack of long-term protection and the requirement of multiple boosters have necessitated the development of other types of vaccines. Recent studies indicate that cellular and not humoral immunity determines the clinical outcome of EV-A71 infections. High levels of cytokines such as IL-1β, IL-6, IL-10 and IFN-γ tend to correlate with clinical severity in patients with pulmonary edema and encephalitis. The live attenuated vaccine may serve as the preferred choice as it can induce excellent humoral and cellular immunity as well as live-long immunity. Expression of certain HLA alleles such as TNF-α promoter type II (-308 allele), HLA-A33 and HLA-DR17 responses have been linked to severe HFMD. However, the high variability of MHC genes could restrict T cell recognition and be a major obstacle in the design of peptide vaccines. Hence, the development of a T cell universal vaccine (incorporating both CD4+ and CD8+ T cell epitopes) that induces broad, multifunctional and cross-reactive CD8+ T cell responses maybe desirable.

Prediction of Multiple Peptide Based Vaccine from E1, E2 and Capsid Proteins of Rubella Virus: An In-Silico Approach

Rubella is a single strand RNA virus in structure that belongs to Togaviridae family. It causes rubella by respiratory droplet transmission and congenital rubella syndrome if infection to the mother occurs during pregnancy. The current life attenuated vaccine is given as part of MMR vaccine. It has many side effects and contraindicated in pregnancy and immunosuppressed persons. The aim of this study is to determine antigenic peptides from E1, E2, and Capsid proteins that can be used for multiple peptide vaccine design using In-Silico study. A total of 189 sequences of three proteins were obtained from NCBI and subjected to multiple sequence alignments using CLUSTALW tool to determine conserved regions. Immune Epitope Data Base tools were used to determine B cell epitopes, these tools are Bepipred Linear B cell epitopes prediction, surface accessibility and antigenicity prediction. Epitope binding to MHC class I and class II and their population coverage were also determined using IEDB software. The analysis results are as follow, for B cell binding from E1 were (PVCQRHSP, QYHPTAC, and QVPPD), from E2 (AQYPP, PAHP and TTAANSTTAATPATA), and (PPPP, PPQQPQPP and PPHT) from capsid protein. All these peptides have high score in Linear B cell epitopes prediction, surface accessibility and antigenicity prediction. On another hand peptides that reacted to MHC class I were (YFNPGGSYY, FVLLVPWVL and FTNLGTPPL) form E1, E2 and capsid protein respectively. It worth noting that the peptide FVLLVPWVL from E2 protein is also binds to MHC class II with high affinity. All T cell peptides had highest population coverage, and the combined coverage for all peptides in this study was found to be 100%. Using In-Silico studies will ensure less risk of virulence and side effects. Evaluation of antibodies response in animal models is needed to confirm efficacy of these epitopes in inducing protective immune response.

Novel Identified HLA-A*0201-Restricted Hantaan Virus Glycoprotein Cytotoxic T-Cell Epitopes Could Effectively Induce Protective Responses in HLA-A2.1/Kb Transgenic Mice May Associate with the Severity of Hemorrhagic Fever with Renal Syndrome.

Hantaan virus (HTNV) infections can cause severe hemorrhagic fever with renal syndrome (HFRS) in humans, which is associated with high fatality rates. Cytotoxic T cell (CTL) responses contribute to virus elimination; however, to date, HLA class I allele-restricted HTNV glycoprotein (GP) epitopes recognized by CTLs have not been reported, limiting our understanding of CTL responses against HTNV infection in humans. In this study, 34 HTNV GP nine-mer epitopes that may bind to HLA-A*0201 molecules were predicted using the BIMAS and SYFPEITHI database. Seven of the epitopes were demonstrated to bind to HLA-A*0201 molecules with high affinity via the T2 cell binding assay and were successfully used to synthesize peptide/HLA-A*0201 tetramers. The results of tetramer staining showed that the frequencies of each epitope-specific CTL were higher in patients with milder HFRS, which indicated that the epitopes may induce protective CTL responses after HTNV infection. IFN-γ-enzyme-linked immunospot analysis further confirmed the immunoreactivity of epitopes by eliciting epitope-specific IFN-γ-producing CTL responses. In an HTNV challenge trial, significant inhibition of HTNV replication characterized by lower levels of antigens and RNA loads was observed in major target organs (liver, spleen, and kidneys) of HLA-A2.1/Kb transgenic mice pre-vaccinated with nonapeptides VV9 (aa8–aa16, VMASLVWPV), SL9 (aa996–aa1004, SLTECPTFL) and LL9 (aa358–aa366, LIWTGMIDL). Importantly, LL9 exhibited the best ability to induce protective CTL responses and showed a prominent effect on the kidneys, potentially preventing kidney injury after HTNV infection. Taken together, our results highlight that HTNV GP-derived HLA-A*0201-restricted epitopes could elicit protective CTL responses against the virus, and that epitope LL9 functions as an immunodominant protective epitope that may advance the design of safe and effective CTL-based HTNV peptide vaccines for humans.

A cell-based high-throughput screening assay system for inhibitor compounds of antigen presentation by HLA class II molecule

A number of autoimmune diseases are associated with the genotypes of human leukocyte antigen class II (HLA), some of which present peptides derived from self-proteins, resulting in clonal expansion of self-reactive T cells. Therefore, selective inhibition of self-peptide loading onto such disease-associated HLA could ameliorate the diseases. To effectively identify such compounds, in this study, we established, for the first time, a cell- and 96-well microplate-based high-throughput screening system for inhibitors of antigen presentation. A panel of DRB1 genes plus DRA*01:01 gene were expressed in HEK293T cells and in 3T3 cells, and their binding with biotinylated known self-antigen peptides was measured by flow cytometry. HLA-DR1 (DRB1*01:01) and DR15 (DRB1*15:01) showed a high affinity with myelin basic protein peptide (MBP83-98). Therefore, in 96-well plate wells, MBP83-99 was allowed to bind to DR1 or DR15 on 3T3 cells in competition with a test compound, and the HLA-bound peptide was detected by streptavidin-conjugated β-galactosidase, thereby identifying inhibitor compounds for rheumatoid arthritis or multiple sclerosis. Our assay system has a potential for broad applications, including designing peptide vaccines.

Epitope-Based Peptide Vaccine Design against Mokola Rabies Virus Glycoprotein G Utilizing In Silico Approaches

Background: Lyssavirus is considered as a neglected, zoonotic and tropical virus. Among all the Lyssavirus species known to exist today, Mokola virus is unique and appears to be exclusive to Africa. This virus is responsible for a meningoencephalomyelitis in mammals therefore; in silico prediction of epitopes of appropriate protein residues is important to produce a peptide vaccine with powerful immunogenic and minimal allergic effect. The aim of this study was to design a vaccine for Mokola virus using its glycoprotein peptides as an immunogen to stimulate protective immune response. Methods and materials: Glycoprotein G Sequences of Mokola was explored from NCBI then the sequences were aligned to obtain conserved regions. The nominees epitopes from Immune Epitope Database were analyzed by different prediction tools for B-cell, T-cell MHC class II and I. Then sequences aligned with the aid of ClustalW implemented in the BioEdit program. Results and conclusions: For Bepipred test of B-cell the total number of conserved epitopes was 85. For Emini surface accessibility prediction, 36 conserved epitopes were passing the default threshold 1.0. In Kolaskar and Tongaonkar antigenicity, 36 conserved epitopes gave score above the default threshold 1.045. However, there are only three epitopes that pass the three tests (LYTIPEK, LAHQK, YPSVPS). The reference glycoprotein strain was analyzed using IEDB MHC-I binding prediction tool to predict T cell epitope. Twenty conserved peptides were predicted to interact with different MHC-I alleles. For MHC-II binding prediction there were 47 conserved epitopes found to interact with MHC-II alleles. The peptides GQILIPEMQ, FRRLSHFRK and FVGYVTTTF had the affinity to bind the highest number of MHC-II alleles. World population coverage for MHC-I most promising 3 peptides FVDLHMPDV, FVGYVTTTF and RLFDGTWVS was 67.42%, while the world population coverage for most promising MHC-II peptides was 99.77%, for the binding to MHC-I and MHC-II, The peptide FVG TTTF world population coverage was 99.31%.

DSP-7888, a Novel Cocktail Design of WT1 Peptide Vaccine, and Its Combinational Immunotherapy with Immune Checkpoint-Blocking Antibody Against PD-1

Background:Wilms' tumor gene 1 (WT1), broadly expressed in hematological malignancies and solid tumors, is a promising candidate for development as a cancer vaccine. WT4869, one of our WT1 vaccine candidates demonstrated early signs of clinical activity in Azacitidine (AZA)-resistant higher-risk MDS patients with a median survival (OS) of 13.0 months in a phase 1/2 study (Suzuki T, Ueda Y, Ogura M, et al. A Phase 1/2 Study of WT1 Peptide Cancer Vaccine WT4869 in Patients with Myelodysplastic Syndromes (MDS). Blood. 2015;126:2868). In this study, we report the characterization of DSP-7888 and the potential synergic effect with anti-PD-1 antibody. DSP-7888, which is a novel cocktail peptide vaccine designed to induce cytotoxic T lymphocytes (CTLs) that recognize WT1 antigen in an HLA-A*02:01, HLA-A*02:06 or HLA-A*24:02 restricted manner, has entered early clinical trials in patients with MDS and pediatric brain cancer in Japan and solid tumors in the U.S.Methods:WT1-specific T cells were measured by WT1 tetramer staining following stimulation of human peripheral blood mononuclear cells (PBMCs) with DSP-7888. In vivo CTL inducing activity of DSP-7888 was evaluated by ELISPOT assay and 51Cr-release assay after immunization of HLA-A2.1/DR1 transgenic (Tg) mice or HLA-A24.2 Tg mice. The response of induced CTLs against the WT1 epitope was measured by IFN-γ ELISA assay following co-culture with irradiated cancer cells. The frequency of PD-1 positive CTLs in spleen and tumor was analyzed by flow cytometry. The anti-tumor effect of DSP-7888 with or without anti-PD-1 antibody was evaluated using HLA-A24.2 Tg mice bearing mouse EL4 cells expressing both HLA-A24.2 and WT1.Results:HLA-A*02:01- or HLA-A*24:02-restricted and WT1-specific CTLs were induced in HLA-A2.1/DR1 Tg mice, HLA-A24.2 Tg mice and human PBMCs. Two groups of DSP-7888-induced CTLs recognized WT1 in an HLA-A*02:01-restricted manner and one in an HLA-A*24:02-restricted manner. Compared to its component vaccine without helper peptide, DSP-7888 induced a large number of WT1-specific CTLs in HLA-A2.1/DR1 Tg mice. The activity of DSP-7888-induced CTLs was relatively maintained in the environment including cancer cells. In addition, it was further activated by treatment with anti-PD-1 antibody. On the other hand, the activity of the component vaccine-induced CTLs was very low even when treated with anti-PD-1 antibody. In DSP-7888-administered tumor-bearing mice, half of WT1-specific CTLs in spleen expressed PD-1; however, in tumor more than 90% of the CTLs expressed this protein. Combination therapy of DSP-7888 and anti-PD-1 antibody showed a higher anti-tumor effect than each monotherapy alone in this model.Conclusions:In this study, DSP-7888 induced CTLs that recognize multiple WT1 epitopes. The helper peptide included in DSP-7888 enhanced the response of the CTL induction, and contributed to the lasting cytotoxic activities even in the tumor immunosuppressive environment, suggesting potential of DSP-7888 as a cancer vaccine. In addition, the in vitro treatment with anti-PD-1 antibody furthermore enhanced the activity of DSP-7888-induced CTLs. The combination of DSP-7888 and anti-PD-1 antibody may induce multiple WT1 epitope-specific CTLs and maintain the intratumoral cytotoxic activity. Further evaluations of DSP-7888 are warranted. DisclosuresGoto:Sumitomo Dainippon Pharma Co.,Ltd: Employment. Nakamura:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Suginobe:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Takasu:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Takanashi:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Ban:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Li:Sumitomo Dainippon Pharma Co.,Ltd.: Employment.

A genomic study on distribution of human leukocyte antigen (HLA)-A and HLA-B alleles in Lak population of Iran

Anthropological studies based on the highly polymorphic gene, human leukocyte antigen (HLA), provide useful information for bone marrow donor registry, forensic medicine, disease association studies, as well as infertility treatment, designing peptide vaccines against tumors, and infectious or autoimmune diseases. The aim of this study was to determine HLA-A and HLA-B allele frequencies in 100 unrelated Lak/lᴂk/individuals from Lorestan province of Iran. Finally, we compared the results with that previously described in Iranian population. Commercial HLA-Type kits from BAG (Lich, Germany) company were used for determination of the HLA-A and HLA-B allele frequencies in genomic DNA, based on polymerase chain reaction with sequence specific primer (PCR-SSP) assay. The differences between the populations in distribution of HLA-A and HLA-B alleles were estimated by chi-squared test with Yate's correction. The most frequent HLA-A alleles were *24 (20%), *02 (18%), *03 (12%) and *11 (10%), and the most frequent HLA-B alleles were *35 (24%), *51 (16%), *18 (6%) and *38 (6%) in Lak population. HLA-A*66 (1%), *74(1%) and HLA-B*48 (1%), *55(1%) were the least observed frequencies in Lak population. Our results based on HLA-A and HLA-B allele frequencies showed that Lak population possesses the previously reported general features of Iranians but still with unique.

In silico proposition to predict cluster of B- and T-cell epitopes for the usefulness of vaccine design from invasive, virulent and membrane associated proteins of C. jejuni.

PurposeCampylobacter jejuni is the one of the leading causes of bacterial diarrheal illness worldwide. This study aims to design specific epitopes for the utility of designing peptide vaccine(s) against C. jejuni by targeting invasive, virulent and membrane associated proteins like FlaA, Cia, CadF, PEB1, PEB3 and MOMP.MethodsIn the present study, various immunoinformatics approaches have been applied to design a potential epitope based vaccine against C. jejuni. The tools include Bepipred, ABCpred, Immune Epitope databse (IEDB) resource portal, Autodock vina etc.ResultsPeptides “EINKN”, “TGSRLN”, “KSNPDI”, “LDENGCE” respectively from FlaA, MOMP, PEB3, CadF proteins were found to be the most potential B cell epitopes while peptides “FRINTNVAA”, “NYFEGNLDM”, “YKYSPKLNF”, “YQDAIGLLV”, “FRNNIVAFV” and “LIMPVFHEL” respectively from Fla, CadF, MOMP, PEB1A, PEB3 and Cia might elicit cell mediated immunity and “IFYTTGSRL” from MOMP protein might elicit both humoral and cell-mediated immunity. All these potential peptidic epitopes showed almost 80–100 % conservancy in different strains of C jejuni with varying proportions of population coverage ranging from 22–60 %. Further authentication of these peptide epitopes as probable vaccine candidate was mediated by their binding to specific HLA alleles using in silico docking technique.ConclusionBased on the present study, it could be concluded that these predicted epitopes might be used to design a vaccine against C. jejuni bacteria and thus, could be validated in model hosts to verify their efficacy as vaccine.Electronic supplementary materialThe online version of this article (doi:10.1186/s40203-016-0020-y) contains supplementary material, which is available to authorized users.

Distribution of HLA-DRB1 and HLA-DQB1 alleles in Lak population of Iran

Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and encode the highly polymorphic molecules critically involved in immune responses. Anthropological studies based on highly polymorphic HLA genes provide useful information for bone marrow donor registry, forensic medicine, disease association studies, as well as designing peptide vaccines against tumors, and infectious or autoimmune diseases. The aim of this study was to determine the HLA-DRB1 and HLA-DQB1 allele frequencies in 100 unrelated Lak individuals from Lorestan province of Iran. Finally, we compared the results with those previously described in four other Iranian populations. Commercial HLA-Type kits were used for determination of the HLA-DRB1 and HLA-DQB1 allele frequencies. Differences between populations in the distribution of HLA-DRB1 and HLA-DQB1 alleles were estimated by χ2 test with Yate’s correction and Fisher’s exact test. The most frequent HLA-DRB1 alleles were *1103=4 (23%), *1502 (9.5%), *0701 (9%), *0301 (8.5%), *1101 (7.5%) and *1501 (6%) while HLA-DQB1*0301 (40%), *0201 (15%), *0502 (10.5%), *0303 (10%), *0602=3 (9.5%), and *0501 (7.5%) were the most frequent alleles in Lak population. HLA-DRB1*0409, *0804, *1102, *1112, *1405, and HLA-DQB1*0503, *0604 were the least observed frequencies in Lak population. Our results based on HLA-DRB1 and HLA-DQB1 allele frequencies showed that the Lak population possesses the previously reported general features of the Lur and Kurd populations but still with unique, decreased or increased frequencies of several alleles. In other words, the Lak population is close to Lurs Khorramabadi and Kurd but far from Lurs Kohkiloyeh/Boyerahmad and Bakhtiari.

A Brief Review of Computer-Assisted Approaches to Rational Design of Peptide Vaccines.

The growing incidences of new viral diseases and increasingly frequent viral epidemics have strained therapeutic and preventive measures; the high mutability of viral genes puts additional strains on developmental efforts. Given the high cost and time requirements for new drugs development, vaccines remain as a viable alternative, but there too traditional techniques of live-attenuated or inactivated vaccines have the danger of allergenic reactions and others. Peptide vaccines have, over the last several years, begun to be looked on as more appropriate alternatives, which are economically affordable, require less time for development and hold the promise of multi-valent dosages. The developments in bioinformatics, proteomics, immunogenomics, structural biology and other sciences have spurred the growth of vaccinomics where computer assisted approaches serve to identify suitable peptide targets for eventual development of vaccines. In this mini-review we give a brief overview of some of the recent trends in computer assisted vaccine development with emphasis on the primary selection procedures of probable peptide candidates for vaccine development.

Design of cocktail peptide vaccine against Cytomegalovirus infection.

Human Cytomegalovirus (HCMV) remains a major morbidity and mortality cause in immuno suppressed patients. Therefore, significant effort has been made towards the development of a vaccine. In this study, the expression of the pp65 and gB fusion peptides and Fc domain of mouse IgG2a as a novel delivery system for selective uptake of antigens by antigen-presenting cells (APCs) in Pichia pastoris yeast system were studied. In this study, four immune dominant sequences in pp65 protein and 3 immuno dominant sequences in gB protein were selected according to literature review. Peptide linker -GGGGS- was used for construction of fusion peptide. This fusion peptide was cloned in the pPICZαA expression vector and transfected into P. pastoris host cells. Dot blot and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) techniques showed that a high level of pp65-gB-Fc fusion peptide was expressed. This CMV pp65-gB-Fc fusion peptide could be a promising candidate for the development of a novel peptide vaccine.

Rational design of peptide vaccines against the Zika virus through sequence descriptors: Techniques and Problems

Rational design of peptide vaccines against the Zika virus through sequence descriptors: Techniques and Problems

Rational Design of Peptide Vaccines Against Multiple Types of Human Papillomavirus.

Human papillomavirus (HPV) occurs in many types, some of which cause cervical, genital, and other cancers. While vaccination is available against the major cancer-causing HPV types, many others are not covered by these preventive measures. Herein, we present a bioinformatics study for the designing of multivalent peptide vaccines against multiple HPV types as an alternative strategy to the virus-like particle vaccines being used now. Our technique of rational design of peptide vaccines is expected to ensure stability of the vaccine against many cycles of mutational changes, elicit immune response, and negate autoimmune possibilities. Using the L1 capsid protein sequences, we identified several peptides for potential vaccine design for HPV 16, 18, 33, 35, 45, and 11 types. Although there are concerns about the epitope-binding affinities for the peptides identified in this process, the technique indicates possibilities of multivalent, adjuvanted, peptide vaccines against a wider range of HPV types, and tailor-made different combinations of the peptides to address frequency variations of types over different population groups as required for prophylaxis and at lower cost than are in use at the present time.

Mapping the Impact of Proteasome Inhibitor Therapy on the Immunopeptidome of Multiple Myeloma: Mass Spectrometry Identifies Robust Targets for T Cell Immunotherapy

Recent studies underscore that multiple myeloma is an immunogenic disease and suggest that it can be effectively treated by T cell based immunotherapy via immunomodulation. This strategy might be synergistically complemented by therapeutic vaccination, which may help induce and guide specific anti-cancer T cell responses. We have recently conducted a study which directly characterized the antigenic landscape of myeloma by mass spectrometric analysis of naturally presented HLA ligands and identified a panel of T cell epitopes characterized by exquisite myeloma-association (Walz, Stickel et. al., Blood 2015). As standard of care in myeloma includes proteasome inhibitor therapy and the proteasome plays a central role in the generation of MHC-presented peptides, it is of great importance to thoroughly characterize and take into account the effects of this treatment on the antigenic landscape of myeloma cells and implement only robustly presented targets for peptide vaccine design. This is even more importantHere we present a mass spectrometry-based study, which longitudinally and semi-quantitatively maps the effects of treatment with the 2nd generation proteasome inhibitor carfilzomib in an in vitro model of multiple myeloma. We observed considerable plasticity of the HLA class I ligandome of MM.1S cells after treatment with carfilzomib with 17.9±1.1.% (mean of 3 biological replicates ± SD) of HLA ligands showing significant modulation (fold change ≥ 4, P ≤ 0.01) at t24h compared to mock-treated controls (down-modulated: 11.5±1.1%, up-modulated: 6.3±0.6%). We were able to longitudinally tracke the abundance of 28 previously defined myeloma antigens, confirming robust (16/28, 57.1%) or even increased presentation (8/28, 28.6%) under treatment for the majority of these peptides. However, - importantly - we observed highly distortive effects of carfilzomib treatment on the HLA allotype distribution of target cells, which manifested as a marked reduction of HLA ligands restricted by HLA-A*23:01 and A*24:02 (-62.5±1.8% and -57.0±0.6%, respectively, at t=24h after treatment). These findings indicate strong allotype-specific effects of carfilzomib on the antigenic landscape of myeloma cells, which we interpret to be a direct reflection of the mechanism of action of this drug. As a significant proportion of the U.S. population are carriers of the affected alleles (A*23:01: 8.2%; A*24:02: 22.6%), these findings could have broad implications for the design or implementation of antigen-specific therapies in patients under proteasome inhibitor treatment. Furthermore, these findings might indicate the possibility of altered cancer immunosurveillance as a consequence of proteasome inhibitor therapy. DisclosuresWeisel:Amgen: Consultancy, Honoraria, Other: Travel Support; Onyx: Consultancy, Honoraria; Novartis: Other: Travel Support; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Noxxon: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support.

High-order neural networks and kernel methods for peptide-MHC binding prediction.

Effective computational methods for peptide-protein binding prediction can greatly help clinical peptide vaccine search and design. However, previous computational methods fail to capture key nonlinear high-order dependencies between different amino acid positions. As a result, they often produce low-quality rankings of strong binding peptides. To solve this problem, we propose nonlinear high-order machine learning methods including high-order neural networks (HONNs) with possible deep extensions and high-order kernel support vector machines to predict major histocompatibility complex-peptide binding. The proposed high-order methods improve quality of binding predictions over other prediction methods. With the proposed methods, a significant gain of up to 25-40% is observed on the benchmark and reference peptide datasets and tasks. In addition, for the first time, our experiments show that pre-training with high-order semi-restricted Boltzmann machines significantly improves the performance of feed-forward HONNs. Moreover, our experiments show that the proposed shallow HONN outperform the popular pre-trained deep neural network on most tasks, which demonstrates the effectiveness of modelling high-order feature interactions for predicting major histocompatibility complex-peptide binding. There is no associated distributable software. renqiang@nec-labs.com or mark.gerstein@yale.edu Supplementary data are available at Bioinformatics online.

Epitope-based peptide vaccine design and target site depiction against Ebola viruses: an immunoinformatics study.

Ebola viruses (EBOVs) have been identified as an emerging threat in recent year as it causes severe haemorrhagic fever in human. Epitope‐based vaccine design for EBOVs remains a top priority because a mere progress has been made in this regard. Another reason is the lack of antiviral drug and licensed vaccine although there is a severe outbreak in Central Africa. In this study, we aimed to design an epitope‐based vaccine that can trigger a significant immune response as well as to prognosticate inhibitor that can bind with potential drug target sites using various immunoinformatics and docking simulation tools. The capacity to induce both humoral and cell‐mediated immunity by T cell and B cell was checked for the selected protein. The peptide region spanning 9 amino acids from 42 to 50 and the sequence TLASIGTAF were found as the most potential B and T cell epitopes, respectively. This peptide could interact with 12 HLAs and showed high population coverage up to 80.99%. Using molecular docking, the epitope was further appraised for binding against HLA molecules to verify the binding cleft interaction. In addition with this, the allergenicity of the epitopes was also evaluated. In the post‐therapeutic strategy, docking study of predicted 3D structure identified suitable therapeutic inhibitor against targeted protein. However, this computational epitope‐based peptide vaccine designing and target site prediction against EBOVs open up a new horizon which may be the prospective way in Ebola viruses research; the results require validation by in vitro and in vivo experiments.

Promiscuous T-cell responses to drugs and drug-haptens

Promiscuous T-cell responses to drugs and drug-haptens

Design of a heterosubtypic epitope-based peptide vaccine fused with hemokinin-1 against influenza viruses.

Influenza viruses continue to emerge and re-emerge, posing new threats for public health. Control and treatment of influenza depends mainly on vaccination and chemoprophylaxis with approved antiviral drugs. Identification of specific epitopes derived from influenza viruses has significantly advanced the development of epitope-based vaccines. Here, we explore the idea of using HLA binding data to design an epitope-based vaccine that can elicit heterosubtypic T-cell responses against circulating H7N9, H5N1, and H9N2 subtypes. The hemokinin-1 (HK-1) peptide sequence was used to induce immune responses against the influenza viruses. Five conserved high score cytotoxic T lymphocyte (CTL) epitopes restricted to HLA-A*0201-binding peptides within the hemagglutinin (HA) protein of the viruses were chosen, and two HA CTL/HK-1 chimera protein models designed. Using in silico analysis, which involves interferon epitope scanning, protein structure prediction, antigenic epitope determination, and model quality evaluation, chimeric proteins were designed. The applicability of one of these proteins as a heterosubtypic epitopebased vaccine candidate was analyzed.