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Glioma is a prevalent form of primary malignant central nervous system tumor, characterized by its cellular invasiveness, rapid growth, and the presence of the blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB). Current therapeutic approaches, such as chemotherapy and radiotherapy, have shown limited efficacy in achieving significant antitumor effects. Therefore, there is an urgent demand for new treatments. Therapeutic peptides represent an innovative class of pharmaceutical agents with lower immunogenicity and toxicity. They are easily modifiable via chemical means and possess deep tissue penetration capabilities which reduce side effects and drug resistance. These unique pharmacokinetic characteristics make peptides a rapidly growing class of new therapeutics that have demonstrated significant progress in glioma treatment. This review outlines the efforts and accomplishments in peptide-based therapeutic strategies for glioma. These therapeutic peptides can be classified into four types based on their anti-tumor function: tumor-homing peptides, inhibitor/antagonist peptides targeting cell surface receptors, interference peptides, and peptide vaccines. Furthermore, we briefly summarize the results from clinical trials of therapeutic peptides in glioma, which shows that peptide-based therapeutic strategies exhibit great potential as multifunctional players in glioma therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for hematological cancers. However, achieving comparable success in solid tumors remains challenging. Factors contributing to these limitations include the scarcity of tumor-specific antigens (TSAs), insufficient CAR-T cell infiltration, and the immunosuppressive tumor microenvironment (TME). Vaccine-based strategies are emerging as potential approaches to address these challenges, enhancing CAR-T cell expansion, persistence, and antitumor efficacy. In this review, we explore diverse vaccine modalities, including mRNA, peptide, viral vector, and dendritic cell (DC)-based vaccines, and their roles in augmenting CAR-T cell responses. Special focus is given to recent clinical advancements combining mRNA-based vaccines with CAR-T therapy for the treatment of genitourinary cancers. In addition, we discuss crucial considerations for optimizing vaccine dosing, scheduling, and delivery to maximize CAR-T synergy, aiming to refine this combination strategy to improve treatment efficacy and safety., Competing Interests: Declaration of Interests L.Y. is a scientific advisor to AlzChem and Amberstone Biosciences, and a cofounder, stockholder and advisory board member of Appia Bio. None of the declared companies contributed to this study. The other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The emergence of effective immunotherapies has revolutionized therapies for many types of cancer. However, current immunotherapy has limited efficacy in certain patient populations and displays therapeutic resistance after a period of treatment. To address these challenges, a growing number of immunotherapy drugs have been investigated in clinical and preclinical applications. The diverse functionality of peptides has made them attractive as a therapeutic modality, and the global market for peptide-based therapeutics is witnessing significant growth. Peptides can act as immunotherapeutic agents for the treatment of many malignant cancers. However, a systematic understanding of the interactions between different peptides and the host's immune system remains unclear. This review describes in detail the roles of peptides in regulating the function of the immune system for cancer immunotherapy. Initially, we systematically elaborate on the relevant mechanisms of cancer immunotherapy. Subsequently, we categorize peptide-based nanomaterials into the following three categories: peptide-based vaccines, anti-cancer peptides, and peptide-based delivery systems. We carefully analyzed the roles of these peptides in overcoming the current barriers in immunotherapy, including multiple strategies to enhance the immunogenicity of peptide vaccines, the synergistic effect of anti-cancer peptides in combination with other immune agents, and peptide assemblies functioning as immune stimulators or vehicles to deliver immune agents. Furthermore, we introduce the current status of peptide-based immunotherapy in clinical applications and discuss the weaknesses and future prospects of peptide-based materials for cancer immunotherapy. Overall, this review aims to enhance comprehension of the potential applications of peptide-based materials in cancer immunotherapy and lay the groundwork for future research and clinical applications.

Over the past few decades, research on cancer immunotherapy has firmly established immune cells as key players in effective cancer treatment. Peptide vaccines directly targeting immune cells have demonstrated immense potential due to their specificity and applicability. However, developing peptide vaccines to generate tumor-reactive T cells remains challenging, primarily due to suboptimal immunogenicity and overcoming the immunosuppressive tumor microenvironment (TME). In this review, we discuss various elements of effective peptide vaccines, including antigen selection, peptide epitope optimization, vaccine adjuvants, and the combination of multiple immunotherapies, in addition to recent advances in tumor neoantigens as well as epitopes bound by non-classical human leukocyte antigen (HLA) molecules, to increase the understanding of cancer peptide vaccines and provide multiple references for the design of subsequent T cell-based peptide vaccines., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Severe acute respiratory coronavirus-2 (SARS-CoV-2) emerged in 2019 as a new virus and caused worldwide outbreaks, quickly turning into a pandemic disease called coronavirus disease-19 (COVID-19). All the existing methodologies were used for developing vaccines for this virus. But sporadic infections of this virus and the emergence of new strains to date suggest the incomplete protection offered by the developed vaccines and the need for new research. In this direction, we identified five epitopes present in the non-RBD region and on the surface of the spike protein by in silico analysis. They are epitope I (aa 80-90), epitope II (aa 262-270), and a small protein with three epitopes (aa 1059-1124). Antigenicity scores of these epitopes were found to be higher than the full length spike protein and its RBD region. These epitopes showed high conserveness across the emerging strains, high immunogenicity, non-toxicity, no homology with human sequences and high affinity for MHC class I & II molecules. Antibodies raised against these epitopes interacted with the bacterially expressed spike protein in western blotting. The antiserum of COVID-19 recovered participants reacted with the developed epitopes (small protein). Furthermore, in the presence of the respective antiserum and COVID-19 convalescent serum, these epitopes successfully fixed the complement, implying a possible role in innate immunity. The epitopes were also found to activate the peripheral blood mononuclear cells (PBMCs) isolated from the blood samples of COVID-19 recovered/vaccinated participants, suggesting a possible role in adaptive immunity. The need for the new SARS-CoV-2 vaccines is further highlighted in light of current reports about the side effects of a developed vaccine (AstraZeneca) and the circulating new strains. The epitopes presented in this study represent the potential immunogens and expect certain pitfalls of the existing vaccines would be sealed., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Musturi Venkataramana reports administrative support and equipment, drugs, or supplies were provided by 10.13039/501100007741University of Hyderabad. Musturi Venkataramana reports a relationship with 10.13039/501100007741University of Hyderabad that includes: employment and non-financial support. Musturi Venkataramana has patent NA pending to NA. Nil., (© 2024 The Author(s).)

Immunotherapy is gaining prominence as a promising strategy for treating triple-negative breast cancer (TNBC). Neoantigens (neoAgs) and cancer-testis antigens (CTAs) are tumor-specific targets originating from somatic mutations and epigenetic changes in cancer cells. These antigens hold great promise for personalized cancer vaccines, as supported by preclinical and early clinical evidence in TNBC. This review delves into the potential of neoAgs and CTAs as vaccine candidates, emphasizing diverse strategies and delivery approaches. It also highlights the current status of vaccination modalities undergoing clinical trials in TNBC therapy. A comprehensive understanding of neoAgs, CTAs, vaccination strategies, and innovative delivery methods is crucial for optimizing neoAg-based immunotherapies in clinical practice., Competing Interests: Declaration of competing interest The author declares that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Peptide-based vaccines have been widely investigated in cancer immunotherapy. Despite their high specificity, safety, and low production cost, these vaccines have shown limited success in clinical studies, owing to their poor immunogenicity. Extensive efforts have been devoted to increasing the immunogenicity of peptide vaccines by mixing peptides with adjuvants and/or promoting their delivery to tumor-draining lymph nodes (TdLNs) for better antigen presentation by and maturation of dendritic cells. Among these efforts, the exploration of various nanoparticles has been at the forefront of the rational design and construction of peptide-based vaccines. Here, we present a nanovaccine platform that is built on a self-assembled RNA origami (RNA-OG) nanostructure. As previously reported, this RNA-OG nanostructure is a potent toll-like receptor (TLR)3 agonist. In addition, due to its robust synthesis and versatility in modification, RNA-OG could be readily linked to peptides of interest. Thus, these RNA-OG nanostructures function as adjuvanted nanocarriers to construct RNA-OG-peptide nanovaccines that are uniform in size, consistent in peptide loading, and highly stable. Here, we demonstrate that the assembled RNA-OG-peptide nanovaccines induced dendritic cell maturation, reduced tumor-mediated immunosuppression, and mobilized tumor-specific CD8 + T cell responses at the tumor site. Together, these actions led to the elicitation of an effective antitumor immunity that increased the survival of tumor-bearing mice. The combination of RNA-OG-based nanovaccines with the α-PD-1 immune checkpoint blockade further enhanced the immunity. Hence, our RNA-OG nanostructures represent a robust, simple, and highly effective platform to empower peptide-based vaccines for cancer immunotherapy.

SARS-CoV-2 remains a major global public health concern. Antibody waning and immune escape variant emergence necessitate the development of next generation vaccines that induce cross-reactive durable immune responses. T cell responses to SARS-CoV-2 demonstrate higher conservation, antigenic breadth, and longevity than antibody responses. Therefore, we sought to identify pathogen-derived T cell epitopes for a potential peptide-based vaccine. We pursued an approach leveraging: 1) liquid chromatography and tandem mass spectrometry (LC-MS/MS)-based identification of peptides from ancestral SARS-CoV-2-infected cell lines, 2) epitope prediction algorithms, and 3) overlapping peptide libraries. From this strategy, we identified 380 unique SARS-CoV-2-derived peptide sequences, including 53 antigenic HLA class I and class II peptides from multiple structural and non-structural/accessory viral proteins. These peptide sequences were highly conserved across variants of concern/interest (VoC/VoIs), and are estimated to achieve coverage of >96% of the world population. Our findings validate this discovery pipeline for peptide identification and immunogenicity testing, and are a crucial step toward the development of a next-generation multi-epitope SARS-CoV-2 peptide vaccine, and a novel vaccine platform methodology., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories. Dr. Poland provides consultative advice to AiZtech; Atria; GlaxoSmithKline; Invivyd; Janssen Global Services, LLC; Merck & Co. Inc.; Moderna; Novavax; and Syneos Health. Dr. Poland is an adviser to the White House and World Health Organization on COVID-19 vaccines and monkeypox, respectively. Drs. Poland and Ovsyannikova hold patents related to vaccinia and measles peptide vaccines. Drs. Kennedy, Poland, and Ovsyannikova hold a patent related to vaccinia peptide vaccines. Drs. Poland, Kennedy, and Ovsyannikova have received grant funding and royalties from ICW Ventures for pre-clinical studies on a peptide-based COVID-19 vaccine. Drs. Poland, Kennedy, Ovsyannikova and Haralambieva hold a patent related to the impact of single nucleotide polymorphisms on measles vaccine immunity. Dr. Kennedy has received funding from Merck Research Laboratories to study waning immunity to mumps vaccine. Dr. Kennedy also offers consultative advice on vaccine development to Merck & Co. and Sanofi Pasteur. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policy.]., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Peptide antibodies have become one of the most important classes of reagents in molecular biology and clinical diagnostics. For this reason, methods for their production and characterization continue to be developed, including basic peptide synthesis protocols, peptide-conjugate production and characterization, conformationally restricted peptides, immunization procedures, etc. Detailed mapping of peptide antibody epitopes has yielded important information on antibody-antigen interaction in general and specifically in relation to antibody cross-reactivity and theories of molecular mimicry. This information is essential for detailed understanding of paratope-epitope dynamics, design of antibodies for research, design of peptide-based vaccines, development of therapeutic peptide antibodies, and de novo design of antibodies with predetermined specificity., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Animal models are essential in medical research for testing drugs and vaccines. These models differ from humans in various respects, so their results are not directly translatable in humans. To address this issue, humanized mice engrafted with functional human cells or tissue can be helpful. We propose using humanized mice that support the engraftment of human hematopoietic stem cells (HSCs) without irradiation to evaluate vaccines that influence patient immunity. For infectious diseases, several types of antigens and adjuvants have been developed and evaluated for vaccination. Peptide vaccines are generally used for their capability to fight cancer and infectious diseases. Evaluation of adjuvants is necessary as they induce inflammation, which is effective for an enhanced immune response but causes adverse effects in some individuals. A trial can be done on humanized mice to check the immunogenicity of a particular adjuvant and peptide combination. Messenger RNA has also emerged as a potential vaccine against viruses. These vaccines need to be tested with human immune cells because they work by producing a particular peptide of the pathogen. Humanized mice with human HSCs that can produce both myeloid and lymphoid cells show a similar immune response that these vaccines will produce in a patient., Competing Interests: No potential conflict of interest relevant to this article was reported., (© Korean Vaccine Society.)

The Hepatitis B virus (HBV) HBx and HBc proteins play a crucial role in associating with covalently closed circular DNA (cccDNA), the primary factor contributing to intrahepatic viral persistence and a major obstacle in achieving a cure for HBV. The cccDNA serves as a reservoir for viral persistence. Targeting the viral HBc and HBx proteins' interaction with cccDNA could potentially limit HBV replication. In this study, we present epitopes identified from global consensus sequences of HBx and HBc proteins that have the potential to serve as targets for the development of effective vaccine candidates. Furthermore, conserved residues identified through this analysis can be utilized in designing novel, site-specific anti-HBV agents capable of targeting all major genotypes of HBV. Our approach involved designing global consensus sequences for HBx and HBc proteins, enabling the analysis of variable regions and highly conserved motifs. These identified motifs and regions offer potent sites for the development of peptide vaccines, the design of site-specific RNA interference, and the creation of anti-HBV inhibitors. The epitopes derived from global consensus sequences of HBx and HBc proteins emerge as promising targets for the development of effective vaccine candidates. Additionally, the conserved residues identified provide valuable insights for the development of innovative, site-specific anti-HBV agents capable of targeting all major genotypes of HBV from A to J.

Background: Cancer, being a complex disease, presents a major challenge for the scientific and medical communities. Peptide therapeutics have played a significant role in different medical practices, including cancer treatment., Method: This review provides an overview of the current situation and potential development prospects of anticancer peptides (ACPs), with a particular focus on peptide vaccines and peptide-drug conjugates for cancer treatment., Results: ACPs can be used directly as cytotoxic agents (molecularly targeted peptides) or can act as carriers (guiding missile) of chemotherapeutic agents and radionuclides by specifically targeting cancer cells. More than 60 natural and synthetic cationic peptides are approved in the USA and other major markets for the treatment of cancer and other diseases. Compared to traditional cancer treatments, peptides exhibit anticancer activity with high specificity and the ability to rapidly kill target cancer cells. ACP's target and kill cancer cells via different mechanisms, including membrane disruption, pore formation, induction of apoptosis, necrosis, autophagy, and regulation of the immune system. Modified peptides have been developed as carriers for drugs, vaccines, and peptide-drug conjugates, which have been evaluated in various phases of clinical trials for the treatment of different types of solid and leukemia cancer., Conclusions: This review highlights the potential of ACPs as a promising therapeutic option for cancer treatment, particularly through the use of peptide vaccines and peptide-drug conjugates. Despite the limitations of peptides, such as poor metabolic stability and low bioavailability, modified peptides show promise in addressing these challenges. Various mechanism of action of anticancer peptides. Modes of action against cancer cells including: inducing apoptosis by cytochrome c release, direct cell membrane lysis (necrosis), inhibiting angiogenesis, inducing autophagy-mediated cell death and immune cell regulation., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Peptide vaccines have shown great potential in cancer immunotherapy by targeting tumor antigens and activating the patient's immune system to mount a specific response against cancer cells. However, the efficacy of peptide vaccines in inducing a sustained immune response and achieving clinical benefit remains a major challenge. In this review, we discuss the current status of peptide vaccines in cancer immunotherapy and strategies to improve their efficacy. We summarize the recent advancements in the development of peptide vaccines in pre-clinical and clinical settings, including the use of novel adjuvants, neoantigens, nano-delivery systems, and combination therapies. We also highlight the importance of personalized cancer vaccines, which consider the unique genetic and immunological profiles of individual patients. We also discuss the strategies to enhance the immunogenicity of peptide vaccines such as multivalent peptides, conjugated peptides, fusion proteins, and self-assembled peptides. Although, peptide vaccines alone are weak immunogens, combining peptide vaccines with other immunotherapeutic approaches and developing novel approaches such as personalized vaccines can be promising methods to significantly enhance their efficacy and improve the clinical outcomes for cancer patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Plasmodium spp. is the etiological agent of malaria, a life-threatening parasitic disease transmitted by infected mosquitoes. Malaria remains a major global health challenge, particularly in endemic regions. Over the years, various vaccine candidates targeting different stages of Plasmodium parasite life-cycle have been explored, including subunit vaccines, vectored vaccines, and whole organism vaccines with Mosquirix, a vaccine based on a recombinant protein, as the only currently approved vaccine for Plasmodium falciparum malaria. Despite the aforementioned notable progress, challenges such as antigenic diversity, limited efficacy, resistant parasites escaping protective immunity and the need for multiple doses have hindered the development of a highly efficacious malaria vaccine. The recent success of mRNA-based vaccines against SARS-CoV-2 has sparked renewed interest in mRNA vaccine platforms. The unique mRNA vaccine features, including their potential for rapid development, scalability, and flexibility in antigen design, make them a promising avenue for malaria vaccine development. This review provides an overview of the malaria vaccines' evolution from the past towards the mRNA vaccine era and highlights their advantages in overcoming the limitations of previous malaria vaccine candidates.

Glioblastoma (GBM) is the most common and aggressive central nervous system tumor, requiring multimodal management. Due to its malignant behavior and infiltrative growth pattern, GBM is one of the most difficult tumors to treat and gross total resection is still considered to be the first crucial step. The deep understanding of GBM microenvironment and the possibility of manipulating the patient's innate and adaptive immune system to fight the neoplasm represent the base of immunotherapeutic strategies that currently express the future for the fight against GBM. Despite the immunotherapeutic approach having been successfully adopted in several solid and haematologic neoplasms, immune resistance and the immunosuppressive environment make the use of these strategies challenging in GBM treatment. We describe the most recent updates regarding new therapeutic strategies that target the immune system, immune checkpoint inhibitors, chimeric antigen receptor T cell therapy, peptide and oncolytic vaccines, and the relevant mechanism of immune resistance. However, no significant results have yet been obtained in studies targeting single molecules/pathways. The future direction of GBM therapy will include a combined approach that, in contrast to the inescapable current treatment modality of maximal resection followed by chemo- and radiotherapy, may combine a multifaceted immunotherapy treatment with the dual goals of directly killing tumor cells and activating the innate and adaptive immune response.

Autoimmune diseases are caused by the dysfunction of the body's immune regulatory system, which leads to the recognition of self-antigens and the destruction of self-tissues and is mediated by immune cells such as T and B cells, and affects 5-10% of the population worldwide. Current treatments such as non-steroidal anti-inflammatory drugs and glucocorticoids can only relieve symptoms of the disease and are accompanied by serious side effects that affect patient quality of life. The recent rise in antigen-specific therapies, especially vaccines carrying autoantigenic peptides, promises to change this disadvantage, where research has increased dramatically in the last decade. This therapy established specific immune tolerance by delivering peptide fragments containing disease-specific self-antigen epitopes to suppress excessive immune responses, thereby exerting a therapeutic effect, with high safety and specificity. This article presents the latest progress on the treatment of autoimmune diseases with autoantigen peptide vaccines. It includes the construction of peptide vaccine delivery system, the mechanism of inducing immune tolerance and its application., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Glioblastoma Multiforme (GBM) has a poor prognosis, with current treatments providing no advantage in terms of survival. Certain new immunotherapy methods, such as peptide vaccines, have been used in clinical trials. In this meta-analysis, the effectiveness of peptide vaccinations on the survival rate of GBM patients was studied., Methods: A comprehensive search was carried out using three electronic databases: PubMed, Scopus, and ISI. The purpose of this research was to assess Overall Survival (OS). The pooled overall one-year and two-year survival rates in GBM with peptide vaccination were calculated using the general inverse variance technique as random effects hazard ratios (HRs). In the study, subgroups of countries were compared with each other. Japan had the highest one-year survival rate, and the US had the highest two-year survival rate., Results: With 95% Confidence Intervals (CIs), the one-year OS rate in GBM patients treated with peptide vaccination increased significantly, but the two-year survival rate did not increase. As a result, while additional research is needed, it cannot be concluded that it is an effective therapy for GBM., Conclusion: Our study found that while peptide vaccination treatment did not increase second-year survival, it improved first-year survival. More research needs to be done to find effective vaccinebased treatments for GBM that can help patients survive longer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Gliomas are highly treatment refractory against immune checkpoint blockade, an immunotherapeutic modality that revolutionized therapy for many tumors. At the same time, technological innovation has dramatically accelerated the development of immunotherapeutic approaches such as personalized tumor-specific vaccine production, dendritic cell vaccine manufacture, patient-individual target selection and chimeric antigen receptor, and T cell receptor T cell manufacture. Here we review recent clinical and translational advances in glioma immunotherapy with a focus on targets and their cognate immune receptor derivates as well as concepts to improve intratumoral T cell effector functions., (© 2022. The Author(s).)

Antigenic differences formed by alterations in gene expression and alternative splicing are predicted in breast cancer cells undergoing epithelial to mesenchymal transition (EMT) and the reverse plasticity known as MET. How these antigenic differences impact immune interactions and the degree to which they can be exploited to enhance immune responses against mesenchymal cells is not fully understood. We utilized a master microRNA regulator of EMT to alter mesenchymal-like EO771 mammary carcinoma cells to a more epithelial phenotype. A computational approach was used to identify neoantigens derived from the resultant differentially expressed somatic variants (SNV) and alternative splicing events (neojunctions). Using whole cell vaccines and peptide-based vaccines, we find superior cytotoxicity against the more-epithelial cells and explore the potential of neojunction-derived antigens to elicit T cell responses through experiments designed to validate the computationally predicted neoantigens. Overall, results identify EMT-associated splicing factors common to both mouse and human breast cancer cells as well as immunogenic SNV- and neojunction-derived neoantigens in mammary carcinoma cells.

COVID-19 pandemic has been the deadliest infectious disease outbreak since Spanish flu. The emerging variant lineages, decay of neutralizing antibodies, and occur of reinfections require the development of highly protective and safe vaccines. As currently approved COVID-19 vaccines that utilize virus-related genetic material are less than ideal, other vaccine types have been also widely investigated. Among them, peptide-based vaccines hold great promise in countering COVID-19 as they may overcome most of the shortcomings of RNA/DNA and protein vaccines. Two basic types of potential peptide vaccines can be developed. The first type are those which rely on cytotoxic T-cell (CTL) responses to kill infected host cells and stop the replication via employing CTL-epitopes as vaccine antigens. The second type of peptide vaccines are those that rely on B-cell peptide epitopes to trigger humoral response via generating SARS-CoV-2-specific antibodies to neutralize and/or opsonize the virus. We propose that combining both cellular and humoral immune responses would be highly protective. Here we discuss opportunities and challenges in the development of an effective and safe peptide-based vaccine against COVID-19., (© 2022 The Authors. Drug Development Research published by Wiley Periodicals LLC.)

Peptide-based cancer vaccines are widely investigated in the clinic but exhibit modest immunogenicity. One approach that has been explored to enhance peptide vaccine potency is covalent conjugation of antigens with cell-penetrating peptides (CPPs), linear cationic and amphiphilic peptide sequences designed to promote intracellular delivery of associated cargos. Antigen-CPPs have been reported to exhibit enhanced immunogenicity compared to free peptides, but their mechanisms of action in vivo are poorly understood. We tested eight previously described CPPs conjugated to antigens from multiple syngeneic murine tumor models and found that linkage to CPPs enhanced peptide vaccine potency in vivo by as much as 25-fold. Linkage of antigens to CPPs did not impact dendritic cell activation but did promote uptake of linked antigens by dendritic cells both in vitro and in vivo. However, T cell priming in vivo required Batf3 -dependent dendritic cells, suggesting that antigens delivered by CPP peptides were predominantly presented via the process of cross-presentation and not through CPP-mediated cytosolic delivery of peptide to the classical MHC class I antigen processing pathway. Unexpectedly, we observed that many CPPs significantly enhanced antigen accumulation in draining lymph nodes. This effect was associated with the ability of CPPs to bind to lymph-trafficking lipoproteins and protection of CPP-antigens from proteolytic degradation in serum. These two effects resulted in prolonged presentation of CPP-peptides in draining lymph nodes, leading to robust T cell priming and expansion. Thus, CPPs can act through multiple unappreciated mechanisms to enhance T cell priming that can be exploited for cancer vaccines with enhanced potency.

Despite recent advances in cancer therapeutics, glioblastoma (GBM) remains one of the most difficult cancers to treat in both the primary and recurrent settings. GBM presents a unique therapeutic challenge given the immune-privileged environment of the brain and the aggressive nature of the disease. Furthermore, it can change phenotypes throughout the course of disease-switching between mesenchymal, neural, and classic gene signatures, each with specific markers and mechanisms of resistance. Recent advancements in the field of immunotherapy-which utilizes strategies to reenergize or alter the immune system to target cancer-have shown striking results in patients with many types of malignancy. Immune checkpoint inhibitors, adoptive cellular therapy, cellular and peptide vaccines, and other technologies provide clinicians with a vast array of tools to design highly individualized treatment and potential for combination strategies. There are currently over 80 active clinical trials evaluating immunotherapies for GBM, often in combination with standard secondary treatment options including re-resection and anti-angiogenic agents, such as bevacizumab. This review will provide a clinically focused overview of the immune environment present in GBM, which is frequently immunosuppressive and characterized by M2 macrophages, T cell exhaustion, enhanced transforming growth factor-β signaling, and others. We will also outline existing immunotherapeutic strategies, with a special focus on immune checkpoint inhibitors, chimeric antigen receptor therapy, and dendritic cell vaccines. Finally, we will summarize key discoveries in the field and discuss currently active clinical trials, including combination strategies, burgeoning technology like nucleic acid and nanoparticle therapy, and novel anticancer vaccines. This review aims to provide the most updated summary of the field of immunotherapy for GBM and offer both historical perspective and future directions to help inform clinical practice., (© 2022. The Author(s).)

Progress in the study of the immune response to pathogens and candidate vaccines has been impeded by limitations in the methods to study the functional activity of T-cell subsets proliferating in response to antigens processed and presented by antigen presenting cells (APC). As described in this review, during our studies of the bovine immune response to a candidate peptide-based vaccine and candidate rel deletion mutants in Mycobacterium avium paratuberculosis ( Map ) and Mycbacterium bovis (BCG), we developed methods to study the primary and recall CD4 and CD8 T-cell responses using an ex vivo platform. An assay was developed to study intracellular killing of bacteria mediated by CD8 T cells using quantitative PCR to distinguish live bacteria from dead bacteria in a mixed population of live and dead bacteria. Through use of these assays, we were able to demonstrate vaccination with live rel Map and BCG deletion mutants and a Map peptide-based vaccine elicit development of CD8 cytotoxic T cells with the ability to kill intracellular bacteria using the perforin-granzyme B pathway. We also demonstrated tri-directional signaling between CD4 and CD8 T cells and antigen-primed APC is essential for eliciting CD8 cytotoxic T cells. Herein, we describe development of the assays and review progress made through their use in the study of the immune response to mycobacterial pathogens and candidate vaccines. The methods obviate some of the major difficulties encountered in characterizing the cell-mediated immune response to pathogens and development of attenuated and peptide-based vaccines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Davis, Mahmoud, Abdellrazeq, Elnaggar, Dahl, Hulubei and Fry.)

The exponential growth in the depositories of biological sequence data has generated an urgent need to store, retrieve and analyse the data efficiently and effectively for which the standard practice of using alignment procedures are not adequate due to high demand on computing resources and time. Graphical representation of sequences has become one of the most popular alignment-free strategies to analyse the biological sequences where each basic unit of the sequences - the bases adenine, cytosine, guanine and thymine for DNA/RNA, and the 20 amino acids for proteins - are plotted on a multi-dimensional grid. The resulting curve in 2D and 3D space and the implied graph in higher dimensions provide a perception of the underlying information of the sequences through visual inspection; numerical analyses, in geometrical or matrix terms, of the plots provide a measure of comparison between sequences and thus enable study of sequence hierarchies. The new approach has also enabled studies of comparisons of DNA sequences over many thousands of bases and provided new insights into the structure of the base compositions of DNA sequences. In this article we review in brief the origins and applications of graphical representations and highlight the future perspectives in this field., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been prevalent in the humans since 2019 and has given rise to a pandemic situation. With the discovery and ongoing use of drugs and vaccines against SARS-CoV-2, there is still no surety of its complete suppression of this disease or if there is a need for additional booster doses. There is an urgent need for alternative treatment strategies against COVID-19. Peptides and peptidomimetics have several advantages as therapeutic agents because of their target selectivity, better interactions, and lower toxicity. Minor structural alterations to peptides can help prevent their fast metabolism and provide long-action. This comprehensive review provides an overview of different peptide-based vaccines and therapeutics against SARS-CoV-2. It discusses the design and mechanism of action of the peptide-based vaccines, peptide immunomodulators, anti-inflammatory agents, and peptides as entry inhibitors of SARS-CoV-2. Moreover, the mechanism of action, sequences and current clinical trial studies are also summarized. The review also discusses the future aspects of peptide-based vaccines and therapeutics for COVID-19., Competing Interests: Conflict of interestThe authors have no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature B.V. 2022.)

In recent years, remarkable progress was registered in the field of cancer research. Though, cancer still represents a major cause of death and cancer metastasis a problem seeking for urgent solutions as it is the main reason for therapeutic failure. Unfortunately, the most common chemotherapeutic agents are non-selective and can damage healthy tissues and cause side effects that affect dramatically the quality of life of the patients. Targeted therapy with molecules that act specifically at the tumour sites interacting with overexpressed cancer receptors is a very promising strategy for achieving the specific delivery of anticancer drugs, radioisotopes or imaging agents. This review aims to give an overview on different strategies for targeting cancer cell receptors localised either at the extracellular matrix or at the cell membrane. Molecules like antibodies, aptamers and peptides targeting the cell surface are presented with advantages and disadvantages, with emphasis on peptides. The most representative peptides are described, including cell penetrating peptides, homing and anticancer peptides with particular consideration on recent discoveries.

Breast cancer is the most common invasive cancer diagnosed among women. A cancer vaccine has been recognized as a form of immunotherapy with a prominent position in the prevention and treatment of breast cancer. The majority of current breast cancer vaccination strategies aim to stimulate antitumor T-cell responses of the HER2/neu oncogene, which is abnormally expressed in breast cancer cells. However, the role of the B-cell humoral response is often underappreciated in the cancer vaccine design. We have advanced this idea by elucidating the role of B-cells in cancer vaccination by designing a chimeric antigenic peptide possessing both cytotoxic T lymphocytes (GP2) and B-cell (P4) peptide epitopes derived from HER2/neu. The chimeric peptide (GP2-P4) was further conjugated to a carrier protein (KLH), forming a KLH-GP2-P4 conjugate. The immunogenicity of KLH-GP2-P4 was compared with KLH-GP2 (lacking the B-cell epitope) in BALB/c mice. Mice immunized with KLH-GP2-P4 elicited more potent antigen-specific neutralizing antibodies against syngeneic TUBO cells (cancer cell line overexpressing HER2/neu) that was governed by a balanced Th1/Th2 polarization in comparison to KLH-GP2. Subsequently, these immune responses led to greater inhibition of tumor growth and longer survival in TUBO tumor-bearing mice in both prophylactic and therapeutic challenge experiments. Overall, our data demonstrated that the B-cell epitope has a profound effect in orchestrating an efficacious antitumor immunity. Thus, a multi-epitope peptide vaccine encompassing cytotoxic T-lymphocytes, T-helper and B-cell epitopes represents a promising strategy in developing cancer vaccines with a preventive and therapeutic modality for the effective management of breast cancer.

There is an urgent need for inexpensive, rapid and specific antigen-based assays to test for vaccine efficacy and detect infection with SARS-CoV-2 and its variants. We have identified a small, synthetic protein (JS7), representing a region of maximum variability within the receptor binding domain (RBD), which binds antibodies in sera from nine patients with PCR-verified COVID-19 of varying severity. Antibodies binding to either JS7 or the SARS-CoV-2 recombinant RBD, as well as those that disrupt binding between a fragment of the ACE2 receptor and the RBD, are proportional to disease severity and clinical outcome. Binding to JS7 was inhibited by linear peptides from the RBD interface with ACE2. Variants of JS7, such as E484K or N501Y, can be quickly synthesized in pure form in large quantities by automated methods. JS7 and related synthetic antigens can provide a basis for specific diagnostics for SARS-CoV-2 infections., (Copyright © 2021. Published by Elsevier Inc.)

The malaria vaccine candidate merozoite surface protein 2 (MSP2) has shown promise in clinical trials and is in part responsible for a reduction in parasite densities. However, strain-specific reductions in parasitaemia suggested that polymorphic regions of MSP2 are immuno-dominant. One strategy to bypass the hurdle of strain-specificity is to bias the immune response towards the conserved regions. Two mouse monoclonal antibodies, 4D11 and 9H4, recognise the conserved C-terminal region of MSP2. Although they bind overlapping epitopes, 4D11 reacts more strongly with native MSP2, suggesting that its epitope is more accessible on the parasite surface. In this study, a structure-based vaccine design approach was applied to the intrinsically disordered antigen, MSP2, using a crystal structure of 4D11 Fv in complex with its minimal binding epitope. Molecular dynamics simulations and surface plasmon resonance informed the design of a series of constrained peptides that mimicked the 4D11-bound epitope structure. These peptides were conjugated to keyhole limpet hemocyanin and used to immunise mice, with high to moderate antibody titres being generated in all groups. The specificities of antibody responses revealed that a single point mutation can focus the antibody response towards a more favourable epitope. This structure-based approach to peptide vaccine design may be useful not only for MSP2-based malaria vaccines, but also for other intrinsically disordered antigens.

Antigen-specific immunotherapies, in particular peptide vaccines, depend on the recognition of naturally presented antigens derived from mutated and unmutated gene products on human leukocyte antigens, and represent a promising low-side-effect concept for cancer treatment. So far, the broad application of peptide vaccines in cancer patients is hampered by challenges of time- and cost-intensive personalized vaccine design, and the lack of neoepitopes from tumor-specific mutations, especially in low-mutational burden malignancies. In this study, we developed an immunopeptidome-guided workflow for the design of tumor-associated off-the-shelf peptide warehouses for broadly applicable personalized therapeutics. Comparative mass spectrometry-based immunopeptidome analyses of primary chronic lymphocytic leukemia (CLL) samples, as representative example of low-mutational burden tumor entities, and a dataset of benign tissue samples enabled the identification of high-frequent non-mutated CLL-associated antigens. These antigens were further shown to be recognized by pre-existing and de novo induced T cells in CLL patients and healthy volunteers, and were evaluated as pre-manufactured warehouse for the construction of personalized multi-peptide vaccines in a first clinical trial for CLL (NCT04688385). This workflow for the design of peptide warehouses is easily transferable to other tumor entities and can provide the foundation for the development of broad personalized T cell-based immunotherapy approaches., Competing Interests: H-GR is shareholder of Immatics Biotechnologies GmbH, Synimmune GmbH, and Curevac AG, and holds a patent application on an adjuvant, XS15. AN, H-GR, and JW are listed as inventors on patents related to peptides described in this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nelde, Maringer, Bilich, Salih, Roerden, Heitmann, Marcu, Bauer, Neidert, Denzlinger, Illerhaus, Aulitzky, Rammensee and Walz.)

Mesoporous silica nanoparticles have drawn increasing attention as promising candidates in vaccine delivery. Previous studies evaluating silica-based vaccine delivery systems concentrated largely on macromolecular antigens, such as inactivated whole viruses. In this study, we synthesized dendritic mesoporous silica nanoparticles (DMSNs), and we evaluated their effectiveness as delivery platforms for peptide-based subunit vaccines. We encapsulated and tested in vivo an earlier reported foot-and-mouth disease virus (FMDV) peptide vaccine (B 2 T). The B 2 T@DMSNs formulation contained the peptide vaccine and the DMSNs without further need of other compounds neither adjuvants nor emulsions. We measured in vitro a sustained release up to 930 h. B 2 T@DMSNs-57 and B 2 T@DMSNs-156 released 23.7% (135 µg) and 22.8% (132 µg) of the total B 2 T. The formation of a corona of serum proteins around the DMSNs increased the B 2 T release up to 61% (348 µg/mg) and 80% (464 µg/mg) for B 2 T@DMSNs-57 and B 2 T@DMSNs-156. In vitro results point out to a longer sustained release, assisted by the formation of a protein corona around DMSNs, compared to the reference formulation (i.e., B 2 T emulsified in Montanide). We further confirmed in vivo immunogenicity of B 2 T@DMSNs in a particle size-dependent manner. Since B 2 T@DMSNs elicited specific immune responses in mice with high IgG production like the reference B 2 T@Montanide™, self-adjuvant properties of the DMSNs could be ascribed. Our results display DMSNs as efficacious nanocarriers for peptide-based vaccine administration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 An, Defaus, Andreu and Rivera-Gil.)

Peptide vaccines incorporating B- and T-cell epitopes have shown promise in the context of various cancers and infections. These vaccines are relatively simple to manufacture, but more immunogenic formulations are considered a priority. We developed tetrabranched derivatives for this purpose based on a novel peptide welding technology (PWT). PWTs provide molecular scaffolds for the efficient synthesis of ultrapure peptide dendrimers, which allow the delivery of multiple ligands within a single macromolecular structure. Peptide vaccines incorporating T-cell epitopes derived from melanoma and B-cell epitopes derived from human immunodeficiency virus, synthesized using this approach, elicited primary immune responses in vitro and in vivo. Subcutaneous administration of the B-cell epitope-based vaccines also elicited more potent humoral responses than subcutaneous administration of the corresponding peptides alone. Highly immunogenic peptide epitope-based vaccines can therefore be generated quickly and easily using a novel PWT.

De novo cancer-targeting immunostimulatory peptides have been designed and developed as synthetic antibody mimics. A series of bifunctional peptides incorporating NKp30-binding and NK-cell-activating domains were synthesized as linear dimers and then extended into branching trimeric peptides by the incorporation of GRP78-targeting and tumor-cell-binding sequences. A selected trimeric peptide from this small set of peptides displayed binding capabilities on GRP78 + HepG2 and A549 target cells. Cell binding diminished in the presence of an anti-GRP78 peptide blocker, thus suggesting GRP78-binding dependence. Similarly, the selected trimeric peptide was also found to exhibit NK cell binding in an NKp30-dependent manner, which translated into NK cell activation as indicated by cytokine secretion. In co-culture, fluorescence microscopy revealed that the target GFP-expressing A549 cells were visibly associated with the effector NK cells when pre-activated with lead trimeric peptide. Accordingly, A549 cells were found to be compromised, as evidenced by the loss of GFP signal and notable detection of early-/late-stage apoptosis. Investigation of the immunological markers related to toxicity revealed detectable secretion of pro-inflammatory cytokines and chemokines, including IFN-γ, TNF-α, and IL-8. Furthermore, administration of peptide-activated NK cells into A549-tumor-bearing mice resulted in a consistent decrease in tumor growth when compared to the untreated control group. Taken together, the identification of a lead trimeric peptide capable of targeting and activating NK cells' immunotoxicity directly towards GRP78 + /B7H6 - tumors provides a novel proof-of-concept for the development of cancer-targeting immunostimulatory peptide ligands that mimic antibody-targeting and -activating functions related to cancer immunotherapy applications., (© 2020 Wiley-VCH GmbH.)

Peptide and dendritic cell vaccines activate the immune system against tumor antigens to combat brain tumors. Vaccines stimulate a systemic immune response by inducing both antitumor T cells as well as humoral immunity through antibody production to cross the blood-brain barrier and combat brain tumors. Recent trials investigating vaccines against peptides (ie, epithelial growth factor receptor variant III, survivin, heat shock proteins, or personalized tumor antigens) and dendritic cells pulsed with known peptides, messenger RNA or unknown tumor lysate targets demonstrate the potential for therapeutic cancer vaccines to become an important therapy for brain tumor treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aims: Photochemical internalization (PCI) is a technology for inducing release of endocytosed antigens into the cell cytosol via a light-induced process. Preclinical experiments have shown that PCI improves MHC class I antigen presentation, resulting in strongly enhanced CD8+ T-cell responses to polypeptide antigens. In PCI vaccination a mixture of the photosensitizing compound fimaporfin, vaccine antigens, and an adjuvant is administered intradermally followed by illumination of the vaccination site. This work describes an open label, phase I study in healthy volunteers, to assess the safety, tolerability, and immune response to PCI vaccination in combination with the adjuvant poly-ICLC (Hiltonol) (ClinicalTrials.gov Identifier: NCT02947854)., Methods: The primary objective of the study was to assess the safety and local tolerance of PCI mediated vaccination, and to identify a safe fimaporfin dose for later clinical studies. A secondary objective was to analyze the immunological responses to the vaccination. Each subject received 3 doses of HPV16 E7 peptide antigens and two doses of Keyhole Limpet Hemocyanin (KLH) protein. A control group received Hiltonol and vaccine antigens only, whereas the PCI groups in addition received fimaporfin + light. Local and systemic adverse effects were assessed by standard criteria, and cellular and humoral immune responses were analyzed by ELISpot, flow cytometry, and ELISA assays., Results: 96 healthy volunteers were vaccinated with fimaporfin doses of 0.75-50 µg. Doses below 17.5 µg were safe and tolerable, higher doses exhibited local tolerability issues in some study subjects, mainly erythema, and pain during illumination. There were few, and only mild and expected systemic adverse events. The employment of PCI increased the number of subjects exhibiting a T-cell response to the HPV peptide vaccine about 10-fold over what was achieved with the antigen/Hiltonol combination without PCI. Moreover, the use of PCI seemed to result in a more consistent and multifunctional CD8+ T-cell response. An enhancement of the humoral immune response to KLH vaccination was also observed., Conclusions: Using PCI in combination with Hiltonol for intradermal vaccination is safe at fimaporfin doses below 17.5 µg, and gives encouraging immune responses to peptide and protein based vaccination., Competing Interests: TO and AH are employees of PCI Biotech AS and own shares and share options in the Company. AH and PS are inventors on several patents and patent Applications on the PCI Technology. HO and SJ work as consultants for PCI Biotech, and SJ is working for ZellNet Consulting, Inc. VE is an employee of PCI Biotech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Otterhaug, Janetzki, Welters, Håkerud, Nedberg, Edwards, Boekestijn, Loof, Selbo, Olivecrona, van der Burg and Høgset.)

Urinary Bladder cancer (UBC) is a diversified disease with an array of clinicopathological attributes. Several studies have shown that cancer susceptibility candidate 5 (CASC5) plays important roles in various types of malignancies; however its expression and clinical significance in human UBC remain largely unknown. This research study was intended to explore mRNA/protein expression pattern of CASC5 as a member of the cancer-testis (CT) gene family and assess its clinical utility in diagnostic management of patients with UBC. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) was employed to appraise the detailed expression profile of CASC5 in patients with UBC. The mRNA over expression of CASC5 was detected in testis tissue and relatively high frequency 59.2% (45 of 76) of CASC5 mRNA was detected in UBC tissues. CASC5 mRNA relative mean fold expression was also significantly (p < 0.01) higher in the muscle-invasive tumor tissues compared to non-muscle-invasive tumor tissues (12.26 ± 9.53 vs. 4.64 ± 2.50, p = 0.005). Heterogeneous staining pattern of CASC5 protein was exclusively detected using IHC. The frequency of CASC5 protein over expression was detected in 67.7% (44 of 65) UBC patients and negative in benign prostatic hyperplasia (BPH). Further, CASC5 protein expression was significantly (p < 0.001) associated with cigarette smoking habit in UBC patients. Our study findings testified that CASC5 over expression among patients with UBC as compared to controls and concludes that CASC5 is a potential CT gene in UBC.

Immunotherapy has changed the landscape of treatment of many solid and hematological malignancies and is at the forefront of cancer breakthroughs. Several circumstances unique to the central nervous system (CNS) such as limited space for an inflammatory response, difficulties with repeated sampling, corticosteroid use for management of cerebral edema, and immunosuppressive mechanisms within the tumor and brain parenchyma have posed challenges in clinical development of immunotherapy for intracranial tumors. Nonetheless, the success of immunotherapy in brain metastases (BMs) from solid cancers such as melanoma and non-small cell lung cancer (NSCLC) proves that the CNS is not an immune-privileged organ and is capable of initiating and regulating immune responses that lead to tumor control. However, the development of immunotherapeutics for the most malignant primary brain tumor, glioblastoma (GBM), has been challenging due to systemic and profound tumor-mediated immunosuppression unique to GBM, intratumoral and intertumoral heterogeneity, and lack of stably expressed clonal antigens. Here, we review recent advances in the field of immunotherapy for neuro-oncology with a focus on BM, GBM, and rare CNS cancers., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Chemical conjugation of peptide epitopes and lipids into a single branched lipopeptide is a promising strategy for the generation of multiantigenic vaccines. We developed a double conjugation strategy that utilizes a mercapto-acryloyl Michael addition reaction between two unprotected peptides, followed by a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) click reaction. The technique proved capable of producing branched multiantigenic vaccine candidates with an overall yield of 78%., (© 2021. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The design for vaccines using in silico analysis of genomic data of different viruses has taken many different paths, but lack of any precise computational approach has constrained them to alignment methods and some alignment-free techniques. In this work, a precise computational approach has been established wherein two new mathematical parameters have been suggested to identify the highly conserved and surface-exposed regions which are spread over a large region of the surface protein of the virus so that one can determine possible peptide vaccine candidates from those regions. The first parameter, w , is the sum of the normalized values of the measure of surface accessibility and the normalized measure of conservativeness, and the second parameter is the area of a triangle formed by a mathematical model named 2D Polygon Representation. This method has been, therefore, used to determine possible vaccine targets against SARS-CoV-2 by considering its surface-situated spike glycoprotein. The results of this model have been verified by a parallel analysis using the older approach of manually estimating the graphs describing the variation of conservativeness and surface-exposure across the protein sequence. Furthermore, the working of the method has been tested by applying it to find out peptide vaccine candidates for Zika and Hendra viruses respectively. A satisfactory consistency of the model results with pre-established results for both the test cases shows that this in silico alignment-free analysis proposed by the model is suitable not only to determine vaccine targets against SARS-CoV-2 but also ready to extend against other viruses., Competing Interests: Conflict of interestThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© The Author(s), under exclusive licence to Springer Nature B.V. 2021.)

Dendrimers are structurally well-defined, artificial polymers with physicochemical characteristics that often imitate biomacromolecules. Consequently, they are encouraging candidates for the delivery of peptide-based vaccines. We developed a synthetic protocol for conjugating a peptide antigen derived from human papillomavirus (HPV) E7 protein to a poly(t-butyl acrylate) dendrimer to construct a vaccine candidate. The synthetic pathway utilized copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) click reaction, and resulted in a 76% substitution ratio of the 8-arm dendrimer. The obtained peptide-polymer construct was self-assembled, dialyzed, and characterized by microanalysis and dynamic light scattering., (© 2021. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Vaccines remain the most efficacious means to avoid and eliminate morbid diseases associated with high morbidity and mortality. Clinical trials indicate the gaining impetus of peptide vaccines against diseases for which an effective treatment still remains obscure. CD4 T-cell-based peptide vaccines involve immunization with antigenic determinants from pathogens or neoplastic cells that possess the ability to elicit a robust T helper cell response, which subsequently activates other arms of the immune system. The available in silico predictors of human leukocyte antigen II (HLA-II) binding peptides are sequence-based techniques, which ostensibly have balanced sensitivity and specificity. Structural analysis and understanding of the cognate peptide and HLA-II interactions are essential to empirically derive a successful peptide vaccine. However, the availability of structure-based epitope prediction algorithms is inadequate compared with sequence-based prediction methods. The present study is an attempt to understand the structural aspects of HLA-II binders by analyzing the Protein Data Bank (PDB) complexes of pHLA-II. Furthermore, we mimic the peptide exchange mechanism and demonstrate the structural implication of an acidic environment on HLA-II binders. Finally, we discuss a structure-guided approach to decipher potential HLA-II binders within an antigenic protein. This strategy may accurately predict the peptide epitopes and thus aid in designing successful peptide vaccines.

Coronaviruses (CoVs) belong to the Coronaviridae-family. The genus Beta-coronaviruses, are enveloped positive strand RNA viruses with club-like spikes at the surface with a unique replication process and a large RNA genome (∼25 kb). CoVs are known as one of the major pathogenic viruses causing a variety of diseases in birds and mammals including humans (lethal respiratory dysfunctions). Recently, a new strain of coronavirus has been identified and named as SARS-CoV-2. A large number of COVID-19 (disease caused by SARS-CoV-2) cases are being diagnosed all over the World especially in China (Wuhan). COVID-19 showed high mortality rate exponentially, however, not even a single effective cure is being introduced yet against COVID-19. In the current study, immunoinformatics approaches were employed to predict the antigenic epitopes against COVID-19 for the development of a coronavirus peptide vaccine. Cytotoxic T-lymphocyte (CTL) and B-cell epitopes were predicted for SARS-CoV-2 coronavirus structural proteins (Spikes, Membrane, Envelope, and Nucleocapsid). The docking complexes of the top 10 epitopes having antigenic sites were analyzed led by binding affinity and binding interactional analyses of top ranked predicted peptides with the MHC-I HLA molecule. The predicted peptides may have potential to be used as peptide vaccine against COVID-19., (Copyright © 2020 Waqas, Haider, Sufyan, Siraj and Sehgal.)

Malaria remains one of the world's most urgent global health problems, with almost half a million deaths and hundreds of millions of clinical cases each year. Existing interventions by themselves will not be enough to tackle infection in high-transmission areas. The best new intervention would be an effective vaccine; but the leading P. falciparum and P. vivax vaccine candidates, RTS,S and VMP001, show only modest to low field efficacy. New antigens and improved ways for screening antigens for protective efficacy will be required. This study exploits the potential of Virus-Like Particles (VLP) to enhance immune responses to antigens, the ease of coupling peptides to the Q beta (Qβ) VLP and the existing murine malaria challenge to screen B-cell epitopes for protective efficacy. We screened P. vivax TRAP (PvTRAP) immune sera against individual 20-mer PvTRAP peptides. The most immunogenic peptides associated with protection were loaded onto Qβ VLPs to assess protective efficacy in a malaria sporozoite challenge. A second approach focused on identifying conserved regions within known sporozoite invasion proteins and assessing them as part of the Qβ. Using this VLP as a peptide scaffold, four new protective B-cell epitopes were discovered: three from the disordered region of PvTRAP and one from Thrombospondin-related sporozoite protein (TRSP). Antigenic interference between these and other B-cell epitopes was also explored using the virus-like particle/peptide platform. This approach demonstrates the utility of VLPs to help identifying new B-cell epitopes for inclusion in next-generation malaria vaccines., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Yersinia pestis , the cause of plague, could be weaponized. Unfortunately, development of new vaccines is limited by lack of correlates of protection. We used pre- and post-vaccination sera and peripheral blood mononuclear cells from a flagellin adjuvanted F1/V vaccine trial to evaluate for protective markers. Here, we report for the first time in humans that inverse caspase-3 levels, which are measures of protective antibody, significantly increased by 29% and 75% on days 14 and 28 post-second vaccination, respectively. In addition, there were significant increases in T-cell responses on day 28 post-second vaccination. The strongest positive and negative correlations between protective antibody levels and gene expression signatures were identified for IFNG and ENSG00000225107 genes, respectively. Flagellin/F1/V subunit vaccine induced macrophage-protective antibody and significant CD4 + T-cell responses. Several genes associated with these responses were identified that could serve as potential correlates of protection., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Elevated low-density lipoprotein cholesterol (LDL-C) increases the risk of atherosclerotic cardiovascular disease. Peptide-based PCSK9 vaccines have shown a promising prospect of reducing LDL-C. In peptide vaccine (pVax) design, the peptide antigens need to conjugate with carrier protein (CP). However, CP incorporation can induce undesirable anti-CP antibodies, which sterically mask peptide epitopes from being recognized by specific B cells and impair subsequent therapeutically antibody production. This epitopic suppression has posed a barrier in clinical translation of conjugate vaccines all along. A model CP (keyhole limpet hemocyanin, KLH) is herein camouflaged with serum albumin (SA) into hybrid nanocarriers (SA@N), with PCSK9 peptide being anchored onto the surface to form nanovaccine (SA@NVax). Such camouflage of KLH via high "self" SA coverage is able to inhibit KLH from extracellular immune recognition and prevent detectable anti-KLH antibody production. Furthermore, the nanovaccine around 70 nm stabilized by intermolecular disulfide network is ideal for internalization and biodegradation by antigen presenting cells as well as better retention in draining lymph nodes and spleen. As expected, the SA@NVax efficiently primes higher anti-PCSK9 IgG antibody titer than PCSK9 pVax., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Immunotherapy has changed the landscape of treatment of many solid and hematological malignancies and is at the forefront of cancer breakthroughs. Several circumstances unique to the central nervous system (CNS) such as limited space for an inflammatory response, difficulties with repeated sampling, corticosteroid use for management of cerebral edema, and immunosuppressive mechanisms within the tumor and brain parenchyma have posed challenges in clinical development of immunotherapy for intracranial tumors. Nonetheless, the success of immunotherapy in brain metastases (BMs) from solid cancers such as melanoma and non-small cell lung cancer (NSCLC) proves that the CNS is not an immune-privileged organ and is capable of initiating and regulating immune responses that lead to tumor control. However, the development of immunotherapeutics for the most malignant primary brain tumor, glioblastoma (GBM), has been challenging due to systemic and profound tumor-mediated immunosuppression unique to GBM, intratumoral and intertumoral heterogeneity, low mutation burden, and lack of stably expressed clonal antigens. Here, we review recent advances in the field of immunotherapy for neuro-oncology with a focus on BM and GBM.

Dogs are the main reservoir of zoonotic visceral leishmaniasis. Vaccination is a promising approach to help control leishmaniasis and to interrupt transmission of the Leishmania parasite. The promastigote surface antigen (PSA) is a highly immunogenic component of Leishmania excretory/secretory products. A vaccine based on three peptides derived from the carboxy-terminal part of Leishmania amazonensis PSA and conserved among Leishmania species, formulated with QA-21 as adjuvant, was tested on naive Beagle dogs in a preclinical trial. Four months after the full course of vaccination, dogs were experimentally infected with Leishmania infantum promastigotes. Immunization of dogs with peptide-based vaccine conferred immunity against experimental infection with L. infantum . Evidence for macrophage nitric oxide production and anti-leishmanial activity associated with IFN-γ production by lymphocytes was only found in the vaccinated group. An increase in specific IgG2 antibodies was also measured in vaccinated dogs from 2 months after immunization. Additionally, after challenge with L. infantum , the parasite burden was significantly lower in vaccinated dogs than in the control group. These data strongly suggest that this peptide-based vaccine candidate generated cross-protection against zoonotic leishmaniasis by inducing a Th1-type immune response associated with production of specific IgG2 antibodies. This preclinical trial including a peptide-based vaccine against leishmaniasis clearly demonstrates effective protection in a natural host. This approach deserves further investigation to enhance the immunogenicity of the peptides and to consider the possible engineering of a vaccine targeting several Leishmania species., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2019.)

Most cancer peptide vaccinations tested so far are capable of eliciting a strong immune response, but demonstrate poor clinical benefits. Since peptide vaccination is safe and well-tolerated, and several indications suggest that it has clear potential advantages over other modalities of treatment, it is important to investigate the reasons for these clinical failures. In this review, the current state of the art in targeting angiogenic proteins via peptide vaccines is presented, and the underlying reasons for both the successes and the failures are analyzed. The review highlights a number of areas critical for future success, including choice of target antigens, types of peptides used, delivery methods and use of proper adjuvants, and suggests ways to achieve better clinical results in the future.

VAC-3S is a therapeutic vaccine comprising a highly conserved HIV-gp41 motif coupled with the CRM197 carrier protein. High levels of anti-3S antibodies (Abs) have been associated with improved protection of CD4 + T-cell survival. A previous phase 1 study demonstrated the safety of VAC-3S. This multicentre, randomised, double-blind, placebo-controlled phase 2 clinical trial enroled between January 2014 and March 2015 HIV-1-infected patients under ART with plasma HIV RNA levels below 50 copies/mL and CD4 counts between 200 and 500 cells/μL. Participants were immunised with 16, 32, or 64 μg of VAC-3S, and compared to placebo. The primary outcome was immunogenicity assessed by changes from baseline of anti-3S Abs levels at week 12. Secondary outcomes included adverse events and the course of plasma HIV RNA level, CD4 count, CD4/CD8 ratio, inflammation and immune checkpoints from week 0 to week 48. Vaccination was well tolerated with no serious adverse events and induced a significant increase in anti-3S Ab response in vaccinated patients ( p  < 0.0001), compared to placebo. In high responders, the robust increased of CD4 count was associated with a significant and sustained reduction of PD-1 expression on CD4 + T cells through week 48 (variance p  = 0.0017). PD-1 expression was correlated with level of anti-3S Abs ( p  = 0.0092, r  = -0.68) and expression of NKp44L ( p  < 0.0001; r  = 0.54) in CD4 + T cells. Our findings regarding the increase of non-exhausted CD4 + T cells have potentially important application in personalised HIV vaccination for HIV-infected patients with high level of PD-1 to improve their T-cell immune function., Competing Interests: Competing interestsV.V. and P.D. are founders of InnaVirVax and consultants for Minka Tx. B.C. is consultant for Minka Tx. S.G. has been consultant for InnaVirVax. D.J. is Chief Operative Officer of Minka Tx. The remaining authors declare no competing interests.