Antigen Selection Research Articles

Distinct modulation of cellular immunopeptidome by the allosteric regulatory site of ER aminopeptidase 1.

ER aminopeptidase 1 (ERAP1) is an ER-resident aminopeptidase that excises N-terminal residues of peptides that then bind onto Major Histocompatibility Complex I molecules (MHC-I) and indirectly modulates adaptive immune responses. ERAP1 contains an allosteric regulatory site that accommodates the C-terminus of at least some peptide substrates, raising questions about its exact influence on antigen presentation and the potential of allosteric inhibition for cancer immunotherapy. We used an inhibitor that targets this regulatory site to study its effect on the immunopeptidome of a human cancer cell line. The immunopeptidomes of allosterically inhibited and ERAP1 KO cells contain high-affinity peptides with sequence motifs consistent with the cellular HLA class I haplotypes but are strikingly different in peptide composition. Compared to KO cells, allosteric inhibition did not affect the length distribution of peptides and skewed the peptide repertoire both in terms of sequence motifs and HLA allele utilization, indicating significant mechanistic differences between the two ways of disrupting ERAP1 function. These findings suggest that the regulatory site of ERAP1 plays distinct roles in antigenic peptide selection, which should be taken into consideration when designing therapeutic interventions targeting the cancer immunopeptidome.

Utilization of Stimuli-Responsive Biomaterials in the Formulation of Cancer Vaccines.

Immunology research has focused on developing cancer vaccines to increase the number of tumor-specific effector cells and their ability to fight cancer over the last few decades. There is a lack of professional success in vaccines compared to checkpoint blockade and adoptive T-cell treatment. The vaccine's inadequate delivery method and antigen selection are most likely to blame for the poor results. Antigen-specific vaccines have recently shown promising results in preclinical and early clinical investigations. To target particular cells and trigger the best immune response possible against malignancies, it is necessary to design a highly efficient and secure delivery method for cancer vaccines; however, enormous challenges must be overcome. Current research is focused on developing stimulus-responsive biomaterials, which are a subset of the range of levels of materials, to enhance therapeutic efficacy and safety and better regulate the transport and distribution of cancer immunotherapy in vivo. A concise analysis of current developments in the area of biomaterials that respond to stimuli has been provided in brief research. Current and anticipated future challenges and opportunities in the sector are also highlighted.

Oral vaccination as a potential strategy to manage chronic wasting disease in wild cervid populations.

Prion diseases are a novel class of infectious disease based in the misfolding of the cellular prion protein (PrPC) into a pathological, self-propagating isoform (PrPSc). These fatal, untreatable neurodegenerative disorders affect a variety of species causing scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt-Jacob disease (CJD) in humans. Of the animal prion diseases, CWD is currently regarded as the most significant threat due its ongoing geographical spread, environmental persistence, uptake into plants, unpredictable evolution, and emerging evidence of zoonotic potential. The extensive efforts to manage CWD have been largely ineffective, highlighting the need for new disease management tools, including vaccines. Development of an effective CWD vaccine is challenged by the unique biology of these diseases, including the necessity, and associated dangers, of overcoming immune tolerance, as well the logistical challenges of vaccinating wild animals. Despite these obstacles, there has been encouraging progress towards the identification of safe, protective antigens as well as effective strategies of formulation and delivery that would enable oral delivery to wild cervids. In this review we highlight recent strategies for antigen selection and optimization, as well as considerations of various platforms for oral delivery, that will enable researchers to accelerate the rate at which candidate CWD vaccines are developed and evaluated.

Cowpox to COVID: History of vaccination in the immunocompromised host.

The use of vaccination to prevent infection has a long history, starting in the 1700s with Jenner. New innovations have led to improvements in the safety and efficacy of vaccines, from live attenuated viruses to subunit vaccines, to RNA-based vaccination for SARS-CoV-2. Despite this progress, however, solid organ transplant (SOT) recipients on immunosuppression demonstrate an impaired vaccine response compared with healthy controls. This issue is important given the increased vulnerability to infection in immunocompromised patients, especially in the setting of the Coronavirus Disease 2019 (COVID-19) pandemic. We reviewed the literature on key topics in vaccination with significant clinical impact on SOT patients. Prior to COVID-19, a large amount of data has been published demonstrating impaired humoral and T-cell responses to multiple vaccinations targeting influenza, hepatitis B, VZV, and Pneumococcus. Poor immunogenicity can be addressed through the use of adjuvants to boost the immune response, even in the setting of senescence related to age or immunosuppression. New vaccines provide hope for preventing infection due to hepatitis C and Cytomegalovirus, and to the emerging infection, monkeypox. The data on the impact of the COVID-19 vaccine in SOT patients is reviewed, with a focus on seroconversion, antibody titer, and antigen-specific T cells. Factors associated with impaired response, including mycophenolate, are described. The history of vaccination demonstrates how scientific breakthroughs can be applied to clinical challenges. New approaches using adjuvants, strategic antigen selection, and RNA-based vaccines offer the potential to improve immune response in SOT recipients. Future innovations are needed to better protect the vulnerable immunocompromised host.

Abstract 6311: ABBV-400: An ADC delivering a novel topoisomerase 1 inhibitor to c-Met-positive solid tumors

Abstract Antibody-drug conjugate (ADC) technology is founded on the premise that antigen-mediated payload delivery selectively targets tumor cells and spares normal tissue. While approval of several ADCs has proven this to be a successful therapeutic approach, there remain opportunities to generate optimized ADCs with tailored selection of antigen matched with payload highly active in the target indication. To this end, ABBV-400 has been developed as an ADC that targets c-Met and topoisomerase-1 (Top1), both of which are overexpressed in solid tumors. The antibody is directed to the cell surface tyrosine kinase receptor, c-Met, a key driver of tumor cell growth and development of resistance to EGFR-targeted and other targeted therapeutics. Supporting this, Teliso-V, a c-Met-targeted ADC with MMAE payload, has been granted Breakthrough Therapy Designation in non-small cell lung cancer (NSCLC). To extend activity of a c-Met-targeted ADC to patients with tumors expressing lower c-Met levels and to indications, such as colorectal cancer (CRC), where MMAE-based ADCs have not been effective, a novel topoisomerase-1 inhibitor linker-drug was developed. Screening over 400 linker-drugs identified a unique, potent Top1 inhibitor with a cleavable valine-alanine linker and stable bromoacetamide attachment designed to minimize systemic payload release. Preclinically ABBV-400 exhibits favorable pharmacokinetics, anti-proliferative activity in vitro, and compelling efficacy in NSCLC, gastroesophageal, and CRC xenograft models. Furthermore, ABBV-400 is well tolerated by cynomolgus monkeys with bone marrow and gastrointestinal tract toxicities common to other Top1 inhibitors. This pairing of a novel linker-drug and an antibody with demonstrated clinical activity provides an exciting opportunity to treat patients with c-Met expression in indications sensitive to Top1 inhibition. ABBV-400 has progressed through dose escalation, and dose expansion is currently ongoing in a Phase 1 FIH clinical study (NCT05029882). All authors were employees of AbbVie during this research. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication Citation Format: Regina M. Reilly, Cheng Ji, Ryan P. Matuszak, Mark G. Anderson, Lora Tucker, Nadezda Klunder, Adelyn L. Lazo, Erwin R. Boghaert, Marybeth A. Pysz, Aloma D’Souza, Laura Kreckler, Milan Bruncko, Brittney J. Mills, Matthew Ravn, George Doherty, Kevin J. Freise, Andrew C. Phillips. ABBV-400: An ADC delivering a novel topoisomerase 1 inhibitor to c-Met-positive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6311.

COVID-19 spike polypeptide vaccine reduces the pathogenesis and viral infection in a mouse model of SARS-CoV-2.

The SARS-CoV-2 coronavirus, which causes a respiratory disease called COVID-19, has been declared a pandemic by the World Health Organization (WHO) and is still ongoing. Vaccination is the most important strategy to end the pandemic. Several vaccines have been approved, as evidenced by the ongoing global pandemic, but the pandemic is far from over and no fully effective vaccine is yet available. One of the most critical steps in vaccine development is the selection of appropriate antigens and their proper introduction into the immune system. Therefore, in this study, we developed and evaluated two proposed vaccines composed of single and multiple SARS-CoV-2 polypeptides derived from the spike protein, namely, vaccine A and vaccine B, respectively. The polypeptides were validated by the sera of COVID-19-vaccinated individuals and/or naturally infected COVID-19 patients to shortlist the starting pool of antigens followed by in vivo vaccination to hACE2 transgenic mice. The spike multiple polypeptide vaccine (vaccine B) was more potent to reduce the pathogenesis of organs, resulting in higher protection against the SARS-CoV-2 infection.

Cancer vaccines based on whole-tumor lysate or neoepitopes with validated HLA binding outperform those with predicted HLA-binding affinity

Antigen selection and prioritization represent crucial determinants of vaccines' efficacy. Here, we compare two personalized dendritic cell-based vaccination strategies using whole-tumor lysate or neoantigens. Data in mouse and in cancer patients demonstrate that peptide vaccines using neoantigens predicted on the sole basis of in silico peptide-major histocompatibility complex (MHC) binding affinity underperform relative to whole-tumor-lysate vaccines. In contrast, effective invitro peptide-MHC binding affinity and peptide immunogenicity significantly improve the prioritization of tumor-rejecting neoepitopes and result in more efficacious vaccines.

Reconstructing B cell lineage trees with minimum spanning tree and genotype abundances

B cell receptor (BCR) genes exposed to an antigen undergo somatic hypermutations and Darwinian antigen selection, generating a large BCR-antibody diversity. This process, known as B cell affinity maturation, increases antibody affinity, forming a specific B cell lineage that includes the unmutated ancestor and mutated variants. In a B cell lineage, cells with a higher antigen affinity will undergo clonal expansion, while those with a lower affinity will not proliferate and probably be eliminated. Therefore, cellular (genotype) abundance provides a valuable perspective on the ongoing evolutionary process. Phylogenetic tree inference is often used to reconstruct B cell lineage trees and represents the evolutionary dynamic of BCR affinity maturation. However, such methods should process B-cell population data derived from experimental sampling that might contain different cellular abundances. There are a few phylogenetic methods for tracing the evolutionary events occurring in B cell lineages; best-performing solutions are time-demanding and restricted to analysing a reduced number of sequences, while time-efficient methods do not consider cellular abundances. We propose ClonalTree, a low-complexity and accurate approach to construct B-cell lineage trees that incorporates genotype abundances into minimum spanning tree (MST) algorithms. Using both simulated and experimental data, we demonstrate that ClonalTree outperforms MST-based algorithms and achieves a comparable performance to a method that explores tree-generating space exhaustively. Furthermore, ClonalTree has a lower running time, being more convenient for building B-cell lineage trees from high-throughput BCR sequencing data, mainly in biomedical applications, where a lower computational time is appreciable. It is hundreds to thousands of times faster than exhaustive approaches, enabling the analysis of a large set of sequences within minutes or seconds and without loss of accuracy. The source code is freely available at github.com/julibinho/ClonalTree.

Clonal evolution and stereotyped sequences of human IgE lineages in aeroallergen-specific immunotherapy

Allergic disease reflects specific inflammatory processes initiated by interaction between allergen and allergen-specific IgE. Specific immunotherapy (SIT) is an effective long-term treatment option, but the mechanisms by which SIT provides desensitization are not well understood. Our aim was to characterize IgE sequences expressed by allergen-specific B cells over a 3-year longitudinal study of patients with aeroallergies who were undergoing SIT. Allergen-specific IgE-expressing clones were identified by using combinatorial single-chain variable fragment libraries and tracked in PBMCs and nasal biopsy samples over a 3-year period with antibody gene repertoire sequencing. The characteristics of private IgE-expressing clones were compared with those of stereotyped or "public" IgE responses to the grass pollen allergen Phleum pratense (Phl p) 2. Members of the same allergen-specific IgE lineages were observed in nasal biopsy samples and blood, and lineages detected at baseline persisted in blood and nasal biopsy samples after 3 years of SIT, including B cells that express IgE. Evidence of progressive class switch recombination to IgG subclasses was observed after 3 years of SIT. Acommon stereotyped Phl p 2-specific antibody heavy chain sequence was detected in multiple donors. The amino acid residues enriched in IgE-stereotyped sequences from seropositive donors were analyzed with machine learning and k-mer motif discovery. Stereotyped IgE sequences had lower overall rates of somatic hypermutation and antigen selection than did single-chain variable fragment-derived allergen-specific sequences or IgE sequences of unknown specificity. Longitudinal tracking of rare circulating and tissue-resident allergen-specific IgE+ clones demonstrates persistence of allergen-specific IgE+ clones, progressive class switch recombination to IgG subtypes, and distinct maturation of a stereotyped Phl p 2 clonotype.

MRNA—From COVID-19 Treatment to Cancer Immunotherapy

This review provides an overview covering mRNA from its use in the COVID-19 pandemic to cancer immunotherapy, starting from the selection of appropriate antigens, tumor-associated and tumor-specific antigens, neoantigens, the basics of optimizing the mRNA molecule in terms of stability, efficacy, and tolerability, choosing the best formulation and the optimal route of administration, to summarizing current clinical trials of mRNA vaccines in tumor therapy.

The variable conversion of neutralizing anti-SARS-CoV-2 single-chain antibodies to IgG provides insight into RBD epitope accessibility.

Monoclonal antibody (mAb) therapies have rapidly become a powerful class of therapeutics with applications covering a diverse range of clinical indications. Though most widely used for the treatment of cancer, mAbs are also playing an increasing role in the defense of viral infections, most recently with palivizumab for prevention and treatment of severe RSV infections in neonatal and pediatric populations. In addition, during the COVID-19 pandemic, mAbs provided a bridge to the rollout of vaccines; however, their continued role as a therapeutic option for those at greatest risk of severe disease has become limited due to the emergence of neutralization resistant Omicron variants. Although there are many techniques for the identification of mAbs, including single B cell cloning and immunization of genetically engineered mice, the low cost, rapid throughput and technological simplicity of antibody phage display has led to its widespread adoption in mAb discovery efforts. Here we used our 27-billion-member naïve single-chain antibody (scFv) phage library to identify a panel of neutralizing anti-SARS-CoV-2 scFvs targeting diverse epitopes on the receptor binding domain (RBD). Although typically a routine process, we found that upon conversion to IgG, a number of our most potent clones failed to maintain their neutralization potency. Kinetic measurements confirmed similar affinity to the RBD; however, mechanistic studies provide evidence that the loss of neutralization is a result of structural limitations likely arising from initial choice of panning antigen. Thus this work highlights a risk of scFv-phage panning to mAb conversion and the importance of initial antigen selection.

Human Leucocyte Antigen System and Selection of Unrelated Hematopoietic Stem Cell Donors: Impact of Patient-Donor (Mis)matching and New Challenges with the Current Technologies.

The selection of hematopoietic stem cell donors for allogeneic transplantation (allo-HSCT) is mainly driven by human leucocyte antigen (HLA) matching between patient and donor, with HLA-identical matched siblings being the preferred choice in most situations. Although other clinical and demographical variables matter, especially, donor age, which is unequivocally associated with better transplant outcomes, the histocompatibility criteria have a central role in the search for the best donor, particularly in the setting of unrelated allo-HSCT where HLA disparities between patient and donor are frequent. The present review is focused on the role of HLA incompatibilities on patient outcome according to the most recent literature, in an attempt to guide transplant physicians and search coordinators during the process of adult unrelated-donor selection. The technological progresses in HLA typing, i.e., with next-generation sequencing (NGS), now allow disclosing a growing number of HLA incompatibilities associated with a heterogeneous and sometimes unknown spectrum of clinical severity. Their immunogenic characteristics, i.e., their position inside or outside the antigen recognition domain (ARD), their permissiveness, their intronic or exonic nature and even the expected expression of the HLA loci where those mismatches occur, will be presented and discussed here, integrating the advances in the immunobiology of transplantation with survival and toxicity outcomes reported in the most relevant studies, within the perspective of improving donor selection in the current practice.

A new perspective in the research of antibody drug conjugate

<p>Antibody drug conjugate (ADC) combines the high specificity of monoclonal antibodies and the high activity of small molecule cytotoxic drugs through linkers to improve the targeting of tumor drugs and reduce the toxic side effects. Due to the advantages of clear targets, mature technology, and good selectivity, ADCs have shown excellent application prospects in hematological and solid tumor therapeutic fields. In this perspective, the selection of ADC-targeting antigens is described in the group of driver gene target antigens and non-driver gene target antigens to make more evident the importance of targeting antigens in advancing ADCs for tumor therapy. In the future, continued research and innovation in this field will help provide more effective, targeted, and personalized treatments for cancer patients, ultimately improving patients�� outcomes and quality of life.</p>

Immunotherapy as a New Therapeutic Approach for Brain and Spinal Cord Tumors.

Historically, the central nervous system (CNS) was considered an immune-privileged organ. However, recent studies have shown that the immune system plays a significant role in the CNS. Thus, there is renewed interest in applying cancer immunotherapy to CNS malignancies with the hope of generating a robust anti-tumor immune response and creating long-lasting immunity in patients. There has been some work with non-specific immunotherapy such as IL-2 for brain metastasis. Unfortunately, the results from non-specific immunotherapy studies were lackluster, so the focus has shifted to more specific CNS immunotherapies including cancer vaccines, immune checkpoint inhibitors, oncolytic virus therapy, and chimeric antigen receptor (CAR) T cell therapy. With respect to cancer vaccines, rindopepimut has been well-studied in glioblastoma (GBM) patients with the EGFRvIII mutation, with early results from phase II trials showing possible efficacy in carefully selected GBM patients. Other antigen-specific CNS tumor vaccines are still in the early stages. Immune checkpoint inhibitors are amongst the most promising and widely studied CNS immunotherapy strategies. Anti-PD-1 showed promising results in many non-CNS solid tumors, however, results from early clinical trials show poor efficacy for anti-PD-1 in GBM patients. Anti-PD-1 is also under investigation for CNS metastasis and showed some efficacy in non-small cell lung cancer and renal cell carcinoma patients. Anti-PD-1 is under early stage investigation for other CNS tumors such as chordoma. Oncolytic virus therapy is the strategy of infecting tumor cells with a virus that in turn triggers an innate immune response leading to tumor cell lysis. Oncolytic viruses currently under investigation include several adenovirus-based therapies and a herpes simplex virus-based therapy. Phase I studies have demonstrated the safety of oncolytic virus therapies in GBM patients. Current studies are evaluating the efficacy of these therapies both alone and in combination with other immunotherapy approaches such as checkpoint inhibition in patients with CNS tumors. CAR T cell therapy is a newer immunotherapy approach. CAR T cell therapies, directed against EGFRvIII mutation and HER-2 mutation, demonstrate an acceptable safety profile, although there is no conclusive evidence of the survival benefit of these therapies in early trials. Studies are currently underway to determine optimal tumor-specific antigen selection and modality of administration for CAR T cell therapy. Overall, the prognosis is generally poor for patients with CNS malignancies. The promising results of cancer immunotherapy for non-CNS tumors have created significant interest in applying these therapies for CNS malignancies. Preliminary results have not demonstrated robust efficacy for CNS immunotherapy. However, it is important to keep in mind that the field is still in its infancy and many clinical trials are still early-phase. Several, clinical trials are currently underway to further explore the role of immunotherapy for CNS malignancies.

Nanovaccines for cancer immunotherapy: Current knowledge and future perspectives

Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years. Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells (APCs) to stimulate a strong immune response to against tumors, representing a potentially therapeutic and prophylactic effect with the long-term anti-cancer benefits. Nevertheless, the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection, immunogenicity, lymph nodes (LNs) targeting ability, lysosomal escape ability, immune evasion, etc. Nanotechnology, aiming to overcome these barriers, has been utilized in cancer vaccine development for decades. Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy. In this review, we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design. In addition, the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.

The race toward a universal influenza vaccine: Front runners and the future directions

Influenza virus is the pathogen of influenza (flu) and millions of people suffer from the infection worldwide, posing a significant health risk. The current influenza vaccines induce neutralizing antibodies against hemagglutinin (HA) to achieve strain-specific neutralization. The effectiveness of seasonal vaccines is usually low and unpredictable because of the antigenic variation and genetic plasticity of viruses, as well as the interference of preexisting immunity. A universal influenza vaccine is urgently needed to prevent a wide variety of influenza viruses. Nevertheless, reaching this difficult optimal goal requires a step-by-step approach. Innovative strategies and vaccine platforms are being developed in order to generate robust cross-protective immunity. In this review, we summarize candidate influenza vaccines that meet two criteria: first, they are designed to provide protection against multiple influenza viruses; second, they had passed regulatory evaluations and have entered various stages of clinical trials. We discuss these vaccine candidates based on the different vaccine-production platforms, with the focus on antigen selection, design, adjuvants, immunomodulators, and routes of vaccine delivery in the development of universal influenza vaccines.

PRAGMATIST: A tool to prioritize foot-and-mouth disease virus antigens held in vaccine banks.

Antigen banks have been established to supply foot-and-mouth disease virus (FMDV) vaccines at short notice to respond to incursions or upsurges in cases of FMDV infection. Multiple vaccine strains are needed to protect against specific FMDV lineages that circulate within six viral serotypes that are unevenly distributed across the world. The optimal selection of distinct antigens held in a bank must carefully balance the desire to cover these risks with the costs of purchasing and maintaining vaccine antigens. PRAGMATIST is a semi-quantitative FMD vaccine strain selection tool combining three strands of evidence: (1) estimates of the risk of incursion from specific areas (source area score); (2) estimates of the relative prevalence of FMD viral lineages in each specific area (lineage distribution score); and (3) effectiveness of each vaccine against specific FMDV lineages based on laboratory vaccine matching tests (vaccine coverage score). The output is a vaccine score, which identifies vaccine strains that best address the threats, and consequently which are the highest priority for inclusion in vaccine antigen banks. In this paper, data used to populate PRAGMATIST are described, including the results from expert elicitations regarding FMD risk and viral lineage circulation, while vaccine coverage data is provided from vaccine matching tests performed at the WRLFMD between 2011 and 2021 (n = 2,150). These data were tailored to working examples for three hypothetical vaccine antigen bank perspectives (Europe, North America, and Australia). The results highlight the variation in the vaccine antigens required for storage in these different regions, dependent on risk. While the tool outputs are largely robust to uncertainty in the input parameters, variation in vaccine coverage score had the most noticeable impact on the estimated risk covered by each vaccine, particularly for vaccines that provide substantial risk coverage across several lineages.

An epitope-directed selection strategy facilitating the identification of Frizzled receptor selective antibodies

The lack of incorporating epitope information into the selection process makes the conventional antibody screening method less effective in identifying antibodies with desired functions. Here, we developed an epitope-directed antibody selection method by designing a directed library favoring the target epitope and a precise "counter" antigen for clearing irrelevant binders in the library. With this method, we successfully isolated an antibody, pF7_A5, that targets the less conserved region on the FZD2/7 CRD as designed. Guided by the structure of pF7_A5-FZD2CRD, a further round of evolution was conducted together with the "counter" antigen selection strategy, and ultimately, an FZD2-specific antibody and an FZD7-preferred antibody were obtained. Because of targeting the predefined functional site, all these antibodies exhibited the expected modulatory activity on the Wnt pathway. Together, the method developed here will be useful in antibody drug discovery, and the identified FZD antibodies will have clinical potential in FZD-related cancer therapy.

Urgency and necessity of Epstein-Barr virus prophylactic vaccines.

Epstein-Barr virus (EBV), a γ-herpesvirus, is the first identified oncogenic virus, which establishes permanent infection in humans. EBV causes infectious mononucleosis and is also tightly linked to many malignant diseases. Various vaccine formulations underwent testing in different animals or in humans. However, none of them was able to prevent EBV infection and no vaccine has been approved to date. Current efforts focus on antigen selection, combination, and design to improve the efficacy of vaccines. EBV glycoproteins such as gH/gL, gp42, and gB show excellent immunogenicity in preclinical studies compared to the previously favored gp350 antigen. Combinations of multiple EBV proteins in various vaccine designs become more attractive approaches considering the complex life cycle and complicated infection mechanisms of EBV. Besides, rationally designed vaccines such as virus-like particles (VLPs) and protein scaffold-based vaccines elicited more potent immune responses than soluble antigens. In addition, humanized mice, rabbits, as well as nonhuman primates that can be infected by EBV significantly aid vaccine development. Innovative vaccine design approaches, including polymer-based nanoparticles, the development of effective adjuvants, and antibody-guided vaccine design, will further enhance the immunogenicity of vaccine candidates. In this review, we will summarize (i) the disease burden caused by EBV and the necessity of developing an EBV vaccine; (ii) previous EBV vaccine studies and available animal models; (iii) future trends of EBV vaccines, including activation of cellular immune responses, novel immunogen design, heterologous prime-boost approach, induction of mucosal immunity, application of nanoparticle delivery system, and modern adjuvant development.

Advances in Tumor Antigen‐Based Anticancer Immunotherapy: Recent Progress, Prevailing Challenges, and Future Perspective

AbstractElimination of tumors by regulating the immune system is the primary research focus in the rapidly developing field of immune‐oncology. Current immunotherapeutic strategies mainly include immune checkpoint blockade therapy, adoptive immune cell therapy, and cancer vaccines. Among them, tumor antigen‐based cancer vaccines can potentially elicit specific and potent anti‐tumor immune responses with less toxicity and side effects, which are recognized as promising treatments in immunotherapy. The selection of tumor antigens is the primary determinant of cancer vaccine design, whereas systematic reviews based on them are scarce. In the present review, currently known tumor antigens and recent developments in cancer vaccines based on tumor antigens, including traditional antigen vaccines, neoantigen vaccines, shared antigen vaccines, and oral antigen vaccines, in hopes of providing fundamental basis for further development of novel cancer vaccine‐based therapies, are summarized.