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40 pages, 3437 KiB  
Review
Nanobodies: From Discovery to AI-Driven Design
by Haoran Zhu and Yu Ding
Biology 2025, 14(5), 547; https://doi.org/10.3390/biology14050547 - 14 May 2025
Viewed by 63
Abstract
Nanobodies, derived from naturally occurring heavy-chain antibodies in camelids (VHHs) and sharks (VNARs), are unique single-domain antibodies that have garnered significant attention in therapeutic, diagnostic, and biotechnological applications due to their small size, stability, and high specificity. This review first traces [...] Read more.
Nanobodies, derived from naturally occurring heavy-chain antibodies in camelids (VHHs) and sharks (VNARs), are unique single-domain antibodies that have garnered significant attention in therapeutic, diagnostic, and biotechnological applications due to their small size, stability, and high specificity. This review first traces the historical discovery of nanobodies, highlighting key milestones in their isolation, characterization, and therapeutic development. We then explore their structure–function relationship, emphasizing features like their single-domain architecture and long CDR3 loop that contribute to their binding versatility. Additionally, we examine the growing interest in multiepitope nanobodies, in which binding to different epitopes on the same antigen not only enhances neutralization and specificity but also allows these nanobodies to be used as controllable modules for precise antigen manipulation. This review also discusses the integration of AI in nanobody design and optimization, showcasing how machine learning and deep learning approaches are revolutionizing rational design, humanization, and affinity maturation processes. With continued advancements in structural biology and computational design, nanobodies are poised to play an increasingly vital role in addressing both existing and emerging biomedical challenges. Full article
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17 pages, 2484 KiB  
Article
Mapping the Binding Sites of CA125-Specific Antibodies on a Revised Molecular Model of MUC16
by Chien-Wei Wang, Anubhuti Srivastava, Eliza K. Hanson, Caitlin R. McEntee, Trisha Nair, Jane C. March and Rebecca J. Whelan
Cancers 2025, 17(9), 1458; https://doi.org/10.3390/cancers17091458 - 26 Apr 2025
Viewed by 344
Abstract
Background: The ovarian cancer biomarker CA125 is a peptide epitope found in multiple tandem repeat domains of the mucin MUC16. Although efforts have been undertaken to characterize the interaction between CA125 and its clinically used antibodies, the molecular nature of the CA125 [...] Read more.
Background: The ovarian cancer biomarker CA125 is a peptide epitope found in multiple tandem repeat domains of the mucin MUC16. Although efforts have been undertaken to characterize the interaction between CA125 and its clinically used antibodies, the molecular nature of the CA125 epitope(s) remains undefined. A recent revision of the molecular model of MUC16 provides an opportunity to fully characterize the binding between CA125-specific antibodies and the tandem repeat region of MUC16. Objectives: The objective of this study was to characterize the binding between CA125 antibodies and expressed tandem repeat proteins from MUC16 as part of a longer-term effort to identify the CA125 epitopes with amino-acid-level precision. Methods: Sixteen MUC16 tandem repeat proteins were expressed and purified. Protein expression was confirmed with high-resolution mass spectrometry. The binding interaction of each tandem repeat protein with four CA125-antibodies—the two used in the clinical test (OC125 and M11) and two clones defined as OC125-like and M11-like—was measured using indirect enzyme-linked immunosorbent assay (ELISA) and localized surface plasmon resonance (SPR). Results: Whereas M11 was found by ELISA to bind to all 16 tandem repeat proteins tested, OC125 does not bind to 5 of the 16 repeats. The recognition pattern of the antibodies was largely in agreement between ELISA and SPR, and cases in which binding is observed in ELISA but not in SPR can be attributed to insufficient contact time in SPR analysis. Conclusions: It can be inferred that the M11 epitope is present on all tandem repeats tested, whereas the OC125 epitope is present on fewer tandem repeats. Full article
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15 pages, 3151 KiB  
Case Report
Expanding the Genetic Framework: Insights into Non-HLA-B27 Contributions to Axial Spondylarthritis
by Ruxandra-Elena Nagit, Ioana Bratoiu, Corina Cianga, Mariana Pavel-Tanasa, Elena Rezus and Petru Cianga
Medicina 2025, 61(5), 793; https://doi.org/10.3390/medicina61050793 - 25 Apr 2025
Viewed by 233
Abstract
Background and Objectives: Spondylarthritis is a complex group of inflammatory diseases closely associated with the HLA-B27 antigen. However, the role of non-HLA-B27 alleles in the disease’s pathogenesis has gained significant scholarly attention in recent years. Case presentation: This case study presents a [...] Read more.
Background and Objectives: Spondylarthritis is a complex group of inflammatory diseases closely associated with the HLA-B27 antigen. However, the role of non-HLA-B27 alleles in the disease’s pathogenesis has gained significant scholarly attention in recent years. Case presentation: This case study presents a 49-year-old male with a history of progressive inflammatory back pain, characterized by morning stiffness and restricted spinal mobility developed over several years. Initially presenting with non-specific symptoms, the patient eventually experienced persistent axial pain and deteriorating functional limitations, which required further evaluation. Radiographic imaging supported the diagnosis of ankylosing spondylitis (AS) by identifying bilateral sacroiliitis. HLA genotyping revealed a negative result for HLA-B27 but positive results for HLA-B13 and HLA-B37. This finding serves as a foundation for exploring alternative genetic factors contributing to spondylarthritis (SpA). HLA-B13 and HLA-B37 exhibit structural and functional similarities to HLA-B27, particularly in their peptide-binding grooves. This resemblance may lead to overlapping peptide repertoires and increased T cell cross-reactivity. Moreover, these alleles belong to overlapping cross-reactive groups (CREGs) and share the Bw4 epitope. This suggests that they may contribute to disease pathogenesis via similar mechanisms, such as molecular mimicry and the dysregulation of natural killer (NK) cell interactions, as observed in HLA-B27. Conclusions: This case emphasizes the necessity of expanding diagnostic criteria to incorporate non-HLA-B27 markers, particularly for patients who are HLA-B27-negative. Enhancing our understanding of the roles of alternative genetic markers can improve diagnostic accuracy, enable personalized treatment approaches, and enhance outcomes for the diverse SpA patient population. Full article
(This article belongs to the Special Issue Autoimmune Diseases: Advances and Challenges)
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20 pages, 2047 KiB  
Article
Design and Preliminary Immunogenicity Evaluation of Nipah Virus Glycoprotein G Epitope-Based Peptide Vaccine in Mice
by Seungyeon Kim, Rochelle A. Flores, Seo Young Moon, Seung Yun Lee, Bujinlkham Altanzul, Jiwon Baek, Eun Bee Choi, Heeji Lim, Eun Young Jang, Yoo-kyoung Lee, In-Ohk Ouh and Woo H. Kim
Vaccines 2025, 13(4), 428; https://doi.org/10.3390/vaccines13040428 - 18 Apr 2025
Viewed by 607
Abstract
Background: The emergence of several paramyxoviruses, including Nipah virus (NiV), makes continued efforts in vaccine development as part of pandemic preparedness efforts necessary. Although NiV is a zoonotic pathogen with high case fatality, there is still no licensed vaccine. Methods: Herein, NiV attachment [...] Read more.
Background: The emergence of several paramyxoviruses, including Nipah virus (NiV), makes continued efforts in vaccine development as part of pandemic preparedness efforts necessary. Although NiV is a zoonotic pathogen with high case fatality, there is still no licensed vaccine. Methods: Herein, NiV attachment glycoprotein G (NiV-G), which is crucial to host cell receptor binding, was used to develop Nipah epitope-based peptide vaccines. A total of 39 B- and T-cell epitopes of NiV-G were shortlisted for peptide synthesis and evaluation using in silico analysis. Results: The in vitro antigenicity evaluation of the peptide candidates showed eight synthesized peptides (G7, stalk-domain epitopes) with relatively high binding to NiV-G antibody-positive serum (A450nm: 1.39–3.78). Moreover, nine-mer (9-mer) peptides were found to be less reactive than their longer peptide counterparts (15–30 aa, G7-1, and G7-4), but 9-mer activity was enhanced with cyclization (NPLPFREYK, A450nm: 2.66) and C-terminal amidation modification (NPLPFREYK-NH2, A450nm: 1.39). Subsequently, in vivo validation in immunized mice revealed the immunogenicity potential of the G7-1 peptide vaccine (30 aa, NENVNEKCKFTLPPLKIHECNISCPNPLPF) to elicit a strong antigen-specific antibody response against their homologous peptide antigen (I.V., A450nm: 1.48 ± 0.78; I.M., A450nm: 1.66 ± 0.66). However, antibody binding to recombinant NiV-G protein remained low, suggesting limited recognition to the native antigen. Conclusions: This study focused on the preliminary screening and validation of peptide vaccines using single formulations with minimal modifications in the peptide candidates. Our findings collectively show the immunogenic potential of the NiV-G stalk-based epitope peptide vaccine as a novel therapeutic for NiV and underscores the need for strategic design, delivery, and formulation optimization to enhance its protective efficacy and translational application. Full article
(This article belongs to the Section Pathogens-host Immune Interface)
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17 pages, 3560 KiB  
Article
Preparation and Evaluation of Novel Epitope-Based ETEC K88-K99 Bivalent Vaccine
by Shuangshuang Wang, Yuxin Yang, Xinru Yue, Zewen Liu, Fangyan Yuan, Keli Yang, Jiajia Zhu, Wei Liu, Yongxiang Tian, Qiong Wu, Ting Gao, Chang Li, Haofei Song, Danna Zhou and Weicheng Bei
Vet. Sci. 2025, 12(4), 381; https://doi.org/10.3390/vetsci12040381 - 18 Apr 2025
Viewed by 355
Abstract
Enterotoxigenic Escherichia coli (ETEC) is one of the primary pathogens causing diarrhea in piglets, causing significant economic losses in the swine farming industry. Due to the numerous serotypes of ETEC, traditional vaccines fail to provide sufficient cross-protection, and subunit vaccines based on epitope [...] Read more.
Enterotoxigenic Escherichia coli (ETEC) is one of the primary pathogens causing diarrhea in piglets, causing significant economic losses in the swine farming industry. Due to the numerous serotypes of ETEC, traditional vaccines fail to provide sufficient cross-protection, and subunit vaccines based on epitope design have emerged as a safer and more effective approach for prevention and control. Unlike vaccine development strategies that involve the tandem arrangement of multiple antigenic epitopes, this study used the K88-FaeG protein as a backbone and incorporated the antigenic epitopes of K99-FanC to achieve a better immunogenicity. By using bioinformatics software to predict B-cell linear epitopes (score of over 0.6), B-cell epitopes from three-dimensional structures (50% amino acid score of ≥0.2), and B-cell epitope IgG antibody subtypes, as well as docking analysis with Sus scrofa aminopeptidase N (APN) receptors, six antigenic epitopes of K99-FanC were selected. Through Western blotting and competitive ELISA, we confirmed that all six recombinant proteins exhibited binding capabilities to K88- and K99-positive serum. The ELISA results showed that the serum levels of specific IgG and IgA antibodies increased after immunization, with FaeG-Ep3 and FaeG-Ep5 inducing the highest antibody titers against FanC-IgG (Log2 = 14.96) and FaeG-IgG (Log2 = 17.96), respectively. Bacterial adhesion assays revealed that only FaeG-Ep3 effectively blocked the adhesion of both K99 and K88 to IPEC-J2 cells. Immunization challenge experiments showed that, in the unimmunized group, mice infected with K88 and K99 experienced weight loss (p < 0.05) with intestinal villus shedding and intestinal wall structural damage. However, in the FaeG-Ep3-immunized group, no significant weight loss occurred after infection, and the villus protection rate (83%) was the same as that in the FaeG and FanC immunized groups. Overall, the FaeG-Ep3 recombinant protein identified in this study shows potential vaccine application value and provides new insights for developing multivalent vaccines against ETEC. Full article
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17 pages, 3611 KiB  
Article
Characterization of Nanobody Binding to Distinct Regions of the SARS-CoV-2 Spike Protein by Flow Virometry
by Mariam Maltseva, Martin A. Rossotti, Jamshid Tanha and Marc-André Langlois
Viruses 2025, 17(4), 571; https://doi.org/10.3390/v17040571 - 15 Apr 2025
Viewed by 436
Abstract
Nanobodies, or single-domain antibodies (VHHs) from camelid heavy-chain-only antibodies, offer significant advantages in therapeutic and diagnostic applications due to their small size and ability to bind cryptic protein epitopes inaccessible to conventional antibodies. In this study, we examined nanobodies specific to [...] Read more.
Nanobodies, or single-domain antibodies (VHHs) from camelid heavy-chain-only antibodies, offer significant advantages in therapeutic and diagnostic applications due to their small size and ability to bind cryptic protein epitopes inaccessible to conventional antibodies. In this study, we examined nanobodies specific to regions of the SARS-CoV-2 spike glycoprotein, including the receptor-binding domain (RBD), N-terminal domain (NTD), and subunit 2 (S2). Using flow virometry, a high-throughput technique for viral quantification, we achieved the efficient detection of pseudotyped viruses expressing the spike glycoprotein. RBD-targeting nanobodies showed the most effective staining, followed by NTD-targeting ones, while S2-specific nanobodies exhibited limited resolution. The simple genetic structure of nanobodies enables the creation of multimeric formats, improving binding specificity and avidity. Bivalent VHH-Fc constructs (VHHs fused to the Fc region of human IgG) outperformed monovalent formats in resolving viral particles from background noise. However, S2-specific monovalent VHHs demonstrated improved staining efficiency, suggesting their smaller size better accesses restricted antigenic sites. Furthermore, direct staining of cell supernatants was possible without virus purification. This versatile nanobody platform, initially developed for antiviral therapy against SARS-CoV-2, can be readily adapted for flow virometry applications and other diagnostic assays. Full article
(This article belongs to the Special Issue Flow Virometry: A New Tool for Studying Viruses)
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16 pages, 4603 KiB  
Article
M2e/NP Dual Epitope-Displaying Nanoparticles Enhance Cross-Protection of Recombinant HA Influenza Vaccine: A Universal Boosting Strategy
by Rui Liu, Lejun Yang, Jin Feng, Songchen Zhang, Liping Wu, Yingying Du, Dexin Kong, Yuhua Xu and Tao Peng
Vaccines 2025, 13(4), 412; https://doi.org/10.3390/vaccines13040412 - 15 Apr 2025
Viewed by 469
Abstract
Background/Objectives: Vaccination remains the most effective means of preventing influenza virus infections. However, the continuous antigenic drift and shift of influenza viruses lead to a reduced efficacy of the existing vaccines, necessitating vaccines capable of broad protection. Methods: To address this, [...] Read more.
Background/Objectives: Vaccination remains the most effective means of preventing influenza virus infections. However, the continuous antigenic drift and shift of influenza viruses lead to a reduced efficacy of the existing vaccines, necessitating vaccines capable of broad protection. Methods: To address this, we developed a modular vaccine strategy pairing a clinical-stage adjuvanted recombinant hemagglutinin (HA) vaccine (SCVC101) with OMN, a heptameric nanoparticle displaying conserved influenza A virus T-cell epitopes from nucleoprotein (NP) and matrix 2 ectodomain (M2e). Results: OMN induced cross-reactive M2e-specific antibodies, binding to diverse influenza A subtypes. Critically, the co-administration of OMN with SCVC101 enhanced cellular immunity and cross-protection without diminishing HA-induced humoral responses. Conclusions: This dual-antigen delivery system enables annual HA component updates, aligned with WHO recommendations, while the conserved OMN nanoparticle acts as a universal booster, leveraging existing production infrastructure. This approach offers a promising strategy for improving the influenza vaccine’s efficacy against emerging viral variants. Full article
(This article belongs to the Special Issue Recombinant Vaccine for Human and Animal Diseases)
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12 pages, 1167 KiB  
Article
Impacts of HLA Genetics on the SARS-CoV-2 Spike Proteins in the Arabian Population
by Amal Haraka, Sanjay Mehta and Tala Al-Rousan
COVID 2025, 5(4), 53; https://doi.org/10.3390/covid5040053 - 10 Apr 2025
Viewed by 264
Abstract
(1) Background: Human Leukocyte Antigen (HLA) genetics substantially affect viral infection outcomes. SARS-CoV-2 continues to evolve, potentially escaping HLA presentation and hindering immune control. However, studies on HLA alleles in diverse non-Western populations remain limited. Therefore, we aimed to investigate whether mutations in [...] Read more.
(1) Background: Human Leukocyte Antigen (HLA) genetics substantially affect viral infection outcomes. SARS-CoV-2 continues to evolve, potentially escaping HLA presentation and hindering immune control. However, studies on HLA alleles in diverse non-Western populations remain limited. Therefore, we aimed to investigate whether mutations in successive SARS-CoV-2 variants have led to viral escape from common HLA class I alleles in the Saudi Arabian population. (2) Methods: The binding affinities of spike protein epitopes for common Saudi HLA alleles (HLA-A02:01, HLA-C06:02, and HLA-B51:01) were predicted across major SARS-CoV-2 strains using NetMHCpan. One-way ANOVA, one-sample t-tests, and pairwise chi-square analyses were performed to assess the differences in binding affinities and epitope binding categories among strains. (3) Results: One-way ANOVA revealed significant differences in binding affinities among SARS-CoV-2 strains for HLA-A02:01 and HLA-C06:02, but not for HLA-B51:01. One-sample t-tests revealed significant differences in mean binding affinity scores compared to a theoretical mean of 0 for all strain–HLA allele combinations, except for HLA-B51:01. Pairwise chi-square analyses identified significant differences in the epitope binding category distribution between Alpha and Epsilon strains, as well as between Epsilon and Gamma strains for HLA-B51:01. (4) Conclusions: The evolution of SARS-CoV-2 has enabled its escape from common HLA alleles in Saudis. Tracking population-specific HLA binding profiles is crucial for the elucidation of associated evasion mechanisms and guiding the design of future vaccines against COVID-19. Full article
(This article belongs to the Section Human or Animal Coronaviruses)
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15 pages, 951 KiB  
Review
Allergen Immunotherapy: Pitfalls, Perks and Unexpected Allies
by Tudor Paul Tamaș and Elena Ciurariu
Int. J. Mol. Sci. 2025, 26(8), 3535; https://doi.org/10.3390/ijms26083535 - 9 Apr 2025
Viewed by 496
Abstract
Allergen immunotherapy (AIT) is a well-established treatment aimed at reducing allergen sensitivity by gradually exposing the immune system to increasing doses of allergens. This promotes desensitization and immune tolerance through multiple mechanisms. AIT offers long-term immune modulation and is considered a potentially curative [...] Read more.
Allergen immunotherapy (AIT) is a well-established treatment aimed at reducing allergen sensitivity by gradually exposing the immune system to increasing doses of allergens. This promotes desensitization and immune tolerance through multiple mechanisms. AIT offers long-term immune modulation and is considered a potentially curative certain forms of allergic diseases. Altered antibody responses is a key mechanism of AIT in the production of allergen-specific IgG4 antibodies, which act as blocking antibodies to prevent allergen binding to IgE on mast cells (MCs) and basophils. However, IgG4 responses are sometimes ineffective due to variations in antibody affinity and epitope targeting. Reverse class switching from IgE to IgG4 and selective depletion of IgE-producing B cells represent potential strategies to improve AIT efficacy. Tregs play a central role in AIT by suppressing Th2-driven allergic responses and promoting immune tolerance through anti-inflammatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β. However, genetic and environmental factors may impair Treg function, leading to AIT failure. AIT reduces MC and basophil activation, leading to long-term suppression of allergic inflammation. It modulates IgE-FcεRI interactions and cytokine signaling pathways, but in some cases, anaphylactic reactions or resistance to MC desensitization may occur. Discussion and conclusions: While AIT is a highly effective allergy treatment, variability in immune responses can impact its success. Advances in biologic therapies offer potential synergies with AIT. Understanding these interactions will help refine AIT strategies and improve patient outcomes. Full article
(This article belongs to the Special Issue Allergic Diseases: Molecular Insights into Immunotherapy)
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23 pages, 6254 KiB  
Article
Computational Immunogenetic Analysis of Botulinum Toxin A Immunogenicity and HLA Gene Haplotypes: New Insights
by Eqram Rahman, Parinitha Rao, Munim Ahmed, William Richard Webb and Jean D. A. Carruthers
Toxins 2025, 17(4), 182; https://doi.org/10.3390/toxins17040182 - 6 Apr 2025
Viewed by 933
Abstract
Botulinum toxin A (BoNT-A) is widely used in both therapeutic and aesthetic settings; however, the formation of neutralizing antibodies (NAbs) remains a critical concern, leading to treatment failure. Immunogenic responses are known to vary between individuals due to HLA polymorphisms. Although some claim [...] Read more.
Botulinum toxin A (BoNT-A) is widely used in both therapeutic and aesthetic settings; however, the formation of neutralizing antibodies (NAbs) remains a critical concern, leading to treatment failure. Immunogenic responses are known to vary between individuals due to HLA polymorphisms. Although some claim that neurotoxin-associated proteins (NAPs) shield BoNT-A from immune detection or are themselves immunogenic, there is limited molecular evidence supporting either view. This study applies computational immunogenetics to explore BoNT-A immunogenicity, focusing on HLA binding and the influence of accessory proteins. Epitope mapping, molecular docking, and HLA binding predictions were used to evaluate interactions between BoNT-A epitopes and selected class II HLA alleles (HLA-DQA1*01:02, HLA-DQA1*03:03, HLA-DQB1*06:04, HLA-DQB1*03:01, and HLA-DRB1*15:01). To assess the potential immunomodulatory role of NAPs, molecular dynamics (MD) simulations, solvent-accessible surface area (SASA) analysis, and electrostatic potential mapping were also conducted. Key epitopes—L11, N25, and C10—showed strong binding affinities to HLA-DQA1*01:02, HLA-DQB1*06:04, and HLA-DQA1*03:03, indicating a potential immunodominant role. NAPs did not obstruct these epitopes but slightly increased their exposure and appeared to stabilize the toxin structure. Electrostatic mapping and binding free energy calculations suggested no significant immunogenic shift in the presence of NAPs. BoNT-A immunogenicity appears to be influenced by HLA allele variability, reinforcing the value of patient-specific genetic profiling. The presumed immunogenic role of NAPs remains unsubstantiated at the molecular level, underscoring the need for evidence-based evaluation over commercial rhetoric. While these findings provide valuable molecular insight, it is important to acknowledge that they are derived entirely from in silico analyses. As such, experimental validation remains essential to confirm the immunological relevance of these predicted interactions. Nonetheless, this computational framework offers a rational basis for guiding future clinical research and the development of HLA-informed BoNT-A therapies. Full article
(This article belongs to the Section Bacterial Toxins)
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18 pages, 2025 KiB  
Article
Immunogenicity of Trypanosoma cruzi Multi-Epitope Recombinant Protein as an Antigen Candidate for Chagas Disease Vaccine in Humans
by Christian F. Teh-Poot, Andrea Alfaro-Chacón, Landy M. Pech-Pisté, Miguel E. Rosado-Vallado, Oluwatoyin Ajibola Asojo, Liliana E. Villanueva-Lizama, Eric Dumonteil and Julio Vladimir Cruz-Chan
Pathogens 2025, 14(4), 342; https://doi.org/10.3390/pathogens14040342 - 3 Apr 2025
Viewed by 621
Abstract
Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is the most significant neglected tropical disease affecting individuals in the Americas. Currently, available drugs, such as nifurtimox and benznidazole (BZN), are both toxic and ineffective in the chronic phase of [...] Read more.
Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is the most significant neglected tropical disease affecting individuals in the Americas. Currently, available drugs, such as nifurtimox and benznidazole (BZN), are both toxic and ineffective in the chronic phase of the disease. A promising alternative is the development of a Chagas disease vaccine, although this effort is hampered by the complexity of the parasite and HLA polymorphisms. In addition, the activation of epitope-specific CD8+ T cells is critical to conferring a robust cell-mediated immune response and protection by producing IFN-γ and perforin. Thus, the antigen (s) for the development of a Chagas vaccine or immunotherapy must include CD8+ T cell epitopes. In this study, we aimed to develop a multi-epitope recombinant protein as a novel human vaccine for Chagas disease. Sixteen database programs were used to predict de novo 40 potential epitopes for the HLA-A*02:01 allele. Nine out of the 40 predicted epitopes were able to elicit IFN-γ production in Peripheral Blood Mononuclear Cells (PBMCs) from Chagas patients. Molecular docking revealed a good binding affinity among the epitopes with diverse HLA molecules. Therefore, a recombinant multi-epitope protein including these nine T. cruzi CD8+ epitopes was expressed and demonstrated to recall an antigen-specific immune response in ex-vivo assays using PBMCs from Chagas patients with the HLA-A*02 allele. These findings support the development of this multi-epitope protein as a promising candidate human vaccine against Chagas disease. Full article
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14 pages, 1893 KiB  
Article
T330M Substitution in the Sodium-Dependent Phosphate Transporter NaPi2b Abolishes the Efficacy of Monoclonal Antibodies Against MX35 Epitope
by Leisan F. Bulatova, Vera S. Skripova, Aisylu R. Sagdeeva, Ramilia A. Vlasenkova, Tatiana A. Bugaenko, Rezeda R. Galimova, Alfiya I. Nesterova, Yuliya V. Filina and Ramziya G. Kiyamova
Antibodies 2025, 14(2), 30; https://doi.org/10.3390/antib14020030 - 1 Apr 2025
Viewed by 474
Abstract
Background: Monoclonal antibodies against the sodium-dependent phosphate transporter NaPi2b (SLC34A2) represent a promising approach in the treatment of ovarian and lung cancer. Of particular interest is the potential cancer-specific MX35 epitope of NaPi2b, as it serves as a target for monoclonal [...] Read more.
Background: Monoclonal antibodies against the sodium-dependent phosphate transporter NaPi2b (SLC34A2) represent a promising approach in the treatment of ovarian and lung cancer. Of particular interest is the potential cancer-specific MX35 epitope of NaPi2b, as it serves as a target for monoclonal antibodies studied at various stages of preclinical and clinical trials. However, variations in the NaPi2b protein structure may limit the efficacy of therapeutic antibodies by affecting the accessibility of the MX35 epitope. Methods: An in silico analysis was performed using data from 101,562 tumor samples. Genomic DNA sequencing was conducted on blood samples from patients with ovarian carcinoma, breast cancer, and renal carcinoma to access the frequency of germline mutations in the SLC34A2 gene region encoding the MX35 epitope. To assess the impact of the selected mutation, we generated a model cell line through site-directed mutagenesis carrying the mutant NaPi2b variant. Results: Using in silico analysis, we identified 17 unique variants in the SLC34A2 gene leading to amino acid substitutions within the MX35 epitope of the NaPi2b. Among these, the most prevalent mutation, c.989C>T, resulting in p.T330M substitution, was detected in 5 out of 64 patients through genomic DNA sequencing. Using site-directed mutagenesis, we created the OVCAR-8/NaPi2bp.T330M model cell line. L3 (28/1) monoclonal antibodies specific to the MX35 epitope failed to recognize the mutant NaPi2bp.T330M variant compared to the wild-type of the NaPi2b in both Western blot and confocal microscopy experiments. Conclusions: The obtained data may serve as a basis for predicting the efficacy of monoclonal antibody-based targeted therapy binding to the MX35 epitope of NaPi2b in the treatment of oncological diseases. Full article
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16 pages, 6130 KiB  
Article
Identification of B-Cell Epitopes Located on the Surface of the S1 Protein of Infectious Bronchitis Virus M41 Strains
by Zichen Gao, Jianing Hu, Yiqin Cai, Ye Liu, Guihu Yin, Xinyu Guo, Ruiying Wang, Meng Zhong, Qingtao Liu and Xiuli Feng
Viruses 2025, 17(4), 464; https://doi.org/10.3390/v17040464 - 24 Mar 2025
Viewed by 296
Abstract
Avian infectious bronchitis is caused by the avian infectious bronchitis virus (IBV), which poses a significant threat to the poultry industry and public health. The S1 protein of IBV plays a crucial role in the process of the virus invading host cells. To [...] Read more.
Avian infectious bronchitis is caused by the avian infectious bronchitis virus (IBV), which poses a significant threat to the poultry industry and public health. The S1 protein of IBV plays a crucial role in the process of the virus invading host cells. To investigate the significant antigenic targets within the S1 protein, in this study, the truncated S1 sequence of the IBV M41 strain was cloned with approximately 660 bp and expressed. After purification and renaturation, the recombinant S1 protein was immunized into BALB/c mice. Then, following fusion with lymphocytes and SP2/0 cells, the indirect ELISA and Western blotting techniques were employed to screen hybridoma cell lines secreting monoclonal antibodies (mAbs) targeting the S1 protein. Antigenic epitopes of the mAbs were identified using truncated S1 fragments and peptide scanning. The results indicated that three hybridoma cell lines stably secreting S1 protein-specific mAbs (2A10, 4E9, and 5E12) were screened. The heavy chains of the three mAbs were IgG1, and all three mAbs contained kappa light chains. The identified minimal B-cell epitopes were 132RVSAMK137 and 142FYNLTV147. Homology analysis showed these both epitopes were conserved across IBV subtypes and located on the S1 protein surface. The conserved β-sheet epitope 132RVSAMK137 and the surface-exposed, flexible loop epitope 142FYNLTV147 serve as ideal targets for broad-spectrum diagnostics and early infection detection, respectively. These epitopes provide unique structural advantages for antibody binding, enabling the design of multivalent epitope vaccines or the development of immunomodulatory drugs. They offer novel biomaterials and targets for antibody-based drug development and rapid detection methods for avian infectious bronchitis virus (IBV), holding significant potential for the prevention and control of IBV. Full article
(This article belongs to the Section Animal Viruses)
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16 pages, 704 KiB  
Review
Anti-ADAMTS13 Autoantibodies in Immune-Mediated Thrombotic Thrombocytopenic Purpura
by Michael R. Snyder and Robert W. Maitta
Antibodies 2025, 14(1), 24; https://doi.org/10.3390/antib14010024 - 10 Mar 2025
Cited by 1 | Viewed by 1214
Abstract
Autoantibodies to ADAMTS13 are at the center of pathology of the immune-mediated thrombotic thrombocytopenic purpura. These autoantibodies can be either inhibitory (enzymatic function) or non-inhibitory, resulting in protein depletion. Under normal physiologic conditions, antibodies are generated in response to foreign antigens, which can [...] Read more.
Autoantibodies to ADAMTS13 are at the center of pathology of the immune-mediated thrombotic thrombocytopenic purpura. These autoantibodies can be either inhibitory (enzymatic function) or non-inhibitory, resulting in protein depletion. Under normal physiologic conditions, antibodies are generated in response to foreign antigens, which can include infectious agents; however, these antibodies may at times cross-react with self-epitopes. This is one of the possible mechanisms mediating formation of anti-ADAMTS13 autoantibodies. The process known as “antigenic mimicry” may be responsible for the development of these autoantibodies that recognize and bind cryptic epitopes in ADAMTS13, disrupting its enzymatic function over ultra large von Willebrand factor multimers, forming the seeds for platelet activation and microthrombi formation. In particular, specific amino acid sequences in ADAMTS13 may lead to conformational structures recognized by autoantibodies. Generation of these antibodies may occur more frequently among patients with a genetic predisposition. Conformational changes in ADAMTS13 between open and closed states can also constitute the critical change driving either interactions with autoantibodies or their generation. Nowadays, there is a growing understanding of the role that autoantibodies play in ADAMTS13 pathology. This knowledge, especially of functional qualitative differences among antibodies and the ADAMTS13 sequence specificity of such antibodies, may make possible the development of targeted therapeutic agents to treat the disease. This review aims to present what is known of autoantibodies against ADAMTS13 and how their structure and function result in disease. Full article
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Article
Predicting Tolerance to Cow’s Milk Allergy in Children Using IgE and IgG4 Peptide Binding Profiles
by Carlos Fernández-Lozano, Sergio Olmos-Piñero, Laura Sánchez-Ruano, Soledad Terrados, Mª del Carmen Diéguez, Montserrat Fernández-Rivas, Cristina Vlaicu, Inmaculada Cerecedo, Alejandro Gonzalo-Fernandez, Belén de la Hoz and Javier Martínez-Botas
Cells 2025, 14(5), 344; https://doi.org/10.3390/cells14050344 - 27 Feb 2025
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Abstract
Cow’s milk allergy (CMA) is the most common food allergy in infants. This study aimed to identify peptide biomarkers predictive of tolerance in a Spanish population of children with CMA. We investigated specific IgE and IgG4 binding to sequential epitopes of the five [...] Read more.
Cow’s milk allergy (CMA) is the most common food allergy in infants. This study aimed to identify peptide biomarkers predictive of tolerance in a Spanish population of children with CMA. We investigated specific IgE and IgG4 binding to sequential epitopes of the five major CM allergens (α-s1-, α-s2-, β-, and κ-caseins as well as β-lactoglobulin) using a microarray-based immunoassay. Microarray analysis was performed in 118 patients at baseline and after 6, 18, 30, 42, and 54 months. Most patients tolerated CM at 6 months (40.7%) and 18 months (35.4%). We found significant differences in IgE and IgG4 binding intensity and diversity between allergic and tolerant patients. No differences were observed at baseline. Combining baseline IgE and IgG4 serology variables and peptide microarray analysis results, a predictive model was developed using the XGBoost algorithm to classify tolerance status at different time points. The generated models showed high predictive value at 6 and 30 months with AUCs of 0.883 and 0.833, respectively. Therefore, using IgE and IgG4 antibody-binding peptides at baseline, we generated two models predicting tolerance in children with cow’s milk allergy at 6 and 30 months. Full article
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