scholarly journals Use of a Novel Peptide Welding Technology Platform for the Development of B- and T-Cell Epitope-Based Vaccines

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 526
Author(s):  
Francesco Nicoli ◽  
Salvatore Pacifico ◽  
Eleonora Gallerani ◽  
Erika Marzola ◽  
Valentina Albanese ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Epitope ◽  
Subcutaneous Administration ◽  
T Cell Epitopes ◽  
Peptide Vaccines ◽  
Peptide Epitope ◽  
Welding Technology

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.

scholarly journals Yellow fever 17D as a vaccine vector for microbial CTL epitopes

2005 ◽  
Vol 201 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Deng Tao ◽  
Giovanna Barba-Spaeth ◽  
Urvashi Rai ◽  
Victor Nussenzweig ◽  
Charles M. Rice ◽  
...  
Keyword(s):  
T Cell ◽  
Yellow Fever ◽  
Cell Epitope ◽  
Parasite Burden ◽  
Plasmodium Yoelii ◽  
Yellow Fever Vaccine ◽  
T Cell Epitopes ◽  
High Level

The yellow fever vaccine 17D (17D) is safe, and after a single immunizing dose, elicits long-lasting, perhaps lifelong protective immunity. One of the major challenges facing delivery of human vaccines in underdeveloped countries is the need for multiple injections to achieve full efficacy. To examine 17D as a vector for microbial T cell epitopes, we inserted the H-2Kd–restricted CTL epitope of the circumsporozoite protein (CS) of Plasmodium yoelii between 17D nonstructural proteins NS2B and NS3. The recombinant virus, 17D-Py, was replication competent and stable in vitro and in vivo. A single subcutaneous injection of 105 PFU diminished the parasite burden in the liver by ∼70%. The high level of protection lasted between 4 and 8 wk after immunization, but a significant effect was documented even 24 wk afterwards. Thus, the immunogenicity of a foreign T cell epitope inserted into 17D mimics some of the remarkable properties of the human vaccine. Priming with 17D-Py followed by boosting with irradiated sporozoites conferred sterile immunity to 90% of the mice. This finding indicates that the immune response of vaccine-primed individuals living in endemic areas could be sustained and magnified by the bite of infected mosquitoes.

scholarly journals Landscape and Selection of Vaccine Epitopes in SARS-CoV-2

2020 ◽  
Author(s):  
Christof C. Smith ◽  
Sarah Entwistle ◽  
Caryn Willis ◽  
Steven Vensko ◽  
Wolfgang Beck ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Epitope Mapping ◽  
Cell Epitope ◽  
Computational Prediction ◽  
Sequence Conservation ◽  
Cell Vaccine ◽  
T Cell Epitopes ◽  
Peptide Vaccines ◽  
B Cell Epitope

AbstractThere is an urgent need for a vaccine with efficacy against SARS-CoV-2. We hypothesize that peptide vaccines containing epitope regions optimized for concurrent B cell, CD4+ T cell, and CD8+ T cell stimulation would drive both humoral and cellular immunity with high specificity, potentially avoiding undesired effects such as antibody-dependent enhancement (ADE). Additionally, such vaccines can be rapidly manufactured in a distributed manner. In this study, we combine computational prediction of T cell epitopes, recently published B cell epitope mapping studies, and epitope accessibility to select candidate peptide vaccines for SARS-CoV-2. We begin with an exploration of the space of possible T cell epitopes in SARS-CoV-2 with interrogation of predicted HLA-I and HLA-II ligands, overlap between predicted ligands, protein source, as well as concurrent human/murine coverage. Beyond MHC affinity, T cell vaccine candidates were further refined by predicted immunogenicity, viral source protein abundance, sequence conservation, coverage of high frequency HLA alleles and co-localization of CD4+ and CD8+ T cell epitopes. B cell epitope regions were chosen from linear epitope mapping studies of convalescent patient serum, followed by filtering to select regions with surface accessibility, high sequence conservation, spatial localization near functional domains of the spike glycoprotein, and avoidance of glycosylation sites. From 58 initial candidates, three B cell epitope regions were identified. By combining these B cell and T cell analyses, as well as a manufacturability heuristic, we propose a set of SARS-CoV-2 vaccine peptides for use in subsequent murine studies and clinical trials.Abstract Figure

scholarly journals Swine T-Cells and Specific Antibodies Evoked by Peptide Dendrimers Displaying Different FMDV T-Cell Epitopes

2021 ◽  
Vol 11 ◽  
Author(s):  
Patricia de León ◽  
Rodrigo Cañas-Arranz ◽  
Sira Defaus ◽  
Elisa Torres ◽  
Mar Forner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
B Cell Epitope ◽  
Mouth Disease Virus ◽  
Ifn Γ

Dendrimeric peptide constructs based on a lysine core that comprises both B- and T-cell epitopes of foot-and-mouth disease virus (FMDV) have proven a successful strategy for the development of FMD vaccines. Specifically, B2T dendrimers displaying two copies of the major type O FMDV antigenic B-cell epitope located on the virus capsid [VP1 (140–158)], covalently linked to a heterotypic T-cell epitope from either non-structural protein 3A [3A (21–35)] or 3D [3D (56–70)], named B2T-3A and B2T-3D, respectively, elicit high levels of neutralizing antibodies (nAbs) and IFN-γ-producing cells in pigs. To assess whether the inclusion and orientation of T-3A and T-3D T-cell epitopes in a single molecule could modulate immunogenicity, dendrimers with T epitopes juxtaposed in both possible orientations, i.e., constructs B2TT-3A3D and B2TT-3D3A, were made and tested in pigs. Both dendrimers elicited high nAbs titers that broadly neutralized type O FMDVs, although B2TT-3D3A did not respond to boosting, and induced lower IgGs titers, in particular IgG2, than B2TT-3A3D. Pigs immunized with B2, a control dendrimer displaying two B-cell epitope copies and no T-cell epitope, gave no nABs, confirming T-3A and T-3D as T helper epitopes. The T-3D peptide was found to be an immunodominant, as it produced more IFN-γ expressing cells than T-3A in the in vitro recall assay. Besides, in pigs immunized with the different dendrimeric peptides, CD4+ T-cells were the major subset contributing to IFN-γ expression upon in vitro recall, and depletion of CD4+ cells from PBMCs abolished the production of this cytokine. Most CD4+IFN-γ+ cells showed a memory (CD4+2E3−) and a multifunctional phenotype, as they expressed both IFN-γ and TNF-α, suggesting that the peptides induced a potent Th1 pro-inflammatory response. Furthermore, not only the presence, but also the orientation of T-cell epitopes influenced the T-cell response, as B2TT-3D3A and B2 groups had fewer cells expressing both cytokines. These results help understand how B2T-type dendrimers triggers T-cell populations, highlighting their potential as next-generation FMD vaccines.

scholarly journals Duobody-CD3xCD20 Shows Unique and Potent Preclinical Anti-Tumor Activity in Vitro and In Vivo, and Is Being Evaluated Clinically in Patients with B-Cell Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1664-1664 ◽  
Author(s):  
Ida H. Hiemstra ◽  
Patrick J. Engelberts ◽  
Bart de Jong ◽  
Danita H Schuurhuis ◽  
Theodora W. Salcedo ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cytotoxic Activity ◽  
Subcutaneous Administration ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
B Cell Malignancies ◽  
Equity Ownership

Abstract DuoBody®-CD3xCD20 (GEN3013) is a bispecific antibody (bsAb), recognizing the T-cell antigen CD3 and the B-cell antigen CD20, that triggers potent T-cell-mediated lysis of CD20-expressing cells. DuoBody-CD3xCD20 is a full-length bispecific IgG1 generated by controlled Fab-arm exchange (cFAE) [1, 2] and contains an effector function-silenced Fc region. In vitro, DuoBody-CD3xCD20 induced potent activation, proliferation and cytotoxic activity of both CD4+ and CD8+ T cells in the presence of CD20-expressing cells, as measured by flow cytometry and bromodeoxyuridine (BrdU) incorporation assays. DuoBody-CD3xCD20 induced T-cell-mediated cytotoxicity towards a diverse panel of cell lines derived from various B-cell malignancies and endogenous B cells, with EC50 values in the low picomolar range (EC50: 0.2-5.0 pM). The CD20-specific antibody 7D8 [3-5] forms the basis for the CD20-specific Fab arm of DuoBody-CD3xCD20. To study the contribution of this specific Fab arm to the observed potency of DuoBody-CD3xCD20, we compared the target binding characteristics and the capacity to induce T-cell-mediated cytotoxicity of a CD3 bsAb based on 7D8, with CD3 bsAbs using B-cell targeting arms derived from alternative CD20 antibodies or from antibodies against other well-known B-cell membrane molecules CD22, CD24, CD37, CD70, CD79b, CD138 and HLA-DR. In addition, target expression levels of the B-cell targets were assessed in a panel of B-cell lines. Using a classic chromium release assay, the 7D8-based CD3 bsAb displayed cytotoxic activity superior to all other B-cell-targeting CD3 bsAbs tested, including alternative CD20-targeting CD3 bsAbs. This unique cytotoxic activity could not be explained by expression levels of the target antigen, nor by the binding affinity or epitope of the B-cell specific Fab arm. This illustrates the complexity of factors that determine the potency of CD3 bsAbs. The anti-tumor activity of DuoBody-CD3xCD20 was confirmed in vivo in humanized mouse models using three different B-cell lymphoma xenograft models, in prophylactic and therapeutic settings. Non-clinical safety studies with DuoBody-CD3xCD20 in cynomolgus monkeys demonstrated profound and long-lasting B-cell depletion (at least 70 days, at dose levels > 0.1 mg/kg) from both peripheral blood and lymphoid organs. B-cell depletion was reversible, with time to B-cell recovery correlating with the treatment dose. Notably, at the same dose level, B-cell depletion was comparable between subcutaneous and intravenous administration. Pharmacokinetic (PK) analysis demonstrated comparable bioavailability for the two administration routes, although peak plasma levels were lower and delayed after subcutaneous administration. Moreover, lower plasma cytokine levels were observed after subcutaneous administration. Based on these data, Genmab has initiated a First-in-Human clinical trial to evaluate the safety and preliminary efficacy of DuoBody-CD3xCD20 by subcutaneous administration in patients with B-cell malignancies. The study is currently enrolling (EudraCT No: 2017-001748-36). References Labrijn, A.F., et al., Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange. Proc Natl Acad Sci U S A, 2013. 110(13): p. 5145-50. Labrijn, A.F., et al., Controlled Fab-arm exchange for the generation of stable bispecific IgG1. Nat Protoc, 2014. 9(10): p. 2450-63. Teeling, J.L., et al., Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood, 2004. 104(6): p. 1793-800. Teeling, J.L., et al., The Biological Activity of Human CD20 Monoclonal Antibodies Is Linked to Unique Epitopes on CD20. Journal of Immunology, 2006. 177(1): p. 362-71. van Meerten, T., et al., HuMab-7D8, a monoclonal antibody directed against the membrane-proximal small loop epitope of CD20 can effectively eliminate CD20 low expressing tumor cells that resist rituximab-mediated lysis. Haematologica, 2010. 95(12): p. 2063-71. Disclosures Hiemstra: Genmab: Employment, Other: Warrants. Engelberts:Genmab: Employment, Other: Warrants. de Jong:Genmab: Employment, Other: Warrants. Schuurhuis:Genmab: Employment, Other: Warrants. Salcedo:Genmab: Employment, Other: Warrants. Verploegen:Genmab: Employment, Equity Ownership. van der Zee:Genmab: Employment, Other: Warrants. Gerritsen:Genmab: Employment, Other: Warrants. Losic:Genmab: Employment, Other: Warrants. Horbach:Genmab: Employment, Other: Warrants. Oliveri:Genmab: Employment, Other: Warrants. Lammerts van Bueren:Genmab: Employment, Other: Warrants. Autzen Usher:Genmab: Employment, Other: Warrants. Schuurman:Genmab: Employment, Other: Warrants. Parren:Genmab: Equity Ownership; Lava Therapeutics: Employment. Breij:Genmab: Employment, Equity Ownership.

scholarly journals Computational Approach for Predicting Common Epitopes in the VP1 Structural Protein of Enterovirus Serotypes EV-D68, EV-D70, and EV-A71

2021 ◽  
Author(s):  
Rihabe Boussettine ◽  
Yassine Kasmi ◽  
Najwa Hassou ◽  
Hlima Bessi ◽  
Moulay Mustapha Ennaji
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Epitope ◽  
Human Enterovirus ◽  
T Cell Epitopes ◽  
Structural Protein ◽  
B Cell Epitopes ◽  
Study Results ◽  
Enterovirus Serotypes

The three human Enterovirus serotypes D-68, D-70, and A-71, are common pathogens that are transmitted by fecal-oral and aerosol routes. These positive RNA viruses were known to exhibit high levels of genetic diversity and variability. Currently, no vaccines are available to protect humans from these three serotypes. Therefore, efforts are needed for the development of a vaccine directed against heterologous viruses. In our study, an immunoinformatics approach is used to identify T- and B-cell epitopes that may help for the generation of a universal vaccine against EV-D70, EV-A71, and EV-D68. B and T cell epitopes were selected based on their length. As a result, 5 B cell epitopes and 18 T cell epitopes were predicted. Our B cell epitope prediction results showed that there are a number of linear regions. Position 150-170 was found to be the most immunogenic for the different strains. Regarding the epitopes of the T lymphocytes, the result of the interactions shows that 95% of the predicted epitopes are common between the 3 sequences and the 5 methods used. These results demonstrate the great immunogenic potential of these sequences and their capacities to trigger immune reactions in people with different HLA alleles. The “VFYDGFAGF” epitope is the most important and most immunogenic for triggering an immune response. Our study results allowed us to identify epitopes to be used in the development of cross-protection vaccines against the three Enterovirus serotypes. However, in vivo and in vitro studies are needed to assess the potential of the epitopes predicted by our study.

scholarly journals Design of T cell epitope-based vaccine candidate for SARS-CoV-2 targeting nucleocapsid and spike protein escape variants

2021 ◽  
Author(s):  
Gabriel Jabbour ◽  
Samantha Rego ◽  
Vincent Nguyenkhoa ◽  
Sivanesan Dakshanamurthy
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
T Cell Epitopes ◽  
Clinical Predictors ◽  
Nucleocapsid Proteins ◽  
Global Concern

AbstractThe current COVID-19 pandemic continues to spread and devastate in the absence of effective treatments, warranting global concern and action. Despite progress in vaccine development, the rise of novel, increasingly infectious SARS-CoV-2 variants makes it clear that our response to the virus must continue to evolve along with it. The use of immunoinformatics provides an opportunity to rapidly and efficiently expand the tools at our disposal to combat the current pandemic and prepare for future outbreaks through epitope-based vaccine design. In this study, we validated and compared the currently available epitope prediction tools, and then used the best tools to predict T cell epitopes from SARS-CoV-2 spike and nucleocapsid proteins for use in an epitope-based vaccine. We combined the mouse MHC affinity predictor and clinical predictors such as HLA affinity, immunogenicity, antigenicity, allergenicity, toxicity and stability to select the highest quality CD8 and CD4 T cell epitopes for the common SARS-CoV-2 variants of concern suitable for further preclinical studies. We also identified variant-specific epitopes to more precisely target the Alpha, Beta, Gamma, Delta, Cluster 5 and US variants. We then modeled the 3D structures of our top 4 N and S epitopes to investigate the molecular interaction between peptide-MHC and peptide-MHC-TCR complexes. Following in vitro and in vivo validation, the epitopes identified by this study may be used in an epitope-based vaccine to protect across all current variants, as well as in variant-specific booster shots to target variants of concern. Immunoinformatics tools allowed us to efficiently predict epitopes in silico most likely to prove effective in vivo, providing a more streamlined process for vaccine development in the context of a rapidly evolving pandemic.

scholarly journals Design of a Novel Multi-Epitope Vaccine Against Echinococcus granulosus in Immunoinformatics

2021 ◽  
Vol 12 ◽  
Author(s):  
Mingkai Yu ◽  
Yuejie Zhu ◽  
Yujiao Li ◽  
Zhiqiang Chen ◽  
Tong Sha ◽  
...  
Keyword(s):  
Molecular Docking ◽  
T Cell ◽  
B Cell ◽  
Echinococcus Granulosus ◽  
The Body ◽  
T Cell Epitopes ◽  
Epitope Vaccine ◽  
B Cell Epitopes

All the time, echinococcosis is a global zoonotic disease which seriously endangers public health all over the world. In order to speed up the development process of anti-Echinococcus granulosus vaccine, at the same time, it can also save economic cost. In this study, immunoinformatics tools and molecular docking methods were used to predict and screen the antigen epitopes of Echinococcus granulosus, to design a multi-epitope vaccine containing B- and T-cell epitopes. The multi-epitope vaccine could activate B lymphocytes to produce specific antibodies theoretically, which could protect the human body against Echinococcus granulosus infection. It also could activate T lymphocytes and clear the infected parasites in the body. In this study, four CD8+ T-cell epitopes, three CD4+ T-cell epitopes and four B-cell epitopes of Protein EgTeg were identified by immunoinformatics methods. Meanwhile, three CD8+ T-cell epitopes, two CD4+ T-cell epitopes and four B-cell epitopes of Protein EgFABP1 were identified. We constructed the multi-epitope vaccine using linker proteins. The study based on the traditional methods of antigen epitope prediction, further optimized the prediction results combined with molecular docking technology and improved the precision and accuracy of the results. Finally, in vivo and in vitro experiments had verified that the vaccine designed in this study had good antigenicity and immunogenicity.

scholarly journals Vaccination With a FAT1-Derived B Cell Epitope Combined With Tumor-Specific B and T Cell Epitopes Elicits Additive Protection in Cancer Mouse Models

2018 ◽  
Vol 8 ◽  
Author(s):  
Alberto Grandi ◽  
Laura Fantappiè ◽  
Carmela Irene ◽  
Silvia Valensin ◽  
Michele Tomasi ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Mouse Models ◽  
Cell Epitope ◽  
T Cell Epitopes ◽  
B Cell Epitope

scholarly journals Novel CD19/CD22 Bicistronic Chimeric Antigen Receptors Outperform Single or Bivalent Cars in Eradicating CD19+CD22+, CD19-, and CD22- Pre-B Leukemia

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 810-810 ◽  
Author(s):  
Haiying Qin ◽  
Sang M Nguyen ◽  
Sneha Ramakrishna ◽  
Samiksha Tarun ◽  
Lila Yang ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Single Chain ◽  
Dual Targeting ◽  
Single Antigen ◽  
Therapeutic Function

Abstract Treatment of pre-B cell acute lymphoblastic leukemia (ALL) using chimeric antigen receptor expressing T cells (CART) targeting CD19 have demonstrated impressive clinical results in children and young adults with up to 70-90% complete remission rate in multiple clinical trials. However, about 30% of patients relapse due to loss of the targeted epitope on CD19 or CART failure. Our CD22-targeted CAR trial has generated promising results in relapsed/refractory ALL, including CD19 antigen negative ALL, but relapse associated with decreased CD22 site density has occurred. Thus, developing strategies to prevent relapses due to changes in antigen expression have the potential to increase the likelihood of durable remissions. In addition, dual targeting of both CD19 and CD22 on pre-B ALL may be synergistic compared to targeting a single antigen, a potential approach to improve efficacy in patients with heterogeneous expression of CD19 and CD22 on leukemic blasts. We describe the systematic development and comparison of the structure and therapeutic function of three different types (over 15 different constructs) of novel CARs targeting both CD19 and CD22: (1) Bivalent Tandem CAR, (2) Bivalent Loop CAR, and (3) Bicistronic CAR. These dual CARs were assembled using CD19- and CD22-binding single chain fragment variable (scFv) regions derived from clinically validated single antigen targeted CARs. They are structurally different in design: both tandem and loop CARs have the CD19 and CD22 scFv covalently linked in the same CAR in different orders, whereas, bicistronic CARs have 2 complete CAR constructs connected with a cleavable linker. The surface expression on the transduced T cell of the CD19/CD22 dual CARs was detected with CD22 Fc and anti-idiotype of CD19 and compared to single CD19 or CD22 CARs. Activities of dual CARs to either CD19 or CD22 were evaluated in vitro with cytotoxicity assays or killing assays against K562 cells expressing either CD19 or CD22 or both antigens and also tested against a leukemia CD19+/CD22+ cell line, NALM6, and NALM6 with CRISPER/CAS9 knockout of CD19 or CD22 or both antigens. Therapeutic function of the top candidates of the dual CARs was then validated in vivo against these NALM6 leukemia lines. Some of these dual CARs were also further tested against patient-derived xenografts. Finally, we tested the dual targeting CARs in an artificial relapse model in which mice were co-injected with a mix of CD19 knockout and CD22 knockout NALM6 leukemia lines. From these studies, we established that the order of the scFv, size of the linker, type of leader sequence, and co-stimulatory domain in the CAR constructs all impact the efficacy of the dual targeting CARs. Tandem, Loop, and Bicistronic CARs all demonstrate some levels of in vitro and in vivo activities, but the bicistronic CAR was most effective at clearing leukemia and preventing relapse. In the CD19+/CD22+ NALM6 model, bicistronic CAR treated mice remain disease free while CD19 CAR or CD22 CAR treated mice already died or relapsed on day 27. In the relapse model, as expected, CD19 or CD22 single CAR T cell treatment resulted in progression of the corresponding antigen-negative NALM6. Treatment with dual targeted bicistronic CARs resulted in clearance of both CD19 and CD22 negative ALL with durable remission. In summary, we described novel CD19/CD22 dual targeting CARs with robust pre-clinical activity against pre-B cell ALL, and validated this approach in the prevention of resistance to single-antigen targeted CARs in preclinical models. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Antigenic Topology of Norovirus as Defined by B and T Cell Epitope Mapping: Implications for Universal Vaccines and Therapeutics

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 432 ◽  
Author(s):  
Jessica M. van Loben Sels ◽  
Kim Y. Green
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Epitope ◽  
T Cell Epitopes ◽  
B Cell Epitopes ◽  
P Domain ◽  
Capsid Protein Vp1 ◽  
Murine Noroviruses ◽  
Acute Nonbacterial Gastroenteritis ◽  
Insight Into

Human norovirus (HuNoV) is the leading cause of acute nonbacterial gastroenteritis. Vaccine design has been confounded by the antigenic diversity of these viruses and a limited understanding of protective immunity. We reviewed 77 articles published since 1988 describing the isolation, function, and mapping of 307 unique monoclonal antibodies directed against B cell epitopes of human and murine noroviruses representing diverse Genogroups (G). Of these antibodies, 91, 153, 21, and 42 were reported as GI-specific, GII-specific, MNV GV-specific, and G cross-reactive, respectively. Our goal was to reconstruct the antigenic topology of noroviruses in relationship to mapped epitopes with potential for therapeutic use or inclusion in universal vaccines. Furthermore, we reviewed seven published studies of norovirus T cell epitopes that identified 18 unique peptide sequences with CD4- or CD8-stimulating activity. Both the protruding (P) and shell (S) domains of the major capsid protein VP1 contained B and T cell epitopes, with the majority of neutralizing and HBGA-blocking B cell epitopes mapping in or proximal to the surface-exposed P2 region of the P domain. The majority of broadly reactive B and T cell epitopes mapped to the S and P1 arm of the P domain. Taken together, this atlas of mapped B and T cell epitopes offers insight into the promises and challenges of designing universal vaccines and immunotherapy for the noroviruses.

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