Статті в журналах: "Immunogeni"

1

Gneiss, C., P. Tripp, F. Reichartseder, R. Egg, R. Ehling, A. Lutterotti, M. Khalil, et al. "Differing immunogenic potentials of interferon beta preparations in multiple sclerosis patients." Multiple Sclerosis Journal 12, no. 6 (November 2006): 731–37. http://dx.doi.org/10.1177/1352458506070941.

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Interferon beta (IFNβ) is a first-line therapy for multiple sclerosis (MS). However, some patients experience a decline in efficacy with continued therapy due to the development of anti-IFNβ neutralizing antibodies (NAb). We investigated the frequency of NAb cross-sectionally in 846 MS patients who were receiving IFNβ-1b, IFNβ-1a im, or IFNβ-1a sc. The frequency of NAb in patients receiving IFNβ-1a im was lower (5%) than in patients treated with any other form of IFNβ (22-35%) (P < 0.0001). Binding antibodies (BAb) were measured in 808 patients. The frequency differed significantly between treatment groups, ranging from 45% (IFNβ-1a im) to 88% (IFNβ-1b). The proportion of NAb-positive patients within the BAb-positive group differed significantly among treatment groups, ranging between 12% (IFNβ-1a im) and 51% (IFNβ-1a sc). The median NAb titer from all IFNβ-1a-treated patients was higher than from IFNβ-1b-treated patients (446 versus 171 NU/mL, P = 0.04). Among NAb-positive patients, the frequency of NAb titers > 100 NU/mL was 71% for IFNβ-1a compared with 58% for IFNβ-1b (P = 0.04). Except for conflicting data regarding IFNβ-1a sc, the results are generally consistent with the literature and together with the differing proportion of NAb-positive patients within the BAb-positive group, provide further insight into the immunogeni-city of the IFNβ preparations.

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Tuveson, D. A., J. M. Ahearn, A. K. Matsumoto, and D. T. Fearon. "Molecular interactions of complement receptors on B lymphocytes: a CR1/CR2 complex distinct from the CR2/CD19 complex." Journal of Experimental Medicine 173, no. 5 (May 1, 1991): 1083–89. http://dx.doi.org/10.1084/jem.173.5.1083.

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The complement system augments the humoral immune response to low concentrations of antigen. This effect may be partly mediated by complement receptors on the surface of B lymphocytes that bind immunogenic complexes bearing fragments of C3 and C4. We have shown by immunoprecipitation analysis that the two complement receptors expressed by B lymphocytes, complement receptor 1 (CR1) and CR2, form a detergent-sensitive complex on the surface of tonsillar B lymphocytes and on K562 erythroleukemia cells that were co-transfected with cDNAs encoding CR1 and CR2. The CR1/CR2 complex is distinct from the CR2/CD19 complex and may assist B cell activation by efficiently capturing C3b-containing immunogens and maintaining such immunogens on the B cell after CR1 and factor I-mediated cleavage to iC3b and C3dg. The complement activating immunogen may then trigger signal transduction by the CR1/CR2 complex, the CR2/CD19 complex, or membrane immunoglobulin.

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&NA;. "Synthetic HIV peptide immunogen ???safe??? and immunogenic." Inpharma Weekly &NA;, no. 1152 (August 1998): 8. http://dx.doi.org/10.2165/00128413-199811520-00014.

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Weaver, Eric A., Zhongjing Lu, Zenaido T. Camacho, Fatiha Moukdar, Hua-Xin Liao, Ben-Jiang Ma, Mark Muldoon, et al. "Cross-Subtype T-Cell Immune Responses Induced by a Human Immunodeficiency Virus Type 1 Group M Consensus Env Immunogen." Journal of Virology 80, no. 14 (July 15, 2006): 6745–56. http://dx.doi.org/10.1128/jvi.02484-05.

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ABSTRACT The genetic diversity among globally circulating human immunodeficiency virus type 1 (HIV-1) strains is a serious challenge for HIV-1 vaccine design. We have generated a synthetic group M consensus env gene (CON6) for induction of cross-subtype immune responses and report here a comparative study of T-cell responses to this and natural strain env immunogens in a murine model. Three different strains of mice were immunized with CON6 as well as subtype A, B, or C env immunogens, using a DNA prime-recombinant vaccinia virus boost strategy. T-cell epitopes were mapped by gamma interferon enzyme-linked immunospot analysis using five overlapping Env peptide sets from heterologous subtype A, B, and C viruses. The CON6-derived vaccine was immunogenic and induced a greater number of T-cell epitope responses than any single wild-type subtype A, B, and C env immunogen and similar T-cell responses to a polyvalent vaccine. The responses were comparable to within-clade responses but significantly more than between-clade responses. The magnitude of the T-cell responses induced by CON6 (measured by individual epitope peptides) was also greater than the magnitude of responses induced by individual wild-type env immunogens. Though the limited major histocompatibility complex repertoire in inbred mice does not necessarily predict responses in nonhuman primates and humans, these results suggest that synthetic centralized env immunogens represent a promising approach for HIV-1 vaccine design that merits further characterization.

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Campbell, M. J., W. Carroll, S. Kon, K. Thielemans, J. B. Rothbard, S. Levy, and R. Levy. "Idiotype vaccination against murine B cell lymphoma. Humoral and cellular responses elicited by tumor-derived immunoglobulin M and its molecular subunits." Journal of Immunology 139, no. 8 (October 15, 1987): 2825–33. http://dx.doi.org/10.4049/jimmunol.139.8.2825.

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Abstract C3H/HeN mice were immunized with idiotypic immunoglobulin M (IgM) and its molecular subunits from the syngeneic 38C13 lymphoma. Immunization with idiotypic IgM (38C-Id) resulted in idiotype-specific humoral and cellular immunity and protection against a lethal tumor cell challenge. Heavy (H38C) and light (L38C) chains were isolated by electroelution from preparative polyacrylamide gels. Both of these immunogens induced significant resistance to a subsequent tumor challenge. Variable region immunogens, in the form of trpE-fusion proteins, were obtained by cloning heavy and light chain variable region genes into the expression plasmid pATH-11. Of these, only the trpE-VH38C immunogen yielded immune resistance to tumor challenge. Finally, the nucleic acid sequence of 38C-Id light chain was determined and, based on the corresponding amino acid sequence and an analysis of predicted secondary structure, a region of potential antigenicity in complementarity-determining region 3 was chosen for the production of a synthetic peptide. Vaccination with this synthetic peptide resulted in significant suppression of tumor growth. Analysis of the humoral and cellular immunity generated by these vaccines revealed the presence of antibodies reactive with native idiotypic IgM only in 38C-Id, H38C, and trpE-VH38C immune sera, although the latter two were not idiotype-specific. Idiotype-specific lymphocytes, which proliferated in response to native 38C-Id, were observed in all immune animals. With the exception of the fusion protein immunogens, conjugation to an immunogenic carrier protein (keyhole limpet hemocyanin or thyroglobulin) was required for optimal humoral and cellular responses.

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Noh, Susan M., Joshua E. Turse, Wendy C. Brown, Junzo Norimine, and Guy H. Palmer. "Linkage between Anaplasma marginale Outer Membrane Proteins Enhances Immunogenicity but Is Not Required for Protection from Challenge." Clinical and Vaccine Immunology 20, no. 5 (February 27, 2013): 651–56. http://dx.doi.org/10.1128/cvi.00600-12.

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ABSTRACTThe prevention of bacterial infections via immunization presents particular challenges. While outer membrane extracts are often protective, they are difficult and expensive to isolate and standardize and thus are often impractical for development and implementation in vaccination programs. In contrast, individual proteins, which are easily adapted for use in subunit vaccines, tend to be poorly protective. Consequently, identification of the specific characteristics of outer membrane-based immunogens, in terms of the antigen contents and contexts that are required for protective immunity, represents a major gap in the knowledge needed for bacterial vaccine development. Using as a modelAnaplasma marginale, a persistent tick-borne bacterial pathogen of cattle, we tested two sets of immunogens to determine whether membrane context affected immunogenicity and the capacity to induce protection. The first immunogen was composed of a complex of outer membrane proteins linked by covalent bonds and known to be protective. The second immunogen was derived directly from the first one, but the proteins were individualized rather than linked. The antibody response induced by the linked immunogen was much greater than that induced by the unlinked immunogen. However, both immunogens induced protective immunity and an anamnestic response. These findings suggest that individual proteins or combinations of proteins can be successfully tested for the ability to induce protective immunity with less regard for overall membrane context. Once protective antigens are identified, immunogenicity could be enhanced by cross-linking to allow a reduced immunogen dose or fewer booster vaccinations.

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Das, Supratik, Rajesh Kumar, Shubbir Ahmed, Hilal Ahmad Parray, and Sweety Samal. "Efficiently cleaved HIV-1 envelopes: can they be important for vaccine immunogen development?" Therapeutic Advances in Vaccines and Immunotherapy 8 (January 2020): 251513552095776. http://dx.doi.org/10.1177/2515135520957763.

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The enormous diversity of HIV-1 is a significant impediment in selecting envelopes (Envs) that can be suitable for designing vaccine immunogens. While tremendous progress has been made in developing soluble, trimeric, native-like Env proteins, those that have elicited neutralizing antibodies (Abs) in animal models are relatively few. A strategy of selecting naturally occurring Envs suitable for immunogen design by studying the correlation between efficient cleavage on the cell surface and their selective binding to broadly neutralizing Abs (bNAbs) and not to non-neutralizing Abs (non-NAbs), properties essential in immunogens, may be useful. Here we discuss some of the challenges of developing an efficacious HIV-1 vaccine and the work done in generating soluble immunogens. We also discuss the study of naturally occurring, membrane-bound, efficiently cleaved (naturally more sensitive to furin) Envs and how they may positively add to the repertoire of HIV-1 Envs that can be used for vaccine immunogen design. However, even with such Envs, the challenges of developing well-folded, native-like trimers as soluble proteins or using other immunogen strategies such as virus-like particles with desirable antigenic properties remain, and are formidable. In spite of the progress that has been made in the HIV-1 vaccine field, an immunogen that elicits neutralizing Abs with significant breadth and potency in vaccines has still not been developed. Efficiently cleaved Envs may increase the number of available Envs suitable for immunogen design and should be studied further.

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8

Watson, Douglas, and Francis Szoka. "Role of lipid structure in the humoral immune response in mice to covalent lipid-peptides derived from the membrane proximal region of HIV-1 gp41 (128.2)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 128.2. http://dx.doi.org/10.4049/jimmunol.182.supp.128.2.

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Abstract The membrane proximal region (MPR) of HIV-1 gp41 is a desirable target for development of a vaccine that elicits neutralizing antibodies since the patient-derived monoclonal antibodies, 2F5 and 4E10, bind to MPR and neutralize primary isolates. The 2F5 and 4E10 antibodies cross-react with lipids and structural studies suggest that MPR immunogens may be presented in a membrane environment. We hypothesized that covalent attachment of lipid anchors would enhance the immunogenicity of MPR-derived peptides presented in liposomal bilayers. In a comparison of eight different lipids conjugated to an extended 2F5 epitope peptide, a sterol, cholesterol hemisuccinate (CHEMS), was found to promote the strongest anti-peptide immune response in BALB/C mice. Differences in immunogenicity amongst the conjugates could not be explained solely by any one factor, such as: the presence of a phosphate in the lipid, membrane partitioning of the lipid anchor or peptide secondary structure. Conjugation to CHEMS also rendered a 4E10 epitope peptide immunogenic. Finally, conjugation of CHEMS to a helically constrained immunogen spanning both epitopes elicited antibodies that bound to each of the individual 4E10 and 2F5 epitopes as well as to an oligomeric recombinant envelope protein. Further research into the mechanism of how structure influences the immune response to the MPR may lead to immunogens that could be useful in prime-boost regimens for focusing the immune response in an HIV vaccine.

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9

Letvin, Norman L., Yue Huang, Bimal K. Chakrabarti, Ling Xu, Michael S. Seaman, Kristin Beaudry, Birgit Korioth-Schmitz, et al. "Heterologous Envelope Immunogens Contribute to AIDS Vaccine Protection in Rhesus Monkeys." Journal of Virology 78, no. 14 (July 15, 2004): 7490–97. http://dx.doi.org/10.1128/jvi.78.14.7490-7497.2004.

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ABSTRACT Because a strategy to elicit broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibodies has not yet been found, the role of an Env immunogen in HIV-1 vaccine candidates remains undefined. We sought to determine whether an HIV-1 Env immunogen genetically disparate from the Env of the challenge virus can contribute to protective immunity. We vaccinated Indian-origin rhesus monkeys with Gag-Pol-Nef immunogens, alone or in combination with Env immunogens that were either matched or mismatched with the challenge virus. These animals were then challenged with a pathogenic simian-human immunodeficiency virus. The vaccine regimen included a plasmid DNA prime and replication-defective adenoviral vector boost. Vaccine regimens that included the matched or mismatched Env immunogens conferred better protection against CD4+ T-lymphocyte loss than that seen with comparable regimens that did not include Env immunogens. This increment in protective immunity was associated with anamnestic Env-specific cellular immunity that developed in the early days following viral challenge. These data suggest that T-lymphocyte immunity to Env can broaden the protective cellular immune response to HIV despite significant sequence diversity of the strains of the Env immunogens and can contribute to immune protection in this AIDS vaccine model.

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10

Yu, Zhe, Li Liu, Xiaobo Yu, Jun Chi, Huanhuan Han, Ying Liu, Wei He, Qihong Sun, Jianen Gao, and Danke Xu. "High-Throughput Antibody Generation Using Multiplexed Immunization and Immunogen Array Analysis." Journal of Biomolecular Screening 15, no. 10 (December 2010): 1260–67. http://dx.doi.org/10.1177/1087057110380045.

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In this work, the authors developed a new screening approach using multiplexed immunization and immunogen array analysis to improve the efficiency of antibody screening for high-throughput antibody generation. The immunogen array is based on a 96-well format in which different immunogens and negative as well as positive controls are immobilized in each well, thus making it possible to screen hundreds of antibody candidates simultaneously. To demonstrate this approach, a model of 4 mixed immunogens immunization was employed. In total, 675 antibody candidates were screened before and after established antibody hybridomas in parallel with immunogen arrays and enzyme-linked immunosorbent assay. The signal intensity, specificity, and cross-reactivity of produced antibody candidates were analyzed using a hierarchical cluster algorithm to track the characteristics of antibody candidates during antibody generation, which might reduce the number of false-positive and false-negative binding of antibodies. Moreover, 4 monoclonal antibodies that were produced successfully recognized their corresponding target antigens.

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Idrees, Muhammad, Muhammad Yasir Noorani, Kalim Ullah Altaf, Eid A. Alatawi, Faris F. Aba Alkhayl, Khaled S. Allemailem, Ahmad Almatroudi, et al. "Core-Proteomics-Based Annotation of Antigenic Targets and Reverse-Vaccinology-Assisted Design of Ensemble Immunogen against the Emerging Nosocomial Infection-Causing Bacterium Elizabethkingia meningoseptica." International Journal of Environmental Research and Public Health 19, no. 1 (December 24, 2021): 194. http://dx.doi.org/10.3390/ijerph19010194.

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Elizabethkingia meningoseptica is a ubiquitous Gram-negative emerging pathogen that causes hospital-acquired infection in both immunocompromised and immunocompetent patients. It is a multi-drug-resistant bacterium; therefore, an effective subunit immunogenic candidate is of great interest to encounter the pathogenesis of this pathogen. A protein-wide annotation of immunogenic targets was performed to fast-track the vaccine development against this pathogen, and structural-vaccinology-assisted epitopes were predicted. Among the total proteins, only three, A0A1T3FLU2, A0A1T3INK9, and A0A1V3U124, were shortlisted, which are the essential vaccine targets and were subjected to immune epitope mapping. The linkers EAAK, AAY, and GPGPG were used to link CTL, HTL, and B-cell epitopes and an adjuvant was also added at the N-terminal to design a multi-epitope immunogenic construct (MEIC). The computationally predicted physiochemical properties of the ensemble immunogen reported a highly antigenic nature and produced multiple interactions with immune receptors. In addition, the molecular dynamics simulation confirmed stable binding and good dynamic properties. Furthermore, the computationally modeled immune response proposed that the immunogen triggered a strong immune response after several doses at different intervals. Neutralization of the antigen was observed on the 3rd day of injection. Conclusively, the immunogenic construct produces protection against Elizabethkingia meningoseptica; however, further immunological testing is needed to unveil its real efficacy.

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Dougan, Gordon, Marjan Ghaem–Maghami, Derek Pickard, Gad Frankel, Gill Douce, Simon Clare, Sarah Dunstan, and Cameron Simmons. "The immune responses to bacterial antigens encountered in vivo at mucosal surfaces." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 355, no. 1397 (May 28, 2000): 705–12. http://dx.doi.org/10.1098/rstb.2000.0610.

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Mammals have evolved a sophisticated immune system for handling antigens encountered at their mucosal surfaces. The way in which mucosally delivered antigens are handled influences our ability to design effective mucosal vaccines. Live attenuated derivatives of pathogens are one route towards the development of mucosal vaccines. However, some molecules, described as mucosal immunogens, are inherently immunogenic at mucosal surfaces. Studies on mucosal immunogens may facilitate the identification of common characteristics that contribute to mucosal immunogenicity and aid the development of novel, non–living mucosal vaccines and immunostimulators.

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Alluhaybi, Khalid A., Rahaf H. Alharbi, Rowa Y. Alhabbab, Najwa D. Aljehani, Sawsan S. Alamri, Mohammad Basabrain, Rehaf Alharbi, et al. "Cellular and Humoral Immunogenicity of a Candidate DNA Vaccine Expressing SARS-CoV-2 Spike Subunit 1." Vaccines 9, no. 8 (August 4, 2021): 852. http://dx.doi.org/10.3390/vaccines9080852.

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The urgent need for effective, safe and equitably accessible vaccines to tackle the ongoing spread of COVID-19 led researchers to generate vaccine candidates targeting varieties of immunogens of SARS-CoV-2. Because of its crucial role in mediating binding and entry to host cell and its proven safety profile, the subunit 1 (S1) of the spike protein represents an attractive immunogen for vaccine development. Here, we developed and assessed the immunogenicity of a DNA vaccine encoding the SARS-CoV-2 S1. Following in vitro confirmation and characterization, the humoral and cellular immune responses of our vaccine candidate (pVAX-S1) was evaluated in BALB/c mice using two different doses, 25 µg and 50 µg. Our data showed high levels of SARS-CoV-2 specific IgG and neutralizing antibodies in mice immunized with three doses of pVAX-S1. Analysis of the induced IgG subclasses showed a Th1-polarized immune response, as demonstrated by the significant elevation of spike-specific IgG2a and IgG2b, compared to IgG1. Furthermore, we found that the immunization of mice with three doses of 50 µg of pVAX-S1 could elicit significant memory CD4+ and CD8+ T cell responses. Taken together, our data indicate that pVAX-S1 is immunogenic and safe in mice and is worthy of further preclinical and clinical evaluation.

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Essig, Andreas, Ulrike Simnacher, Milorad Susa, and Reinhard Marre. "Analysis of the Humoral Immune Response toChlamydia pneumoniae by Immunoblotting and Immunoprecipitation." Clinical Diagnostic Laboratory Immunology 6, no. 6 (November 1, 1999): 819–25. http://dx.doi.org/10.1128/cdli.6.6.819-825.1999.

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ABSTRACT Chlamydia pneumoniae is a widely spread agent of respiratory tract infections in humans. A reliable serodiagnosis of the disease is hampered by the poor knowledge about immunodominant antigens in C. pneumoniae infections. We applied a novel strategy to identify immunogenic proteins of C. pneumoniae TW183 combining metabolic radiolabeling of de novo-synthesized chlamydial antigens with immunoprecipitation. By this technique C. pneumoniae antigens of approximately 160, 97 to 99, 60 to 62, 40, 27, and 15 kDa were detected in the vast majority of sera from patients with a current C. pneumoniae infection. By immunoblotting purified elementary bodies of C. pneumoniae TW183 with the same sera, only the 60- to 62-kDa antigen could be detected consistently. Sequential immunoprecipitation performed at different stages of the chlamydial developmental cycle revealed that the 60- to 62-kDa antigen is strongly upregulated after 24 to 48 h of host cell infection and is presented as a major immunogen in both C. pneumoniae-infected patients and mice. We conclude that, due to its high sensitivity and concurrent preservation of conformational epitopes, metabolic radiolabeling of chlamydial antigens combined with immunoprecipitation may be a useful method to reveal important immunogens in respiratory C. pneumoniae infection which might have been missed by immunoblot analysis.

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Castelli, Matteo, Francesca Cappelletti, Roberta Antonia Diotti, Giuseppe Sautto, Elena Criscuolo, Matteo Dal Peraro, and Nicola Clementi. "Peptide-Based Vaccinology: Experimental and Computational Approaches to Target Hypervariable Viruses through the Fine Characterization of Protective Epitopes Recognized by Monoclonal Antibodies and the Identification of T-Cell-Activating Peptides." Clinical and Developmental Immunology 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/521231.

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Defining immunogenic domains of viral proteins capable of eliciting a protective immune response is crucial in the development of novel epitope-based prophylactic strategies. This is particularly important for the selective targeting of conserved regions shared among hypervariable viruses. Studying postinfection and postimmunization sera, as well as cloning and characterization of monoclonal antibodies (mAbs), still represents the best approach to identify protective epitopes. In particular, a protective mAb directed against conserved regions can play a key role in immunogen design and in human therapy as well. Experimental approaches aiming to characterize protective mAb epitopes or to identify T-cell-activating peptides are often burdened by technical limitations and can require long time to be correctly addressed. Thus, in the last decade many epitope predictive algorithms have been developed. These algorithms are continually evolving, and their use to address the empirical research is widely increasing. Here, we review several strategies based on experimental techniques alone or addressed byin silicoanalysis that are frequently used to predict immunogens to be included in novel epitope-based vaccine approaches. We will list the main strategies aiming to design a new vaccine preparation conferring the protection of a neutralizing mAb combined with an effective cell-mediated response.

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Alomran, Nessrin, Jaffer Alsolaiss, Laura-Oana Albulescu, Edouard Crittenden, Robert A. Harrison, Stuart Ainsworth, and Nicholas R. Casewell. "Pathology-specific experimental antivenoms for haemotoxic snakebite: The impact of immunogen diversity on the in vitro cross-reactivity and in vivo neutralisation of geographically diverse snake venoms." PLOS Neglected Tropical Diseases 15, no. 8 (August 18, 2021): e0009659. http://dx.doi.org/10.1371/journal.pntd.0009659.

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Background Snakebite is a neglected tropical disease that causes high global rates of mortality and morbidity. Although snakebite can cause a variety of pathologies in victims, haemotoxic effects are particularly common and are typically characterised by haemorrhage and/or venom-induced consumption coagulopathy. Antivenoms are the mainstay therapeutic for treating the toxic effects of snakebite, but despite saving thousands of lives annually, these therapies are associated with limited cross-snake species efficacy due to venom variation, which ultimately restricts their therapeutic utility to particular geographical regions. Methodology/Principal findings In this study we explored the feasibility of generating globally effective pathology-specific antivenoms to counteract the haemotoxic signs of snakebite envenoming. Two different immunogen mixtures, consisting of seven and twelve haemotoxic venoms sourced from geographically diverse and/or medically important snakes, were used to raise ovine polyclonal antibodies, prior to characterisation of their immunological binding characteristics and in vitro neutralisation profiles against each of the venoms. Despite variability of the immunogen mixtures, both experimental antivenoms exhibited broadly comparable in vitro venom binding and neutralisation profiles against the individual venom immunogens in immunological and functional assays. However, in vivo assessments using a murine preclinical model of antivenom efficacy revealed substantial differences in venom neutralisation. The experimental antivenom generated from the seven venom immunogen mixture outperformed the comparator, by providing protective effects against venom lethality caused by seven of the eight geographically diverse venoms tested, including three distinct venoms that were not used as immunogens to generate this antivenom. These findings suggest that a core set of venom immunogens may be sufficient to stimulate antibodies capable of broadly neutralising a geographically diverse array of haemotoxic snake venoms, and that adding additional venom immunogens may impact negatively on the dose efficacy of the resulting antivenom. Conclusions/Significance Although selection of appropriate immunogens that encapsulate venom toxin diversity without diluting antivenom potency remains challenging and further optimisation is required, the findings from this pilot study suggest that the generation of pathology-specific antivenoms with global utility is likely to feasible, thereby highlighting their promise as future modular treatments for the world’s tropical snakebite victims.

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Blish, Catherine A., D. Noah Sather, George Sellhorn, Leonidas Stamatatos, Yide Sun, Indresh Srivastava, Susan W. Barnett, Brad Cleveland, Julie Overbaugh, and Shiu-lok Hu. "Comparative Immunogenicity of Subtype A Human Immunodeficiency Virus Type 1 Envelope Exhibiting Differential Exposure of Conserved Neutralization Epitopes." Journal of Virology 84, no. 5 (December 16, 2009): 2573–84. http://dx.doi.org/10.1128/jvi.01687-09.

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ABSTRACT Development of broadly cross-reactive neutralizing antibodies (NAbs) remains a major goal of HIV-1 vaccine development, but most candidate envelope immunogens have had limited ability to cross-neutralize heterologous strains. To evaluate the immunogenicity of subtype A variants of HIV-1, rabbits were immunized with pairs of closely related subtype A envelopes from the same individual. In each immunogen pair, one variant was readily neutralized by a variety of monoclonal antibodies and plasma antibodies, while the other was neutralization resistant, suggesting differences in the exposures of key epitopes. The breadth of the antibody response was evaluated against subtype A, B, C, and D variants of HIV-1. The specificity of the immunogen-derived neutralizing antibody response was also compared to that of the infected individuals from whom these variants were cloned. None of the immunogens produced broad neutralizing antibodies in immunized animals, and most of the neutralizing antibodies were directed to the variable loops, particularly the V3 loop. No detectable antibodies to either of the potentially exposed conserved epitopes, the membrane proximal external region, or the CD4 binding site were found with immunized rabbits. In contrast, relatively little of the neutralizing activity within the plasma samples of the infected individuals was directed to linear epitopes within the variable loops. These data indicate that immunogens designed to expose conserved regions did not enhance generation of broadly neutralizing antibodies in comparison with the immunogens that failed to expose those regions using this immunization approach.

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Fernández-Fernández, M. Rosario, Jorge L. Martínez-Torrecuadrada, Fernando Roncal, Elvira Domínguez, and Juan Antonio García. "Identification of Immunogenic Hot Spots within Plum Pox Potyvirus Capsid Protein for Efficient Antigen Presentation." Journal of Virology 76, no. 24 (December 15, 2002): 12646–53. http://dx.doi.org/10.1128/jvi.76.24.12646-12653.2002.

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ABSTRACT PEPSCAN analysis has been used to characterize the immunogenic regions of the capsid protein (CP) in virions of plum pox potyvirus (PPV). In addition to the well-known highly immunogenic N- and C-terminal domains of CP, regions within the core domain of the protein have also shown high immunogenicity. Moreover, the N terminus of CP is not homogeneously immunogenic, alternatively showing regions frequently recognized by antibodies and others that are not recognized at all. These results have helped us to design efficient antigen presentation vectors based on PPV. As predicted by PEPSCAN analysis, a small displacement of the insertion site in a previously constructed vector, PPV-γ, turned the derived chimeras into efficient immunogens. Vectors expressing foreign peptides at different positions within a highly immunogenic region (amino acids 43 to 52) in the N-terminal domain of CP were the most effective at inducing specific antibody responses against the foreign sequence.

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Zegeye, Ephrem Debebe, Yuleima Diaz, and Pål Puntervoll. "Vaccine Candidate Double Mutant Variants of Enterotoxigenic Escherichia coli Heat-Stable Toxin." Vaccines 10, no. 2 (February 4, 2022): 241. http://dx.doi.org/10.3390/vaccines10020241.

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Heat-stable enterotoxin (ST) producing enterotoxigenic Escherichia coli (ETEC) strains are among the top four enteropathogens associated with moderate-to-severe diarrhea in children under five years in low-to-middle income countries, thus making ST a target for an ETEC vaccine. However, ST must be mutated to abolish its enterotoxicity and to prevent a potential immunological cross-reaction due to its structural resemblance to the human peptides uroguanylin and guanylin. To reduce the risk of eliciting cross-reacting antibodies with our lead STh-A14T toxoid, L9 was chosen as an additional mutational target. A double mutant vaccine candidate immunogen, STh-L9A/A14T, was constructed by conjugation to the synthetic virus-like mi3 nanoparticle using the SpyTag/SpyCatcher technology. This immunogen elicited STh neutralizing antibodies in mice, but with less consistency than STh-A14T peptide control immunogens. Moreover, individual sera from mice immunized with both single and double mutant variants displayed varying levels of unwanted cross-reacting antibodies. The lowest levels of cross-reacting antibodies were observed with STh-L9K/A14T control immunogens, suggesting that it is indeed possible to reduce the risk of eliciting cross-reacting antibodies by mutation. However, mutant-specific antibodies were observed for most double mutant immunogens, demonstrating the delicate balancing act between disrupting cross-reacting epitopes, keeping protective ones, and avoiding the formation of neoepitopes.

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Vu, Hai M., David Myers, Robert de Lorimier, Thomas J. Matthews, M. Anthony Moody, Craig Heinly, Jose V. Torres, Barton F. Haynes, and Leonard Spicer. "Nuclear Magnetic Resonance Analysis of Solution Conformations in C4-V3 Hybrid Peptides Derived from Human Immunodeficiency Virus (HIV) Type 1 gp120: Relation to Specificity of Peptide-Induced Anti-HIV Neutralizing Antibodies." Journal of Virology 73, no. 1 (January 1, 1999): 746–50. http://dx.doi.org/10.1128/jvi.73.1.746-750.1999.

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ABSTRACT Immunogenic peptides containing epitopes of the gp120 C4 and V3 regions from human immunodeficiency virus strains MN and EV91 have been studied by nuclear magnetic resonance and molecular modeling and used as immunogens in rhesus monkeys. The results, combined with those for other peptides, suggest a correlation between solution conformation and immunologic cross-reactivity.

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21

Hayashibe, K., Y. Mishima, and S. Ferrone. "Cloning and in vitro expression of a melanoma-associated antigen immunogenic in patients with melanoma." Journal of Immunology 147, no. 3 (August 1, 1991): 1098–104. http://dx.doi.org/10.4049/jimmunol.147.3.1098.

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Abstract The purpose of this study was to identify human melanoma-associated Ag (MAA) that are immunogenic in patients, because these molecules may be useful immunogens to implement active specific immunotherapy. To this end, an expression cDNA library constructed from the human melanoma cell line A375 was screened with sera from patients with melanoma. A 1029-bp cDNA (designated D-1) was isolated. Its nucleotide sequence showed no significant homology with viral and mammalian sequences stored in GE-NETYX. cDNA D-1 hybridized to a 2.0-kb mRNA species from human melanoma, neuroblastoma, erythroleukemia, B lymphoid, and T lymphoid cell lines but not from a renal carcinoma cell line, PBL, and cultured skin fibroblasts. The D-1 clone produced a fusion protein that displayed a significantly higher reactivity with sera from patients with melanoma than from healthy controls. Furthermore, D-1 fusion protein induced in mice antibodies that immunoprecipitated a 50-kDa component from cultured human melanoma cells. The structural properties of D-1 MAA are different from those of previously described MAA. These results suggest that the approach we have applied may be useful to identify novel MAA expressed by melanoma cells. Furthermore, the immunogenicity of recombinant D-1 protein suggests that it may be a valuable immunogen to implement active specific immunotherapy in patients with melanoma, if additional experiments show that it has the appropriate tissue distribution.

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22

McGuire, Andrew T., Anita M. Dreyer, Sara Carbonetti, Jolene A. Glenn, Johannes F. Scheid, Hugo Mouquet, and Leo Stamatatos. "Minimizing Undesirable Epitope Immunodominance on HIV-1 Env Immunogens through Rational Immunogen Modification." AIDS Research and Human Retroviruses 30, S1 (October 2014): A8. http://dx.doi.org/10.1089/aid.2014.5004.abstract.

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23

Smith, Allen D., Sheila C. Geisler, Anne A. Chen, Dawn A. Resnick, Birgit M. Roy, Paul J. Lewi, Edward Arnold, and Gail Ferstandig Arnold. "Human Rhinovirus Type 14:Human Immunodeficiency Virus Type 1 (HIV-1) V3 Loop Chimeras from a Combinatorial Library Induce Potent Neutralizing Antibody Responses against HIV-1." Journal of Virology 72, no. 1 (January 1, 1998): 651–59. http://dx.doi.org/10.1128/jvi.72.1.651-659.1998.

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ABSTRACT In an effort to develop a useful AIDS vaccine or vaccine component, we have generated a combinatorial library of chimeric viruses in which the sequence IGPGRAFYTTKN from the V3 loop of the MN strain of human immunodeficiency virus type 1 (HIV-1) is displayed in many conformations on the surface of human rhinovirus 14 (HRV14). The V3 loop sequence was inserted into a naturally immunogenic site of the cold-causing HRV14, bridged by linkers consisting of zero to three randomized amino acids on each side. The library of chimeric viruses obtained was subjected to a variety of immunoselection schemes to isolate viruses that provided the most useful presentations of the V3 loop sequence for potential use in a vaccine against HIV. The utility of the presentations was assessed by measures of antigenicity and immunogenicity. Most of the immunoselected chimeras examined were potently neutralized by each of the four different monoclonal anti-V3 loop antibodies tested. Seven of eight chimeric viruses were able to elicit neutralizing antibody responses in guinea pigs against the MN and ALA-1 strains of HIV-1. Three of the chimeras elicited HIV neutralization titers that exceeded those of all but a small number of previously described HIV immunogens. These results indicate that HRV14:HIV-1 chimeras may serve as useful immunogens for stimulating immunity against HIV-1. This method can be used to flexibly reconstruct varied immunogens on the surface of a safe and immunogenic vaccine vehicle.

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Yan, Lin, Jin Qiu, Jianbo Chen, Bridgett Ryan-Payseur, Dan Huang, Yunqi Wang, Lijun Rong, Jody A. Melton-Witt, Nancy E. Freitag, and Zheng W. Chen. "Selected prfA* Mutations in Recombinant Attenuated Listeria monocytogenes Strains Augment Expression of Foreign Immunogens and Enhance Vaccine-Elicited Humoral and Cellular Immune Responses." Infection and Immunity 76, no. 8 (May 12, 2008): 3439–50. http://dx.doi.org/10.1128/iai.00245-08.

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ABSTRACT While recombinant Listeria monocytogenes strains can be explored as vaccine candidates, it is important to develop attenuated but highly immunogenic L. monocytogenes vaccine vectors. Here, prfA* mutations selected on the basis of upregulated expression of L. monocytogenes PrfA-dependent genes and proteins were assessed to determine their abilities to augment expression of foreign immunogens in recombinant L. monocytogenes vectors and therefore enhance vaccine-elicited immune responses (a prfA* mutation is a mutation that results in constitutive overexpression of PrfA and PrfA-dependent virulence genes; the asterisk distinguishes the mutation from inactivation or stop mutations). A total of 63 recombinant L. monocytogenes vaccine vectors expressing seven individual viral or bacterial immunogens each in nine different L. monocytogenes strains carrying wild-type prfA or having prfA* mutations were constructed and investigated. Mutations selected on the basis of increased PrfA activation in recombinant L. monocytogenes prfA* vaccine vectors augmented expression of seven individual protein immunogens remarkably. Consistently, prime and boost vaccination studies with mice indicated that the prfA(G155S) mutation in recombinant L. monocytogenes ΔactA prfA* strains enhanced vaccine-elicited cellular immune responses. Surprisingly, the prfA(G155S) mutation was found to enhance vaccine-elicited humoral immune responses as well. The highly immunogenic recombinant L. monocytogenes ΔactA prfA* vaccine strains were as attenuated as the recombinant parent L. monocytogenes ΔactA vaccine vector. Thus, recombinant attenuated L. monocytogenes ΔactA prfA* vaccine vectors potentially are better antimicrobial and anticancer vaccines.

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Chersi, Alberto, Francesca di Modugno, and Giuliana Falasca. "Specifities of Rabbit Antisera to Multiple Antigen (MAP) Peptides." Zeitschrift für Naturforschung C 50, no. 9-10 (October 1, 1995): 735–38. http://dx.doi.org/10.1515/znc-1995-9-1023.

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Abstract Two multiple antigen peptides consisting of 6 and 7 amino acid residues, respectively, plus a 12-residue fragment, used as a control, all linked to a polylysine core, were used as immunogens in rabbits in order to obtain an immune response. Rabbit antisera against such polymers were then tested in ELISA against a panel of antigens in order to analyze the specificites of the resulting antibodies. The responses were different for all three immunogens, being partially or totally directed, for two of the three compounds, including the 12-residue control MAP peptide, against the polylysyl core, which is considered as non immunogenic. The third MAP polymer was practically unable to elicit an immune response

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26

Manoutcharian, Karen, Luis Ignacio Terrazas, Goar Gevorkian, Gonzalo Acero, Pavel Petrossian, Miriam Rodriguez, and Tzipe Govezensky. "Phage-Displayed T-Cell Epitope Grafted into Immunoglobulin Heavy-Chain Complementarity-Determining Regions: an Effective Vaccine Design Tested in Murine Cysticercosis." Infection and Immunity 67, no. 9 (September 1, 1999): 4764–70. http://dx.doi.org/10.1128/iai.67.9.4764-4770.1999.

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ABSTRACT A new type of immunogenic molecule was engineered by replacing all three complementarity-determining-region (CDR) loops of the human immunoglobulin (Ig) heavy-chain variable (VH) domain with the Taenia crassiceps epitope PT1 (PPPVDYLYQT) and by displaying this construct on the surfaces of M13 bacteriophage. When BALB/c mice were immunized with such phage particles (PIgphage), a strong protection against challenge infection in very susceptible female hosts was obtained. When specifically stimulated, the in vivo-primed CD4+ and CD8+ T cells isolated from mice immunized with PT1, both as a free peptide and as the PIgphage construct, proliferated in vitro, indicating efficient epitope presentation by both major histocompatibility complex class II and class I molecules in the specifically antigen-pulsed macrophages used as antigen-presenting cells. These data demonstrate the immunogenic potential of recombinant phage particles displaying CDR epitope-grafted Ig VH domains and establish an alternative approach to the design of an effective subunit vaccine for prevention of cysticercosis. The key advantage of this type of immunogen is that no adjuvant is required for its application. The proposed strategy for immunogen construction is potentially suitable for use in any host-pathogen interaction.

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27

Ching, Lance, and Leonidas Stamatatos. "Alterations in the Immunogenic Properties of Soluble Trimeric Human Immunodeficiency Virus Type 1 Envelope Proteins Induced by Deletion or Heterologous Substitutions of the V1 Loop." Journal of Virology 84, no. 19 (July 21, 2010): 9932–46. http://dx.doi.org/10.1128/jvi.00868-10.

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ABSTRACT HIV-1 gp140 envelope immunogens express conserved epitopes that are targeted by broadly cross-reactive neutralizing antibodies, but they fail to elicit similar antibodies upon immunization. The poor immunogenicity of conserved epitopes on gp140 could be linked to the high immunogenicity of variable Env regions on such constructs. Previous studies have shown that the first hypervariable region (V1 loop) is immunogenic on soluble gp140s but elicits type-specific antibodies. To address issues related to the high immunogenicity of the V1 loop, two conceptually opposite approaches were tested. In the first approach, we eliminated the V1 loop from our gp140 construct and examined how V1 deletion altered the immunogenic properties of other Env regions. In the second approach, we took advantage of the high immunogenicity of the V1 loop and engrafted four diverse V1 loops onto a common gp140 Env “scaffold.” These four scaffolds were used as a cocktail of immunogens to elicit diverse anti-V1 antibodies, under the hypothesis that eliciting diverse anti-V1 antibodies would expand the neutralizing breadth of immune sera. Our study indicates that three of four heterologous V1 loops were immunogenic on the common Env backbone “scaffold,” but heterologous anti-V1 neutralizing responses were observed in only one case. Both types of V1 modification dampened the immunogenicity of the V3 loop, differentially altered the immunogenicity of the transmembrane gp41 subunit, and altered the relative immunogenicities of unknown Env regions, including potentially the CD4-binding site (CD4-bs) and trimer-specific targets, which elicited cross-reactive neutralizing antibodies but of limited breadth.

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Shedlock, Devon J., Kendra T. Talbott, Stephan J. Wu, Christine M. Wilson, Kar Muthumani, Jean D. Boyer, Niranjan Y. Sardesai, Sita Awasthi, and David B. Weiner. "Vaccination with synthetic constructs expressing cytomegalovirus immunogens is highly T cell immunogenic in mice." Human Vaccines & Immunotherapeutics 8, no. 11 (November 24, 2012): 1668–81. http://dx.doi.org/10.4161/hv.22447.

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29

Salwa, S., M. C. Whelan, G. Casey, M. MacConmara, J. A. Lederer, D. Soden, K. Collins, M. Tangney, and G. C. O'Sullivan. "301 Combined immunogene therapy and Treg inactivation in treatment of weakly immunogenic solid tumours." European Journal of Cancer Supplements 8, no. 5 (June 2010): 78. http://dx.doi.org/10.1016/s1359-6349(10)71105-8.

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30

Corder, Brigette N., Brianna L. Bullard, Jennifer L. DeBeauchamp, Natalia A. Ilyushina, Richard J. Webby, and Eric A. Weaver. "Influenza H1 Mosaic Hemagglutinin Vaccine Induces Broad Immunity and Protection in Mice." Vaccines 7, no. 4 (November 23, 2019): 195. http://dx.doi.org/10.3390/vaccines7040195.

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Annually, influenza A virus (IAV) infects ~5–10% of adults and 20–30% of children worldwide. The primary resource to protect against infection is by vaccination. However, vaccination only induces strain-specific and transient immunity. Vaccine strategies that induce cross-protective immunity against the broad diversity of IAV are needed. Here we developed and tested a novel mosaic H1 HA immunogen. The mosaic immunogen was optimized in silico to include the most potential B and T cell epitopes (PBTE) across a diverse population of human H1 IAV. Phylogenetic analysis showed that the mosaic HA localizes towards the non-pandemic 2009 strains which encompasses the broadest diversity in the H1 IAV population. We compared the mosaic H1 immunogen to wild-type HA immunogens and the commercial inactivated influenza vaccine, Fluzone. When analyzed by ELISA, the mosaic immunogen induced stronger antibody responses against all four diverse H1 HA proteins. When analyzing T cell responses, again the mosaic immunogen induced stronger cellular immunity against all 4 diverse HA strains. Not only was the magnitude of T cell responses strongest in mosaic immunized mice, the number of epitopes recognized was also greater. The mosaic vaccinated mice showed strong cross-protection against challenges with three divergent IAV strains. These data show that the mosaic immunogen induces strong cross-protective immunity and should be investigated further as a universal influenza vaccine.

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Barnett, S. W., S. Lu, I. Srivastava, S. Cherpelis, A. Gettie, J. Blanchard, S. Wang, et al. "The Ability of an Oligomeric Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Antigen To Elicit Neutralizing Antibodies against Primary HIV-1 Isolates Is Improved following Partial Deletion of the Second Hypervariable Region." Journal of Virology 75, no. 12 (June 15, 2001): 5526–40. http://dx.doi.org/10.1128/jvi.75.12.5526-5540.2001.

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ABSTRACT Partial deletion of the second hypervariable region from the envelope of the primary-like SF162 virus increases the exposure of certain neutralization epitopes and renders the virus, SF162ΔV2, highly susceptible to neutralization by clade B and non-clade B human immunodeficiency virus (HIV-positive) sera (L. Stamatatos and C. Cheng-Mayer, J. Virol. 78:7840–7845, 1998). This observation led us to propose that the modified, SF162ΔV2-derived envelope may elicit higher titers of cross-reactive neutralizing antibodies than the unmodified SF162-derived envelope. To test this hypothesis, we immunized rabbits and rhesus macaques with the gp140 form of these two envelopes. In rabbits, both immunogens elicited similar titers of binding antibodies but the modified immunogen was more effective in eliciting neutralizing antibodies, not only against the SF162ΔV2 and SF162 viruses but also against several heterologous primary HIV type 1 (HIV-1) isolates. In rhesus macaques both immunogens elicited potent binding antibodies, but again the modified immunogen was more effective in eliciting the generation of neutralizing antibodies against the SF162ΔV2 and SF162 viruses. Antibodies capable of neutralizing several, but not all, heterologous primary HIV-1 isolates tested were elicited only in macaques immunized with the modified immunogen. The efficiency of neutralization of these heterologous isolates was lower than that recorded against the SF162 isolate. Our results strongly suggest that although soluble oligomeric envelope subunit vaccines may elicit neutralizing antibody responses against heterologous primary HIV-1 isolates, these responses will not be broad and potent unless specific modifications are introduced to increase the exposure of conserved neutralization epitopes.

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Greenfield, Edward A., James DeCaprio, and Mohan Brahmandam. "Selecting the Antigen." Cold Spring Harbor Protocols 2021, no. 12 (December 2021): pdb.top099945. http://dx.doi.org/10.1101/pdb.top099945.

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The classical method for generating polyclonal or monoclonal antibodies relies on the in vivo humoral response of animals. Here we describe the factors that antigens can have that might influence the strength and quality of an antibody response. This introduction is divided into three sections: (1) an overview of immunogenicity, (2) choosing the best form for the immunogen, and (3) methods for modifying antigens to make them more immunogenic.

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Antenucci, Fabio, Armen Ovsepian, Agnieszka Wrobel, Hanne Cecilie Winther-Larsen, and Anders Miki Bojesen. "Design and Characterization of a Novel Tool for the Antigenic Enrichment of Actinobacillus pleuropneumoniae Outer Membrane." Pathogens 9, no. 12 (December 2, 2020): 1014. http://dx.doi.org/10.3390/pathogens9121014.

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Production and isolation of recombinant proteins are costly and work-intensive processes, especially in immunology when tens or hundreds of potential immunogens need to be purified for testing. Here we propose an alternative method for fast screening of immunogen candidates, based on genetic engineering of recombinant bacterial strains able to express and expose selected antigens on their outer membrane. In Actinobacillus pleuropneumoniae, a Gram-negative porcine pathogen responsible for extensive economic losses worldwide, we identified a conserved general secretion pathway (GSP) domain in the N-terminal part of the outer membrane protein ApfA (ApfA stem: ApfAs). ApfAs was used as an outer membrane anchor, to which potential immunogens can be attached. To enable confirmation of correct positioning, ApfAs, was cloned in combination with the modified acyl carrier protein (ACP) fluorescent tag ACP mini (ACPm) and the putative immunogen VacJ. The chimeric construct was inserted in the pMK-express vector, subsequently transformed into A. pleuropneumoniae for expression. Flow cytometry, fluorescence imaging and mass spectrometry analysis were employed to demonstrate that the outer membrane of the transformed strain was enriched with the chimeric ApfAs-ACPm-VacJ antigen. Our results confirmed correct positioning of the chimeric ApfAs-ACPm-VacJ antigen and supported this system’s potential as platform technology enabling antigenic enrichment of the outer membrane of A. pleuropneumoniae.

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34

Govea-Alonso, Dania O., Ashwini Malla, Omayra C. Bolaños-Martínez, Sornkanok Vimolmangkang, and Sergio Rosales-Mendoza. "An Algae-Made RBD from SARS-CoV-2 Is Immunogenic in Mice." Pharmaceuticals 15, no. 10 (October 21, 2022): 1298. http://dx.doi.org/10.3390/ph15101298.

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Despite the current advances in global vaccination against SARS-CoV-2, boosting is still required to sustain immunity in the population, and the induction of sterilizing immunity remains as a pending goal. Low-cost oral immunogens could be used as the basis for the design of affordable and easy-to-administer booster vaccines. Algae stand as promising platforms to produce immunogens at low cost, and it is possible to use them as oral delivery carriers since they are edible (not requiring complex purification and formulation processes). Herein, a Chlamydomonas-made SARS-CoV-2 RBD was evaluated as an oral immunogen in mice to explore the feasibility of developing an oral algae-based vaccine. The test immunogen was stable in freeze-dried algae biomass and able to induce, by the oral route, systemic and mucosal humoral responses against the spike protein at a similar magnitude to those induced by injected antigen plus alum adjuvant. IgG subclass analysis revealed a Th2-bias response which lasted over 4 months after the last immunization. The induced antibodies showed a similar reactivity against either Delta or Omicron variants. This study represents a step forward in the development of oral vaccines that could accelerate massive immunization.

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Srivastava, Indresh K., Keating VanDorsten, Lucia Vojtech, Susan W. Barnett, and Leonidas Stamatatos. "Changes in the Immunogenic Properties of Soluble gp140 Human Immunodeficiency Virus Envelope Constructs upon Partial Deletion of the Second Hypervariable Region." Journal of Virology 77, no. 4 (February 15, 2003): 2310–20. http://dx.doi.org/10.1128/jvi.77.4.2310-2320.2003.

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ABSTRACT Immunization of macaques with the soluble oligomeric gp140 form of the SF162 envelope (SF162gp140) or with an SF162gp140-derived construct lacking the central region of the V2 loop (ΔV2gp140) results in the generation of high titers of antibodies capable of neutralizing the homologous human immunodeficiency virus type 1 (HIV-1), SF162 virus (Barnett et al. J. Virol. 75 :5526-5540, 2001). However, the ΔV2gp140 immunogen is more effective than the SF162gp140 immunogen in eliciting the generation of antibodies capable of neutralizing heterologous HIV-1 isolates. This indicates that deletion of the V2 loop alters the immunogenicity of the SF162gp140 protein. The present studies were aimed at identifying the envelope regions whose immunogenicity is altered following V2 loop deletion. We report that the antibodies elicited by the SF162gp140 immunogen recognize elements of the V1, V2, and V3 loops, the CD4-binding site, and the C1 and C2 regions on the homologous SF162 gp120. With the exception of the V1 and V2 loops, the same regions are recognized on heterologous gp120 proteins. Surprisingly, although a minority of the SF162gp140-elicited antibodies target the V3 loop on the homologous gp120, the majority of the antibodies elicited by this immunogen that are capable of binding to the heterologous gp120s tested recognize their V3 loops. Deletion of the V2 loop has two effects. First, it alters the immunogenicity of the V3 and V1 loops, and second, it renders the C5 region immunogenic. Although deletion of the V2 loop does not result in an increase in the immunogenicity of the CD4-binding site per se, the relative ratio of anti-CD4-binding site to anti-V3 loop antibodies that bind to the heterologous gp120s tested is higher in sera collected from the ΔV2gp140-immunized animals than in the SF162gp140-immunized animals. Overall, our studies indicate that it is possible to alter the immunogenic structure of the HIV envelope by introducing specific modifications.

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Habte, Habtom H., Saikat Banerjee, Heliang Shi, Yali Qin, and Michael W. Cho. "Immunogenic properties of a trimeric gp41-based immunogen containing an exposed membrane-proximal external region." Virology 486 (December 2015): 187–97. http://dx.doi.org/10.1016/j.virol.2015.09.010.

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37

Kraft, Zane, Katharine Strouss, William F. Sutton, Brad Cleveland, For Yue Tso, Patricia Polacino, Julie Overbaugh, Shiu-Lok Hu, and Leonidas Stamatatos. "Characterization of Neutralizing Antibody Responses Elicited by Clade A Envelope Immunogens Derived from Early Transmitted Viruses." Journal of Virology 82, no. 12 (April 9, 2008): 5912–21. http://dx.doi.org/10.1128/jvi.00389-08.

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ABSTRACT The vast majority of studies with candidate immunogens based on the human immunodeficiency virus envelope (Env) have been conducted with Env proteins derived from clade B viruses isolated during chronic infection. Whether non-clade B Env protein immunogens will elicit antibodies with epitope specificities that are similar to those of antibodies elicited by clade B Envs and whether the antibodies elicited by Envs derived from early transmitted viruses will be similar to those elicited by Envs derived from viruses isolated during chronic infection are currently unknown. Here we performed immunizations with four clade A Envs, cloned directly from the peripheral blood of infected individuals during acute infection, which differed in lengths and extents of glycosylation. The antibody responses elicited by these four Envs were compared to each other and to those elicited by a well-characterized clade B Env immunogen derived from the SF162 virus, which was isolated during chronic infection. Only one clade A Env, the one with the fewer glycosylation sites, elicited homologous neutralizing antibodies (NAbs); these did not target the V1, V2, or V3 regions. In contrast, all four clade A Envs elicited anti-V3 NAbs against “easy-to-neutralize” clade B and clade A isolates, irrespective of the variable region length and extent of glycosylation of the Env used as an immunogen. These anti-V3 NAbs did not access their epitopes on homologous and heterologous clade A, or B, neutralization-resistant viruses. The length and extent of glycosylation of the variable regions on the clade A Env immunogens tested did not affect the breadth of the elicited NAbs. Our data also indicate that the development of cross-reactive NAbs against clade A viruses faces similar hurdles to the development of cross-reactive anti-clade B NAbs.

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Francica, Joseph R., Wei Shi, Gwo-Yu Chuang, Steven J. Chen, Lais Da Silva Pereira, S. Katie Farney, Barbara J. Flynn, et al. "Design of Alphavirus Virus-Like Particles Presenting Circumsporozoite Junctional Epitopes That Elicit Protection against Malaria." Vaccines 9, no. 3 (March 18, 2021): 272. http://dx.doi.org/10.3390/vaccines9030272.

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The most advanced malaria vaccine, RTS,S, includes the central repeat and C-terminal domains of the Plasmodium falciparum circumsporozoite protein (PfCSP). We have recently isolated human antibodies that target the junctional region between the N-terminal and repeat domains that are not included in RTS,S. Due to the fact that these antibodies protect against malaria challenge in mice, their epitopes could be effective vaccine targets. Here, we developed immunogens displaying PfCSP junctional epitopes by genetic fusion to either the N-terminus or B domain loop of the E2 protein from chikungunya (CHIK) alphavirus and produced CHIK virus-like particles (CHIK-VLPs). The structural integrity of these junctional-epitope–CHIK-VLP immunogens was confirmed by negative-stain electron microscopy. Immunization of these CHIK-VLP immunogens reduced parasite liver load by up to 95% in a mouse model of malaria infection and elicited better protection than when displayed on keyhole limpet hemocyanin, a commonly used immunogenic carrier. Protection correlated with PfCSP serum titer. Of note, different junctional sequences elicited qualitatively different reactivities to overlapping PfCSP peptides. Overall, these results show that the junctional epitopes of PfCSP can induce protective responses when displayed on CHIK-VLP immunogens and provide a basis for the development of a next generation malaria vaccine to expand the breadth of anti-PfCSP immunity.

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Magez, Stefan, Zeng Li, Hang Thi Thu Nguyen, Joar Esteban Pinto Torres, Pieter Van Wielendaele, Magdalena Radwanska, Jakub Began, Sebastian Zoll, and Yann G. J. Sterckx. "The History of Anti-Trypanosome Vaccine Development Shows That Highly Immunogenic and Exposed Pathogen-Derived Antigens Are Not Necessarily Good Target Candidates: Enolase and ISG75 as Examples." Pathogens 10, no. 8 (August 19, 2021): 1050. http://dx.doi.org/10.3390/pathogens10081050.

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Salivarian trypanosomes comprise a group of extracellular anthroponotic and zoonotic parasites. The only sustainable method for global control of these infection is through vaccination of livestock animals. Despite multiple reports describing promising laboratory results, no single field-applicable solution has been successful so far. Conventionally, vaccine research focusses mostly on exposed immunogenic antigens, or the structural molecular knowledge of surface exposed invariant immunogens. Unfortunately, extracellular parasites (or parasites with extracellular life stages) have devised efficient defense systems against host antibody attacks, so they can deal with the mammalian humoral immune response. In the case of trypanosomes, it appears that these mechanisms have been perfected, leading to vaccine failure in natural hosts. Here, we provide two examples of potential vaccine candidates that, despite being immunogenic and accessible to the immune system, failed to induce a functionally protective memory response. First, trypanosomal enolase was tested as a vaccine candidate, as it was recently characterized as a highly conserved enzyme that is readily recognized during infection by the host antibody response. Secondly, we re-addressed a vaccine approach towards the Invariant Surface Glycoprotein ISG75, and showed that despite being highly immunogenic, trypanosomes can avoid anti-ISG75 mediated parasitemia control.

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Barbour, Alan G., Algimantas Jasinskas, Matthew A. Kayala, D. Huw Davies, Allen C. Steere, Pierre Baldi, and Philip L. Felgner. "A Genome-Wide Proteome Array Reveals a Limited Set of Immunogens in Natural Infections of Humans and White-Footed Mice with Borrelia burgdorferi." Infection and Immunity 76, no. 8 (May 12, 2008): 3374–89. http://dx.doi.org/10.1128/iai.00048-08.

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ABSTRACT Humans and other animals with Lyme borreliosis produce antibodies to a number of components of the agent Borrelia burgdorferi, but a full accounting of the immunogens during natural infections has not been achieved. Employing a protein array produced in vitro from 1,292 DNA fragments representing ∼80% of the genome, we compared the antibody reactivities of sera from patients with early or later Lyme borreliosis to the antibody reactivities of sera from controls. Overall, ∼15% of the open reading frame (ORF) products (Orfs) of B. burgdorferi in the array detectably elicited an antibody response in humans with natural infections. Among the immunogens, 103 stood out on the basis of statistical criteria. The majority of these Orfs were also immunogenic with sera obtained from naturally infected Peromyscus leucopus mice, a major reservoir. The high-ranking set included several B. burgdorferi proteins hitherto unrecognized as immunogens, as well as several proteins that have been established as antigens. The high-ranking immunogens were more likely than nonreactive Orfs to have the following characteristics: (i) plasmid-encoded rather than chromosome-encoded proteins, (ii) a predicted lipoprotein, and (iii) a member of a paralogous family of proteins, notably the Bdr and Erp proteins. The newly discovered antigens included Orfs encoded by several ORFs of the lp36 linear plasmid, such as BBK07 and BBK19, and proteins of the flagellar apparatus, such as FliL. These results indicate that the majority of deduced proteins of B. burgdorferi do not elicit antibody responses during infection and that the limited sets of immunogens are similar for two different host species.

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41

Darwish, Ibrahim A., Abdulrahman A. Almehizia, Awwad A. Radwan, and Rashed N. Herqash. "Preparation and Characterization of Two Immunogens and Production of Polyclonal Antibody with High Affinity and Specificity for Darunavir." Molecules 25, no. 18 (September 7, 2020): 4075. http://dx.doi.org/10.3390/molecules25184075.

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Darunavir (DRV) is a potent antiviral drug used for treatment of infections with human immunodeficiency virus (HIV). Effective and safe treatment with DRV requires its therapeutic drug monitoring (TDM) in patient’s plasma during therapy. To support TDM of DRV, a specific antibody with high affinity is required in order to develop a sensitive immunoassay for the accurate determination of DRV in plasma. In this study, two new and different immunogens were prepared and characterized. These immunogens were the DRV conjugates with keyhole limpet hemocyanin (KLH) protein. The first immunogen (DRV-KLH) was prepared by zero-length direct linking of DRV via its aromatic amino group with the tyrosine amino acid residues of KLH by diazotization/coupling reaction. The second immunogen (G-DRV-KLH) was prepared by conjugation of the N-glutaryl derivative of DRV (G-DRV) with KLH. The 5-carbon atoms-spacing G-DRV hapten was synthesized by reaction of DRV via its aromatic amino group with glutaric anhydride. The reaction was monitored by HPLC and the chemical structure of G-DRV was confirmed by mass, 1H-NMR, and 13C-NMR spectroscopic techniques. The hapten (G-DRV) was linked to the KLH protein by water-soluble 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) coupling procedure. The pertinence of the coupling reactions of haptens to protein was confirmed, and the immunogens were characterized by ultraviolet (UV) spectrophotometry. Both DRV-KLH and G-DRV-KLH were used for the immunization of animals and the animal’s antiserum that showed the highest affinity was selected. The collected antiserum (polyclonal antibody) had very high affinity to DRV (IC50 value = 0.2 ng mL−1; defining IC50 as the DRV concentration that can inhibit antibody binding by 50% of its maximum binding) and high specificity to DRV among other drugs used in the combination therapy with DRV. Cumulative results from direct and competitive enzyme-linked immunosorbent assay (ELISA) using this polyclonal antibody proved that the immunogens were highly antigenic and elicited a specific polyclonal antibody. The produced polyclonal antibody is valuable for the development of highly sensitive and selective immunoassays for TDM of DRV.

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42

van Houten, Nienke Elizabeth, George P. Smith, and Jamie K. Scott. "Engineering filamentous phage as carriers that focus antibody responses against a peptide (47.11)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S68. http://dx.doi.org/10.4049/jimmunol.178.supp.47.11.

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Abstract Antibody (Ab) responses to a B-cell epitope can be produced by immunization with a peptide bearing the epitope of interest. Such peptides are often poor immunogens, requiring conjugation or fusion to carrier proteins that provide T-cell help. However, carrier proteins may also divert the Ab response away from the targeted peptide via its own B-cell epitopes. Thus, an ideal peptide carrier should provide T-cell help to drive B-cell responses but contain relatively few B-cell epitopes. The Ab response to filamentous phage is restricted to the 12 N-terminal residues of the major coat protein (pVIII) and the external domains of the minor coat protein, pIII. Previously, we reported that the Ab response against a synthetic peptide conjugated to phage was more focused on the peptide compared to ovalbumin as the carrier. In some cases, the anti-peptide Ab titer exceeded the anti-carrier Ab titer by > 20 fold. The reduced complexity of the phage surface compared to ovalbumin’s may be responsible for this. Here, we tested the hypothesis that Ab responses to weakly immunogenic peptides would be improved by removing immunodominant epitopes from the phage surface; immunogenic residues on pVIII were altered, and the external domains of pIII were truncated. The phage were tested alone as immunogens, and as carriers for pVIII-displayed peptides. The results and the implication for vaccine design are discussed. Supported by NIH R01AI-49111

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43

Guest, Johnathan D., and Brian G. Pierce. "Structure-Based and Rational Design of a Hepatitis C Virus Vaccine." Viruses 13, no. 5 (May 5, 2021): 837. http://dx.doi.org/10.3390/v13050837.

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A hepatitis C virus (HCV) vaccine is a critical yet unfulfilled step in addressing the global disease burden of HCV. While decades of research have led to numerous clinical and pre-clinical vaccine candidates, these efforts have been hindered by factors including HCV antigenic variability and immune evasion. Structure-based and rational vaccine design approaches have capitalized on insights regarding the immune response to HCV and the structures of antibody-bound envelope glycoproteins. Despite successes with other viruses, designing an immunogen based on HCV glycoproteins that can elicit broadly protective immunity against HCV infection is an ongoing challenge. Here, we describe HCV vaccine design approaches where immunogens were selected and optimized through analysis of available structures, identification of conserved epitopes targeted by neutralizing antibodies, or both. Several designs have elicited immune responses against HCV in vivo, revealing correlates of HCV antigen immunogenicity and breadth of induced responses. Recent studies have elucidated the functional, dynamic and immunological features of key regions of the viral envelope glycoproteins, which can inform next-generation immunogen design efforts. These insights and design strategies represent promising pathways to HCV vaccine development, which can be further informed by successful immunogen designs generated for other viruses.

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44

Kilpeläinen, Athina, Narcís Saubi, Núria Guitart, Alex Olvera, Tomáš Hanke, Christian Brander, and Joan Joseph. "Recombinant BCG Expressing HTI Prime and Recombinant ChAdOx1 Boost Is Safe and Elicits HIV-1-Specific T-Cell Responses in BALB/c Mice." Vaccines 7, no. 3 (August 2, 2019): 78. http://dx.doi.org/10.3390/vaccines7030078.

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Despite the availability of anti-retroviral therapy, HIV-1 infection remains a massive burden on healthcare systems. Bacillus Calmette-Guérin (BCG), the only licensed vaccine against tuberculosis, confers protection against meningitis and miliary tuberculosis in infants. Recombinant BCG has been used as a vaccine vehicle to express both HIV-1 and Simian Immunodeficiemcy Virus (SIV) immunogens. In this study, we constructed an integrative E. coli-mycobacterial shuttle plasmid, p2auxo.HTI.int, expressing the HIVACAT T-cell immunogen (HTI). The plasmid was transformed into a lysine auxotrophic Mycobacterium bovis BCG strain (BCGΔLys) to generate the vaccine BCG.HTI2auxo.int. The DNA sequence coding for the HTI immunogen and HTI protein expression were confirmed, and working vaccine stocks were genetically and phenotypically characterized. We demonstrated that the vaccine was stable in vitro for 35 bacterial generations, and that when delivered in combination with chimpanzee adenovirus (ChAd)Ox1.HTI in adult BALB/c mice, it was well tolerated and induced HIV-1-specific T-cell responses. Specifically, priming with BCG.HTI2auxo.int doubled the magnitude of the T-cell response in comparison with ChAdOx1.HTI alone while maintaining its breadth. The use of integrative expression vectors and novel HIV-1 immunogens can aid in improving mycobacterial vaccine stability as well as specific immunogenicity. This vaccine candidate may be a useful tool in the development of an effective vaccine platform for priming protective responses against HIV-1/TB and other prevalent pediatric pathogens.

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45

Mirsaliotis, Antonis, Kulpash Nurkiyanova, Daniel Lamb, Jenny M. Woof, and David W. Brighty. "Conformation-Specific Antibodies Targeting the Trimer-of-Hairpins Motif of the Human T-Cell Leukemia Virus Type 1 Transmembrane Glycoprotein Recognize the Viral Envelope but Fail To Neutralize Viral Entry." Journal of Virology 81, no. 11 (March 21, 2007): 6019–31. http://dx.doi.org/10.1128/jvi.02544-06.

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ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) entry into cells is dependent upon the viral envelope glycoprotein-catalyzed fusion of the viral and cellular membranes. Following receptor activation of the envelope, the transmembrane glycoprotein (TM) is thought to undergo a series of fusogenic conformational transitions through a rod-like prehairpin intermediate to a compact trimer-of-hairpins structure. Importantly, synthetic peptides that interfere with the conformational changes of TM are potent inhibitors of membrane fusion and HTLV-1 entry, suggesting that TM is a valid target for antiviral therapy. To assess the utility of TM as a vaccine target and to explore further the function of TM in HTLV-1 pathogenesis, we have begun to examine the immunological properties of TM. Here we demonstrate that a recombinant trimer-of-hairpins form of the TM ectodomain is strongly immunogenic. Monoclonal antibodies raised against the TM immunogen specifically bind to trimeric forms of TM, including structures thought to be important for membrane fusion. Importantly, these antibodies recognize the envelope on virally infected cells but, surprisingly, fail to neutralize envelope-mediated membrane fusion or infection by pseudotyped viral particles. Our data imply that, even in the absence of overt membrane fusion, there are multiple forms of TM on virally infected cells and that some of these display fusion-associated structures. Finally, we demonstrate that many of the antibodies possess the ability to recruit complement to TM, suggesting that envelope-derived immunogens capable of eliciting a combination of neutralizing and complement-fixing antibodies would be of value as subunit vaccines for intervention in HTLV infections.

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46

Steele, J. K., R. Singhai, A. T. Stammers, and J. G. Levy. "Immunization of DBA/2 mice with a T cell hybridoma-derived TsF increases immune resistance to the syngeneic tumors P815 and L1210." Journal of Immunology 137, no. 9 (November 1, 1986): 3025–30. http://dx.doi.org/10.4049/jimmunol.137.9.3025.

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Abstract The ability of a tumor-specific T suppressor factor (TsF) isolated from a T cell hybridoma, A10, to act as an immunogen in DBA/2 mice was investigated. The TsF was affinity purified from ascites over an immunoadsorbent column containing a monoclonal antibody (B16G) that has specificity for the TsF molecule, or over columns containing membrane extracts of the P815 mastocytoma (the tumor for which A10 is specific). The specificity control was BW5147 (the fusion partner for A10) membrane extracts treated in the same way as A10. DBA/2 mice were immunized with the affinity-purified material or PBS and were subsequently challenged with either the P815 tumor or the L1210 DBA/2 thymoma. When mice were immunized with material affinity purified over B16G, eluted material from both A10 ascites and BW5147 membrane extracts enhanced resistance to both P815 and L1210 challenge, indicating that B16G was binding immunogenic material derived from both preparations, which exerted a tumor-protective effect. However, when a P815 affinity column was used, protective material was eluted only from A10 ascites, and this bestowed resistance to both P815 and L1210. When irradiated whole cells were used as immunogens, only A10 cells stimulated anti-tumor immunity, and this appeared to be directed specifically to the P815 tumor. The implications of these findings in terms of the potential for immune modulation with anti-suppressor therapy, and the specificity of the B16G monoclonal, are discussed. The demonstration of B16G binding material (TsF) in the membranes (but not the ascites) of the BW5147 line is also of significance to investigators using BW5147 fused suppressor hybridomas.

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47

Pasare, Chandrashekhar, Vivian Morafo, Maureen Entringer, Pratima Bansal, Anna George, Vineeta Bal, Satyajit Rath та Jeannine M. Durdik. "Presence of Activated Antigen-Binding B Cells During Immunization Enhances Relative Levels of IFN-γ in T Cell Responses". Journal of Immunology 160, № 2 (15 січня 1998): 778–87. http://dx.doi.org/10.4049/jimmunol.160.2.778.

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Abstract To examine the influence of Ag presentation by B cells on immune responses, we have used mice transgenic for an Ig heavy chain from a monoclonal anti-azobenzenearsonate (Ars) Ab to deliver Ag to B cells during immunization. A large proportion of transgene-expressing B cells in these mice binds Ars, while transgenic serum Ig shows poor Ars binding. Transgenic B cells present Ars proteins better than their nonhaptenated counterparts. This is associated with an increase in the proliferative responses of transgenic T cells to Ars protein immunization. Although B cell numbers in the transgenic mice are lower, many B cells in them show an activated phenotype, as identified by altered surface levels of peanut agglutinin reactivity, CD23, CD24, CD44, CD62L, and CD86. Even against nonhaptenated immunogens, transgenic responses show significant enhancement in the relative proportions of the Th1 cytokine IFN-γ over the Th2 cytokines IL-4 and IL-10. Haptenated immunogens further enhance the predilection of transgenic mice to produce relatively more IFN-γ. Consistent with this, there is an increase in IgG2a/IgG1 ratios in serum Abs in response to haptenated immunogens in transgenic mice. Adoptive transfer of primed hapten-specific secondary B cells into nontransgenic mice also induces an increase in relative levels of IFN-γ in response to haptenated immunogens. Thus, presentation of immunogen in vivo by activated Ag-binding B cells contributes to enhanced immunogenicity and a Th1 cytokine bias.

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48

Shinagawa, Kunihiro, Katsuhiko Omoe, Naonori Matsusaka, and Shunji Sugii. "Immunological studies on staphylococcal enterotoxin D: production of murine monoclonal antibodies and immunopurification." Canadian Journal of Microbiology 37, no. 8 (August 1, 1991): 586–89. http://dx.doi.org/10.1139/m91-099.

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Eight murine monoclonal antibodies (MAbs) against staphylococcal enterotoxin D (SED) were obtained by fusion of myeloma cells with mouse spleen cells immunized with SED only or a combination of SED and either enterotoxin A (SEA) or enterotoxin E (SEE). When only SED was used as an immunogen, six MAbs were specific for SED only, whereas one MAb was reactive with both SED and SEE when both SEs were used as immunogens. One MAb reacted with SEA, SED, and SEE when both SEA and SED were used as immunogens. A MAb with the highest reactivity to SED was used to prepare an immunosorbent for purification of SED by immunoaffinity chromatography. Approximately 70% of the partially purified SED was recovered in the eluate. The purified SED was electrophoretically and antigenically pure. Immunoaffinity chromatography proved useful in the purification of SED in terms of ease of purification, percent enterotoxin, and enterotoxin purity. Key words: enterotoxin D, monoclonal antibodies, Staphylococcus aureus.

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49

Nichols, Kasie L., Sean K. Bauman, Fredda B. Schafer, and Juneann W. Murphy. "Differences in Components at Delayed-Type Hypersensitivity Reaction Sites in Mice Immunized with Either a Protective or a Nonprotective Immunogen of Cryptococcus neoformans." Infection and Immunity 70, no. 2 (February 2002): 591–600. http://dx.doi.org/10.1128/iai.70.2.591-600.2002.

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ABSTRACT Cell-mediated immunity is the major protective mechanism against Cryptococcus neoformans. Delayed swelling reactions, i.e., delayed-type hypersensitivity (DTH), in response to an intradermal injection of specific antigen are used as a means of detecting a cell-mediated immune (CMI) response to the antigen. We have found previously that the presence of an anticryptococcal DTH response in mice is not always indicative of protection against a cryptococcal infection. Using one immunogen that induces a protective anticryptococcal CMI response and one that induces a nonprotective response, we have shown that mice immunized with the protective immunogen undergo a classical DTH response characterized by mononuclear cell and neutrophil infiltrates and the presence of gamma interferon and NO. In contrast, immunization with the nonprotective immunogen results in an influx of primarily neutrophils and production of tumor necrosis factor alpha (TNF-α) at the DTH reaction site. Even when the anticryptococcal DTH response was augmented by blocking the down-regulator, CTLA-4 (CD152), on T cells in the mice given the nonprotective immunogen, the main leukocyte population infiltrating the DTH reaction site is the neutrophil. Although TNF-α is increased at the DTH reaction site in mice immunized with the nonprotective immunogen, it is unlikely that TNF-α activates the neutrophils, because the density of TNF receptors on the neutrophils is reduced below control levels. Uncoupling of DTH reactivity and protection has been demonstrated in other infectious-disease models; however, the mechanisms differ from our model. These findings stress the importance of defining the cascade of events occurring in response to various immunogens and establishing the relationships between protection and DTH reactions.

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50

Hovav, Avi-Hai, Mark J. Cayabyab, Michael W. Panas, Sampa Santra, John Greenland, Ralf Geiben, Barton F. Haynes, William R. Jacobs, and Norman L. Letvin. "Rapid Memory CD8+ T-Lymphocyte Induction through Priming with Recombinant Mycobacterium smegmatis." Journal of Virology 81, no. 1 (October 18, 2006): 74–83. http://dx.doi.org/10.1128/jvi.01269-06.

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ABSTRACT The most promising vaccine strategies for the induction of cytotoxic-T-lymphocyte responses have been heterologous prime/boost regimens employing a plasmid DNA prime and a live recombinant-vector boost. The priming immunogen in these regimens must elicit antigen-specific memory CD8+ T lymphocytes that will expand following the boosting immunization. Because plasmid DNA immunogens are expensive and their immunogenicity has proven disappointing in human clinical trials, we have been exploring novel priming immunogens that might be used in heterologous immunization regimens. Here we show that priming with a prototype recombinant Mycobacterium smegmatis strain expressing human immunodeficiency virus type 1 (HIV-1) gp120-elicited CD4+ T lymphocytes with a functional profile of helper cells as well as a CD8+ T-lymphocyte population. These CD8+ T lymphocytes rapidly differentiated to memory cells, defined on the basis of their cytokine profile and expression of CD62L and CD27. Moreover, these recombinant-mycobacterium-induced T lymphocytes rapidly expanded following boosting with a recombinant adenovirus expressing HIV-1 Env to gp120-specific CD8+ T lymphocytes. This work demonstrates a remarkable skewing of recombinant-mycobacterium-induced T lymphocytes to durable antigen-specific memory CD8+ T cells and suggests that such immunogens might be used as priming vectors in prime/boost vaccination regimens for the induction of cellular immune responses.

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