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1
Agrati, Chiara, Concetta Castilletti, Delia Goletti, Silvia Meschi, Alessandra Sacchi, Giulia Matusali, Veronica Bordoni, et al. "Coordinate Induction of Humoral and Spike Specific T-Cell Response in a Cohort of Italian Health Care Workers Receiving BNT162b2 mRNA Vaccine." Microorganisms 9, no. 6 (June 16, 2021): 1315. http://dx.doi.org/10.3390/microorganisms9061315.
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Vaccination is the main public health measure to reduce SARS-CoV-2 transmission and hospitalization, and a massive worldwide scientific effort resulted in the rapid development of effective vaccines. This work aimed to define the dynamics of humoral and cell-mediated immune response in a cohort of health care workers (HCWs) who received a two-dose BNT162b2-mRNA vaccination. The serological response was evaluated by quantifying the anti-RBD and neutralizing antibodies. The cell-mediated response was performed by a whole blood test quantifying Th1 cytokines (IFN-γ, TNF-α, IL-2), produced in response to spike peptides. The BNT162b2-mRNA vaccine induced both humoral and cell-mediated immune responses against spike peptides in virtually all HCWs without previous SARS-CoV-2 infection, with a moderate inverse relation with age in the anti-RBD response. Spike-specific T cells produced several Th1 cytokines (IFN-γ, TNF-α, and IL-2), which correlated with the specific-serological response. Overall, our study describes the ability of the BNT162b2 mRNA vaccine to elicit a coordinated neutralizing humoral and spike-specific T cell response in HCWs. Assessing the dynamics of these parameters by an easy immune monitoring protocol can allow for the evaluation of the persistence of the vaccine response in order to define the optimal vaccination strategy.
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Ramakrishnan, Amritha, Keri Altoff, Andrew Pekosz, and Jay Bream. "Immune Response to Seasonal Influenza Vaccination (92.18)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 92.18. http://dx.doi.org/10.4049/jimmunol.184.supp.92.18.
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Abstract The emergence of new pandemic strains of influenza highlights the need to better understand the immune response to vaccination in order to develop novel vaccine strategies. The goal of our study was to identify and assess novel markers of immune activation after vaccination. To this end, 100 healthy adults who received either the seasonal Live Attenuated Vaccine (LAIV) or the Inactivated Vaccine (TIV) were enrolled from 2006-2008. First, we measured the serum antibody titers against vaccine strains of the virus. We found that while TIV induced a robust increase in anti-influenza serum antibody titers, LAIV induced only a modest increase. We next measured the levels of 10 cytokines in the serum of vaccine recipients. Vaccination with TIV resulted in a significant reduction in the levels of TNF-α while LAIV had no effect on any of the measured cytokines. Finally, we assessed the ability of seasonal vaccination to induce neutralizing antibody titers against the pandemic 2009 H1N1 strain. Vaccination with TIV was able to induce a significant increase in cross reactive antibodies against different seasonal H1N1 strains but not against the 2009 pandemic H1N1 strain. In all, these data suggest that 1) different influenza A vaccine formulations induce unique cytokine responses in the periphery and 2) seasonal influenza vaccination does not illicit strong cross-reactive serum antibodies with 2009 H1N1.
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Shen, Chih-Lung, Tso-Fu Wang, Chao-Zong Liu, and Yi-Feng Wu. "Platelet Activation and Cytokine Release of Interleukin-8 and Interferon-Gamma-Induced Protein 10 after ChAdOx1 nCoV-19 Coronavirus Vaccine Injection." Vaccines 11, no. 2 (February 16, 2023): 456. http://dx.doi.org/10.3390/vaccines11020456.
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Coronavirus disease 2019 (COVID-19) vaccines are associated with serious thromboembolic or thrombocytopenic events including vaccine-induced immune thrombocytopenia and thrombosis and immune thrombocytopenia, particularly AZD1222/ChAdOx1. According to the proposed mechanism, COVID-19 vaccines stimulate inflammation and platelet activation. In this study, we analyzed the role of AZD1222/ChAdOx1 vaccines in the activation of platelets and the release of anti-PF4 antibodies and inflammatory cytokines in a cohort of healthy donors without vaccine-induced immune thrombotic thrombocytopenia (VITT). Forty-eight healthy volunteers were enrolled in this study. Blood samples were collected from peripheral blood at three time points: before vaccination and 1 and 7 days after vaccination. Compared with the prevaccination data, a decrease in the leukocyte and platelet counts was observed 1 day after vaccination, which recovered 7 days after injection. The percentage of activated GPIIb/IIIa complex (PAC-1) under high ADP or thrombin receptor-activating peptide stimulation increased 1 day after vaccination. Furthermore, interluekin-8 (IL-8) and interferon-gamma-induced protein 10 (IP-10) increased significantly. Additionally, platelet activation and inflammation, with the release of cytokines, were observed; however, none of the individuals developed VITT. Mild thrombocytopenia with platelet activation and inflammation with an elevation of IL-8 and IP-10 were observed after AZ vaccination.
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Trofin, Felicia, Olivia Simona Dorneanu, Daniela Constantinescu, Eduard Vasile Nastase, Cătălina Luncă, Luminița Smaranda Iancu, Ioana-Maria Andrioaie, et al. "Cytokines and Chemokines in Breastmilk of SARS-CoV-2 Infected or COVID-19 Vaccinated Mothers." Vaccines 10, no. 12 (November 24, 2022): 2001. http://dx.doi.org/10.3390/vaccines10122001.
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Introduction: The COVID-19 disease and anti-SARS-CoV-2 vaccination were accompanied by alterations in several inflammatory markers. The aim of our research was to check to what extent such cytokines are transferred to infants via the breastmilk of SARS-CoV-2-infected or vaccinated mothers. Thus, we wanted to check if breastfeeding is safe during SARS-CoV-2 infection or after COVID-19 mRNA-vaccination. Material and method: The Luminex Multiplexing Assay was used for quantifying 10 cytokine in the human breastmilk of SARS-CoV-2-infected or COVID-19-vaccinated mothers, compared with anti-SARS-CoV-2 IgG naïve mothers. Two milk samples were collected at 30 and 60 days either after the booster dose or afterthe onset of symptoms. A single milk sample was collected from the mothers within the control group. Results: The cytokine concentrations were mostly found within the reference intervals for all mothers. The status of the vaccinated/infected mother, the age of the breastfed child, the parity of the mother and the maternal age were variation factors of the above-mentioned cytokine concentrations. The type of birth and the presence of IgG in the milk had no influence on these cytokine concentrations in milk. Furthermore, no statistically significant differences were recorded between the cytokine concentrations of the two milk samples. Conclusion: Our study provides data that support the safety of breastfeeding in the case of mild COVID-19 infection or after Pfizer or Moderna vaccinations.
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Gazzinelli, R. T., F. T. Hakim, S. Hieny, G. M. Shearer, and A. Sher. "Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine." Journal of Immunology 146, no. 1 (January 1, 1991): 286–92. http://dx.doi.org/10.4049/jimmunol.146.1.286.
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Abstract BALB/c mice vaccinated with a temperature-sensitive mutant (TS-4) of Toxoplasma gondii develop complete resistance to lethal challenge with a highly virulent toxoplasma strain (RH). This immunity is known to be dependent on IFN-gamma synthesis. In vitro and in vivo T cell depletions were performed in order to identify the subsets responsible for both protective immunity and IFN-gamma production. When stimulated with crude tachyzoite Ag in vitro, CD4+ cells from vaccinated mice produced high levels of TH1 cytokines (IL-2 and IFN-gamma) but not TH2 cytokines (IL-4 and IL-5). CD8+ cells, in contrast, produced less IFN-gamma and no detectable IL-2. Nevertheless, they could be induced to synthesize IFN-gamma when exposed in culture to exogenous IL-2. In vivo treatment with anti-CD4 plus anti-CD8 or anti-IFN-gamma antibodies during challenge infection completely abrogated resistance to T. gondii. In contrast, treatment with anti-CD4 alone failed to reduce immunity, whereas anti-CD8 treatment partially decreased vaccine-induced resistance. These results suggest that although IFN-gamma and IL-2-producing CD4+ lymphocytes are induced by vaccination, IFN-gamma-producing CD8+ T cells are the major effectors of immunity in vivo. Nevertheless, CD4+ lymphocytes appear to play a synergistic role in vaccine-induced immunity, probably through the augmentation of IFN-gamma synthesis by the CD8+ effector cells. This hypothesis is supported by the observation that when giving during vaccination, as opposed to after challenge, anti-CD4 antibodies are capable of blocking protective immunity.
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Weir, Rosemary E., Gillian F. Black, Hazel M. Dockrell, Sian Floyd, Paul E. M. Fine, Steven D. Chaguluka, Sally Stenson, et al. "Mycobacterial Purified Protein Derivatives Stimulate Innate Immunity: Malawians Show Enhanced Tumor Necrosis Factor Alpha, Interleukin-1β (IL-1β), and IL-10 Responses Compared to Those of Adolescents in the United Kingdom." Infection and Immunity 72, no. 3 (March 2004): 1807–11. http://dx.doi.org/10.1128/iai.72.3.1807-1811.2004.
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ABSTRACT To investigate the role of innate immunity in variable efficacy of Mycobacterium bovis BCG vaccination in Malawi and the United Kingdom, we examined 24-h tumor necrosis factor alpha, interleukin-1β (IL-1β), and IL-10 responses to mycobacterial purified protein derivatives (PPDs). The rank order in stimulatory potency for different PPDs was the same for all three cytokines. Before vaccination Malawians made higher pro- and anti-inflammatory responses than did United Kingdom subjects. Fewer than 5% of United Kingdom subjects made IL-10 in response to any PPD, compared to 19 to 57% responders among Malawians. Priming for regulatory IL-10 may contribute to the smaller increase in gamma interferon responses in Malawians compared to United Kingdom subjects following BCG vaccination.
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Khare, Priyanka, Saleem Javed, Swatantra Jain, Om Singh, and Rahul Pal. "Potential roles of human chorionic gonadotropin in tumorigenesis and the development of novel vaccination strategies (P2116)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 132.48. http://dx.doi.org/10.4049/jimmunol.190.supp.132.48.
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Abstract Human chorionic gonadotropin (hCG) is associated with poor prognosis in several cancers, but causative molecular events remain inadequately described. In this study, tumor cells were found to express message for both hormonal subunits. Along with increasing cell viability, exogenous hCG enhanced several key tumor-promoting mechanisms. It induced the transcriptional activation and secretion of the angiogenic factors VEGF and IL8. Matrix-degrading enzymes associated with invasion (MMP2 and MMP9) were also enhanced, as was invasiveness. hCG up-modulated secretion of the proteoglycan versican and the consequent secretion of the inflammatory cytokines IL6 and TNFα from macrophages. hCG up-regulated FOXP3 in tumor cells, leading to the increased secretion of the immunosuppressive cytokines IL10 and TGFβ and up-modulation of CTLA-4; co-culture hCG-stimulated tumor cells with mature BMDCs heightened the secretion of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase. Anti-hCG antibodies restricted the growth of human tumor xenografts, and immunization with a novel anti-hCG vaccine formulation (βhCG-TT + Mycobacterium indicus pranii) synergistically attenuated tumor development and prolonged survival in syngeneic mice. By preventing autocrine and subsidiary paracrine hCG-induced effects on multiple pathways, new generation anti-hCG vaccines may therefore hold considerable promise as adjunct therapy in patients of gonadotropin-sensitive tumors.
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Ponikowska, Irena, Przemysław Adamczyk, and Zbigniew Kupis. "Balneotherapy in Stimulating Resistance to Infections – the Little-used Health Resort’s Potential During the COVID-19 Pandemic." Acta Balneologica 64, no. 3 (2021): 264–68. http://dx.doi.org/10.36740/abal202203111.
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To function properly, the human immune system must be adequately stimulated. Immune activity is stimulated as a result of the use of vaccines as well as the exposure of the body to infections. This type of stimulation only increases the specific humoral immunity, characterized by relatively short duration, and targeted at a well-defined antigen. In the case of the COVID-19 virus, immune memory cells persist for up to one year. In parallel with specific stimulation, it is necessary to develop non-specific immunity. It is the body’s first line of defense against infection, affects many microorganisms, and supports specific immunity. We can develop and strengthen this immunity using non-pharmacological methods, including balneotherapy, physical activity, and an appropriate diet. There is now much scientific evidence showing the effectiveness of balneotherapy in improving innate immunity. In in vitro and in vivo studies with high scientific credibility, the following effects of balneotherapy on the immune system were demonstrated: stimulation of the proliferation of T lymphocytes (especially CD4), normalization of the ratio between lymphocytes with different cytotoxic and anti-inflammatory effects, increased number of granulocytes and stimulation of the phagocytic activity of granulocytes and macrophages, lowering the concentration of proinflammatory cytokines and stimulating the secretion of anti-inflammatory cytokines, CRP, prostaglandins (PGE2), as well as antioxidant and neurohormonal activity. Among treatments with balneoimmunostimulatory effects, one should mention sulfide baths, peloid compresses, brine baths, radon treatments, and hot baths. These treatments are mainly used as part of health resort treatment. In Poland, health resort treatment represents excellent health potential. Unfortunately, it is very modestly used in activities aimed at improving the immunity of Polish society. This treatment would be best combined in patients after vaccination and in a certain period before vaccination, which would significantly increase the effectiveness of prophylactic vaccinations.
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Blackwood, Catherine B., Emel Sen-Kilic, Dylan T. Boehm, Jesse M. Hall, Melinda E. Varney, Ting Y. Wong, Shelby D. Bradford, et al. "Innate and Adaptive Immune Responses against Bordetella pertussis and Pseudomonas aeruginosa in a Murine Model of Mucosal Vaccination against Respiratory Infection." Vaccines 8, no. 4 (November 3, 2020): 647. http://dx.doi.org/10.3390/vaccines8040647.
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Whole cell vaccines are frequently the first generation of vaccines tested for pathogens and can inform the design of subsequent acellular or subunit vaccines. For respiratory pathogens, administration of vaccines at the mucosal surface can facilitate the generation of a localized mucosal immune response. Here, we examined the innate and vaccine-induced immune responses to infection by two respiratory pathogens: Bordetella pertussis and Pseudomonas aeruginosa. In a model of intranasal administration of whole cell vaccines (WCVs) with the adjuvant curdlan, we examined local and systemic immune responses following infection. These studies showed that intranasal vaccination with a WCV led to a reduction of the bacterial burden in the airways of animals infected with the respective pathogen. However, there were unique changes in the cytokines produced, cells recruited, and inflammation at the site of infection. Both mucosal vaccinations induced antibodies that bind the target pathogen, but linear regression and principal component analysis revealed that protection from these pathogens is not solely related to antibody titer. Protection from P. aeruginosa correlated to a reduction in lung weight, blood lymphocytes and neutrophils, and the cytokines IL-6, TNF-α, KC/GRO, and IL-10, and promotion of serum IgG antibodies and the cytokine IFN-γ in the lung. Protection from B. pertussis infection correlated strongly with increased anti-B-pertussis serum IgG antibodies. These findings reveal valuable correlates of protection for mucosal vaccination that can be used for further development of both B. pertussis and P. aeruginosa vaccines.
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Hammer, Adam, Jonathan Eby, Emily Gilbert, Safia Kahn, Daniel Dilling, and I. Le Poole. "Vaccination with GD3 synthase provides tumor protection against melanoma in mice (P4461)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 126.14. http://dx.doi.org/10.4049/jimmunol.190.supp.126.14.
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Abstract Expression of GD3 synthase (GD3s) in cells defines upregulated GD3 expression by melanoma tumor cells. GD3 presented in the context of CD1d is recognized by invariant NKT cells, which can generate cytokines conducive to anti-tumor responses. We hypothesized that DNA vaccination with GD3s could induce effective anti-tumor responses targeting GD3. C57BL/6 mice were subjected to weekly gene gun vaccination introducing DNA encoding either GD3s and adjuvant HSP70i, or TRP-1 ee/ng and HSP70i, versus empty vector DNA as control groups. Mice were challenged with 2.5x105 B16 mouse melanoma cells. Tumor growth was followed and any remaining tumor was resected for fluorocytometric analysis of immune infiltrates and cytokine expression by qRT-PCR. hGD3s-based vaccination provided similar protection from a B16 tumor challenge as the positive control group (60 and 62% reduced tumor sizes at 19 days, respectively). hGD3s vaccinated mice showed increased NKT abundance (2.27% ) compared to TRP-1 (1.11%) or empty vector (0.74%) among vaccinated mice. Increased CD8+ (3.3-fold), and CD4+ (1.2-fold) compared to the negative control group were also observed, combined with an increased abundance in IL-4 and IL-17 transcripts. In conclusion, GD3s based vaccination provided anti-tumor protection associated with inflammatory cytokine expression and increased (NK)T cell recruitment to tumor sites, offering an attractive concept for melanoma treatment.
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FIGUEIREDO, BARBARA CASTRO PIMENTEL, NATAN RAIMUNDO GONÇALVES DE ASSIS, SUELLEN BATISTONI DE MORAIS, VICENTE PAULO MARTINS, NATASHA DELAQUA RICCI, RODRIGO MARQUES BICALHO, CARINA DA SILVA PINHEIRO, and SERGIO COSTA OLIVEIRA. "Immunological characterization of a chimeric form ofSchistosoma mansoniaquaporin in the murine model." Parasitology 141, no. 10 (May 1, 2014): 1277–88. http://dx.doi.org/10.1017/s0031182014000468.
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SUMMARYAquaporin (SmAQP) is the most abundant transmembrane protein in the tegument ofSchistosoma mansoni. This protein is expressed in all developmental stages and seems to be essential in parasite survival since it plays a crucial role in osmoregulation, nutrient transport and drug uptake. In this study, we utilized the murine model to evaluate whether this protein was able to induce protection against challenge infection withS. mansonicercariae. A chimeric (c) SmAQP was formulated with Freund's adjuvant for vaccination trial and evaluation of the host's immune response was performed. Our results demonstrated that immunization with cSmAQP induced the production of high levels of specific anti-cSmAQP IgG antibodies and a Th1/Th17 type of immune response characterized by IFN-γ, TNF-αand IL-17 cytokines. However, vaccination of mice with cSmAQP failed to reduceS. mansoniworm burden and liver pathology. Finally, we were unable to detect humoral immune response anti-cSmAQP in the sera ofS. mansoni-infected human patients. Our results lead us to believe that SmAQP, as formulated in this study, may not be a good target in the search for an anti-schistosomiasis vaccine.
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Gil-Manso, Sergio, Diego Carbonell, Verónica Astrid Pérez-Fernández, Rocío López-Esteban, Roberto Alonso, Patricia Muñoz, Jordi Ochando, et al. "Cellular and Humoral Responses Follow-up for 8 Months after Vaccination with mRNA-Based Anti-SARS-CoV-2 Vaccines." Biomedicines 10, no. 7 (July 12, 2022): 1676. http://dx.doi.org/10.3390/biomedicines10071676.
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Vaccination against SARS-CoV-2 has become the main method of reducing mortality and severity of COVID-19. This work aims to study the evolution of the cellular and humoral responses conferred by two mRNA vaccines after two doses against SARS-CoV-2. On days 30 and 240 after the second dose of both vaccines, the anti-S antibodies in plasma were evaluated from 82 volunteers vaccinated with BNT162b2 and 68 vaccinated with mRNA-1273. Peripheral blood was stimulated with peptides encompassing the entire SARS-CoV-2 Spike sequence. IgG Anti-S antibodies (humoral) were quantified on plasma, and inflammatory cytokines (cellular) were measured after stimulation. We observed a higher response (both humoral and cellular) with the mRNA-1273 vaccine. Stratifying by age and gender, differences between vaccines were observed, especially in women under 48 and men over 48 years old. Therefore, this work could help to set up a vaccination strategy that could be applied to confer maximum immunity.
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Zhou, Jingying, Allen Cheung, Zhiwu Tan, and Zhiwei Chen. "Mechanisms of soluble program death 1 fusion DNA vaccine with antigen-specific enhanced adaptive immunity (P4497)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 179.11. http://dx.doi.org/10.4049/jimmunol.190.supp.179.11.
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Abstract Previously a well-defined dendritic cell (DC)-targeting strategy of anti-DEC205 based vaccine shows highly enhanced CD4+ T cell immunity. We have demonstrated that a DNA vaccine with soluble (s)PD1 fused with HIV-1 p24 antigen can greatly enhance p24-specific humoral and cellular immune responses in mice by targeting DCs. Consequently, we compared the efficacies of the two vaccines in our system and found that sPD1-based DNA vaccination induced higher functional CD8+ T cell responses. Although the binding and uptake of encoded fusion proteins are similar between sPD1-p24 and anti-DEC205-p24 in DCs in vitro, transfer of DCs pulsed with these proteins into mice resulted in the sPD1-p24 group eliciting higher IFN-γ releasing CD8+ T cells. These data suggests that different mechanistic pathways exist between the two DC-targeting strategies. We examined the route of antigen processing/presentation by confocal microscopy and found that sPD1-p24 protein co-localized to both Rab14 and Lamp1 endosomal compartments used for MHC class I and II presentation, respectively, while anti-DEC205-p24 was only found in the latter. In addition, sPD1 DNA vaccination resulted in draining lymph node DCs with elevated CD40 and MHC class II expression with higher production of IL-12 compared to anti-DEC205. The mechanism of sPD1-based vaccination in enhancing CD8+ T cells immunity is likely dependent on DC-targeting and activation, production of Th1 cytokines and antigen cross-presentation.
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Chen, Tingting, Ninghua Liu, Jinxuan Liu, Xiaoying Zhang, Zhen Huang, Yuhui Zang, Jiangning Chen, Lei Dong, Junfeng Zhang, and Zhi Ding. "Gua Sha, a press-stroke treatment of the skin, boosts the immune response to intradermal vaccination." PeerJ 4 (September 14, 2016): e2451. http://dx.doi.org/10.7717/peerj.2451.
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ObjectiveThe skin is an important immunological barrier of the body as well as an optimal route for vaccine administration. Gua Sha, which involves press-stroke treatment of the skin, is an effective folk therapy, widely accepted in East Asia, for various symptoms; however, the mechanisms underlying its therapeutic effects have not been clarified. We investigated the influence of Gua Sha on the immunological features of the skin.MethodsGua Sha was performed on BALB/c mice and the effects were evaluated using anatomical, histological, and cytometric methods as well as cytokine determination locally and systemically. The effect on intradermal vaccination was assessed with antigen-specific subtype antibody responses.ResultsBlood vessel expansion, erythrocyte extravasation, and increased ratios of immune active cells were observed in the skin tissue following the treatment. Pro-inflammatory cytokines were up-regulated, and immunosuppressive cytokines, down-regulated, in the treated and untreated skin and systemic circulation; no obvious variations were detected in case of anti-inflammatory cytokines. Interestingly, intradermal delivery of a model vaccine following Gua Sha induced about three-fold higher IgG titers with a more Th1-biased antibody subtype profile.ConclusionGua Sha treatment can up-regulate the innate and adaptive immune functions of the skin and boost the response against intradermal antigens. Thus, Gua Sha may serve as a safe, inexpensive, and independent physical adjuvant for intradermal vaccination.
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Hemann, Emily A., John B. Grigg, Courtney R. Wilkins, Megan Knoll, Shawn P. Iadonato, Kristin Bedard, Peter Probst, Yueh-Ming Loo, and Michael Gale. "A small-molecule RIG-I agonist functions to enhance vaccine protection against influenza A virus infection." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 76.1. http://dx.doi.org/10.4049/jimmunol.196.supp.76.1.
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Abstract Viral sensing by RIG-I and downstream activation of antiviral defenses along with the induction of innate immune cytokines is essential from protection against influenza A virus (IAV) infection. We have identified a novel, small-molecule RIG-I agonist, KIN1148, which binds and activates RIG-I to signal the activation of IRF3 and the innate immune response. We are developing this molecule as an adjuvant to enhance vaccination against pandemic H1N1 (pH1N1) IAV. Ex vivo treatment of dendritic cells with KIN1148 leads to their activation and maturation. We determined the ability of KIN1148 to enhance suboptimal IAV vaccine responses in vivo. Administration of KIN1148 leads enhanced protection during high dose pH1N1 infection following a single, intramuscular administration of KIN1148 with IAV vaccine. This increase in protection is accompanied by a significant reduction in virus titers, as well as lung pathology. Analysis of the immune response induced following vaccination with KIN1148 as well as challenge demonstrates an increase in chemoattractant cytokines, germinal center B cells, IAV-specific antibodies, and IAV-specific CD4 and CD8 T cells compared to vaccination alone, indicating the induction of a broad anti-IAV immune response. Together these results demonstrate that prophylactic drug targeting of the RIG-I pathway with a small molecule enhances vaccine protection and highlight the potential of KIN1148 to enhancing vaccines against RNA virus infection.
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Schirmbeck, R., and J. Reimann. "Enhancing the Immunogenicity of Exogenous Hepatitis B Surface Antigen-Based Vaccines for MHC-I-Restricted T Cells." Biological Chemistry 380, no. 3 (March 1, 1999): 285–91. http://dx.doi.org/10.1515/bc.1999.039.
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AbstractVaccination with either exogenous hepatitis B surface antigen (HBsAg) lipoprotein particles without adjuvants, or plasmid DNA encoding secreted small HBsAg stimulate long-lasting, potent antibody responses in H-2d(BALB/c) and C57Bl/6 (H-2b) mice. Vaccination with exogenous HBsAg primes MHC-I restricted cytotoxic T lymphocyte (CTL) responses to HBsAg in H-2dbut not H-2bmice, while DNA vaccination primes HBsAg-specific CTL responses in both mouse strains. We defined vaccination strategies that could elicit CTL responses to exogenous HBsAg in ‘low responder’ C57Bl/6 mice. We found that the bacterial plasmid DNA itself, synthetic oligodeoxynucleotides containing immunostimulating sequences, or recombinant Th1 cytokines (IL12, IFNγ) efficiently support priming of CTL responses to exogenous HBsAg in ‘low responder’ H-2bmice, but have only minor effects on CTL priming in ‘high responder’ H-2dmice in the high dose range tested. These molecularly well defined adjuvants can thus efficiently support priming of anti-viral T cell responses under ‘low responder’ conditions.
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Imami, Nesrina, Gareth Hardy, Catherine Burton, Antonio Pires, Jeffrey Pido-Lopez, Ron Moss, Brian Gazzard, and Frances Gotch. "Immune responses and reconstitution in HIV-1 infected individuals: impact of anti-retroviral therapy, cytokines and therapeutic vaccination." Immunology Letters 79, no. 1-2 (November 2001): 63–76. http://dx.doi.org/10.1016/s0165-2478(01)00267-x.
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Bancos, Simona, and Richard Phipps. "Non-steroidal anti-inflammatory drugs blunt antibody production in human B lymphocytes from older volunteer (84.10)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 84.10. http://dx.doi.org/10.4049/jimmunol.184.supp.84.10.
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Abstract Older individuals respond poorly to vaccination. B lymphocytes are responsible for the synthesis of antibodies that are generated in response to infection and vaccination. Our laboratory has shown that activated human B cells isolated from younger subjects (18-35 years old) express cyclooxygenase-2 (Cox-2) and that inhibition of Cox-2 by non-steroidal anti-inflammatory drugs (NSAIDs) blunts antibody production. However, NSAIDs are highly used by people over 60 years old. There is no information regarding Cox-2 expression in B cells in older human subjects (over 60 years old). We hypothesize that Cox-2 activity is reduced in B cells from older individuals. Young (18-35 years old) and older subjects (over 60 years old) were enrolled in the study. B cells were isolated from peripheral blood, stimulated in vitro with anti-Ig plus ODN CpG 2395 in the presence or absence of NSAIDs and Cox-2 expression, prostaglandin production, cytokines and antibody synthesis determined. Cell viability and proliferation were also assayed. Compared to younger subjects, B cells from older volunteers had reduced Cox-2 expression and also produced less antibody. Furthermore, in these individuals, antibody levels were further decreased by NSAIDs. Thus, NSAIDs and low intrinsic Cox-2 expression could be responsible for the poor antibody response to vaccination in the elderly.
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Li, Shamin, Yannick Simoni, Summer Zhuang, Austin Gabel, Shaokang Ma, Jonathan Chee, Laura Islas, et al. "Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies." Proceedings of the National Academy of Sciences 118, no. 30 (July 20, 2021): e2025570118. http://dx.doi.org/10.1073/pnas.2025570118.
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Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti–PD-1 and anti–CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8+ T cells in a tumor that is resistant to ICB and neoantigen vaccination. Leveraging the use of mass cytometry combined with multiplex major histocompatibility complex (MHC) class I tetramer staining, we screened and identified tumor neoantigen–specific CD8+ T cells in the Lewis Lung carcinoma (LLC) tumor model (mRiok1). We observed an expansion of mRiok1-specific CD8+ tumor-infiltrating lymphocytes (TILs) after ICB targeting PD-1 or CTLA-4 with no sign of tumor regression. The expanded neoantigen-specific CD8+ TILs remained phenotypically and functionally exhausted but displayed cytotoxic characteristics. When combining both ICB treatments, mRiok1-specific CD8+ TILs showed a stem-like phenotype and a higher capacity to produce cytokines, but tumors did not show signs of regression. Furthermore, combining both ICB treatments with neoantigen vaccination did not induce tumor regression either despite neoantigen-specific CD8+ TIL expansion. Overall, this work provides a model for studying neoantigens in an immunotherapy nonresponder model. We showed that a robust neoantigen-specific T-cell response in the LLC tumor model could fail in tumor response to ICB, which will have important implications in designing future immunotherapeutic strategies.
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Patrizio, Armando, Silvia Martina Ferrari, Giusy Elia, Francesca Ragusa, Sabrina Rosaria Paparo, Valeria Mazzi, Alessandro Antonelli, and Poupak Fallahi. "Graves’ Disease Following SARS-CoV-2 Vaccination: A Systematic Review." Vaccines 10, no. 9 (September 1, 2022): 1445. http://dx.doi.org/10.3390/vaccines10091445.
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(1) Background: Autoimmune diseases, including autoimmune endocrine diseases (AIED), are thought to develop following environmental exposure in patients with genetic predisposition. The vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could represent a new environmental trigger for AIED, including Graves’ disease (GD). (2) Methods: We performed a literature search of MEDLINE/PubMed databases regarding thyroid dysfunction after SARS-CoV-2 vaccination since 1 January 2020 to 31 July 2022, considering only cases of thyrotoxicosis that meet the 2016 American Thyroid Association guidelines criteria for the diagnosis of GD and arising after administration of the anti-SARS-CoV-2 vaccine, regardless of the number of doses. (3) Results: A total of 27 articles were identified, consisting of case reports or case series, of which 24 describe the appearance of 48 new diagnoses of GD and 12 GD recurrences arising after the administration of the anti-SARS-CoV-2 vaccine, and 3 papers that instead report only 3 cases of GD relapse following vaccination. (4) Conclusions: physicians should be aware of the possibility of developing GD and other autoimmune sequelae following SARS-CoV-2 vaccination. Regardless of the underlying pathogenetic mechanisms (autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), cytokines induction, molecular mimicry, and cross-reactivity), an individual predisposition seems to be decisive for their development.
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Filippenko, A. V., N. D. Omelchenko, N. I. Pasyukova, A. A. Trufanova, and I. A. Ivanova. "IMPROVEMENT OF SPECIFIC CHOLERA PREVENTION USING IMMUNOMODULATORS." Medical Immunology (Russia) 23, no. 4 (October 19, 2021): 915–20. http://dx.doi.org/10.15789/1563-0625-ios-2248.
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It is known that the combined use of vaccines, cytokines and various immunomodulatory drugs contributes to the development of a full-fledged immune response. This approach makes it possible to enhance the immunogenicity of modern vaccines and to direct the development of immune responses according to the humoral or cellular type, depending on the properties of the pathogen of a particular disease. The improvement of preventive drugs due to their combined use with cytokines and immunomodulators increases the intensity of immunity, increases the level of production of specific immunoglobulins, the protectivity of antigens, and also reduces the manifestation of adverse reactions leading to post-vaccination complications.Immunomodulators are already successfully used in drugs intended for the treatment and prevention of chronic herpes infections and influenza vaccines. Numerous experimental and clinical data indicate a positive effect of the use of immunomodulatory drugs in the vaccination of various viral and bacterial infections, including particularly dangerous ones.Improving the specific prevention of cholera can be achieved through immunomodulatory agents that can stimulate the formation of a local and systemic immune response.We conducted a comparative assessment of the feasibility of the combined use of the cholera bivalent chemical vaccine (the Federal Government Health Institution Antiplague Research Institute “Microbe”) and immunomodulators in order to increase the effectiveness of cholera vaccination.Since the cholera vaccine causes the activation of the humoral immune response, the production of specific immunoglobulins in the body of vaccinated experimental animals and the effect of immunomodulators on this process at different times of the post-vaccination period were evaluated.The ability of immunomodulators to increase the protective activity of the cholera vaccine was studied by infecting animals with a virulent strain of cholera one month and seven months after vaccination.It was found that immunomodulators increase the immunogenicity and protectivity of antigens that are part of the anti-cholera vaccine. The use of all immunopreparations increases the production of specific immunoglobulins in the serum of vaccinated experimental animals. It was shown that in the first month after vaccination, polyoxidonium most effectively stimulated the formation of antibodies, but lycopide contributed to a longer retention of anti-cholera immunoglobulins in the serum of vaccinated rabbits. The combined use of the vaccine and lycopide prevented the development of cholera in all animals taken in the experiment, including those vaccinated with a reduced dose. In the long-term post-vaccination period, this immunomodulator increased the protectiveness of the anti-cholera vaccine by three times. Polyoxidonium and derinate also increased the protective effect of the cholera vaccine, but were slightly inferior to lycopide. The combined use of cholera vaccine and immunomodulators, especially lycopide, can be used to improve specific cholera prevention.
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Fard, Ali Mahdavi, Jeffrey Desilets, and Sangita Patel. "Recurrence of Herpetic Keratitis after COVID-19 Vaccination: A Report of Two Cases." Case Reports in Ophthalmological Medicine 2022 (May 19, 2022): 1–3. http://dx.doi.org/10.1155/2022/7094893.
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Background. Recurrence of herpetic keratitis following vaccination has been documented following vaccination with the Zostavax, trivalent flu, hepatitis A, and rabies vaccines. The USFDA and WHO have acknowledged that the novel COVID-19 vaccines similarly have a risk of reactive immunologic-based inflammation, namely, myositis, pericarditis, and Guillain-Barré syndrome. Case Presentation. We present two patients with latent herpetic keratitis who experienced reactivation of keratitis within weeks of COVID-19 vaccination despite prolonged periods of prior latency. A 52-year-old healthy male with no herpes simplex virus (HSV) keratitis recurrences in two years developed visual decline and patchy stromal haze within 24-48 hours of receiving the second Pfizer-BioNTech (COVID-19 BNT162b2) vaccine. A 67-year-old female with chronic neurotrophic keratitis developed her most severe exacerbation of herpes zoster keratitis in over 10 years occurring 2-3 weeks after her first Moderna (mRNA-1273) vaccine, which was later complicated by bacterial superinfection. Conclusions. The COVID-19 vaccines work by generating both adaptive humoral and cellular immune responses in humans, including elevation of anti-spike neutralizing antibody titers, antigen-specific CD4+ and CD8+ T-cell responses, and increased levels of proinflammatory cytokines such as interferon gamma (IFNγ). The general activation of the T-cell-mediated immune response and proinflammatory cytokines such as IFNγ may underlie the role of the COVID vaccines in reactivation of herpetic stromal keratitis and the clinical findings in our reported cases.
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Williams, M. E., P. Caspar, I. Oswald, H. K. Sharma, O. Pankewycz, A. Sher, and S. L. James. "Vaccination routes that fail to elicit protective immunity against Schistosoma mansoni induce the production of TGF-beta, which down-regulates macrophage antiparasitic activity." Journal of Immunology 154, no. 9 (May 1, 1995): 4693–700. http://dx.doi.org/10.4049/jimmunol.154.9.4693.
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Abstract C57BL/6 mice immunized intradermally (i.d.) with bacillus Calmette Guerin (BCG) plus killed skin-stage schistosomula are protected against subsequent infection with Schistosoma mansoni, whereas immunization by i.v. or i.m. routes is not protective. Moreover, previous immunization via the nonprotective i.v. route interfered with the ability to subsequently induce protection by i.d. vaccination, suggesting that inhibitory responses are invoked. Given the evidence that activated macrophages (M phi) play a role as effector cells in protection against schistosomiasis, we investigated the ability of spleen cells from protected and nonprotected immunized mice to produce M phi activating and deactivating cytokines. Exposure to supernatant fluids (SNs) from Ag stimulated spleen cells of i.d., but not i.v. or i.m., immunized mice activated inflammatory M phi for in vitro killing of schistosome larvae, through a mechanism dependent on both IFN gamma and TNF-alpha. No evidence was observed for the preferential induction of the M phi activating Th1 cytokines IFN-gamma and IL-2 in i.d. immunized mice, nor did spleen cells from nonprotected animals produce higher levels of the Th2 associated cytokines IL-4 and IL-10, which are known to prevent M phi activation. TGF-beta was, however, detected in SNs from unprotected mice. Moreover, the M phi inhibitory activity detected in these SNs was heat stable and neutralized by anti-TGF-beta Abs, suggesting that production of TGF-beta is at least partially responsible for the failure of i.m. and i.v. immunized mice to develop immunity to S. mansoni. Thus, the induction of down-regulatory cytokines may be an important factor limiting the efficacy of certain vaccination protocols.
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Lim, Xin Rong, Justina Wei Lynn Tan, Grace Yin Lai Chan, Jinfeng Hou, Linlin Xie, Vivian Hui Li Goh, Joewee Boon, et al. "Evaluation of Patients with Vaccine Allergies Prior to mRNA-Based COVID-19 Vaccination." Vaccines 10, no. 7 (June 27, 2022): 1025. http://dx.doi.org/10.3390/vaccines10071025.
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During the initial rollout of coronavirus disease 2019 (COVID-19) vaccination in Singapore, the Ministry of Health (MOH) issued a recommendation that patients with a history of any previous vaccine allergy be referred to an allergist for further review of their suitability to proceed with mRNA-based COVID-19 vaccines. Patients fulfilling the above criterion were divided into three groups: immediate reaction (Group A), delayed reaction (Group B) and no/irrelevant reaction (Group C). They were subjected to either a skin prick test (SPT) and intradermal test (IDT) with polyethylene glycol (PEG) or polysorbate-containing products; direct injection with the Pfizer BNT162b2 vaccine in the allergy clinic; or injection at community vaccination centres, respectively. Groups A and B were also invited to complete a questionnaire survey on post-vaccination reactions, and blood sampling pre-vaccination and 1 h after the first dose of the BNT162b2 vaccine to measure immunoglobulin (Ig) G, IgM and IgE antibodies to the Pfizer BNT162b2 vaccine via ELISA assays immobilised with the BNT162b2 vaccine, as well as levels of allergic cytokines interleukin (IL)-4 and IL-33, complement C5a and the endothelial activation marker intercellular adhesion molecule-1 (ICAM-1). Groups A and B comprised 62 (20.5%) patients each. In Group A, two subjects (3.2%) with equivocal IDT results tolerated both doses of the BNT162b2 vaccine without major allergic reactions. The remaining 60 (96.8%) in Group A and 62 (100%) in Group B completed both doses of BNT162b2 vaccination without major adverse reactions. Among the 99 who completed the questionnaire survey, 13 (13%) patients reported mild allergic reactions after the first dose of the vaccine. Immunoglobulin (Ig) G and M antibodies, but not IgE antibodies to the Pfizer BNT162b2 vaccine were detected in 67 subjects prior to vaccination. The presence of anti-Pfizer BNT162b2 IgG and IgM prior to vaccination did not result in major allergic reactions nor increases in Th2-related cytokines (IL-4, IL-33), complement activation products (C5a) or endothelial activation (ICAM-1). The majority of those with suspected reactions to non-COVID-19 polysorbate-containing vaccines tolerated the BNT162b2 vaccine. Excipient skin tests for PEG and polysorbate prior to vaccination are unnecessary.
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Chrisikos, Taylor T., Yifan Zhou, Haiyan S. Li, Rachel L. Babcock, Xianxiu Wan, Bhakti Patel, Kathryn Newton, James J. Mancuso, and Stephanie S. Watowich. "STAT3 Inhibits CD103+ cDC1 Vaccine Efficacy in Murine Breast Cancer." Cancers 12, no. 1 (January 4, 2020): 128. http://dx.doi.org/10.3390/cancers12010128.
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Conventional dendritic cells (cDCs) are a critical immune population, composed of multiple subsets, and responsible for controlling adaptive immunity and tolerance. Although migratory type 1 cDCs (CD103+ cDC1s in mice) are necessary to mount CD8+ T cell-mediated anti-tumor immunity, whether and how tumors modulate CD103+ cDC1 function remain understudied. Signal Transducer and Activator of Transcription 3 (STAT3) mediates the intracellular signaling of tumor-associated immunosuppressive cytokines, such as interleukin (IL)-10; thus, we hypothesized that STAT3 restrained anti-tumor immune responses elicited by CD103+ cDC1s. Herein, we show that in vitro-derived STAT3-deficient (Stat3∆/∆) CD103+ cDC1s are refractory to the inhibitory effects of IL-10 on Toll-like receptor 3 (TLR3) agonist-induced maturation responses. In a tumor vaccination approach, we found Stat3∆/∆ CD103+ cDC1s restrained mammary gland tumor growth and increased mouse survival more effectively than STAT3-sufficient CD103+ cDC1s. In addition, vaccination with Stat3∆/∆ CD103+ cDC1s elicited increased amounts of tumor antigen-specific CD8+ T cells and IFN-γ+ CD4+ T cells in tumors and tumor-draining lymph nodes versus phosphate-buffered saline (PBS)-treated animals. Furthermore, IL-10 receptor-deficient CD103+ cDC1s controlled tumor growth to a similar degree as Stat3∆/∆ CD103+ cDC1s. Taken together, our data reveal an inhibitory role for STAT3 in CD103+ cDC1 maturation and regulation of anti-tumor immunity. Our results also suggest IL-10 is a key factor eliciting immunosuppressive STAT3 signaling in CD103+ cDC1s in breast cancer. Thus, inhibition of STAT3 in cDC1s may provide an important strategy to improve their efficacy in tumor vaccination approaches and cDC1-mediated control of anti-tumor immunity.
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Ramos-Martinez, Espiridión, Ramcés Falfán-Valencia, Gloria Pérez-Rubio, Warrison Athanasio Andrade, Jorge Rojas-Serrano, Enrique Ambrocio-Ortiz, Dennisse S. Galicia-Álvarez, Isaac Bárcenas-Montiel, Andrea Velasco-Medina, and Guillermo Velázquez-Sámano. "Effect of BCG Revaccination on Occupationally Exposed Medical Personnel Vaccinated against SARS-CoV-2." Cells 10, no. 11 (November 15, 2021): 3179. http://dx.doi.org/10.3390/cells10113179.
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The production of specific neutralizing antibodies by individuals is thought to be the best option for reducing the number of patients with severe COVID-19, which is the reason why multiple vaccines are currently being administered worldwide. We aimed to explore the effect of revaccination with BCG, on the response to a subsequent anti-SARS-CoV-2 vaccine, in persons occupationally exposed to COVID-19 patients. Two groups of 30 randomized participants were selected: one group received a BCG revaccination, and the other group received a placebo. Subsequently, both groups were vaccinated against SARS-CoV-2. After each round of vaccination, the serum concentration of Th1/Th2 cytokines was determined. At the end of the protocol, neutralizing antibodies were determined and the HLA-DRB loci were genotyped. The participants from the BCG group and anti-SARS-CoV-2 vaccine group had increased serum cytokine concentrations (i.e., IL-1β, IL-4, IL-6, IL-12p70, IL-13, IL-18, GM-CSF, INF-γ, and TNF-α) and higher neutralizing antibody titers, compared to the group with Placebo–anti-SARS-CoV-2. Twelve HLA-DRB1 alleles were identified in the Placebo–anti-SARS-CoV-2 group, and only nine in the group revaccinated with BCG. The DRB1*04 allele exhibited increased frequency in the Placebo–anti-SARS-CoV-2 group; however, no confounding effects were found with this allele. We conclude that revaccination with BCG synergizes with subsequent vaccination against SARS-CoV-2 in occupationally exposed personnel.
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Ichinohe, Takeshi, Izumi Watanabe, Satoshi Ito, Hideki Fujii, Masami Moriyama, Shin-ichi Tamura, Hidehiro Takahashi, et al. "Synthetic Double-Stranded RNA Poly(I:C) Combined with Mucosal Vaccine Protects against Influenza Virus Infection." Journal of Virology 79, no. 5 (March 1, 2005): 2910–19. http://dx.doi.org/10.1128/jvi.79.5.2910-2919.2005.
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ABSTRACT The mucosal adjuvant effect of synthetic double-stranded RNA polyriboinosinic polyribocytidylic acid [poly(I:C)] against influenza virus was examined under intranasal coadministration with inactivated hemagglutinin (HA) vaccine in BALB/c mice and was shown to have a protective effect against both nasal-restricted infection and lethal lung infection. Intranasal administration of vaccine from PR8 (H1N1) with poly(I:C) induced a high anti-HA immunoglobulin A (IgA) response in the nasal wash and IgG antibody response in the serum, while vaccination without poly(I:C) induced little response. Intracerebral injection confirmed the safety of poly(I:C). In addition, we demonstrated that administration of poly(I:C) with either A/Beijing (H1N1) or A/Yamagata (H1N1) vaccine conferred complete protection against PR8 challenge in this mouse nasal infection model, suggesting that poly(I:C) possessed cross-protection ability against variant viruses. To investigate the mechanism of the protective effect of poly(I:C), mRNA levels of Toll-like receptors and cytokines were examined in the nasal-associated lymphoid tissue after vaccination or virus challenge. Intranasal administration of HA vaccine with poly(I:C) up-regulated expression of Toll-like receptor 3 and alpha/beta interferons as well as Th1- and Th2-related cytokines. We propose that poly(I:C) is a new effective intranasal adjuvant for influenza virus vaccine.
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Serradell, Marianela C., Pablo R. Gargantini, Alicia Saura, Sergio R. Oms, Lucía L. Rupil, Luciana Berod, Tim Sparwasser, and Hugo D. Luján. "Cytokines, Antibodies, and Histopathological Profiles duringGiardiaInfection and Variant-Specific Surface Protein-Based Vaccination." Infection and Immunity 86, no. 6 (March 19, 2018): e00773-17. http://dx.doi.org/10.1128/iai.00773-17.
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ABSTRACTGiardiasis is one of the most common human intestinal diseases worldwide. Several experimental animal models have been used to evaluateGiardiainfections, with gerbils (Meriones unguiculatus) being the most valuable model due to their high susceptibility toGiardiainfection, abundant shedding of cysts, and pathophysiological alterations and signs of disease similar to those observed in humans. Here, we report cytokine and antibody profiles both during the course ofGiardiainfection in gerbils and after immunization with a novel oral vaccine comprising a mixture of purified variant-specific surface proteins (VSPs). Transcript levels of representative cytokines of different immune profiles as well as macro- and microtissue alterations were assessed in Peyer's patches, mesenteric lymph nodes, and spleens. During infection, cytokine responses showed a biphasic profile: an early induction of Th1 (gamma interferon [IFN-γ], interleukin-1β [IL-1β], IL-6, and tumor necrosis factor [TNF]), Th17 (IL-17), and Th2 (IL-4) cytokines, together with intestinal alterations typical of inflammation, followed by a shift toward a predominant Th2 (IL-5) response, likely associated with a counterregulatory mechanism. Conversely, immunization with an oral vaccine comprising the entire repertoire of VSPs specifically showed high levels of IL-17, IL-6, IL-4, and IL-5, without obvious signs of inflammation. Both immunized and infected animals developed local (intestinal secretory IgA [S-IgA]) and systemic (serum IgG) humoral immune responses against VSPs; however, only infected animals showed evident signs of giardiasis. This is the first comprehensive report of cytokine expression and anti-Giardiaantibody production during infection and VSP vaccination in gerbils, a reliable model of the human disease.
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Lee, Sang Beom, Jing Pan, Donghai Xiong, Katie Palen, Bryon Johnson, Jeffrey E. Green, Shizuko Sei, et al. "Abstract IA015: Immunoprevention of triple negative breast cancer by TOP2A derived peptide vaccination." Cancer Prevention Research 15, no. 12_Supplement_2 (December 1, 2022): IA015. http://dx.doi.org/10.1158/1940-6215.tacpad22-ia015.
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Abstract Top2A is a key enzyme involved in DNA replication and is a therapeutic target for several cancer types including breast cancer. Overexpression of Top2A has been observed in both human and mouse triple-negative breast cancer (TNBC). The present study evaluated both immunogenicity and antitumor efficacy of a newly formulated multi-peptide vaccine targeting multiple epitopes of the Top2A protein. Top2A-specific MHC II epitopes with optimal binding affinity were identified using a combined scoring system, which predicted their potential to elicit a Th1 immune response. The formulated vaccine contained top three Top2A peptides, which elicited the strongest immunologic response and showed 100% sequence homology between human and mouse. Anti-tumor efficacy of the Top2A vaccine was initially evaluated in a syngeneic TNBC mouse model, in which pre-graft preventive vaccination was associated with significantly decreased tumor growth as compared to the adjuvant controls. The Top2A peptide vaccine exhibited striking efficacy in a genetically engineered TNBC mouse model (C3(1)/Tag), reducing tumor burden by >90% when compared with adjuvant alone. Splenocytes collected from vaccinated animals showed a robust immunologic response to the immunizing peptides. There were no overt toxicities observed with the Top2A vaccination. To explore potential mechanisms underlying the anti-tumor response induced by Top2A vaccine treatment, scTCR-seq of tumors in both control and Top2A vaccine groups revealed new T cell clones as a consequence of Top2A vaccination. Furthermore, in vitro stimulation of these splenocytes by the vaccinated Top2A peptides resulted in the secretion of cytokines indicative of Th1 responses but with minimal secretion of Th2-related cytokines. Our data indicate that the newly developed multi-peptide Top2A vaccine is immunogenic and efficacious in the prevention of TNBC development and progression in vivo. Citation Format: Sang Beom Lee, Jing Pan, Donghai Xiong, Katie Palen, Bryon Johnson, Jeffrey E. Green, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Ming You. Immunoprevention of triple negative breast cancer by TOP2A derived peptide vaccination [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA015.
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Toptygina, A. P., and V. A. Alioshkin. "Influence of the Рriorix vaccination on cytokine profile and IgE level in healthy children and patients with atopic dermatitis." Russian Journal of Allergy 10, no. 3 (December 15, 2013): 30–34. http://dx.doi.org/10.36691/rja619.
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Background. The aim of the study was to investigate peculiarities of immune responses on the vaccination with Priorix in healthy children and patients with atopic dermatitis. Methods. Thirty five healthy children aged 1-2 years old (Group 1) and 15 children the same age with atopic dermatitis (Group 2) were vaccinated with Priorix. Serum level of IgE was measured by ELISA, and serum concentrations of 7 cytokines: IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, and TNF-α were measured by BioPlex technology before vaccination, 7 days, and 30 days after. Serum level of IgE was measured by ELISA. Results. The level of serum IgE relatively decreased or increased on seventh day after vaccination. In a month IgE level returned back. It was found that in group1 51,4% children demonstrated Th1 type response and 48,6% children showed Th2 type response on the vaccination. Similar distribution was obtained in group 2 (53,3% children showed Th1 type response and 46,7% children demonstrated Th2 type). A significant positive correlation was observed between IgE level increasing and Th2 type of immune response. It was shown that 68,6% of children of group 1 and 66,7% of children of group 2 demonstrated after vaccination the superiority of anti-inflammatory IL-10 over pro-inflammatory TNF-α. We suppose that children with atopic dermatitis can be vaccinated with Priorix.
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Hamers, Linda A. C., Matthijs Kox, Rob J. W. Arts, Bastiaan Blok, Jenneke Leentjens, Mihai G. Netea, and Peter Pickkers. "Gamma-Irradiated Bacille Calmette-Guérin Vaccination Does Not Modulate the Innate Immune Response during Experimental Human Endotoxemia in Adult Males." Journal of Immunology Research 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/261864.
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Bacille Calmette-Guérin (BCG) vaccine exerts nonspecific immunostimulatory effects and may therefore represent a novel therapeutic option to treat sepsis-induced immunoparalysis. We investigated whether BCG vaccination modulates the systemic innate immune response in humansin vivoduring experimental endotoxemia. We used inactivated gamma-irradiated BCG vaccine because of the potential risk of disseminated disease with the live vaccine in immunoparalyzed patients. In a randomized double-blind placebo-controlled study, healthy male volunteers were vaccinated with gamma-irradiated BCG (n=10) or placebo (n=10) and received 1 ng/kg lipopolysaccharide (LPS) intravenously on day 5 after vaccination to assess thein vivoimmune response. Peripheral blood mononuclear cells were stimulated with various related and unrelated pathogens 5, 8 to 10, and 25 to 35 days after vaccination to assessex vivoimmune responses. BCG vaccination resulted in a scar in 90% of vaccinated subjects. LPS administration elicited a profound systemic immune response, characterized by increased levels of pro- and anti-inflammatory cytokines, hemodynamic changes, and flu-like symptoms. However, BCG modulated neither thisin vivoimmune response, norex vivoleukocyte responses at any time point. In conclusion, gamma-irradiated BCG is unlikely to represent an effective treatment option to restore immunocompetence in patients with sepsis-induced immunoparalysis. This trial is registered withNCT02085590.
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Jones, Leigh A., David A. Skibinski, Lin Wu Xie, Bijin Au, Bernett Lee, Yuan Zhu, Anna-Marie Fairhurst, et al. "Type-1 T cell responses and gene signatures driven by a novel virus-like particle (VLP) influenza A (H1N1) vaccine." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 215.7. http://dx.doi.org/10.4049/jimmunol.196.supp.215.7.
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Abstract Effective influenza vaccination is currently assessed by the induction of antibodies directed against the influenza virus envelope glycoprotein hemagglutinin (HA; HAI test) otherwise known as seroconversion. However, protective antibody responses are sub-optimal in some vaccinated populations, particularly in the elderly. Furthermore, many clinical studies highlight the importance of T cells in driving protection. Therefore, a need exists for vaccine strategies which can engage both the humoral and cell mediated arms of the immune response. Herein, we describe the induction of anti-influenza T cell responses following vaccination with a novel VLP vaccine. Peripheral blood mononuclear cells (PBMCs) stimulated ex vivo with either influenza or vaccine specific antigens led to increased CD4+ and CD8+ T cell proliferation and increased production of cytokines such as IL-17A, IL-17F, IL-5, IL-13, IL-9, IL-10, IL-21 and, most significantly, IFN-γ. A subset of individuals demonstrated a shift from a pre-vaccination IL-5- and IL-13- driven type-2 response to a more protective IFN-γ driven type-1 response following vaccination with VLP. Microarray of whole blood samples collected pre- and post-vaccination with VLP revealed significantly different transcriptional profiles. The top most significantly downregulated gene following VLP vaccination, DEAD Box Helicase 17 (DDX17), was also found to have reduced protein expression in PBMCs by flow cytometry. Finally, weighted gene correlation network analysis (WGCNA) revealed that the post vaccination reduction in protein expression of DDX17, increase in HAI titres and increase in T cell proliferation correlates with particular gene modules.
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Suschak, John, Shixia Wang, Karen Remington, Katherine Fitzgerald, and Shan Lu. "Involvement of the Aim2 inflammasome pathway in generating antibody responses elicited by DNA vaccination. (P4313)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 123.20. http://dx.doi.org/10.4049/jimmunol.190.supp.123.20.
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Abstract Recent human study data suggests that DNA priming immunization can substantially enhance the protective antibody responses elicited by conventional influenza vaccines, but their mechanisms remain completely unknown. The current study explored the roles of innate immunity in regulating acquired immunity elicited by influenza vaccines. Innate pattern recognition receptors (PRRs), and their downstream signaling molecules, were investigated for their effect on DNA vaccination. Of particular interest is the absent in melanoma 2 (AIM2) protein pathway and its effects on the antigen-specific antibody response. AIM2 is a cytosolic DNA sensor important in both the maturation of the pro-inflammatory cytokines, IL-1b, IL-18, and an inflammatory form of cell death known as pyroptosis. Aim2 knockout mice and wild type controls were immunized with a DNA vaccine expressing the hemagglutinin antigen (HA) of H1 subtype influenza virus. Mouse serum anti-H1HA antibodies and B cell responses revealed that deletion of the Aim2 pathway led to a significant reduction of the anti-HA antibody response. Interestingly, non-antigen specific cytokine profile analysis did not demonstrate a dramatic change in cytokine signaling between wild type and knockout mice. Furthermore, deletion of IL-1 signaling did not significantly affect the anti-HA antibody responses. These results suggested that the Aim2 pathway plays an important role in shaping the antigen specific antibody response to DNA vaccines.
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Woan, Karrune, Axel Heiser, Philipp Dahm, Johannes Vieweg, and Zhen Su. "Delivery of mRNA into Dendritic Cells Using Novel Transfer Peptides Leads to Prolonged Antigen Expression and Potent Immune Responses In Vivo." Blood 110, no. 11 (November 16, 2007): 4884. http://dx.doi.org/10.1182/blood.v110.11.4884.4884.
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Abstract We have previously shown that vaccination with RNA-transfected DC is a potent strategy to stimulate CTL and antitumor immunity in cancer patients. In this study, we investigated whether novel transfer peptides derived from the RNA-binding region of the HIV-1 nucleocapsid protein could be utilized for effective delivery of mRNA into human monocyte-derived dendritic cells (DC). Here we show that both peptide-mediated mRNA delivery and electroporation of DC with mRNA resulted in efficient gene transfer. However, the use of transfer peptides led to prolonged antigen expression and did not negatively affect the viability of DC, the migratory capacity of matured DC, and the production of cytokines by these cells in vitro. In murine studies, DC loaded with transfer peptide-mRNA complexes were clearly superior, compared to mRNA-electroporated DC, in stimulating antigen-specific CTL, CD4+ T cell, and antibody responses. Importantly, no transfer peptide-specific cellular or humoral immune responses were detected in vaccinated mice. Our data suggest that vaccination with transfer peptide-mRNA-loaded DC may represent a promising strategy to stimulate potent anti-tumor immune responses in a vaccination setting.
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Cuadros, Camilo, Francisco J. Lopez-Hernandez, Ana Lucia Dominguez, Michael McClelland, and Joseph Lustgarten. "Flagellin Fusion Proteins as Adjuvants or Vaccines Induce Specific Immune Responses." Infection and Immunity 72, no. 5 (May 2004): 2810–16. http://dx.doi.org/10.1128/iai.72.5.2810-2816.2004.
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ABSTRACT Vaccination is the most efficient prophylaxis against a variety of infectious diseases. New vaccination strategies rely on the incorporation of effective adjuvants, which stimulate the innate immune response and, in turn, activate the adaptive immune response. It is well established that flagellin induces inflammatory responses through the activation of antigen-presenting cells (APCs). In order to evaluate whether flagellin can serve as a carrier for the development of adjuvants or vaccines, we prepared a flagellin-enhanced green fluorescent protein (EGFP) fusion protein. Our results demonstrate that a flagellin-EGFP fusion protein is capable of stimulating APCs, resulting in the maturation of these cells and secretion of proinflammatory cytokines. Furthermore, APCs pulsed with the flagellin-EGFP fusion protein effectively process and present EGFP antigens. More importantly, animals immunized with the flagellin-EGFP fusion protein developed specific anti-EGFP T-cell responses. In contrast, recombinant EGFP was not able to stimulate APCs, nor did it induce a T-cell response. Thus, recombinant-flagellin fusion proteins may be suitable carriers as adjuvants or vaccines for the development of new vaccination strategies to induce and boost immune responses against infectious diseases and cancer.
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Zhang, Yao, Jie Zeng, Yan Yan Song, Shao Rong Long, Ruo Dan Liu, Peng Jiang, Xi Zhang, Jing Cui, and Zhong Quan Wang. "Vaccination of Mice with a Novel Trypsin from Trichinella spiralis Elicits the Immune Protection against Larval Challenge." Vaccines 8, no. 3 (August 5, 2020): 437. http://dx.doi.org/10.3390/vaccines8030437.
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Trichinella spiralis is a major foodborne parasite and has a serious threat to meat safety. Development of anti-Trichinella vaccines is prospective to eliminate Trichinella infection in food animal. The aim of this study was to assess the biological properties of a novel T. spiralis trypsin (TsT) and its elicited immune protection against larval challenge. The cDNA sequence of TsT gene was cloned and expressed. Western blotting showed rTsT was identified by infection serum and anti-TsT serum. RT-PCR results revealed that TsT gene was transcribed at diverse T. spiralis lifecycle stages. The IIFT results showed that natural TsT was principally expressed at epicuticle of 5-6 day adult worms, indicating that TsT is a worm somatic antigen and adult-stage specific surface antigen. Vaccination of mice with rTsT triggered an evident humoral immune response (high levels of serum IgG, IgG1/IgG2a, and enteral sIgA), and it also induced the systemic and enteral local cellular immune response, demonstrated by an significantly elevation of cytokines IFN-γ and IL-4. The mice vaccinated with rTsT exhibited a 33.17% reduction of enteral adult worms and a 37.80% reduction of muscle larvae after larval challenge. The results showed that TsT might be considered as a candidate target antigen for anti-T. spiralis vaccines.
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Gehrcken, Laura, Tatjana Sauerer, Niels Schaft, and Jan Dörrie. "T-Cell Responses in Merkel Cell Carcinoma: Implications for Improved Immune Checkpoint Blockade and Other Therapeutic Options." International Journal of Molecular Sciences 22, no. 16 (August 12, 2021): 8679. http://dx.doi.org/10.3390/ijms22168679.
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Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with rising incidence and high mortality. Approximately 80% of the cases are caused by the human Merkel cell polyomavirus, while the remaining 20% are induced by UV light leading to mutations. The standard treatment of metastatic MCC is the use of anti-PD-1/-PD-L1-immune checkpoint inhibitors (ICI) such as Pembrolizumab or Avelumab, which in comparison with conventional chemotherapy show better overall response rates and longer duration of responses in patients. Nevertheless, 50% of the patients do not respond or develop ICI-induced, immune-related adverse events (irAEs), due to diverse mechanisms, such as down-regulation of MHC complexes or the induction of anti-inflammatory cytokines. Other immunotherapeutic options such as cytokines and pro-inflammatory agents or the use of therapeutic vaccination offer great ameliorations to ICI. Cytotoxic T-cells play a major role in the effectiveness of ICI, and tumour-infiltrating CD8+ T-cells and their phenotype contribute to the clinical outcome. This literature review presents a summary of current and future checkpoint inhibitor therapies in MCC and demonstrates alternative therapeutic options. Moreover, the importance of T-cell responses and their beneficial role in MCC treatment is discussed.
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Saha, Asim, Sunil K. Chatterjee, Kenneth A. Foon, Esteban Celis, and Malaya Bhattacharya-Chatterjee. "CpG DNA augments dendritic cell-based therapy of colon cancer in transgenic mice (48.21)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S78. http://dx.doi.org/10.4049/jimmunol.178.supp.48.21.
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Abstract Induction of potent and sustained anti-tumor immunity depends on the efficient activation of CD8+ and CD4+ T cells. Immunization using dendritic cells (DC) loaded with tumor Ag has shown promising results in cancer immunotherapy. Recently we have reported that in DC based immunization protocol in therapeutic setting with 7-day-old established MC-38-CEA-A2Kb tumors, mice (transgenic for both CEA and HLA-A2) immunized with agonist peptide for CEA691 (YMIGMLVGV, peptide-1) or mice immunized with agonist peptide for CAP-1 (YLSGADLNL, peptide-2) along with 3H1 (anti-idiotype Ab mimicking CEA) induced significant increase in survival with complete tumor eradication in 50% and 67.5% of the mice respectively. In this study, we attempted to augment anti-tumor immunity by the combination of 3H1-pulsed DC plus peptide-1-pulsed DC or peptide-2-pulsed DC along with immuno-stimulatory CpG (ODN–1826) in a therapeutic setting. Co-administration of CpG ODN provided significant increase in tumor free survival compared with mice immunized with peptide-pulsed DC plus 3H1-pulsed DC alone. Combined vaccination with CpG ODN resulted in increased secretion of Th1 cytokines such as IFN-γ and TNF-α, and HLA-A2-restricted CEA-specific CTL responses were also enhanced. Thus, the combination of Ag-loaded DC and CpG ODN is an effective vaccination strategy for future clinical application. Supported by the NIH grant RO1 CA104804.
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Geluk, Annemieke, Anouk Van Hooij, Elisa Tjon El Fat, Kosrhed Alam, Sipho Dlamini, Moises Batista Da Silva, John Spencer, Claudio Salgado, Jan Hendrik Richardus, and Paul Corstjens. "OC 8244 QUANTITATIVE LATERAL FLOW ASSAY FOR DETECTION OF M. LEPRAE INFECTION USING FINGERSTICK BLOOD." BMJ Global Health 4, Suppl 3 (April 2019): A2.3—A3. http://dx.doi.org/10.1136/bmjgh-2019-edc.4.
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BackgroundLeprosy is a debilitating, infectious disease caused by Mycobacterium leprae leading to skin and nerve damage and often lifelong handicaps. The unabated rate of new leprosy case detection indicates that transmission of M. leprae is persistent and that current measures for prevention and multidrug therapy (MDT) are insufficient. Contact with M. leprae-infected individuals is a risk factor for development of leprosy. Thus, detection of M. leprae-infected individuals without clinical symptoms, allowing informed decision making on who needs treatment at a preclinical stage, is vital to interrupt transmission and can help prevent leprosy.Immunoprophylaxis by vaccination or post-exposure prophylaxis (PEP) with antibiotics provide effective strategies for the prevention of leprosy. To target individuals unknowingly spreading leprosy bacilli, methods allowing objective measurement of M. leprae infection are needed. Besides antibody (Ab) levels that correspond with bacterial load and higher risk of progression to leprosy, detection of cytokine profiles can provide significant added value to identify infection.MethodsQuantitative detection of anti-PGL-I IgM antibodies, and cytokines such as IP-10 was performed on lateral flow (LF) test strips utilising the luminescent up-converting particle (UCP) technology. Precise amounts of fingerstick (FS)-blood samples were collected using disposable heparinised capillaries. Ab and cytokine levels in both FS-blood and serum from leprosy patients in South-Africa, Brazil, Bangladesh and the Netherlands and (their) contacts were measured using a portable reader.ResultsExcellent correlation was demonstrated between data for anti-PGL-I IgM Ab and cytokines obtained with serum and FS blood from the same individuals.ConclusionThe quantitative UCP-LF test strips detecting anti-PGL-I IgM Ab and cytokines for the detection of M. leprae infection is compatible with fingerstick blood allowing near-patient testing and immediate appropriate follow-up counselling.
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Walline, Crystal, Sarita Sehra, Amanda Fisher, Lynette Guindon, David Wilkes, Randy Brutkiewicz, Mark Kaplan, and Janice Blum. "Allergic lung inflammation decreases the anti-viral response to vaccinia virus (175.3)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 175.3. http://dx.doi.org/10.4049/jimmunol.188.supp.175.3.
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Abstract Despite the global eradication of smallpox following widespread vaccination with vaccinia virus (VV), other members of the poxviridae family persist and continue to infect animal and human hosts. Although the lung is the most lethal route of poxvirus infection, there is little known about the local immune response to pulmonary VV infection. Moreover, VV vaccination is contraindicated in patients with atopic dermatitis as the pro-allergic milieu diminishes anti-VV responses. Our goal was to determine the role of allergic airway disease (AAD) on the local immune response to VV infection. Our studies demonstrated increased weight loss, airway hyperreactivity, mucus gene expression, lung pathology and virus titer in mice with AAD. In contrast to observations from cells exposed to pro-allergic cytokines, expression of antimicrobial peptide genes in the lung tissue of infected mice was similar in control mice, and mice with AAD. At 4 days post infection (dpi) there was a more robust innate response in mice with AAD as evidenced by increased infiltration of lung macrophages and granulocytes. By 10 dpi, there were increased numbers of IL-10+CD8+ and IFNγ+CD8+ T cells and enhanced secretion of IL-10 and IFNγ in the bronchoalveolar lavage fluid of mice with AAD, compared to controls. Mice with AAD also had increased VV-specific IgG1 and IgM serum antibodies. These studies suggest the allergic lung microenvironment may influence the anti-viral immune response to pulmonary VV infection.
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Kim, Ki-Hye, Young-Tae Lee, Hye suk Hwang, Eun-Ju Ko, Youri Lee, Yu-Jin Jung, and Sang-Moo Kang. "Type II interferon signaling plays a critical role in inducing T helper type 1 immune responses and adaptive immunity after influenza vaccination." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 125.29. http://dx.doi.org/10.4049/jimmunol.200.supp.125.29.
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Abstract The roles of interferons (IFN) remain poorly understood in generating long-term protective immune responses to vaccination despite their well-known anti-viral innate immunity. We investigated the roles of IFN receptor (IFNR) signaling in inducing adaptive immune responses and protective immunity to influenza virus-like particle (VLP) vaccination by using A129 and AG129 mouse models. AG129 mice showed a significant defect in raising IgG2a Th1 antibody responses despite of the induction of comparable IgG1 Th2 type and hemagglutination inhibiting antibodies compared to those in A129 mice. After lethal challenge infection, the AG129 vaccinated mice were not protected as evidenced by 20% severe weight loss, high airway hyperresponsiveness, histopathology, excessive infiltration of neutrophils, inflammatory chemokine and cytokines, and 80 folds higher lung viral titers compared to the A129 vaccinated mice that were 100% protected without displaying weight loss. AG129 mice were not able to induce rapid recall of plasma cells, germinal center B cells, and IFN-r+ CD4 and CD8 T cells. Depletion of T cells in A129 mice after vaccination resulted in lower efficacy of protection. The role of type I IFNR were determined in AB6 mice by comparing with B6 mice after vaccination. The AB6 mice did not show significant defects in developing IgG1 and IgG2c antibodies and in conferring protection after vaccination and challenge, despite of inability to recruit monocytes, compared to those in B6 mice. These results suggest that type II IFNR signaling plays a more critical role in developing adaptive immunity after vaccination than type I IFNR signaling, and that both type I and II IFNR signaling is required for effective control of influenza virus infection.
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Sagiv Barfi, Idit, Debra K. Czerwinski, Tanaya Shree, and Ronald Levy. "In Situ Vaccination with Cpg and Anti-OX40 Antibody: Preclinical Optimization for Clinical Translation." Blood 132, Supplement 1 (November 29, 2018): 2943. http://dx.doi.org/10.1182/blood-2018-99-117872.
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Abstract In-situ vaccination is a local intervention in which immune enhancing agents are injected locally into one site of tumor, triggering a T cell immune response locally that then travels to attack cancer throughout the body. We have employed a preclinical strategy whereby the same syngeneic tumor is implanted at two separate sites in the body. One tumor is then injected with the test agents and the resulting systemic immune response, if any, is detected by the regression of the distant, untreated tumor. In this test for abscopal therapeutic effects, the combination of unmethylated CG-enriched oligodeoxynucleotide (CpG) - a TLR9 ligand - and agonist anti-OX40 antibody has provided impressive results. This combination lead to durable disease control and long-term treatment-free survival in multiple mouse models of cancer. CpG induced myeloid cells to secrete cytokines, which subsequently induced OX40 expression on T cells. Thus, we hypothesized that administration sequence and timing may affect the anti-tumor responses of in-situ vaccination. In order to screen for the best sequence and timing we implanted A20 lymphoma tumors bilaterally in opposite sides of the abdomen of Balb/C mice. After tumors were established, one tumor was injected at the selected sequence and timing with the test agents and the resulting immune response was monitored by the measuring growth of the distant, untreated tumor. As opposed to our usual schedule of three injections, even a single injection of CpG (50µg) and anti-OX40 (8µg) resulted in a fully protective systemic immune response. In addition, the cured animals were protected from re-challenge with the same A20 tumor but not unrelated tumors. Decreasing the dose even further to 10µg CpG and 1µg anti-OX40 partially preserved the therapeutic response with a long-term survival of 60%. Concurrent administration of CpG and anti-OX40 resulted in eradication of both local and distant disease. Sequential administration of CpG followed by anti-OX40 preserved the therapeutic efficacy. However, the opposite order of anti-OX40 followed by CpG significantly attenuated the therapeutic effect. While CpG followed by a 24- or 48-hour-delayed anti-OX40 treatment preserved the therapeutic efficacy, a 72h delay in anti-OX40 administration resulted in reduced therapeutic effect. These data demonstrate the importance of the administration sequence for fully protective anti-tumor immune responses. Our data suggest that the anti-OX40 antibody should be administered at the same time as CpG or with only a slight delay but not in the reverse order. Low-dose radiotherapy (2×2 Gy) is an effective treatment for patients with indolent non-Hodgkin's lymphoma. This treatment results in high response rates at the treated site. Since immune infiltrating cells in the tumor microenvironment are essential for in situ vaccination of CpG and anti-OX40 we aimed to assess the effect of adding radiation in our pre-clinical models of lymphoma. We found that the addition of 2x2 Gy radiation did not interfere with the induction of a protective immune response by of CpG and anti-OX40. Given the effectiveness of low dose radiotherapy for local control and its lack of interference with the immune related abscopal response in the pre-clinical model, we are including radiation in our current clinical trials. In addition, we have incorporated our findings in the preclinical model regarding dosing and scheduling of CpG and anti-OX40 antibody to the design of our current in situ vaccination lymphoma clinical trial. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Munson, Erik L., Brian K. Du Chateau, Dean A. Jobe, Steven D. Lovrich, Steven M. Callister, and Ronald F. Schell. "Production of Borreliacidal Antibody to Outer Surface Protein A In Vitro and Modulation by Interleukin-4." Infection and Immunity 68, no. 10 (October 1, 2000): 5496–501. http://dx.doi.org/10.1128/iai.68.10.5496-5501.2000.
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ABSTRACT Borreliacidal antibody production is one of several parameters for establishing the effectiveness of Borrelia burgdorferivaccines. The production of borreliacidal antibody was studied in vitro by culturing immune lymph node cells with macrophages and B. burgdorferi. We showed that borreliacidal antibody, directed primarily against outer surface protein A (OspA), was readily produced by lymph node cells obtained from C3H/HeJ mice vaccinated with formalin-inactivated B. burgdorferi in aluminum hydroxide, but not recombinant OspA. Anti-OspA borreliacidal antibody was detected in supernatants of cultures of lymph node cells obtained on day 7 after vaccination, peaked on day 17, and rapidly declined. The borreliacidal activity was attributable to immunoglobulin G1 (IgG1), IgG2a, and IgG2b antibodies. When lymph node cells were treated with interleukin-4 (IL-4), production of borreliacidal antibody was inhibited but was unaffected by treatment with anti-IL-4 antibodies. These results suggest that other cytokines, but not IL-4, are mainly responsible for production of the secondary borreliacidal antibody response.
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Bakkari, Mohammed Ali, Sivakumar S. Moni, Abdulrahman Alshammari, Muhammad H. Sultan, Osama A. Madkhali, Yosif Almoshari, Mohammad Firoz Alam, and Mohamed Eltaib Elmobark. "Induction of Innate and Adaptive Immune Response against Recombinant HBsAg Protein Entrapped in Docosahexaenoic Acid Nanovesicles through Biomarkers." Vaccines 11, no. 2 (February 16, 2023): 457. http://dx.doi.org/10.3390/vaccines11020457.
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The present study focused on demonstrating the induction of humoral and cell-mediated immunity through the establishment of a cytokine network. We hypothesized the anti-inflammatory, pro-inflammatory, and IgE antibody levels after vaccination with lyophilized recombinant HBsAg-loaded docosahexaenoic acid nanovesicles (LRPDNV), and the efficacy compared well with standard commercial recombinant hepatitis B vaccine. The cytokine network was efficiently regulated by striking a balance between pro-inflammatory cytokines IL-6, IL-8R, and IL-12 and anti-inflammatory cytokines such as IL-2, IL-4, IL-10, and IFN-γ immune response on the 14th and 30th day after primary and booster immunization. The acute phase protein CRP level was increased due to IL-6 after immunizing with LRPDNV. On the other hand, the IgE level was not significantly increased to induce any allergic reactions after immunization with LRPDNV. The study concluded that after immunizing with LRPDNV, a significant immunological response was established, implying that DHA nanovesicles have significant potential as an adjuvant method for delivering recombinant HBsAg protein. On the other hand, following immunization with LRPDNV, the IgE level was not noticeably elevated enough to cause any adverse reactions. The study concludes that a robust immune response was developed after immunizing with LRPDNV and suggests that DHA nanovesicles have much potential to deliver recombinant HBsAg protein.
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Pacheco, Iván, Marinela Contreras, Margarita Villar, María Angeles Risalde, Pilar Alberdi, Alejandro Cabezas-Cruz, Christian Gortázar, and José de la Fuente. "Vaccination with Alpha-Gal Protects Against Mycobacterial Infection in the Zebrafish Model of Tuberculosis." Vaccines 8, no. 2 (April 24, 2020): 195. http://dx.doi.org/10.3390/vaccines8020195.
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The alpha-Gal syndrome (AGS) is associated with tick bites that can induce in humans high levels of IgE antibodies against the carbohydrate Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) present in glycoproteins and glycolipids from tick saliva that mediate primarily delayed anaphylaxis to mammalian meat consumption. It has been proposed that humans evolved by losing the capacity to synthesize α-Gal to increase the protective immune response against pathogens with this modification on their surface. This evolutionary adaptation suggested the possibility of developing vaccines and other interventions to induce the anti-α-Gal IgM/IgG protective response against pathogen infection and multiplication. However, the protective effect of the anti-α-Gal immune response for the control of tuberculosis caused by Mycobacterium spp. has not been explored. To address the possibility of using vaccination with α-Gal for the control of tuberculosis, in this study, we used the zebrafish-Mycobacterium marinum model. The results showed that vaccination with α-Gal protected against mycobacteriosis in the zebrafish model of tuberculosis and provided evidence on the protective mechanisms in response to vaccination with α-Gal. These mechanisms included B-cell maturation, antibody-mediated opsonization of mycobacteria, Fc-receptor (FcR)-mediated phagocytosis, macrophage response, interference with the α-Gal antagonistic effect of the toll-like receptor 2 (TLR2)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)-mediated immune response, and upregulation of pro-inflammatory cytokines. These results provided additional evidence supporting the role of the α-Gal-induced immune response in the control of infections caused by pathogens with this modification on their surface and the possibility of using this approach for the control of multiple infectious diseases.
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Radhakrishnan, Rajesh Kumar, Ramya Sivangala Thandi, Deepak Tripathi, Padmaja Paidipally, Madeline McAllister, Sachin Mulik, Buka Samten, and Ramakrishna Vankayalapati. "BCG vaccination reduces the mortality of Mycobacterium tuberculosis-infected type 2 diabetes mellitus (T2DM) mice through the induction of CXCR3+ T-regulatory cells." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 85.11. http://dx.doi.org/10.4049/jimmunol.204.supp.85.11.
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Abstract Diabetes is a significant risk factor for the development of active tuberculosis. In this study, we used mouse model of Streptozotocin/Nicotinamide (STZ/NA) induced non-obese type 2 diabetes mellitus (T2DM) to determine the effect of prior BCG vaccination on survival and immune responses to Mycobacterium tuberculosis (Mtb) infection. We found that at 6–7 months post-Mtb infection, 90% of the Mtb-infected T2DM mice died, whereas only 50% of BCG-vaccinated T2DM-Mtb-infected mice died. Moreover, 40% of the PBS-treated uninfected T2DM mice and 30% of the uninfected BCG-vaccinated T2DM mice died, whereas all uninfected and infected nondiabetic mice survived. BCG vaccination was less effective in reducing the lung bacterial burden of Mtb infected T2DM mice compared to Mtb-infected non-diabetic mice, however it reduced immunopathology of lung tissues. Further, we found increased survival of BCG vaccinated Mtb infected T2DM mice is associated with 2-fold expansion of IL-13 producing CXCR3+ T-regulatory cells as measured by flow cytometry, qRT-PCR and confocal microscopy. We also found that prior BCG vaccination restored the immunosuppressive function of T-regulatory cells of Mtb-infected T2DM mice and reduced inflammation. IL-13 producing T-regulatory cells of BCG vaccinated Mtb-infected T2DM mice converted proinflammatory M1 macrophages (iNOS) to anti-inflammatory M2 macrophage (Arg1) phenotype to suppress the inflammation. In contrast, anti-IL-13R antibody inhibited the conversion of macrophages from M1 to the M2 phenotype and enhanced the inflammatory cytokines (IL-6 and TNF-α) production. Our findings suggest a novel role for BCG in preventing excessive inflammation and mortality in T2DM mice infected with Mtb.
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Roberts, Lydia M., Tyler J. Evans, and Catharine M. Bosio. "Pulmonary resident effector CD4+ T cells fail to effectively utilize glycolysis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 67.16. http://dx.doi.org/10.4049/jimmunol.202.supp.67.16.
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Abstract The transition of T cells from naïve to effector cells has been reported to require a metabolic shift from oxidative phosphorylation to glycolysis for the production of effector molecules such as IFN-γ. This phenomenon is primarily restricted to study of splenic T cells and it is largely unknown if T cells in other organs undergo the same metabolic shift. Intranasal vaccination establishes a pool of lung tissue-resident, effector memory T cells (trTem) that are typically sufficient to control a secondary infection via production of cytokines. Therefore, we hypothesized trTem would be highly glycolytic upon activation. To test this hypothesis, we compared the metabolic activity of both trTem and circulating Tem (cTem) isolated from mice vaccinated with either Bordetella pertussis or Francisella tularensis. As expected, regardless of the vaccinating pathogen, CD4+ cTem readily shifted to glycolysis following activation with anti-CD3/CD28 beads. In contrast, CD4+ trTem cells did not shift to glycolysis following the same activation scheme, nor did they increase mitochondrial respiration as a mechanism to compensate for the absence of glycolysis. Consistent with an inability to shift to glycolysis, ex vivo stimulation of trTem with antigen also resulted in limited uptake of glucose as compared to cTem. These data suggested that, unlike previous reports, pulmonary CD4+ trTem do not rapidly shift to glycolysis even in the presence of antigen. Together these data highlight the unique environment of the pulmonary compartment and present critical information that will influence our understanding of pulmonary T cell responsiveness during infection which may shape future vaccination strategies.
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Wynn, T. A., D. Jankovic, S. Hieny, A. W. Cheever, and A. Sher. "IL-12 enhances vaccine-induced immunity to Schistosoma mansoni in mice and decreases T helper 2 cytokine expression, IgE production, and tissue eosinophilia." Journal of Immunology 154, no. 9 (May 1, 1995): 4701–9. http://dx.doi.org/10.4049/jimmunol.154.9.4701.
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Abstract Vaccination of mice with radiation-attenuated cercariae of Schistosoma mansoni results in a highly significant but partial protection against challenge infection. This immunity is dependent on CD4+ T cells, and because of its suppression by anti-IFN-gamma, appears to be caused by a Th1 response. Nevertheless, both Th1 and Th2 lymphokines are expressed in vaccinated and challenged mice, and we hypothesized that the expression of the latter group of down-regulatory cytokines may be responsible for the failure to obtain complete protection. Because IL-12 is a key cytokine that suppresses Th2-like responses, we asked whether IL-12 could increase vaccine-induced immunity to S. mansoni. Indeed, administration of IL-12 significantly reduced worm burdens following a challenge infection. IL-12-treated animals displayed a marked increase in pulmonary IFN-gamma and IL-12 p40 mRNA expression, while levels of IL-4, IL-5, and IL-13 were suppressed significantly during the period of vaccination. A marked decrease in serum IgE and tissue eosinophilia, two responses regulated by Th2 cytokines, was also observed. Surprisingly, IL-12-treated/vaccinated mice failed to demonstrate a significant increase in IFN-gamma, TNF-alpha, or nitric oxide synthase mRNA at the time of challenge infection when compared with vaccinated controls, but did, however, display significantly suppressed Th2 cytokine mRNA production. Together, these data demonstrate that exogenous IL-12 regulates Th1/Th2 responses during immunization with irradiated cercariae, and suggest that this cytokine may be used to increase vaccine-induced immunity to S. mansoni.
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al-Ramadi, Basel K., Mariam H. Al-Dhaheri, Nada Mustafa, Mounir AbouHaidar, Damu Xu, F. Y. Liew, Miodrag L. Lukic, and Maria J. Fernandez-Cabezudo. "Influence of Vector-Encoded Cytokines on Anti-Salmonella Immunity: Divergent Effects of Interleukin-2 and Tumor Necrosis Factor Alpha." Infection and Immunity 69, no. 6 (June 1, 2001): 3980–88. http://dx.doi.org/10.1128/iai.69.6.3980-3988.2001.
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ABSTRACT Attenuated Salmonella strains are of interest as new vaccine candidates and as vectors of cloned genes of other organisms. Attenuated strains expressing specific cytokines were constructed as a means of manipulating the immune response in various disease settings. In the present study, interleukin-2 (IL-2)-expressing (GIDIL2) or tumor necrosis factor alpha (TNF-α)-expressing (GIDTNF) strains were compared with the parent strain (BRD509) for the effect of cytokines on anti-Salmonella immunity. Expression of IL-2 resulted in a rapid clearance of the organism soon after vaccination. The reduction in GIDIL2 CFU was 50- to 300-fold higher than that of BRD509 and correlated with a markedly decreased splenomegaly. Furthermore, no evidence for any significant activation, including upregulation of surface markers and production of nitric oxide (NO), was observed in spleens of GIDIL2-injected mice. In contrast, the host response to GIDTNF was marked by an early, strong, splenic cellular influx, but surprisingly, the degree of induced splenomegaly and NO secretion was only 50% of that observed in BRD509-treated mice. Despite this, bacterial colonization of the spleen in GIDTNF-immunized animals was either slightly decreased from or equivalent to that of the BRD509-treated group, suggesting the induction of additional antimicrobial mechanisms by TNF-α. In vivo protection studies demonstrated that, at limiting doses, GIDIL2 was inferior to GIDTNF and BRD509 in its capacity to protect against virulent challenge. At high doses, however, all three strains exhibited equal protective efficacy. These results demonstrate that the immune response against intracellular bacteria can be manipulated by pathogen-expressed cytokines and open the way for further fine tuning of immune responses not only to Salmonella strains themselves but also to the heterologous gene(s) carried by them.
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Shurygina, A. P. S., N. V. Zabolotnykh, T. I. Vinogradova, K. A. Vasilyev, Zh V. Buzitskaya, and M. A. Stukova. "Lung memory T-cell response in mice following intranasal immunization with influenza vector expressing mycobacterial proteins." Russian Journal of Infection and Immunity 10, no. 3 (August 7, 2020): 506–14. http://dx.doi.org/10.15789/2220-7619-iol-1232.
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Improving specific prevention of tuberculosis continues to be a top priority in phthisiology. “Prime-boost” vaccination schemes aim to maintain adequate levels of specific immunity while forming long-term protection. They are based on sequential use of BCG vaccine and new vaccine candidates expressing protective mycobacterial proteins. The development of new tuberculosis prevention approaches requires an understanding of how the anti-tuberculosis immune response forms and which mechanisms provide TB protection. Since tuberculosis is an airborne infection, vaccine effectiveness largely depends on mucosal immunity based on the formation of long-lived, functionally-active memory T-lymphocytes in the respiratory tract. We have previously shown that the influenza vector expressing ESAT-6 and Ag85A mycobacterial proteins (Flu/ESAT-6_Ag85A) in vaccination scheme of intranasal boost immunization resulted in significant increase of BCG's protective effect according to key indicators aggregate data in experimental tuberculosis infection. The aim of this work was to study the effect of intranasal immunization with the Flu/ESAT-6_Ag85A influenza vector on the formation of antigen-specific central and effector memory T cells and the cytokine-producing activity of effector T cells (TEM) in BCG standard and “BCG prime — influenza vector boost” vaccination schemes in mice. Intranasal immunization with the influenza vector has been shown to increase the proportion of antigen-specific CD4+ central memory T cells (TCM) in the pool of activated lymphocytes of lung and spleen reaching significant differences from the BCG group in the percentage of spleen CD4+ TCM (p < 0.01). In contrast to BCG, vaccination with the studied vaccine candidate was accompanied by accumulation of highly differentiated CD8 effector cells in lung, the target organ during tuberculosis infection. Comparative evaluation of the cell-mediated, post-vaccine immune response after immunization with influenzavector-based vaccine candidate (intranasal/mucosal) or BCG vaccine (subcutaneous) showed advantages in the mucosal group: in formation of functionally active subpopulations of effector CD4 and CD8 T lymphocytes (CD44highCD62Llow) in lungs secreting IL-2 as well as polyfunctional cells capable of coproducing two cytokines (IFNγ/TNFα or IFNγ/IL-2) or three cytokines (IFNγ/TNFα/IL-2). Due to their more pronounced effector function, polyfunctional T-lymphocytes can be considered to be potential immunological markers of protective immunity in tuberculosis.